TW201244717A - Treatment of attention deficit/hyperactivity disease - Google Patents

Abstract

The present invention relates to methods and uses for (2S, 3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof.

Description

201244717 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to (23, 3 ft)-meaning (2-((3-° ratio) thiol)-1-azabicyclo[2.2_2] Method and use of oct-3-yl)benzopyran-2-ylamine or a pharmaceutically acceptable salt thereof. [Prior Art] Compound (2S,3R)-N-(2-((3- °-pyridyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzopyrene Indoleamine (including a method of synthesis) is described in the disclosure of U.S. Patent Application Serial No. 12/184,312, the disclosure of which is incorporated herein by reference. Each patent is incorporated herein by reference in its entirety. This compound can be referred to as TC-5619. Attention deficit hyperactivity disorder (ADHD or ad/HD or ADD) is a neurobehavioral developmental disorder. The main feature of ADHD is that the problem of attention and overactivity coexist, with each behavior rarely appearing alone. ADHD is a chronic condition in which 30% to 50% of individuals diagnosed in childhood enter the adulthood and continue to develop symptoms. Adolescents and adults with ADHD tend to develop mechanisms to counteract some or all of the damage. ADHD is diagnosed by psychiatric evaluation to rule out other underlying causes or comorbidities, but physical examination, radiological imaging, and laboratory testing can be used. In North America, DSM guidelines are often the basis of diagnosis, such as the American Psychiatric Association's 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The principle of advocacy. Base 163062.doc 201244717 In the DSM-IV guidelines listed below, ADHD is currently divided into three types: (i) combined ADHD; (ii) predominantly intenttent type ADHD; Iii) is mainly a Predominantly Hyperactive-Impulsive Type ADHD. According to a recent revision of DSM, the previously used phrase ADD (Attention Deficit Disorder) is no longer used. Therefore, the term ADHD is currently used to describe this condition as either manifesting itself as causing hyperactivity/impulsivity (mainly hyperactive impulsive ADHD) or under-attention (mainly under-attention ADHD type) or both ( The main deficiencies of the combined ADHD) are different conditions. In the tenth edition / «ierwaiiowa/ Statistical Classification of Diseases and Related Health (ICD-10), the symbol of ADHD is named "overactive disease". When a behavioral disorder (as defined by ICD_10) is present, the condition is referred to as "hyperkinetic conduct disorder." Otherwise, the illness is classified as "Disturbance of Activity and Attention", "Other Overactive Disorders" or "Hyperkinetic Disorders (Unspecified)". The latter is sometimes referred to as "Hyperkinetic Syndrome". The diagnosis, symptoms and terminology of each of DSM-IV and ICD-10 are incorporated herein by reference. The present invention relates to treatments associated with such conditions. With reference to DSM-IV, if an individual presents six or more of the defined deficit deficit symptoms for at least six months, it is considered to be interfering and inappropriate. The extent to which ADHD is applied is mainly for the diagnosis of under-reported subtypes 163062.doc 201244717. Similarly, 'if the individual reaches the defined test set at least six months if it is considered to be interfering and inappropriate. The six or more of a series of hyperactive/impulsive symptoms defined by ADHD are primarily diagnosed as hyperactive-impulsive subtypes. Similarly, when an individual presents two series of symptoms, then the application is combined. Type of diagnosis. Stimulators (whether long-acting or short-acting) work relatively quickly (acting on the day) where the effect value (ie the amount of 'therapeutic effect) is about 〇.8 to 〇.9. Presents a high tendency to abuse and is usually a scheduled drug. In addition, these agents are often accompanied by a less desirable tolerance curve including hypertension, tachycardia, insomnia, drug effects, excitability or mood Fluctuations. Non-irritants act slower, with an effect value of about 〇 5. Although the & propensity is resolved, the tolerance curve is similar to the stimulator. The relative disability tolerance curve with minimal abuse tendency is relatively The fast acting agent will greatly benefit patients suffering from ADHD. SUMMARY OF THE INVENTION The present invention encompasses the administration of a therapeutically effective amount of (2S 3r)_n_(2_((3 i^ dimethyl)methyl)-1· A method for the treatment of ADHD with azabicyclo[2·2·2]octyl-3-yl)benzofuran-2-amine or a pharmaceutically acceptable salt thereof. The present invention encompasses the treatment of diagnosed attention A method of insufficiency in a subtype of ADHD, comprising administering a therapeutically effective amount of (28,3Κ)·ν·(2·((3-〇λ 1,3-yl)indolyl)-1-azabicyclo[2_2.2] Oct-3-yl)benzofuran-2-carbamamine or a pharmaceutically acceptable salt thereof. The present invention includes an improvement in need A method of attention, comprising administering a therapeutically effective amount of (2S,3R)-N-(2-((3)-hexidyl)methyl)_ azabi 163062.doc 201244717 ring [2.2. 2] 辛·3-yl) benzofuran-2-amine or a pharmaceutically acceptable salt thereof. One aspect of the present invention includes a method for treating attention deficit, which comprises administering a therapeutically effective amount (2S) , 3R)-N-(2-((3-)pyridyl)methyl)-1-azabicyclo[2.2.2]octyl-3-yl)benzofuran-2-amine or its medicine Acceptable salt. The present invention encompasses the early onset of symptoms associated with ADHD (i.e., within one week of administration) of (2S,3R)_N_(2_((3_„pyridyl)methyl)-丨·azabicyclo[2.2. 2] oct-3-yl)benzofuran-2-carbamide or a pharmaceutically acceptable salt thereof. These symptoms include, but are not limited to, the Conners Adult ADHD Rating Scale (Conners Adult ADHD Rating Scale, CAARS) Overall Performance, Overdrive 'Impact and ADHD Index Subscale. The present invention includes a sustained effect (ie, maintained for 4 weeks or more after administration) (28.311) -> 1-(2-((3) -°-pyridyl)methyl)-1 -azabicyclo[2.2.2]oct-3-yl)benzopyran-2-carboxamide or a pharmaceutically acceptable salt thereof associated with ADHD Symptoms 'which include (but are not limited to) hyperactivity, lack of attention, self-concept, anger, hostility, confusion, and confusion. The present invention includes (2S,3R)-N-(2-((3-«-pyridyl)) Mercapto)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, or another alpha 7 agonist and one or more irritants Combination for treating combined and under-focused Over/impact type ADHD. The present invention includes (23.311)-;^-(2-((3-«-pyridyl)methyl)-1-azabicyclo[2.2_2]oct-3-yl)benzo Furan-2-carboxamide or a pharmaceutically acceptable salt thereof, or another combination of an agonist and one or more antidepressants for the treatment of combined, underpowered or overactive/impulsive ADHD » 本The invention includes (2S,3R)-N-(2- 163062.doc -6 - 201244717 (9) μ group) methyl) small azabicyclo[2.22] osin-3 guanamine or a pharmaceutically acceptable salt thereof, ^ Another combination of a cx7 agonist and a plurality of anti-hypertensive agents for the treatment of combined, underpowered or overactive/impulsive ADHD. The invention includes (2S,3R)-N-(2- ((3 (four) base) „bicyclo[2.2.2] 辛.3_基) stupid and cough, snail amine or its medicinally acceptable salt of the party, or another 7 agonist agonist and — or a variety of stimuli a combination of one or more of the agent, or a plurality of anti-suppressants and one or more antihypertensive agents, the treatment of combined, & sufficiency or overdrive/impulsive ADHD °, in this regard, Invented sentence cup γ is included (2S, 3R)-N-(2- ((3·pyridyl)methyl H-azabicyclo[2.2.2]oct-3-yl)benzoxyl...the amine or its pharmaceutically acceptable salt and for the treatment of ADHD (including combination type, attention A combination of another therapeutic agent of insufficient or overactive/impulsive type. The various terms used herein, but not otherwise defined, may be defined in the section of the protocol. [Embodiment] (2S'3R)-N-(2-((3-Chloryl)methylhydrazinium] azabicyclo[2.2.2]octyl-3-yl)benzoquinone-2-cartoamine Or a pharmaceutically acceptable salt thereof, (2s, 3r)_n· (2·((3" than dimethyl) methyl azabicyclo[2 2 2] octyl _3·yl) The brewing amine (including the synthetic method) is described in U.S. Patent No. 7,981, the entire disclosure of which is hereby incorporated by reference in its entirety in its entirety in its entirety in Each of the patents is incorporated herein by reference in its entirety. (2S, 3R)-N-(2-((3-n-Byridinyl)indolyl)-1_indobicyclo[2 2 2]oct-3-yl) Benzophenan-2-amine or its pharmaceutically acceptable salt selectivity... 163062.doc 201244717 NNR Agonist (2S,3R)_N-(2-((3-pyridyl)methyl) ····azabicyclo[2.2.2]oct-3-yl) benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof is effective in a preclinical model of memory and is in healthy volunteers There was generally good tolerance in phase 1 trials in which 67 mg (2S,3R)-N-(2-((3-)pyridyl)methyl was administered. _ι_azabicyclo[2 2 2]oct-3-yl) benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof exhibits a steady improvement in attention. See Hauser TA, Kucinski A, Jordan KG, Gatto GJ ^ Lippiello PM > Bencherif M : (2S,3R)-N-(2-((3-pyridinyl) methyl)-l-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a A pharmaceutically acceptable salt thereof: An a7 NNR selective agonist that demonstrates efficacy in animal models of schizophrenia, Biochem. Pharmacol. 1009; 78: 803-812, which is incorporated herein by reference. The present invention is derived from ADHD Tested in adults (2s, 3R)-N-(2-((3-)pyridyl)indolyl)-i-azabicyclo[2 2 2]oct-3-yl)benzofuran-2 - Clinical trials conducted by the action of guanamine or its pharmaceutically acceptable salt. This study will be 135 male or female adults (age 18) diagnosed with ADHD according to DSM-IV-TR guidelines at various locations in the United States. · 65 years old) randomized. Subjects were randomized to place placebo (η = 67) or (23,311)_1^(2-((3〃pyridyl)indolyl)-1-azabicyclo[222]oct-3-yl)benzene And furan 2-amine or its pharmaceutically acceptable salt (n=68: 1 mg po qd for 4 weeks, then 5 mg po qd for 4 weeks, and the last 25 mg p〇qd for 4 weeks) Up to 12 weeks. 163062.doc 201244717 Main Outcome Measures (Connor Adult ADHD Rating Scale - Investigator [CAARS-Inv] Total Score) No support was shown at Week 4, Week 8 or Week 12 (2S, 3R)-N-(2-((3-pyridyl)methyl)-oxazabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable compound thereof A statistically significant benefit of salt (p < 〇. 10); and therefore the study did not meet the pre-defined success criteria. However, CAARS-Inv showed support (28,311)-:^-(2-((3-)pyridyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl) at week 1. A significant benefit of benzofuran-2-carbamide or a pharmaceutically acceptable salt thereof (p=0.0191). In the secondary yield measure, (2S,3R)-N-(2-((3-pyridyl)indolyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2 - The brewin or its pharmaceutically acceptable salt shows statistically significant benefits at different times on the following scales: CAARS-Inv Hyper-Motion Scale; CAARS-Subject (CAARS-S) ADHD Index, Objective Meter, Self-Concept Scale, and Objective Measurement in CogState ADHD Test Battery [CATB: Stop Signal Reaction Time) (Behavioral inhibition test), Groton Maze Learning Test (GMLT), Detection task (Psychological Action History Test) and International Shopping List Task (Chinese Learning List Task) )]; overall clinical global impression (CGI), CGI-severity (CGI-S) and CGI·improvement (CGM) scales; and behavioral items, on anger-hostility and confusion-confused emotional state Evaluation Table (Profile of )63062.doc 201 244717

Mood States, POMS). In the post-analysis of the ADHD subtype (p〇st hoc analysis), it was found that the attention deficit type (n=3〇) not only drives the support of (2S,3r)n(2_((3-pyridyl)methyl)-1 • A significant benefit of azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carbamide or a pharmaceutically acceptable salt thereof, and also a significant improvement in the CAARS-In total score. Therefore 'although the main result measure did not support (2S,3R)-N-(2-((3-pyridyl)indolyl)-1- azabicyclo ring at week 4, week 8 or week 12 [2.2.2] oct-3-yl) stupid and carbamoyl 2-carbalamine or its pharmaceutically acceptable salt benefits 'but in various CAARS-Inv and CAARS-S scales, CATB projects, CGI- The positive benefits of supporting this compound were observed in the S, CGI-Ι and POMS projects. Moreover, in the post hoc analysis of patients with predominantly under-focused ADHD, not only the primary outcome measure (CAARS-In total score) but also various secondary outcome measures were shown to support (2S, 3R)_N_(2-(( Statistically significant benefit of 3-"pyridyl)methyl)- 1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof . In summary, these results indicate that (28,311)-;^_(2-((3-pyridyl)methyl)_1-azabicyclo[2.2.2]oct-3-yl)benzopyran-2- Formamide or a pharmaceutically acceptable salt thereof produces cognitive and clinical benefits in adults with ADHD. L compound The compound of the invention is (2S,3R)-N(2-((3-)pyridyl)indolyl-1-azabicyclo[2.2.2]oct-3-yl)benzofuran_2 - Methionamine (hereinafter referred to as Compound A) or a pharmaceutically acceptable salt form of Compound A. 163062.doc •10· 201244717

(2S,3R)-N(2-((3-»-pyridyl)indolyl)-1-azabicyclo[2.2.2]octyl-3-yl)benzofuran-2-indoleamine (Compound A Is a highly selective full agonist of the a7 NNR receptor, which has a very low EC5〇 (for activation) value and a good separation between <:50 and IC5〇 (for residual inhibition), thus being useful in a wider treatment Functional agonism is provided in the concentration range. II. (2S,3R)-N-(2-((3-Acryl)methyl)-1-azabicyclo[2.22]oct-3-yl) benzofuran-2-carbamamine Amplification Synthesis Specific synthesis steps vary in compliance with amplification. Reactions have been found to lack amplification for a variety of reasons, including safety concerns, reagent costs, difficulty handling (w〇rk_Up) or purification, reaction energetics (thermodynamics or kinetics), and reaction yields. (2S,3R)-N-(2-((3-Pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)benzopyrene 2__ has been described herein. The synthesis of formamide to produce a kilogram quantity of material' and the component reaction has been carried out in high yield on a scale of several kilograms. The synthesis can be carried out using a racemic ketone (2-((3-<>> Dynamic resolution of bicyclo [2.2.2] octan-3-one) and stereoselective reduction of methylbenzylamine imide derivatives by resolution of ketones (())-1-aza 163062.doc 201244717 Both reductive aminations. The synthetic sequences reported herein can be easily amplified without purification by chromatography. III·(2S,3R)-N-(2-((3-pyridyl)methyl_1_ azabicyclo) The preparation of the salt form of [2 2 2]oct-3-yl)benzofuran-2-carbamamine is in the form of free (2S,3R)_N_(2_((3_e-pyridyl)methylazide Bicyclo[2.2.2]oct-3-yl)benzofuran-2-carbamamine is an amorphous powder with very limited water solubility. The free base can react with both inorganic and organic acids to produce certain acid additions. Salt formation, such acid addition salts have physical and chemical properties that facilitate the preparation of pharmaceutical compositions Qualities, hydrazines include, but are not limited to, crystallization & 'water solubility and stability. The stoichiometry of the salts of the invention may vary. The manner in which the salts described herein are formed may be blocked during salt formation. The crystal structure of the solvent present. Therefore, the salts may exist in the form of hydrates and other prodrugs, wherein the solvent is relative to ((3·.pyridyl)methyl·i•azabicyclo[2 2 2] The stoichiometry of xin-3-3 benzopyran-2-amine may vary. The method for preparing the salt form may vary. (2S, 3r)_n_(2_((3_d-pyridyl)) The preparation of the base 1 azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carbamide salt form is generally involved. (1) the free base or free base solution (ie, present in the appropriate agent) (2S,3R)-N-(2-((3_.pyridyl)methyl-azabicyclo[2.2.2]oct-3-yl)benzopyrazine·2_bristamine) Pure acid or mixed in a suitable solvent: acid solution; (iia) if necessary, cooling the resulting salt solution to cause precipitation; or (iib) adding a suitable anti-solvent to cause precipitation; or (1) c) evaporating the first solvent and adding a new solvent and Re-step (4) or step (iib); and (iv) 163062.doc -12· 201244717; Consider and collect the obtained salt. The stoichiometry, solvent mixture, solute concentration and temperature may vary. It can be used to prepare salt forms or Representative solvents for recrystallization in salt form include, but are not limited to, ethanol, methanol, isopropanol, acetone, ethyl acetate, and acetonitrile. Examples of suitable pharmaceutically acceptable salts include inorganic acid addition salts, such as vapors, Bromide, sulfate, phosphate and nitrate; organic acid addition salts such as acetate, galactose, propionate, succinate, lactate, glycolate, malate, tartrate, Citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate and ascorbate; and salts with amino acids such as aspartate and glutamate. In the upper 隋 shape, the S-Shenzhen salt can be a hydrate or an ethanol solvate. Representative salts are provided as described in U.S. Patent No. 5,597,919 to Dull et al., U.S. Patent No. 5,61,716 to Dull et al., and U.S. Patent No. 5,663,356, the entire disclosure of each of which is incorporated by reference. For the free base (23,311)-^[-(2-((3-)pyridyl)methyl-1_azabicyclo[2.2.2]oct-3-yl) The salt of the guanamine screen shows that although a number of salts of pharmaceutically acceptable acids can be formed, only a few of these salts have commercially acceptable properties. Therefore, the characteristics exemplified by commercially viable salts cannot be predicted. The acid (that is, the salt showing some crystallinity) depends on the method for preparing the salt, including hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, galactonic acid (mucosic acid), D. mandelic acid, D-tartaric acid. , sulfonic acid, R_1〇_ camphoric acid and S-10-camphorsulfonic acid, maleic acid, ketoglutaric acid and hippuric acid. Among these salts, hydrochloric acid, phosphoric acid, maleic acid and p-toluenesulfonic acid Salts exhibit other desirable properties 'including if}, good water solubility and low moisture absorption. The salt of the 163062.doc -13- 2012 The properties of the invention are unexpected. Ιν·Pharmaceutical Compositions The pharmaceutical compositions of the present invention comprise the salts described herein, either in neat form or in combination with any other potentially inert or physiologically active pharmaceutical compatible product. The resulting pharmaceutical composition can be used to prevent a condition or disorder in an individual susceptible to the condition or disorder, and/or to treat an individual having the condition or disorder. The pharmaceutical composition described herein includes a compound of the invention and/or a medicament thereof Acceptable salts. The manner in which the compounds are administered may vary. The compositions are preferably stomatologically and (for example, in the form of a liquid in a solvent such as an aqueous or non-aqueous liquid, or in a solid carrier) Preferred compositions for oral administration include pills, troches, capsules, capsules, syrups and solutions, including hard gelatin capsules and sustained release capsules. Standard excipients include binders, fillers, coloring Agents, solubilizers and the like. The compositions may be formulated in unit dosage form or in multiple doses or subunit dosages. Preferred compositions may be in liquid or semi-solid form. Compositions comprising a liquid pharmaceutical inert carrier such as water or other pharmaceutical phase liquid or semi-solid. The use of such liquids and semi-solids is well known to those skilled in the art. The compositions may also be administered via injection (i.e., intravenous). Intra-, intramuscular, subcutaneous, intraperitoneal, intra-arterial, intrathecal, and intraventricular administration. Intravenous administration is a preferred method of injection. Suitable carriers for injection are well known to those skilled in the art and include 5 % dextrose solution, saline and phosphate buffered saline. The pharmaceutical product may also be administered as an infusion or injection (for example, as a suspension or emulsion in a pharmaceutically acceptable liquid or liquid mixture). Doc 201244717 Formulations can also be administered by other means (eg rectal administration). Formulations such as suppositories that can be administered by rectal administration are familiar to those skilled in the art: mouth. The pharmaceutical product may also be administered by inhalation (e.g., in the form of an aerosol, or by nasal delivery or by delivery of a delivery article of the type described in U.S. Patent No. 4,922 '9G1 to the name of Brooks et al. The disclosure is incorporated herein in its entirety; in a topical manner (eg, in the form of a lotion) percutaneous (eg, using a transdermal patch) or ion permeation; or sublingual or frequency-administered. The chemical form is administered as a compound, but the pharmaceutical product is preferably presented in the form of a pharmaceutical composition or formulation for efficient and effective administration. An exemplary method for administering a compound will be apparent to those skilled in the art. The availability of the article may depend on the particular composition employed and the particular subject being treated. The formulation may contain a liquid carrier which may be oily, aqueous, emulsifying or containing a solvent suitable for the mode of administration. Group σ can be administered to a warm-blooded animal in a batch manner or at a gradual, continuous, constant or controlled rate (eg, mammals such as mice, rats, cats, rabbits, dogs, , cattle or monkeys, but beneficially administered to humans. In addition, the time and number of times of administration of the pharmaceutical formulation may vary. Other methods suitable for administration of the compounds of the invention are set forth in the application of 8〇1丨讣U.S. Patent No. 5,604,231, the disclosure of which is incorporated herein by reference in its entirety in its entirety in the the the the the the the the the the the the the And, for example, 163062.doc 201244717 one aspect of the invention includes (2S,3R)-N-(2-((3-.pyridyl)methyloxazabicyclo[2.2.2] s- Combination of 3-yl)benzofurancarbamide or a pharmaceutically acceptable salt thereof, or another ct7 agonist with one or more stimulants for the treatment of combined, underpowered or overactive/impulsive Addh Another aspect includes (2S,3R)-N-(2-((3-indolyl)methyl)-i-azabicyclo[2 2 2]oct-3-yl)benzofuran 2_methantamine or a pharmaceutically acceptable salt thereof, or another combination of an alpha 7 agonist and one or more antidepressants for treating a combined, inactive or Over/impact type ADHD. Another aspect includes (2S,3R)-N_(2-((3-pyridyl)indolyl)-1_azabicyclo[2 2 2]octyl)benzindole Combination of -2-nonylamine or a pharmaceutically acceptable salt thereof, or another ... agonist with one or more antihypertensive agents for the treatment of combined, underpowered or overactive/impulsive ADHD. A further aspect includes (2S,3R)-N-(2-((3-)pyridyl)methyl)-indolylbicyclo[2 2 2]octyl-3-yl)benzofuran_ 2 - Combination of methotrexate or a pharmaceutically acceptable salt thereof, or another alpha 7 agonist with one or more stimulating agents, one or more antidepressants, and one or more antihypertensive agents To treat combined type 'attention deficit or overactive/impulsive ADHD. There are many irritants that can be used to treat ADHD. Common irritants include (but are not limited to): Adderall®, racemic amphetamine, aspartate monohydrate, racemic amphetamine sulfate, dextroamphetamine, and dextroamphetamine sulfate ; Concerta®, methylphenidate; Dexedrine®, dextroamphetamine; Metadate®, methylfenida; and mepruline ), methyl fenida; Ritalin®, methylfenni 163062.doc -16· 201244717 达; or Vyvanse® lisdexamfetamine. In addition, precise mechanisms of action such as Provigil® (modafinil) and Nuvigil® (armodafinil) are unknown but provide similar sympathomimetic Agents which act as agents are considered to be within the scope of the invention. Antihypertensive agents for the treatment of ADHD include, but are not limited to, Catapres® (clonidine); and Tenex® (guanfacine). The use of such drugs is usually directed at the symptoms of aggression and impulsivity that cannot be controlled by other ADHD drugs. Antidepressants used to treat ADHD include, but are not limited to, bupropion (bupropion); tricyclic antidepressants such as (Pamelor®) (nortriptyline) )), Aventyl® (norstatin), T〇franiL® (imipramine); and Campamine (Norpramin® (desipramine) ); Effexor® (venlafaxine); monoamine oxidase (MAO) inhibitors, including Nardil® (phenelzine) or Parnate® (Parnate®) Tranylcypromine; and selective norepinephrine reuptake inhibitors, such as Strattera® (atomoxetine). The compounds of the invention may be used alone or in combination with other treatments. The pharmaceutically active agent combination can be administered together or separately, and when administered separately, the administration can be carried out simultaneously or in any order. The amount of the compound or agent and the relative timing of administration It should be selected to achieve the desired therapeutic effect. Combinational administration can be simultaneously administered by: (1) including A single medicine of a compound 163062.doc 17 201244717 medicine! The mouthpiece ' or (2) each includes a respective pharmaceutical composition of a compound. Alternatively, the combination may be administered separately in a sequential manner, and t is first administered to a treatment. And then administered another therapeutic agent, or vice versa. The sequential administration can be separated by a shorter period of time or longer. The compounds of the invention can be used to treat a variety of conditions and conditions, and thus, the compounds of the invention can be Other suitable therapeutic agents that can be used to treat or prevent such conditions or conditions are used in combination. The appropriate dose of the compound is an amount effective to prevent the onset of symptoms or to effectively treat some of the symptoms of the patient's condition. As described herein, "effective Amount, "therapeutic amount" or "effective dose" means an amount sufficient to elicit a desired pharmacological or therapeutic effect, thereby making it effective to prevent or treat a condition. In the treatment of a CNS disorder such as ADHD, an effective amount of the compound is sufficient to wear. Through the blood-brain barrier of an individual, binding to relevant receptor sites in the individual's brain and modulating the activity of the relevant NNR subtype (eg, providing neural transmission) An amount of secretion that is thereby made effective to prevent or treat a condition. Examples of preventing a condition appear to delay the onset of symptoms of the condition. Examples of treating a condition are manifested by reducing the symptoms associated with the condition or improving the recurrence of symptoms of the condition. Preferably, an effective amount is sufficient to achieve the desired result, but is insufficient to cause significant side effects. The effective dosage can vary depending on factors such as the condition of the patient, the severity of the symptoms of the condition, and the manner in which the pharmaceutical composition is administered. For human patients, an effective dose of a typical compound will generally require administration of the compound in an amount sufficient to modulate the activity of the relevant NNRs, but this amount should not be sufficient to induce any significant effect of skeletal muscle and ganglia. The effective dose of the compound will of course vary from patient to patient, but will generally include an amount that begins to develop a CNS effect or other desired therapeutic effect in 163062.doc 18 _ 201244717 but below the observed muscle effect. When used in an effective amount according to the methods described herein, the compounds described herein may, to a lesser extent, prevent progression of the CNS or other condition, improve its symptoms, or, to a lesser extent, improve its recurrence. The effective amount of such compounds is > f below the concentration concentration required to elicit any significant side effects, such as those associated with the skeletal muscle or ganglion. Such compounds can be administered in a therapeutic window where certain CNS disorders or other conditions are treated and certain side effects are avoided. Desirably, an effective amount of a compound described herein is sufficient to provide the desired effect on the condition' but insufficient (i.e., not sufficiently high) to provide an undesirable side effect. Preferably, such compounds are administered in an amount effective to treat (10) a dose or condition of a condition or other condition, but less than, usually less than 1/5, and usually less than ι/ι, causing any significant side effects of any significant degree. The optimal 'effective dose' is the very low concentration at which maximum effect and minimal side effects are observed. Typically, an effective dose of such compounds will generally require administration of the compound in an amount less than the weight of the Wkg patient. Typically, the compounds of the invention are administered in an amount of less than about i mg/kg of the patient's body weight and usually less than about 1 〇〇晞kg of the patient's body weight, but often between about 1 gram and the patient's body weight to less than _Pg/kg of the patient's body weight. versus. The above effective dose generally represents one or more doses administered in an amount of f-dose or administered during a 24-hour period. For human patients, an effective dose of a typical compound will generally require administration of the compound in an amount of at least about 1 mg/24 hr/patient, at least about 1 mg/24 匕/patient, and at least about 100 mg/24 hr/patient. For human patients, the effective dose of a typical sigma needs to be administered to a compound generally no more than about 5 (8) mg / 24 hr / patient, usually no more than about _ called hr / patient and often not] 63062.doc •19· 201244717 over ' Force 300 mg / 24 hr / patient. Additionally, the composition is advantageously administered in an effective dose such that the concentration of the compound in the patient's plasma normally does not exceed 50 ng/mL, typically does not exceed 3 ng/mL and often does not exceed i 〇 ^ in one of the present invention In the examples, the effective dose is between about 1 mg and 50 mg over a 24 hour period. Method of Using a Pharmaceutical Composition As used herein, "intrinsic activity" or "potency" refers to a measure of the biological effectiveness of a binding partner complex. For receptor pharmacology, the context in which the activity or potency should be defined will depend on the context of the binding partner (e.g., receptor/ligand) complex and the activity associated with the particular biological result. For example, in some cases, the intrinsic activity may vary depending on the particular second courier system involved. See H〇yer, D. and Boddeke, H., Heart/>/^waco/·%·14(7): 27〇·5 (1993), the contents of which are incorporated herein by reference. It will be apparent to those skilled in the art that the context specific assessments are relevant and how such may be relevant in the context of the present invention. As used herein, a neurotransmitter that mediates release by a compound described herein includes, but is not limited to, acetylcholine, dopamine, norepinephrine, serotonin, and alanine, and The compounds described herein act as modulators at the a7 subtype of Cns NNR. As used herein, the term "preventing" or "preventing" includes reducing the progression of, or delaying, the progression of a disease, condition or condition to any degree. The term includes providing a protective effect against a particular disease, disorder, or condition and improving the recurrence of the disease, disorder, or condition. Thus, in another aspect, the invention provides a method of treating an individual having an NNR or nAChR mediated disorder or having a risk of developing or experiencing recurrence of the disorder. The compounds of the invention and pharmaceutical compositions are useful for achieving beneficial therapeutic or prophylactic effects in, for example, individuals with CNS dysfunction. As described above, the free base and salt compounds of the present invention modulate the a7 NNR# type (characteristics of the CNS) and can be used to modulate a7 in individuals suffering from or susceptible to various conditions or conditions, including those of the CNS. NNR to prevent or treat such conditions or conditions. Such compounds have the ability to selectively bind to a7 nnr and exhibit nicotinic pharmacology, for example, as agonists, partial agonists, antagonists, as set forth herein. For example, when a compound of the invention is administered to a patient in need thereof in an amount effective to prevent the progression of the Cns disorder (ie, providing a protective effect) to a certain extent 'improving the symptoms of the CNS disorder, or improving the CNS disorder< relapse, or Its combination. The compounds of the present invention are useful in the treatment or prevention of conditions and conditions in which they have been proposed or shown to be useful as therapeutic agents for other types of nicotinic compounds. See, for example, the references previously listed above and Williams et al.

Drwg 7(4): 205 (1994); Arneric et al.

Drwg~ν·1(1): 1-26 (1995); Arneric et al., £; φ.〇ρΖ·«· /«vesi. Drwgs 5(1): 79-100 (1996), Bencherif et al.丄尸/larwacc»/.心;?. 77zer. 279: 1413 (1996); Lippiello et al., corpse Zmrmaci?/· hp. 77?er. 279: 1422 (1996); Damaj et al., Pharmacol. Exp Ther. 291: 390 (1999) ; Chiari et al., Anesthesiology 91: 1447 (1999), Lavand'homme and

Eisenbach, Jnesi/iesioioa 91: 1455 (1999); Holladay et al. 163062.doc 21 201244717 Person, 丄MeA CTiem. 40(28): 4169-94 (1997); Bannon et al, Science 279: 77 (1998); PCT WO 94/08992 ' PCT WO 96/31475, PCT WO 96/40682, and U.S. Patent No. 5,583,140 issued to Bencherif et al., issued 5, 597, 919 to Dull et al., issued to Smith et al. No. 5,852,041 to Cosford et al., the disclosure of which is incorporated herein by reference. Such compounds and pharmaceutical compositions thereof are useful for treating or preventing a variety of CNS disorders, including age-related or other cognitive deficits and dysfunctions, and attention disorders &, in particular, ADHD. Mental health professionals use the American Academy of Psychiatry's Diagnostic and Statistical Manual _IV text revision (DSM-IV-TR) to help diagnose ADHD. This diagnostic criteria helps ensure that people have been properly diagnosed and treated for ADHD. Using the same criteria across groups will help determine the prevalence and public health impact of ADHD. As mentioned above, two types of ADHD have been identified: combined ADHD: if the past few months meet the specific criteria for attention deficit and overactivity/impulsivity; mainly for attention deficit ADHD: if in the past 6 The month meets the criteria for lack of attention but does not meet the criteria for over/impulsiveness; and is mainly for the impulsive impulse type ADHD: if the criteria for over/impulsiveness are met in the past 6 months but not for attention, no attention is given ^ Guidelines. The above conditions and conditions are discussed in more detail in, for example, the American Psychiatry School. Cognac. Diagnostic and Statistical Manual of Psychiatry, Fourth Edition, Text Revision, w hi

Washington, dc, American Academy of Psychiatry's 2_: its content on the definition of such conditions and conditions is hereby incorporated by reference. More details on symptoms and diagnostic characteristics are also available. 163062.doc •22· 201244717 Refer to this manual to better treat or prevent diseases, conditions and conditions without significant adverse motor effects, including, for example, significant increases in blood pressure and heart rate. Significant negative effects on the gastrointestinal tract and significant effects on skeletal muscle. According to the compound of the present invention, when used in an effective amount, the 'tongue' of a7 NNR is adjusted to have no significant interaction with the nicotine subtype characterized by human ganglions, as caused by the lack of adrenal chromaffin tissue or skeletal muscle. The strength of nicotine function has been confirmed to be further confirmed by the lack of ability to elicit a final function in cell preparations that exhibit muscle-type nicotinic receptors. It is believed that these compounds are capable of treating or preventing diseases, conditions and diseases; brothers, without causing significant side-effect-related activities at ganglia and neuromuscular sites. Accordingly, it is believed that administration of such compounds provides a therapeutic window in which certain diseases, conditions, and conditions are provided (4) and certain side effects are avoided. That is, it is believed that an effective dose of the compound is sufficient to provide the desired effect on the money, but is believed to be insufficient (i.e., not sufficiently high) to provide undesirable side effects. Thus the invention provides the use of a compound of the invention or a pharmaceutically acceptable salt thereof for use in therapy, such as the above therapies. V·Synthesis Examples The following synthesis examples are provided to illustrate the invention and are not intended to limit the scope of the invention. In these examples, unless otherwise stated, the parts and percentages are by weight. Except (iv), all liquids are aqueous solutions. ° Otherwise all dissolved examples 1: (2S, 3R)-N-(2_((34 ntyl)f) sin·3·yl) benzo with ... amine (compound sentence and J = I63062.doc -23· 201244717 3S)-N-(2-((3-"-pyridyl)methyl)^ azabicyclo[2·2·2] xin_3_yl) benzofuran-2-carboxamide Scale synthesis of 2-((3-pyridyl)methylene)_ι_azabicycloindole 2 2 2]oct-3-yl ketone Potassium hydroxide (56 g' 0.54 mol) in decyl alcohol (420 mL) 3-Quinuclidinone hydrochloride (75 g, 0.49 mol) was added and the mixture was stirred at ambient temperature for 3 min. Add 3-pyridine furfural (58 g, 0.54 mol) And the mixture was stirred at ambient temperature for 16 hours. "The reaction mixture turned yellow during this time and the solids caked on the walls of the flask. The solids were scraped from the walls and the agglomerates were broken. Water was added under rapid stirring (390 When the solids were dissolved, the mixture was allowed to cool overnight at 4 ° C. The crystals were collected by filtration, washed with water, and air-dried to obtain 8 g of a yellow solid. The filtrate was concentrated to about 10% of its previous volume. And cooled down The second crop (8 g) was obtained. Both harvests were pure enough for further conversion (88 g, 82% yield). 2-((3-Pyridinyl)methyl)-1 -Azabicyclo[2.2.2]oct-3-one makes 2-((3·«-pyridyl)methylene)-1 azabicyclo[2·2·2]oct-3-one (2〇 g, 93 mmol) was suspended in methanol (200 mL) and treated with 46 mL of 6 EtOAc. EtOAc <RTI ID=0.0> The mixture was removed from the filtrate by rotary evaporation, thereby providing crude 2-((3-pyridyl)methyl 1-isobicyclo[2.2.2]oct-3-one hydrochloride as a white gum. Salt (20 g), which was then treated with 2 μ of sodium hydroxide (50 mL) and mp (50 mL) and stirred for one hour. Separate the gas-like layer and use 2 Μ sodium hydroxide (about 5 mL 'sufficient The pH was raised to a saturated aqueous solution of sodium sulphate (25 mL) to treat the aqueous phase. Extracted with gas (3 x 1 〇 mL) 163062.doc • 24-201244717 This aqueous mixture was dried (anhydrous magnesium sulfate). Extract and concentrate by rotary evaporation. Residues (丨8 g) Dissolve in warm B_ (320 mL) and cool to 4 ° C. Filter off a white solid, wash the strip with a small portion of cold B and air dry. Concentrate the filtrate to about 丨〇% of its previous volume and Cooling at 4 ° C produces a second harvest. A combined yield of 16 g (79%) was obtained. 3-Amino-2-((3-pyridyl)methylbu-azabicyclo[2.2.2]octane under nitrogen to 2-((3-η-pyridyl)methyldip-aza Bicyclo[2.2.2]oct-3-yl ketone (3.00 g, 13.9 mmol) in a stirred solution of anhydrous methanol (2 mL) was added to a solution of zinc sulfate in diethyl ether (2.78 mL, 2.78 mmol) After stirring at ambient temperature for 30 minutes, the mixture was treated with solid ammonium decanoate (10.4 g, 167 mmol). After stirring at ambient temperature for an additional 1 hour, it was added portionwise. Solid sodium cyanoborohydride (1.75 g) , 27.8 mmol). The reaction was then stirred at ambient temperature overnight and quenched by the addition of water (approximately 5 mL). Partitioned between 5 NaOH (10 mL) and EtOAc (20 mL) The reaction was quenched. The aqueous layer was extracted with EtOAc (EtOAc) (EtOAc)EtOAc. A 1:9 mixture of amines and a trace of the corresponding alcohol (98% total mass recovery). (2R,3S) and (2S,3R)-3-amino-2-((3-"pyridyl) Methyl)-1-azabicyclo[2·2·2]octane Add bis-p-tolylhydrazin-D-tartaric acid (5.33 g, 13.8 mmol) to crude 3-amino-2-((3-pyridinyl)indolyl-1-azabicyclo[2.2.2 ] Octane (6.00 g, 27.6 mmol of 1:9 cis/reverse mixture) in methanol (20 mL) stirred in 163062.doc •25-201244717 solution. After complete dissolution, then clarified by rotary evaporation The solution is concentrated to a solid material. The solid is dissolved in a minimum amount of boiling sterol (about 5 mL). The solution is slowly cooled, first cooled to ambient temperature (丨 hours), then held at 5 ° C for about 4 hours, and finally The overnight precipitation was carried out by suction filtration, and the precipitated salt was collected by suction filtration and recrystallized from 5 mL of methanol. After air drying, 丨4^ white solid was left, which was taken in the mixture (5 mL) and 2 Μ sodium hydroxide ( 5 mL) was partitioned. 5 mL of the gas-like extract of the gas-like layer and the aqueous layer was combined, dried (anhydrous sodium sulfate) and concentrated to give a colorless oil (0.434 g). By diverting a portion to its N-(t-butoxycarbonyl)-L-indoleamine, then analyzing its diastereomeric purity (98%) using LCMS. Measured.

The mother liquor from the initial crystallization was made alkaline with 2 Μ sodium hydroxide (about pH and extracted twice with gas (10 mL). The extract was dried (anhydrous sodium sulfate) and concentrated to give an oil. 3.00 g, 13.8 mmol) was dissolved in decyl alcohol (〇mL) and treated with 1-p-toluene-L-tartaric acid (2.76 g, 6.90 mmol). The mixture was allowed to warm to aid dissolution and then slowly cooled to 5 C, kept at this temperature overnight. The sediment was collected by suction filtration and recrystallized from decyl alcohol and dried. This left 1. 5 g of a white solid. The salt was converted to the free base (yield = 〇 364 g), and the enantiomeric purity (97%) was evaluated using the amidoxime method as described above for the other enantiomer.

Ν·(2·((3_°-pyridyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran·2_cartoamine trans-enantiomer Body A Diphenyl phosphate (0.35 mL, 0.46 g, 1.7 mmol) was added dropwise to 163062.doc -26 - 201244717 Stupid 2-pyruic acid (〇28 g,} 7 mm〇1) and three Ethylamine (〇 24 mL, 〇i7 g, 1.7 mm 〇1) was dissolved in anhydrous di-methane (5 mL). After stirring for 30 minutes under ambient/diagonal conditions, (2S3R)3amino-2((3-pyridyl)indolyl)_1•azabicyclo[2·2.2]octane (0.337 g, 1_55 mmol) was added ( A solution of mono-p-tolylmethyl-D-tartrate and triethylamine (0.24 mL, 0.17 g, 1.7 mmol) in anhydrous di-methane (5 mL). The reaction mixture was stirred at ambient temperature overnight and then treated with 10% sodium hydroxide (1 mL). The two-phase mixture was separated, and the organic layer was concentrated on a Geneva evaporator. The residue was dissolved in methanol (6 mL) and acetonitrile/water gradient (with hydrazine) was applied to the 匚丨8 stone 5% trifluoroacetic acid) was purified by HPLC as an eluent. The selected fractions were concentrated, and the obtained residue was partitioned between methylene chloride and saturated aqueous sodium hydrogencarbonate, and evaporated to give 〇3i〇g 42% yield) white powder (95% pure, determined by GCMS). Nmr (300 MHz, CDC13) δ 8.51 (d, 1Η), 8.34 (dd, 1H), 7.66 (d, 1H), 7.58 (dt, 1H), 7.49 (d, 1H), 7.44 (s, 1H), 7.40 (dd, 1H), 7.29 (t, 1H), 7.13 (dd, 1H), 6.63 (d, 1H), 3.95 (t, 1H) 3.08 (m, 1H), 2.95 (m, 4H), 2.78 ( m, 2H), 2.03 (m, 1H), 1.72 (m, 3H), 1.52 (m, 1H). This material (trans enantiomer A) was then confirmed to be identical to the material having an absolute configuration of 2S, 3R (established by X-ray crystallographic analysis) by palm chromatography analysis.

Trans-enantiomer of N-(2-((3-acridinyl)methyl)-1.azabicyclo[2.2.2]oct-3-yl)benzoc- -2-pyranamine Body B Dichloroacetic acid diphenyl vinegar (96 μΐ^, 124 mg, 0.46 mmol) was added dropwise to 163062.doc •27- 201244717 benzofuran-2-carboxylic acid (75 mg, 0.46 mmol) and triethylamine ( 64 μ, 46 mg, 0.46 mmol) in a solution of anhydrous di-methane (1 mL). After stirring at ambient temperature for 45 minutes, (2r,3S)-3-amino-2-((3-pyridyl)indenyl)-1-azabicyclo[2.2.2]octane (〇.1) was added. 〇g, 0.46 mmol) (from di-p-tolylmethyl-L-tartrate) and triethylamine (64 μί, 46 mg, 0.46 mmol) in anhydrous di-methane (1 mL) . The reaction mixture was stirred at ambient temperature overnight and then treated with 1% aqueous sodium hydroxide EtOAc. The two-phase mixture was separated, and the organic layer and the aqueous layer of the gas-like extract were concentrated by rotary evaporation (2) the residue was dissolved in methanol and the acetonitrile/water gradient was applied to a C18 cartridge column (containing 5% 5%) The fluoroacetic acid was purified by HPLC as an eluent. The selected fractions were concentrated, and the obtained residue was partitioned between methylene chloride and saturated aqueous sodium hydrogencarbonate and evaporated to give 82.5 mg (50% yield). White powder. The NMR spectrum is the same as that obtained for the 28,311 isomer. Due to the direct precursor of this material (trans enantiomer B) 2S, the direct precursor of the 3R compound (trans enantiomer a) The enantiomers' are presumed to be the absolute configuration of the trans-enantiomer B, 2R, 3S. Example 2: (2S,3R)-N-(2-((3-«-pyridyl)) • azabicyclo[2 2 2]oct-3-yl)benzofuran-2-carboxamide and (2S,3R)-N-(2-((3-pyridyl)methyl)-1 Large-scale synthesis of 2-((3-acridinyl)methylene) by a large-scale synthesis of azabicyclobutene P.2.2]oct-3-yl)·1·benzopyrene-2_carbamidine p-toluenesulfonate -1-Azabicycloindole 2·2·2] octyl-3-yl ketone will be 3-quinone under nitrogen atmosphere Ninthone ketone hydrochloride (8.25 kg, 51.0 mol) and methanol (49.5 L) were added to a 100 L glass reaction flask equipped with a mechanical stirrer, temperature probe and condenser" via a powder funnel for approximately 3 minutes. Add argon argon (5.55 1^, 99.〇111〇1) between 163062.doc -28- 201244717, which makes the reaction temperature from 50. (: rise to 56 ° C. After about 2 hours will be 3 · Pyridinecarboxaldehyde (4 8 〇 kg, 44 9 mol) was added to the reaction mixture. The resulting mixture was stirred under a minimum of 12 hours while the reaction was monitored by thin layer chromatography (TLC). Upon completion of the reaction, filtered through a fritted glass funnel. The reaction mixture was washed with decyl alcohol (74.2 L). The filtrate was concentrated, transferred to a reaction flask, and water (66.0 L) was added. The suspension was stirred for a minimum of 3 min, filtered and washed with water (90.0 L) Filter cake until the {11 of the rinse solution is 7_9. The solid is dried in vacuum at 50 ° C at 5 ° C for a minimum of 12 hours to obtain 8.58 kg (89.3%) 2-((3-pyridine) Methyl)methylene)_ι_azabicyclo[2 2 2]oct-3-ylketone β(2S)-2-((3-acridinyl)methyl)-1-aza Ring [2·2·2丨辛_3_keto-di-p-tolylmethyl-D-tartrate in an inert atmosphere. 2-((3-«-pyridyl)-indenyl)_丨_ Azabicyclo[2.2.2]oct-3-one (5,40 kg, 25.2 mol) and methanol (40.5 L) were added to a machine equipped with a mechanical stirrer, temperature probe, low pressure gas regulator system and pressure gauge 72 L in the reaction vessel. The headspace was filled with nitrogen and the mixture was searched to obtain a clear yellow solution. Add 1% carbon (humidity 5 〇%) (270 g) to the flask. The atmosphere in the reactor was evacuated using a vacuum pump and the headspace was replaced with hydrogen to a water pressure of 10 inches to 20 inches. It was evacuated and hydrogen-pressed twice more to maintain the reactor under a hydrogen pressure of 2 Torr after the third press. The reaction mixture was stirred at 2 (TC ± 5 ° C for a minimum of 12 hours) and the reaction was monitored via TLC. Upon completion of the reaction, the suspension was filtered on a sintered glass funnel via a bed of Celite® 545 (1.9 kg) with methanol 163062 .doc -29- 201244717 (10.1 L) Washing filter cake. Concentrate the filter cake to obtain a semi-solid, transfer it to a 200 L reaction flask equipped with an organic (four) stirrer, condenser and temperature probe under a gas atmosphere. The semi-solid was dissolved in ethanol (57.2 L) and di-p-methyl-bromo-D-tartaric acid (DTTA) (9 74 kg, 25 2 m〇i) was added. The reaction mixture was refluxed. Heat for a minimum of 丨 hours and additionally maintain a minimum of 12 hours while cooling the reactants to between hunger and 30 t. Filter the suspension using a tabletop filter and wash the filter cake with ethanol (114 L) Dry the product under vacuum and ambient temperature to obtain ιΐ 6 kg (76.2% yield, 59 5% considering purity factor) (2s) 2 (indolyl) fluorenyl)-1-azabicyclo[ 2_2.2] 辛·3_keto-p-tolylmethyl hydrazine-d tartrate. (2S,3R)m_2_((3Kyl)methyl)]•heterobicyclo[222]octane bis-p-tolylhydrazyl-D-tartrate water (46.25 L) and sodium arsenate (4.35 kg) , 51.8 m〇i) was added to a 2 〇〇L flask. When completely dissolved, di-halogen methane (69 4 l) was added. Add (2S)-2-((3-acridinyl)indenyl)-indole-azabicyclo[2 2 2]oct-3-one di-p-tolylmethyl-D-tartrate (11.56 kg, 19.19 m 〇 1), and the reaction mixture is stirred for 2 minutes to 1 minute. The layers were separated for a minimum of 2 minutes (additional water (20 L) was added as needed to dispense the layers). The organic phase was removed and dried over anhydrous sodium sulfate. Dioxane methane (34.7 L) was added to the remaining aqueous phase and the suspension was stirred for 2 minutes to 1 minute. The layers were separated for 2 minutes to 1 minute. The organic phase was again removed and dried over anhydrous sodium sulfate. The aqueous phase was extracted once with dihalomethane (34.7 L) as described above. Samples submitted for each extraction were submitted for analysis by palm HPLC. The sodium sulfate was removed by filtration, and the filtrate was concentrated 163062.doc -30-201244717 to obtain (2S)-2-((3-»pyridyl)indolyl)-1 azabicyclo[2] as a solid. · 2.2] Xin-3· Brewing) (4.0 kg). Transferring (2S)-2-((3-.pyridyl)methyl)-1-azabicyclo[2.2.2]oct-3-one (3.8 kg) to a mechanically mixed mixture under a nitrogen atmosphere Clean the device and temperature probe in a 10 玻璃L glass reaction flask. Add anhydrous tetrahydrogen. South (7.2 4 L) and (+)-(R)-a-methylbenzylamine (2.55 L, 20.1 mol). Titanium (IV) isopropoxide (6.47 L, 21.8 mol) was added to the stirred reaction mixture over a period of 1 hour. The reaction was stirred under a nitrogen atmosphere for a minimum of 12 hours. Ethanol (36.17 L) was added to the reaction mixture. The reaction mixture was cooled to below _5 and sodium borohydride (1.53 kg, 40.5 mol) was added portionwise to keep the reaction temperature below 15 °C (this addition took several hours). The reaction mixture was then stirred at 15 ° C ± 10 ° C for a minimum of 1 hour. The reaction was monitored by HPLC and upon completion of the reaction (shown as less than 0.5% of (2S)-2-((3-)pyridyl)methyl)-1-azabicyclo[2.2.2] s- 3-ketone), 2 Μ sodium hydroxide (15.99 L) was added and the mixture was mixed for a minimum of 丨〇 minutes. The reaction mixture was filtered through a bed of Cente® 545 in a bench funnel. The filter cake was washed with ethanol (15 23 L), and the filtrate was concentrated to give an oil. The concentrate was transferred under an inert atmosphere to a clean 1 L glass reaction flask equipped with a mechanical stirrer and a temperature probe. Water (1 L) was added and the mixture was allowed to cool to hydrazine. 〇±5. (:) 2 Μ hydrochloric acid (24 L) was added to the mixture to adjust the pH of the mixture to ΡΗ 1. The mixture was then stirred for a minimum of 1 Torr, and 2 Μ sodium hydroxide (24 L) was slowly added to mix the mixture. ρΗ was adjusted to pH 14. The mixture was stirred for at least 1 〇 minutes, and the aqueous phase was extracted with a gas purge (3 x 15.23 L). Anhydrous sodium sulfate (2 〇 let "dry organic 163062.doc • 31 · 201244717 phase, Filtration and concentration 'obtained (2S,3R)-N-((1R)-phenylethyl)-3•amino-2-((3-.pyridyl)indolyl))_1-azabicyclo[2.2 .2] Octane (4.80 for £84.7% yield). (2S,3R)-N-((1R)-Phenylethyl)-3-amino-2- (3- Transfer of pyridyl)methyl)_丨·azabicyclo[2.2.2]octane to a 22 L glass flask equipped with a mechanical stirrer and temperature probe. Add water (4.8 L) and stir the mixture Cool to 5 ° C ± 5 ° C. Concentrated hydrochloric acid (2.97 L) was slowly added to the reaction flask to keep the temperature of the mixture below 25. It was transferred under an inert atmosphere to contain ethanol L) and equipped With mechanical agitator, temperature In a 72 L reaction flask with a probe and a condenser, 10% palladium carbon (humidity 50%) (311.1 g) and cyclohexene (14 36 L) were added to the flask. The reaction mixture was heated under reflux. At least 12 hours, and the reaction was monitored by TLc. Upon completion of the reaction, the reaction mixture was cooled to below 45, and it was transferred to a bed of Celite® 545 (1.2 kg) on a sintered glass funnel. The filter cake was rinsed and the filtrate was concentrated to obtain an aqueous phase. Water (5 mL) was added to the concentrated filtrate, and the combined aqueous layer was washed with methyl butyl ether (MTBE) (2M. Add 2 argon argon (19.5 L) to the aqueous phase to adjust the pH of the mixture to pH Η 14. Then stir the mixture for a minimum of 10 minutes. Extract the aqueous phase with a gas imitation (4xll 96 L) and pass anhydrous sulfuric acid Sodium (2.34 kg) was dried and the combined organic phases were filtered and the filtrate was concentrated to give (2S,3r)_3_amino-2-((3-pyridyl)methyl)-1-azabicyclohexane as an oil. [2.2.2] Octane (3.49 kg, > quantitative yield). (2S,3R)-3.Amino-2-((3-.pyridyl)indenyl)- under an inert atmosphere 1_ Heterobicyclo[2.2.2]octane was transferred to a clean 100 L reaction flask equipped with a mechanical stirrer, condenser and 163062.doc •32·201244717 temperature probe. Add ethanol (38.4 1〇 and 2·pair) Formamyl-D-tartaric acid (3.58 kg, 9.27 mol). The reaction mixture was heated under gentle reflux for a minimum of 1 hour. The reaction mixture was then stirred for a minimum of 12 hours while allowing it to cool to between 丨5. (: between 30 ° C. Filter the resulting suspension ' and wash the filter cake with ethanol (5.76 L). Transfer the filter cake to a clean 100 L equipped with a mechanical stirrer, temperature probe and condenser under an inert atmosphere. In a glass reaction flask, add 9:1 ethanol/water solution (30.7 L), and heat the resulting slurry under gentle reflux for a minimum of 1 hour. Then stir the reaction mixture for a minimum of 12 hours while cooling to between 15 ° C and 30 °C. The mixture was filtered and the filter cake was washed with ethanol (5·76 L). The product was collected and dried under vacuum at 50 ° C ± 5 ° C for a minimum of 12 hours to obtain 5.63 kg (58.1% yield) (2S, 3R) --3-amino-2-((3-.pyridyl)indolyl)-1-azabicyclo[2.2.2]octanedi-p-quinone-fluorenyl-tartrate. (2S , 3R)-N-(2-((3-pyridyl)methyl)-indole-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide in an inert atmosphere (2S,3R)-3-amino-2-((3-acridinyl)indolyl)-^ anthracene bicyclo[2.2.2]octanedi-p-indole-d-tartrate ( 3.64 kg, 5.96 mol) and 10% sodium sulphate solution (14.4 L, 46.4 mol) added to the organic In a 72 L glass reaction flask with a mechanical stirrer, add 5 Μ sodium hydroxide (5.09 L) to the stirred mixture to adjust the ρ 混合物 of the mixture to ρ Η 14. Then stir the mixture for a minimum of 1 〇 minutes. χ丨2 〇L) The aqueous solution was extracted, and the combined organic layers were dried over anhydrous sodium sulfate (1.72 kg). The combined organic layer was filtered, and the filtrate was concentrated to give (2S,3R)-3-amine group as oil. -2-((3-pyridyl)methyl)·ΐ-azabicyclo[2.2.2]octane I63062.doc •33- 201244717 (1.27 kg). (2S,3R)-3 under inert atmosphere -Amino-2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane was transferred to a 50 L glass reaction flask equipped with a mechanical stirrer. Dioxethane (16.5) L), triethylamine (847 mL, 6.08 mol), benzofuran-2-carboxylic acid (948 g, 5,85 mol) and hexafluorophosphate 0-(benzotriazol-1-yl)·Ν, Ν , hydrazine, 1-tetradecylurea rust salt (HBTU) (2.17 kg, 5.85 mol) was added to the reaction mixture. The mixture was stirred at ambient temperature for a minimum of 4 hours' and the reaction was monitored by HPLC. Will be 1 〇〇 / 〇 An aqueous solution of carbonic acid clock (12.7 L, 17.1 mol) was added to the reaction mixture and the mixture was stirred for a minimum of 5 minutes. The layers were separated and washed with 1% aqueous brine (12.7 L). The layers were separated and the organic phase was cooled to 15eC ± 1 (TC. 3 Μ hydrochloric acid (8.0 L) was slowly added to the reaction mixture to adjust the pH of the mixture to pH 1. The mixture was then stirred for a minimum of 5 minutes and the layers were partitioned At least 5 minutes. Filter the solids using a bench filter. Separate the layers of the filtrate and transfer the aqueous phase and solids from the funnel to the reaction flask. Add 3 Μ sodium hydroxide (9.0 L) slowly to the flask. The pH of the mixture was adjusted to pH 14. The aqueous phase was extracted with trichloromethane (2×16.5 L). The combined organic phases were dried over anhydrous sodium sulfate (1.71 kg). The mixture was filtered and concentrated to give a yellow solid. Form (2S,3R)-N-(2-((3-pyridyl)methyl)·1-heterobicyclo[2.2.2]oct-3-yl) Ben and Coward Shout-2·A Amine (Kg kg, 77.0% yield). (2S,3R)-N-(2-((3-nb))-1-azabicyclo[2 2 2]oct-3-yl] Benzofuran-2-carboxamide p-toluenesulfonate (2S,3R)-N-(2-((3-)pyridyl)methylazabicyclo[2.2.2]octyl I63062.doc • 34· 201244717 -3-yl)benzoxofkon-2-anthraceneamine (1 .62 kg, 4.48 mol) and two gas brothels (8.60 kg) were added to the carboy. The weight/weight percentage of the material in the solution was determined by HPLC analysis. The solution was concentrated to an oil and acetone was added. 4 L) 'and concentrate the mixture into an oily solid. Add additional acetone (12 L) to the oily solid in a rotary evaporator • bulb and transfer the resulting slurry to a mechanical stirrer under an inert atmosphere , 50 liter glass reaction flask with condenser, temperature probe and condenser. Heat the reaction mixture to 50 ° C ± 5 ° C. Add water (80.7 g) to the solution and spoil it for at least 10 minutes. Toluenesulfonic acid (853 g, 4.44 m〇l) was added portionwise to the reaction mixture over about 15 minutes. The reaction mixture was heated to reflux and kept at this temperature for a minimum of 30 minutes to obtain a solution. The reaction was cooled to 40 C ± 5 C over 2 hours. Acetate isopropyl acetate (14.1 L) was added over a period of about 1.5 hours. The reaction mixture was slowly cooled to ambient temperature over a minimum of 10 hours. The transition mixture was combined with isopropyl acetate ( 3.5 L) Wash the filter cake in vacuum and 1〇5± The isolated product was dried at 5 ° C for 2 hours to 9 hours to obtain 2.19 kg (88.5% yield) of (28,311)-> 1-(2-((3-acridinyl)indolyl)-1 -Azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carbamimido-methyl sulfonate, „11> 226-228. . .咕NMR (500 MHz, D20) δ 8.29 (s, 1H), 7.78 (m, > 5.1, 1H), 7.63 (d, *7 = 7.9, 1H), 7.54 (d, J = 7.8, 1H), 7.49 (d, J=8.1, 2H), 7.37 (m, J=8.3, 1H), 7.33 (m, J=8.3, 6.9, 1.0, 1H), 7.18 (m, “7=7.8, 6.9, 1.0, 1H), 7.14 (d, "7=8.1, 2H), 7.09 (s, 1H), 6.99 (dd, /=7.9, 5.1, 1H), 4.05 (m, J=7.7, 1H), 3.74 (m, 1H), 3.47 (m, 2H), 3.28 (m, 1H), 3.22 (m, 1H), 3.15 (dd, /=13.2, 4.7, 1H), 3.02 (dd} 7=13.2, 11.5, 1H), 163062.doc •35- 201244717

2.19 (s, 3H), 2·02 (m, 2H), 1.93 (m, 2H), 1.79 (m, 1H). 13C NMR (126 MHz, D2〇) 5 157.2, 154.1, 150.1, 148.2, 146.4, 145.2, 138.0, 137.0, 130.9, 128.2(2), 126.9, 126.8, 125.5(2), 123.7, 123.3, 122.7, 111.7, 100.7, 61.3, 50.2, 48.0, 40.9, 33.1, 26.9, 21.5, 20.8, 17.0.

A sample of this material was converted to Compound A free base (for salt selection studies) by treatment with aqueous sodium hydroxide and by gas-extraction. The gas was completely evaporated to leave an off-white powder, mp 167-17 (TC, which had the following spectral characteristics: positive ion electrospray MS [M+H] + ion m/z = 362. 4 NMR (500 MHz, DMSO- D6) δ 8.53 (d, J=7.6 Hz, 1H), 8.43 (d, 1.7 Hz, 1H) S 8.28 (dd, 7=1.6, 4.7 Hz, 1H), 7.77 (d, J=1.1

Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.63 (dt, J=1.7, 7.7 Hz, 1H), 7.52 (s, 1H)} 7.46 (m, 7=8.5, 7.5 Hz, 1H ), 7.33 (m, 7.5 Hz, 1H), 7.21 (dd, J=4.1, 7.7 Hz, 1H), 3.71 (m, •7=7.6 Hz, 1H), 3.11 (m,1H),3 〇2 ( m,1H),2 8〇(m,2H), 2.69 (m,2H),2.55 (m,1H), 1.80 (m,1H), 1.77 (m,1H), 1.62 (m, 1H), 1.56 (m, 1H), 1.26 (m, 1H) 〇13C NMR (126 MHz, DMSO-d6) δ 158.1, 154.1, 150.1, 149.1, 146.8, 136.4, 135.4, 127.1, 126.7, 123.6, 122.9, 122.6, 111.8, 109.3, 61.9, 53_4'49·9, 40.3, 35.0, 28 1 26 ι ι96. The monohydrochloride salt of Compound A (see Example 3) was used for X-ray crystallography. The resulting Japanese body structure was established as the 2S, 3R absolute configuration of Compound A. Example 3 Synthesis of (2S,3R).N.(2_((3.eHl-indenyl)methyl)small (tetra)bicyclo[2 2 oct-3-yl)benzoguanamine hydrochloride 163062.doc • 36 - 201244717 Monohydrochloride: A hydrochloric acid/THF solution was prepared by dropwise addition of concentrated hydrochloric acid (1.93 mL, 12 M, 23.2 mmol) to 8.5 mL of THF. Allow the solution to warm to ambient temperature. Add (2S,3R)-N-(2-((3-pyridyl)indolyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran_2_ to a round bottom flask Formamide

(8.49 g, 23.5 mmol) and propylene (85 mL). The mixture was stirred and heated at 45 ° C to 50 ° C until a complete solution was obtained. The hydrochloric acid/THF solution prepared above was added dropwise over 5 minutes, and additional THF (1.5 mL) was used in the transfer. During the addition of the acid solution, a granular white solid began to form. The mixture was allowed to cool to ambient temperature and stirred overnight (丨6 h). The solids were washed by suction and washed with acetone (1 mL) and the solid was suction dried for 30 minutes. In a vacuum oven at 75. The solid was further dried under ankle for 2 hours to obtain 8.79 g of fine white crystals (94% yield), mp 255-2 62 ς. The palmity analysis showed a purity of 98 8% (27 〇 nm). H-NMR (DMSO-d6) showed no residual solvent and a single stoichiometry was confirmed. Towel NMR (300 MHz, DMSO-d6) δ 10.7 (wide single peak, 1H_ quaternary ammonium), 8·80 (wide single peak '1H• guanamine H), 8.54 (s, 1H), 8 23 (4) ih) , 7 knives 8 (d, 1H), 7.74 (d, 1H), 7.60 (d, 1H), 7.47 (m, 2H), 7.33 (m, 1H), 7.19 (m, 1H), 4.19 (m, 1H) ), 4.08 (m, 1H), 3.05-3.55 (m, 6H), 2.00-2.10 (m, 3H)' 1,90 (m, 1H), 1.70 (m, ih). X-ray crystallographic analysis of this salt establishes stereochemical arrangements and stoichiometry. Dihydrochloride: Slowly bubbling hydrogenation gas to (2S,3R)_N_(2<(3_°pyridyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl) Benzofuranamine (1.9 g, 5.3 mmol) was taken in ice cold solution in dry ether (25 mL). The volatiles were first removed in a stream of nitrogen and then with a high vacuum (sodium hydroxide in a high vacuum line 163062.doc • 37·201244717 scrubber). The residue was triturated several times with a small amount of dry diethyl ether (discarded) and the remaining solid was dried under high vacuum. This gave 2.17 g (94% yield) of off-white powder, mp 21 〇 212β (: (absorption of palmarity to palmity LC analysis showed a purity of 93.7% (27 〇 nm positive ion electrospray river 8 [M+H] + Ion m/z = 362. NMR (300 MHz, CD3 〇 D) δ 9.15 (s, 1H), 8.84 (d, 1H), 8.63 (d, 1H), 7.97 (t, 1H), 7.75 (d, 1H), 7.61 (d, 1H), 7.52 (m, 2H), 7.35 (t, 1H), 4.50 (m, 1H), 4.32 (m, 1H), 3.40-3.85 (m, 6H), 1.95-2.40 (m, 5H) VI. Evaluation (2S,3R)-N-(2-((3· «-Acryl)methylazabicyclo[2.2.2]oct-3-yl)benzofuran_2 Double-blind, randomized, placebo-controlled, multicenter, fixed-dose escalation study of the efficacy, safety, and tolerability of methotrexate or its pharmaceutically acceptable salts in attention deficit/hyperactivity disorder (ADHD) PERFORMANCE RESULTS The present invention is derived from the test (2S,3R)-N-(2-((3·.pyridyl)indolyl)·ι· azabicyclo[2·2 2] in adults with ADHD. a test carried out by the action of octyl-3-furan-2-cartoamine or a pharmaceutically acceptable salt thereof. This study will be diagnosed according to DSM-IV-TR guidelines from various locations in the United States. 135 of ADHD Male or female adults (age 18·65 years) were randomized. Subjects were randomized to place placebo (η=67) or (2S,3R)-N-(2-((3-«^) )methyl)-1-azabicyclo[2.2.2]oct-3-yl) benzofuran-2-indoleamine or a pharmaceutically acceptable salt thereof (n=68: 1 mg p〇qd for 4 Week, then 5 mg P〇qd for 4 weeks, and the last 25 mg po qd for 4 weeks) treatment for 12 weeks. The following clinical study plan No. TC-5619-238-CRD-002 provides detailed instructions. 163062.doc -38 - 201244717

(T^lRGACEPT Proposal Document Control Number: PRO-05619-CRD-002 Version · 00 _ Effective Date: December 22, 2009 _ _ Study Number: TC-5619-238-CRD-002_ Evaluation TC-5619 is suffering Double-blind, randomized, placebo-controlled, multicenter, fixed-quantity-increasing research secrets of efficacy, safety, and tolerability in adults with attention deficit/hyperactivity disorder (ADHD)-39

Targacept Company 163062.doc

201244717 (TMGACEPT PRO-05619-CRD-002 (00) Effective date: 2009 December 22, said the signature page of TARGACEPT: Signature: Date: medical director / manager, security officer pharmacokinetic study research scientist τ Signature: Date: Approved : Head of Clinical Development and Regulatory Affairs

Clinical surgery supervisor

Targacept Company 163062.doc Confidential -40-

201244717(TARGACEPT PRO-05619-CRD-002(00) Effective date: December 22, 2009 TARGACEPT clinical research certificate evaluation TC-5619 in adults with attention deficit/hyperactivity disorder (ADHD) Double-blind, randomized, placebo-controlled, multicenter, fixed-dose escalation study of efficacy, safety, and tolerability Study No.: TC-5619-238-CRD-002 Contact Information Test Delegate: Targacept, Inc. 200 East First Street, Suite 300 Winston-Salem, North Carolina 27101 -4165 Phone: Fax: Test Client Contact:

Targacept Medical Contact: Total Trial Moderator: Trusted Research Institution: This study will be conducted in accordance with the Program and in accordance with Good Clinical Practice (GCP) and other applicable regulatory requirements.

Targacept Confidential 163062.doc *41 · 201244717 (Τ/lRGACEPT PRO-05619-CRD-〇02(00) Effective Date·· December 22, 2009 Clinical Plan Summary.......... .................................................. .....................................46 Abbreviation list.... .................................................. .................................................. ............52 1. Xian..................................... .................................................. ................................54 1.1. Description of test drugs..... .................................................. ..............................54 1.2. Summary of results......... .................................................. ......................................54 1.2.1. Non Clinical research................................................ .................................54 1.2.2. Clinical research.... .................................................. .....................................56 1.2.3. Background News................................................. ....................................58 1.3. Potential risks and benefits. .................................................. ...................................58 1.4. Theoretical basis for dose selection. .................................................. .................................58 1.5. Implementation of the test......... .................................................. .................................59 1.6. Research groups... .................................................. ..........................................59 1.7 The theoretical basis of research............................................. .........................................59 1.7. 1. Cholinergic system involved in cognitive impairment in ADHD................................59 1.7. 2. Adult ADHD and Cholinergic System.......................................... ....................60 1.7.3 Effect of nicotine stimulation on clinical symptoms of ADHD.................. ...........................60 2. Research purpose................................................ .................................................. .................61 2.1. Main purpose......................... .................................................. ..........................61 2.2. Minor g 63⁄4................. .................................................. ...............................61 3. Overview of research design....... .................................................. .................................................. 61 3.1. Research Design............................................. .................................................. .........61 11·1· Μ%##................................ .................................................. .........62 3.2. Theoretical basis for research design.................................... .................................................. .64 3.3. Research Procedures............................................ .................................................. ..........61 3.3.1. Every visit The program of time............................................ ........................................65 3.4. Research limit................................................. .................................................. .....69 3.5. ^......................................... .................................................. .....................70 3.6. Minimization of deviation........................... .................................................. ........................70 3.6.1. Randomization................... .................................................. ......................................70 3.6.2. Blind彳匕................................................ .................................................. ...................71 3.7. Research treatment and clinical trial supply........................... .................................................. ....71 3.7.1. Physical description of research drugs.................................... ...................................71 3.7.2. Drug packaging and labeling... .......................:.......................... ..........................71 3.7.3. Dosage and Dosage Plan............... .................................................. ................................71 3_7.4. Drug storage........... .................................................. ..........................................72 3.7 .5. Drug Distribution................................................ .................................................. ..............72 Confidential-42-

Targacept Company 163062.doc PRO-05619-CRD-002(00) 201244717

mRGACEPT Effective Date: December 22, 2009 3.8. Study Duration and Tracking................................. .................................................. .72 3.9. Interruption criteria................................................ .................................................. ..........72 3.10. Research drug classes are expensive.................................... .................................................. ...........73 3.10.1. Inventory records.................................... .................................................. .......73 3.10.2. Disposal of unused supplies.................................... ..................................73 3.11. Crack the program of randomization coding. .................................................. ...........................73 3·12. Completion of the case report form............. .................................................. .......................73 4. Research groups..................... .................................................. .....................................74 74. Inclusion criteria................................................ .................................................. ...74 4.2. Exclusion criteria.......................................... .................................................. ...............74 4.3. Completion and withdrawal of subjects........................ .................................................. .........75 4.3.1. Completion of the subject.............................. .................................................. ..75 4·3·2. Patient withdrawal (early interruption study).................................. ...............................75 4.3.3·Reporting Interruption............ .................................................. ........................76 4.3.4• Replacement of patients.................. .................................................. ...................76 5. Treatment of the subject...................... .................................................. ...............................76 5.1. Dose and Administration............ .................................... .................................................. ..76 5.2. Treatment allocation........................................... .................................................. ...........77 5.3. Combined therapy..................................... .................................................. ....................77 5.3.1. Permitted Pharmacy....................... .................................................. ....................................77 5.3.2. Prohibited and restricted pharmacy.... .................................................. .................................77 5.3.3. Non-pharmacological therapy... .................................................. .................................................. ..77 5.4. Compliance........................................... .................................................. ...............77 6. Pharmacokinetic evaluation............................ .................................................. .........................77 6.1. Sample collection and processing.................. .......... .................................................. ..............77 6.2·Analytical Procedures.............................. .................................................. .......................78 6.3. Pharmacokinetic parameters................... .................................................. ......................78 7. Performance Evaluation....................... .................................................. ....................................78 7.1. Effectiveness... .................................................. .................................................. .78 7.1.1. Conor Adult ADHD Assessment Scale - Trial Host Version (CAARS-INV) and Subject Version (CAARS-S)................ .................................................. .78 7.1.2. CogState ADHD Complete Test and Stop Signal Tasks.................................... .78 7.1.3. Clinical Overall Impression (CGI) Scale.................................... ..............................78 7.1.4. Emotional Status Scale (POMS)....... ........................... ................................79 7·2. Effectiveness analysis.......... .................................................. ..............................79 8. Security evaluation........ .................................................. .................................................. ...79 8.1. Security parameters..................................... .................................................. .........79 8.1.1. Blood samples............................... .................................................. .......80 Confidential-43-

Targacept Company 163062.doc 201244717

Cf/lRGACEPT PRO'05619"CRD'002(00) Effective Date: December 22, 2009 8.1.2. Urinalysis...................... .................................................. .......................80 8.1.3. No & events.................. .................................................. .......................80 8.1.4. Pregnancy........................ .................................................. ............................80 8.1.5. Security parameter analysis............ .................................................. ................81 8.2. Adverse Event Report.............................. .................................................. ..................81 8.2.1. Definitions......................... .................................................. .......................81 8.2.2. Adverse Event Report........................ .................................................. ..............82 8.2.3. Laboratory anomalies as adverse events........................ ...................................82 8.2.4•Strength price................................................. ....................................83 8.2.5. Causality evaluation .................................................. .................................83 8.2.6. Report of adverse events......... .................................................. ........................84 8.2.7. Leading out adverse event reports................. .................................................. ........84 8.2.8. SAE reporting procedure.................................... .................................................. .84 8.2.9. Management of overdose.......................................... .................................85 8.2.10. Reporting safety information to the IRB .................................................. .................86 8.2.11. Proof of the plan due to an emergency or adverse event ................. .............86 8.3. Tracking of adverse events.............................. .................................................. ............87 9. m\..................... .................................................. .................................................. ..87 9.1. Description of statistical methods...................................... .................................................. .87 9.1.1. Quantitative parameters.......................................... ...........................................87 9.1.2. Qualitative parameters................................................ .........................................88 9.1. 3. Baseline data analysis............................................. ................................88 9.1.4. Main Performance Endpoint Analysis: .................................................. .......................88 9.1.5. Pharmacokinetic Analysis.................. .................................................. ...........88 9.2. Sample size.................................... .................................................. ...................89 9.3. Significance level......................... .................................................. ........................89 9.4. Procedures for taking into account missing, unused and falsified data............ .....................................89 9.5. Exiting the study early Analysis of patients........................................... .....................89 9.6. Choice of patients to be included in the analysis ................. .................................................. 89 10. Directly view source data/files...................................... .................................................. 90 10.1. Monitoring .............................................. .................................................. .............90 10.2. Review of original subject records.............................. .................................................. 90 11. Quality Control and Quality Assurance.......................................... .................................................. 91 11.1. Approval by the regulatory body................................................ ...........................................91 11.2. Revision of the plan. .................................................. ........................................91 12. Ethics .................................................. .................................................. ....................91 12.1. Ethical principles........................ .................................................. ..........................91 12.2. Informed consent........................ .................................................. ................................92

Targacept Company Confidential 163062.doc -44- PRO-05619-CRD-002(00) 201244717

c imojACEPT Effective Date·· December 2009 22曰12.3. Human Test Committee................................. .................................................. .....93 12.4. Test host report requirements.................................... .....................................93 13. Data Processing and Recording save................................................. ....................................94 13.1. Submission of documents: .................................................. ......................................94 13.2. Case report form And source files............................................... .................................94 13.3. The study site is closed........... .................................................. ...............................95 13.4. Reservation of research documents............ .................................................. ..........................95 13.5. Providing research results and information to the trial host............ ......................................96 13.6. Exposure and invention............................................ ...................................96 13.6.1. Ownership... .................................................. ................................96 13.6.2. Confidentiality... .................................................. .................................96 96 13.6.3. Public..... .................................................. ..................................96 96.6.4. Data Management... ...................... 97 14. References......................... .................................................. ................................98 15. 瞒........ .................................................. .................................................. ..........103 Appendix List Page Ma Appendix 1. Pharmacokinetic Sample Collection, Handling and Transportation ....................... ................................104 Appendix 2. CogStateADHD test set..... .................................................. ........................ 106 Appendix 3. Prohibited and restricted combined use of drugs.................................... .................................................. ..............................108 Appendix 4. Clinical Laboratory Testing............ .................................................. ...............................110 Appendix 5. Conor Adult ADHD Assessment Form - Trial Host Version (CAARS) -Inv)..........................Ill Appendix 6. Conor Adult ADHD Rating Form - Subject Version (CAARS-S )...............................112 Appendix 7. Clinical Overall Impression Scale... .................................................. ....................................113 Appendix 8. Emotional Status Scale (POMS).. .................................................. ............................115 Appendix 9. Colombia Suicide Severity Rating Scale........... .................................................. ....116 Appendix 10: MINI International Neuropsychiatric Interview.................................... .....................................121 Appendix 11. Signature and Note Date Test Host Contract Page.......................................... ............145

Targacept Confidential 163062.doc - 45 - 201244717 CtMgacept PRO-05619-CRD-002(00) Effective Date: December 22, 2009 Summary of Clinical Plan Name of Active Substance: TC-5619 Company Name: Name of Finished Product:

Targacept_丨TC-S619-238________ ___ Study Title: Double-blind, randomized, placebo for evaluating the efficacy, safety, and tolerability of TC-5619 in adults with attention deficit/hyperactivity disorder (ADHD) Control, multicenter, fixed-dose escalation study TC-5619-238-CKD-002; cut-off book PRO-05619-CRD-002 trial host: TBD — '~~—- Clinical laboratory: tbd Research phase: 17 Week' includes a 3-week screening phase, a 12-week treatment phase, and a 2-week follow-up phase. Purpose: • To evaluate the efficacy of TC-5619 in improving the core symptoms of ADHD in adults with ADHD. · • Evaluate the safety and tolerability of TC-5619 in adults with ADHD. - Record TC-5619 plasma exposure by sparse sampling: double-blind, randomized, placebo-controlled, fixed-dose-infertile subjects: At least 125 subjects will be recruited and divided into 2 cohorts To ensure that at least 1 subject is completed; this assumes a 20% midway exit rate. The number of study subjects was calculated based on the following sample sizes: This = ability to show a dose between the TC-5619-238 and placebo from baseline (Day 1) to the end of the 4-week treatment period (1 mg : Day 1 to Week 4; 5 mg: Week 5 to Week 8; and 25 mg: Week 9 to Week 12) ER^ADHD Rating Scale - Test Host Full Version (CAARS.Inv) Total Score The number of subjects required for the change of statistics is 50, using the paste test to detect the difference of 4,0 'points with 8°% test power and τα 〇ιί显ί $ level ΐ<〇· 〇) Assuming a standard deviation (SD) of 7.5, using the Hochberg program to adjust for multiplicity, and a normal distribution error after the selection phase, the subject will be machined in a double-blind gauge to one of the following two queues. Or T&5619. Subjects in the TC-5619 cohort will undergo a fixed dose escalation every 4 weeks: 1: - ^25 mgp.o.qd (^8it-^ 1孳 blind'/0 treatment 13⁄4 segment will last for 12 weeks. After the end of the stage, there will be 2 adjustments to the lead. Inclusion guidelines - ----

The score of the S-bed overall impression and severity (CGI-S) index of at least 6 of the 9 items in at least 1 subscale of at least one subscale of ADHD 4 was diagnosed according to the DSM-IV TR criteria ^4 (at least moderate) Age 18 -65 years old, men or women who have not made bribes and quantified negative urine within 1 year after the completion of the stipulations can be understood and signed informed consent confidential -46·

Targacept Company 163062.doc 201244717 ^TARGACEPT PR°'056l9'CRD'002(°〇) Effective Period: December 22, 2009 曰 Division Name: Targacept I Finished Product Name: TC-5619-238丨Active Substance ▲ τ<:·56Ϊ^~ Exclusion criteria: Current DSM-IV spindle I, psychosis other than ADHD; use Miniature International Neuropsychiatric Inventory (MINI) to rule out other major DSM. IV TR psychiatric diagnosis According to the above definition (inclusion criteria), the current use of tobacco is known or suspected to be positive for urine drug screening for illegal or over-the-counter drugs during screening for 6 months prior to screening. The moderator judges suicide or endangers Patients who are at risk for themselves or others are using drugs that affect cognitive function within 3 weeks prior to Day 1. This includes the use of any combination medication ADHD (Appendix 3, proposal) for the treatment of ajjhd. All medications must be completed within 3 cycles between screening and Day 3 » any other restricted or banned drug (Appendix 3). Other concomitant medications that have changed within 4 weeks prior to screening cannot follow the study protocol (including the CogState ADHD kit). Important other major or unstable nerves, metabolism, liver, kidney, hematology, lung, CV , (diagnosis of πλ abbey history, or diagnosis of major depression) 心肌 有 过去 过去 过去 过去 过去 过去 过去 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 HbAlC>7.4 15. BMI<15 or>33; male Zhao weight <1〇〇lbs; female body weight < 80 lbs. 16. Current TB or known systemic infection (HBV, HCV, HIV) 17. Body Clinical H-members in the nuclear investigation # discovery - ' 18. Clinically significant laboratory or ECG abnormalities that may cause safety problems in the study, including qTcF > 450 (male) or QTcF > 480 msec (female) Includes LFT greater than 3 times the upper limit of normal. 19. Women and men of childbearing age who are unwilling or unable to use accepted methods of contraception ° 20. Women who are positive for pregnancy or breastfeeding 21. Participate in another clinical trial in the last 3 months prior to screening Test 22. On-site staff or trial client Workers 1. 246 8. 9. 10. 11. 12

Test product, dosage, and administration mode, batch number: ' --- R&D: TC-5619-238 will be supplied in the form of white opaque gelatin capsules in the form of mg, 5 mg and 25 m (in terms of strength). Subjects will take 1 mg T05619, 5 mg TC.5619, 25 mgl TCdeigse matched with placebo and take one knee capsule once a day. One control: a placebo will be provided in exactly the same shape, size and appearance. Batch number: TBD duration of treatment: 12 weeks in the treatment phase' screening period lasts 3 weeks, and after the treatment of the knot, the instrument is combined with medication restrictions: ' ---- Cognitive enhancement drugs and / or for the treatment of ADHD Pharmacy. See Appendix 3 (Plan).

Targacept Confidential 163062.doc 201244717 (T^IRGACEPT ^<-)"^^^19-crd-o〇2(〇〇) m 2009 #-12 ^ 22 a Company Name: Targac Printed Product Name: TC-S619-238~~|Active substance; g: τ〇5619_ End of efficacy (time of evaluation): --- The main efficacy end point is the total score of CAARS-INV, obtained 7 times: 3 weeks, the first 1 day, week 、, week 4 (1 mg dose); week 8 (5 mg dose); week 12 (25 mg dose); and week 14. The primary efficacy comparison will be from Day 1 to Week 4; Day 1 to Week 8: and 3 CAARS-Inv points from Day 1 to Week 12. Secondary efficacy endpoints: 〇CAARS-Inv subscale: Attention deficit, hyperactivity-impulse and adhd index, at week -3, day 1, week 1, week 4, week 8, 12th Week or early exit (EW), and week 14 to get. 〇 The CogState ADHD Package Test (CATB) was obtained on Days -3, Day 1, Week 1, Week 4, Week 8, Week 12 or EW, and Week 14. 〇 CogState stop signal task, obtained on the 3rd, 1st, 1st, 4th, 8th, 12th, or ew, and 14th week. 〇 Conor Adult ADHD Ratings - Total Subject Version (CAARS-S) total score, at week -3, day 1, week 1, week 4, week 8, week 12 or EW , and obtained in the 14th week. 〇 Clinical overall severity impression (CGI-S); at week -3, day 1, week 1, week 4, week 8, week 12, week 14 or EW. 〇Clinical Overall Impression - Overall Improvement (CGI-I); At the 1st, 4th, 8th, and 12th week or EW, and Week 14 〇Emotional Status Scale (POMS) score; Weeks - 3, 4, 8 and 12 or EW. Safety endpoint: Physical examination, at week -3, day 1, week 1, week 4, week 12, or EW, and week 14 (tracking visit). • AE evaluation 'on week -3, day 1, week 1, week 4, week 12, or EW, and week 14; and any unscheduled visits • Completion of Colombian suicide severity assessment Scale (CSSRS), at Day -1, Week 1, Week 4, Week 8, Week 12 or EW, and Week 14 at Week -3. Sitting and standing vital signs 'on the 3rd, 1st, 1st, 4th, 8th, 12th or EW, and 14th week; these are on the 1st, 4th Weeks, Weeks 8 and 12 or EW were administered +3 hours after administration and +6 hours after administration after administration. When collecting sitting vital signs, BP and heart rate will be recorded after the subject has been sitting for at least 5 minutes. BP and heart rate will be recorded when standing for at least 2 minutes and no more than 3 minutes. 12-lead digital ECG in triplicate, at -3, 1st, 1st, 4th, 8th, 12th or EW' and 14th week; The first day, the first week, the fourth week, the eighth week, and the twelfth week or EW were performed before the administration and at about +3 hours and +6 hours after the administration. • Clinical laboratory tests (hematology, plasma biochemistry, liver function tests [LFT], bilirubin and urinalysis), at weeks -3, 1st, 1st, 4th, 8th, And week 12 or EW, and week 14. These will be performed on an empty stomach on Days 1 and 12 or EW; and a fast panei will be added to the list of tests obtained from such visits. • Urine drug screening 'on week -3, day 1, week 4, week 8 and week 12 - urine pregnancy test for premenopausal women, on week -3, day 1 and 12 weeks or EW. PK endpoint: _ Sparse blood samples used to record blood exposure of TC-5619 will be administered on days 1 and 4 'week 8 and 12 before administration, 3 hours after administration and administration After 6 hours collection »

Targacept Company Confidential I63062.doc -48 -

201244717^ im^ACEPT PRO-05619-CRD-002(00) Effective date: December 22, 2009 Gold name: Targacept 丨 Finished product name: TC-S619-238 i Active substance name: TC-5619 Statistical methods General statistics Consideration: The categorical variables will be aggregated by presenting the number and percentage of subjects in each category. The continuous variables will be aggregated by presenting η, mean, median, standard error (SE), standard deviation (SD), minimum, and stretch values. To assess possible treatment differences, the Chi-square test will be used to analyze binary and order category measures; the ANCOVA model will be used to analyze all continuous measures. Unless otherwise noted below, all statistical tests used for analysis were performed using a one-tailed test at a significance level of ρ < 〇.1〇. For efficacy analysis, the primary endpoint (CAARS-Inv) will be evaluated 3 times: from day 1 to week 4 (1 mg dose); from day 1 to week 8 (5 mg dose); and from day 1 to day Changes in CAARS-Inv total scores at 12 weeks (25 mg dose). These endpoints will be analyzed using the Analysis of Covariance (ANCOVA) technique at a total alpha (one-tail) of 0.10 to examine the difference between the TC-5619 and placebo treatment groups. The ANCOVA model will include treatment as the primary factor and baseline CAARS-Inv and CGI-S scores as covariates. When plotted in a statistical analysis plan, other covariates can be used. Since the primary endpoint is evaluated 3 times, the Hochberg method will be used to control multiple comparisons. To ensure a significance level of 10% between three independent tests, the p value will be adjusted for each successive test: 10% for the first test; then second if the first test does not reach the 10% significance level The second test should be 5%; and finally 'if the first test and the second test do not reach the predetermined significance level, the third test should be 3.33%. Any attempt to reject the null hypothesis in these endpoints will prompt the trial to be successful. • For the Intent-to-Treat (ITT) population and the Per Protocol (PP) population, the primary efficacy endpoint will be used to implement Main performance analysis. The results of the ITT population effectiveness analysis included predetermined measures of successful trials for the primary endpoint. To account for missing data, the last observed-carried-forward (LOCF) method will be used, i.e., the observed values in the treatment available at the end of the test i will be used to estimate subsequent missing data. • The next-term endpoint will be from baseline (Day 1) to Week 1, Week 4, Week 8 and Week 12 in the CAARS-Inv subscale (attention deficit, hyperactivity-impulse and ADHD index) Changes; changes in the CATB combination score from i-line to week 1, week 4, week 8 and week 12; stop from baseline to week 1, week 4, week 8 and week 12 Changes in signal task scores; changes in CAARS-S total scores from baseline to week, week 4, week 8 and week 12; from baseline to week 1, week 4, week 8 and Changes in CGI-S and CGI-Ι scores at week 12; and changes in p〇MS scores from baseline to week 4, week 8 and week 2 for I and PP groups, will be implemented All secondary analysis. The results of the ITT group effectiveness analysis included a predetermined measure of successful trials for the secondary endpoint. Security Analysis: Two will implement all security analysis. Adverse events will be encoded by system organ classification and prioritization terms. Treatment Emergency Adverse Events (TEAE) were tabulated and summarized to show the number and percentage of patients in each treatment group. • The number two vital signs and laboratory data will be tabulated and subsequently read using narrative statistics. Inferential statistical analysis will not be performed.丨 丨 • • • • • • • • • • • • • • • • • 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨.药物 Pharmacokinetic analysis: The individual values of Tc*5619 blood concentration at the time of collection and scheduling were collected using a descriptive system. PK data of cakes since then

Targacept Company 163062.doc Confidential -49-

201244717(TARGACEPT PRO-05619-CRD-002(00) Effective date: December 22, 2009 Company name: Targacept Product name: TC-5619-238 Active substance name: TC-S619 Time and event schedule

Event Visit 1 (Screening) Day 3 Visit 2 (BL) Day 1 Visit 3 Week 1 Visit 4 Week 4 Visit 6 Week 8 Visit 7 Week 12 Visit 8 (F/ U) Week 14 Informed Consent X Social Habits XXX DSM-IV Assessment (+MINI) X CAARS-ENV XXXXXXX CGI-S XXXXXXX Inclusion/Exclusion Criteria XX Medical/Psychiatric History X Drug History X Concomitant XXXXXXX Contraceptive Advice, WOCBP and Male XXXXXXX Adverse event history (including CSSRS) XXXXXXX Physical examination XXXXXXX Vital signs (including standing BP), oral temperature, height and weight 1 XXXXXXX Laboratory (Chem7, CBC, LFT, bilirubin, fasting lipid 6) X X2 XXXXX Heme AlC(HbAlC) X Urinalysis XXXXXX X2 Urine can be butyl content, including quantification XXX Urine drug screening XXXXX Urine pregnancy test XXX PK value 3 XXXX ECG4 XXXXXX X5 CogState ADHD test set and stop signal task XXXXXXX CAARS-S XXXXXXX POMS XXXXX CGI-I XXXXX Start Dosing X Outpatient drug X X X X Drug distribution X X X X Research drug compliance and class X X X X

Targacept Confidential 163062.doc -50- ^ lAKhACEPT PR〇'05619'CRI)-〇02(〇〇) Effective Date: December 22, 2009 曰1 will sit at least on the subject at each visit After 5 minutes, BP and heart rate were recorded to obtain the sitting vital signs. At each opportunity to obtain a sitting vital sign, the standing vital signs will also be obtained by recording BP and heart rate after standing for at least 2 minutes and no more than 3 minutes. On Days, 1st, 4th, 8th, and 12th week, the sitting and standing vital signs will be administered before administration, about 3 hours and 6 hours after administration. You will get weight and height at the time of screening. You will also get your weight at week 12. 2 Laboratory samples at Day 1 and Week 14 will be collected only for subjects with abnormal values at or below the 12th week. Prior to the day of the subject, the subject must receive the laboratory results from the repeated evaluations during the screening period. Sparse blood samples for TC-5619 content will be obtained at the following time points on the DAY, 4, 8 and 12 weeks after the outpatient administration: before administration, 3 hours and 6 hours after administration . Samples after administration will be obtained immediately after ECG evaluation after administration. The ECg will be recorded in triplicate in digital format after the subject has rested in the supine position for 5 minutes. These ECGs will be available prior to and after administration at the first, fourth, eighth and twelfth visits. If an abnormality is found only in the 12th week ECG, the ECG will be obtained during the follow-up visit. 6 Laboratory evaluations at screening, week 12, and follow-up visits will be obtained after an overnight fasting, resulting in a fasting lipid group test. Laboratory evaluations at other visits were not fasting and did not include the lipid group test. Confidential '51 -

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Targacept Company 163062.doc Confidential-52· 201244717 umoACEPT PRO-05619-CRD-〇〇2(〇〇) Effective Date: December 22, 2009 曰ICH IEC IRB ITT IUD LC-MS/MS LFT * LOCF LOQ MedDRA International Coordination The ethics committee of the conference organization human trial committee intends to treat intrauterine device liquid chromatography-mass spectrometry/mass spectrometry liver function test final observation value estimation quantitative limit medical use of 5 dictionary - drug management transaction dictionary (Medical dictionary of regulatory affaris) MINI MRD MTD NNR NOAEL NOEL PK po POMS PP PR qd QRS QT QTcB QTcF RR SAE SD SRD SSRT Tmax TB TEAE ULN VAS WHO WOCBP Mini International Neuropsychiatrics Symptoms Multiple increasing doses Maximum tolerated dose Neuronal nicotinic receptors No doses observed for adverse effects (N〇Observed Effect Levels). Pharmacokinetics Oral (Per so) Emotional Status Scale According to the plan PR conduction interval once a day QRS conduction interval QT conduction interval QT Interval of Bazett corrected conduction interval Fridericia corrected RR conduction interval major adverse event standard deviation single incremental dose Stop signal reaction time reaches the maximum mortar concentration time Tuberculosis treatment Emergency adverse events Normal value upper limit Visual analog scale World Health Organization Childbearing age female Targacept Company 163062.doc Confidential-53- 201244717 (T^lRGACEPT PRO'05619'CRD-〇02 ( 〇°) Effective Date: December 22, 2009 1. Introduction 1.1. Description of Test Drugs TC-5619 is a new chemical entity targeting α7 neuronal nicotinic receptor _ ft. Tc_5619 is highly specific for the α7 nicotinic receptor, which exhibits a selectivity to α7 of more than three thousand times that of the α4β2 receptor subtype (Moore, May 2006a). In non-clinical studies, TC-5619 does not produce a detectable effect on muscle or gangliokinin receptor subtypes, suggesting that it is significantly selective for the central nervous system (CNS) relative to the peripheral nervous system (PNS) (PNS) Moore, 2006b). In toxicology studies, TC-5619 is well tolerated in rodents and dogs. In humans, Tc·5619 is administered up to and including a single oral dose of 600 mg (toluene hydrochloride; Targacept study TC-5619-238-CLP-001) and multiple oral doses of 300 mg per day for 10 days. ▲ sulfonate; Targacept study TC-5619-238-CLP-002) showed excellent tolerance. In behavioral pharmacology studies, TC-5619 was also effective in doses of 〇3 mg/kg in the animal model of dentate animals, suggesting that it may have a broad therapeutic index. In multiple escalating dose studies (Targacept study TC-5619-238-CLP-002), the subject's attention strength was measured after administration of TC-5619 at a dose of 1 mg (toluene acid salt). (Use the Cognitive Drug Research (CDR) set of tests) to show a statistically significant increase. The effect was observed on day 1 and day 1 and was greater in magnitude than the 1 mg dose compared to the 50 mg dose. Therefore, the industry is developing TC-5619 for the treatment of ADHD in adults. For more details, please refer to the test host manual of TC-5619. 1.2. Summary of Results 1.2.1. Non-Clinical Studies Non-clinical studies provide data to support the safe administration of TC-5619 to humans. An in vitro study was performed to characterize the pharmacological, electrophysiological, and genotoxic potential of TC-5619, and an in vivo study was performed to study the safety, pharmacokinetics/metabolism, and toxicity of TC-5619. GLP safety pharmacology studies have been completed to assess the effects of TC_5619 on gastrointestinal and respiratory work and the motility effects in rats. Other GLP studies completed included: acute single oral and intravenous doses in rats; 3 days and 9 days in rats and dogs; hERG (human ether-a-go-go related genes) Channel inhibition studies, which are in dogs' studies; and in vitro/in vivo genotoxicity studies. Wide

Receptor screening showed that TC-5619 has high selectivity for a7 NNR, and its inhibition constant (Ki) for α7, sputum only sodium site 2 and serotonin (5HT3) receptors is! _, 13 μΜ and > 10 μΜ «Τ05619 exhibit competitive binding selectivity for m, M2 (non-selective central muscarinic receptors and non-peripheral toxic base receptors). 1 ^ In human embryonic kidney (HEK293) cells, TC-5619 exhibited approximately 5 〇 of EC5 for hERG channel inhibition. . In telemetry dogs, TC-5619 did not cause significant changes in the qT interval at 10 mg/kg, 25 mg/kg, and the agent tube function. I ^ All doses were expressed as free base equivalents. $ PT

163062.doc ,54- U/i/iJ/\C£Pr PRa05619_CRD-002(00) Effective Date: December 22, 2009, in the GLP Safety Pharmacology Study, no dose was observed (NOEL) ) is 25 mg/kg (for the gastrointestinal system) and 1 mg/kg (for the nervous and respiratory systems). In rats, the acute oral NOEL was 100 mg/kg after single oral administration, and the acute NOEL was 15 mg/kg after single intravenous administration. In dogs, the acute oral NOEL was 20 mg/kg in a single oral administration and 2 mg/kg in the acute NOEL after intravenous administration. The NOEL was 67.7 mg/kg/day in rats administered with TC-5619 at 16.9 mg/kg/day, 67.7 mg/kg/day, and 338.5 mg/kg/day for 30 days. At high doses, tremors, partial closure of the eyelids, and arch-back posture were observed. In dogs treated with TC-5619 at 10 mg/kg/day, 30 mg/kg/day or 100/80 mg/kg/day for 30 days, the male NOEL line was 10 mg/kg/day and the female was slightly smaller. 10 mg/kg/day. In the intermediate and high dose treatment groups, the dogs showed tremors and partially closed eyelids. These effects were also noted in one of the female dogs in the low dose group. In the 1()0 mg/kg group, dogs showed significantly reduced food consumption and weight loss during the first week of administration, thereby reducing the dose of sputum from 100 mg/kg to 80 mg/kg. TC-5619-238 was well tolerated in rats and dogs in a 90-day repeated dose toxicity study with a 28-day recovery phase. In rats, NOEL is 50 mg/kg/day. At the 150 mg/kg/day and 350 mg/kg/day, sag, taro, dilated pupil and squat gait were observed, and activity was observed at 350 mg/kg/day "at 150 mg/kg/ An increase in the conversion rate of 'red blood cells' at day and 350 mg/kg/day was associated with increased spleen weight and extramedullary hematopoiesis. Kidney weight gain at 350 mg/kg/day was associated with multiple tubular degeneration/regeneration at 15 mg/kg/day and 350 mg/kg/day and a transparent urinary column at 350 mg/kg/day. Also see serum If, about and fill and increase the protein content of urine. Increased liver weight at 15〇mg/kg/day and 350 mg/kg/day with central lobular hypertrophy and serum lactate dehydrogenase, alanine transaminase, alkaline phosphatase, cholesterol, triglycerides and/or phospholipids Increase the correlation. Biliary epithelial hypertrophy/cavitation and follicular cell hypertrophy in the squamous gland were seen at 35 〇 mg/kg/day. In the lung, alveolar globular disease occurred at 35 〇 r^g/kg/day with an increase in mononuclear cells at 150 mg/kg/day and 35 〇 mg/kg/day. Except for bile duct epithelial hypertrophy/cavitation, tubular degeneration/regeneration, and urine protein, all findings were reversible. In dogs, NOAEL 5 mg/kg/day showed dilated pupils at all doses. At 30 mg/kg/day and 60 mg/kg/day, salivation, tremor, uveal prolapse, ptosis, and vomiting were observed. At 5 mg/kg/day, tremor was observed in one animal. Food consumption and weight loss were observed during the first two weeks of 60 mg/kg/day. Reduced direct pupillary reflex and ipsilateral pupillary reflex and mucosal redness were recorded at 60 mg/kg/day. At 60 mg/kg/day, male liver weight increased slightly and was associated with minimal hepatic cell hypertrophy. Except for mucous membrane redness, all findings are reversible. No significant adverse effects were observed in the reproductive toxicity study. In the fertility or early embryo development studies in rats, the parental NOAEL line was 150 mg/kg/day and the reproductive NOEL line was 350 mg/kg/. The rats and rabbits were subjected to embryo and fetal development studies. In the rat, both the maternal N〇EL and the fetal NOAEL were 5 mg/kg/day, and no progestation was observed up to 450 mg/kg/day. In rabbits, the 'maternal NOAEL line 35 mg/kg/day, embryonic and fetal development n〇EL line 70 mg/kg/day' and up to 15 mg/kg/day did not reveal teratogenicity. Confidential • 55·

Targacept Company 163062.doc 201244717 (WRGACEPT pr〇-°5619-crd-002(00) Effective Date: December 22, 2009 It has been evaluated to find that 619 is caused by the administration of toluene hydrochloride. Analysis of mouse red blood cells and analysis of chromosomal domain changes in hamster (C) cells in the Ames test (Ames test), Amway test and micronucleus analysis of mouse red blood cells in vivo The result was negative. In the in vitro CH chromosomal aberration analysis, the compound was also negative at 500 ng/mL, but it was positive at 1 〇〇〇μβΛη£ and 15〇〇μβ/ηΛ with and without It has metabolic activation. Other tests performed in the live rib and lymphocyte test did not show evidence of genotoxicity. Three doses of TC-56 were administered to humans every day. 9 should produce approximately at steady state! pg/mL The average maximum concentration provides a safety margin of at least 5 times the maximum exposure expected in the proposed study. Together, these data indicate that the risk of genotoxicity associated with TC-5619 is extremely low. For more details, please refer to TC- Test host manual for 5619. 1.2. 2. Clinical studies to date have been studied in a single incremental dose (SRD) study (Targacept study TC_5619_238_ CLP-001) and in multiple incremental dose (mrd) studies (Targacept study TC-5619-238-CLP-002), TC-5619 was administered to normal subjects. All doses quoted in these studies were administered as tosylate. The equivalent base equivalents of the doses were 677 times the salt dose quoted. · 2·1· SRD study found that in the SRD study, 'TC-5619 (η=65 subjects) or placebo (n=l8 subjects) was administered as a single oral form to 68 〇^ A dose of 6〇9 mg (free base) was administered to normal healthy men. TC-5619 was well tolerated at all doses (up to and including 406 mg). After a single dose of 609 mg ' 5 Three of the subjects presented one or more of the following moderate to severe adverse events: nausea, standing hypotension/tachycardia, vomiting, and/or headache. No major adverse events were reported. A few vital signs Exceeding the normal range, and the observed abnormalities are transient and judged to be not clinically significant. In ECG parameters (package) There were no clinically significant changes in qTcB (Bazett correction) and QTcF (Frederica correction). Both EEG and B〇nd and Lader VAS effects indicate brain availability and certain sedative potential of TC-5619 in most exploratory doses, but Equal effects are only occasionally statistically significant. There were no clinically significant changes in hematology, clinical chemistry or urinalysis parameters. The Cmax and AUC of TC-5619 exhibited a dose-related and linear increase in the 90-fold dose range of 6.8 mg to 609 mg. The elimination half-life was about 15 hours to 2 hours. Based on the findings in this study, the maximum tolerated dose (MTD) was defined as the dose between 4〇6 mg and 609 mg TC-5619 (free test). Confidential -56-

Targacept Company 163062.doc w/i/^C£Pr _5619 Lu 002(00) Effective Date: December 22, 2009 1.2.2.2· MRD Research found that 32 subjects were divided into 4 queues, each queue Eight patients (6 active, 2 placebo) received their study drug once a day for 10 days. Start with 6.8 mg (free base) and progress to a dose of 33.9 mg, 102 mg and 203 mg (free base) per day. "Evaluate safety, tolerability and PK at each dose, while in two Cognitive evaluation (cognitive drug research kit test: cdr) was completed at a lower dose (1 〇 mg & 5 〇 mg per day). TC-5619-238 exhibits excellent tolerance at all doses administered. Mainly due to the exposure limit defined in the single incremental, volume (SRD) study, the drug was suspended after completion of the 2〇3 mg dose; any meaningful increase in the dose above 203 mg per day would result in near or exceeding the SRD study. The defined exposure of MTD (>/=406 mg) is generally mild in nature and has no rare AE clusters in any particular organ system. The laboratory and cardiovascular parameters observed were generally not significant. One of the weightlifter subjects in the 6.8 mg cohort had abnormal creatine kinase values at baseline with a small increase in ALT and AST (<2xULN). An increase in the three parameters (AST, alt, and CK) is known to occur for at least 7 days after weight lifting. No other significant changes in CK or transaminase were noted during the study. On the first day of the study, one of the 2〇3 mg cohorts showed transient τ·wave inversion in the inferior and anterior wall leads. The cardiologist's tracing shows that the most likely cause is autonomic tension changes, which may be related to a sudden wake up before the EKG is about to be recorded, and is not clinically significant. No other significant changes in EKG were noted during the study. - Assessment of cognition using the CDR computerized set of tests revealed attention (mean maximum placebo corrected change of approximately _2 〇〇 msec) and simple response time (mean maximum placebo corrected change on day 1 and day 1) Statistically significant changes of -125 msec), and a beneficial trend in attention continuity, working memory quality, digital alerting speed, and information processing speed at a dose of 68 mg. The most dramatic change occurs about 2 to 6 hours after administration, which corresponds to the closest estimate of CNS Tmax. Some trends were observed at the 33.9 mg dose, but did not reach the same magnitude or consistency as noted at the 68 mg dose. As the dose increased from 6.8 mg to 203 mg, the 'exposure parameter (Cmax & AUC) increased in a nearly f-like manner. Tmax (about 2 hr) and half-life (about 24 hr) and dose-free I. In all doses, about 20% of TC-5619 is excreted in the urine in an unaltered form, ie 3% to 5% TC_ 5619 It does not appear to bind to plasma proteins. As expected for compounds with a half-life of about 24 hours, multiple administrations produced approximately 18-fold accumulation as of the 10th day of the study. The findings of this study, TC_5619, were well tolerated after 2 〇 3 mg (free test) per day. MTD was not defined in this study. Company gas 201244717

Cf^lRGACEPT PRO'05619-CRD-002(00) Effective Date: December 22, 2009 1.2.3. Background Information Attention deficit/hyperactivity disorder (ADHD) is one of the most common childhood psychological disorders. Appears in as many as 3% to 5% of children (APA 1994). Although ADHD is a "disease in childhood, up to 80% of children diagnosed with ADHD show symptoms that persist until adolescence (Barkley et al. '1991, Barkley et al., 1990) and adulthood (Biederman et al., 2000, Hervey et al., 2004). The clinical diagnosis of ADHD includes symptomatic onset of symptoms at least 6 months prior to age 7 and significant functional impairment in at least 2 functional areas (APA 1994). Insufficient groups (ie, easy to distract, difficult to pay attention to) and over/impulsive groups (ie, difficult to sit or feel restless, difficult to wait, often interrupted). The diagnosis of ADHD is based on the number of symptoms presented and Types are performed. The diagnosis of ADHD is further in subtypes. As described in DSM-IV-TR, there are three subtypes; ADHD-mainly under-attention (ADHD-I; 6 or more symptoms of attention deficit) And less than 6 hyperactivity/impulsive symptoms), mainly overactive/impulsive (ADHD-HI; 6 or more hyperactivity/impulsive symptoms and less than 6 attention deficit symptoms), and combined ( ADHD-C; 6 or more symptoms in each group) (AP A 1994). 1.3. Potential risks and benefits TC-5619 toluene acid salt (TC-5619-238) has been administered to 65 in a single incremental dose study (Targacept study TC-5619-238-CLP-001). Healthy volunteers and 28 healthy volunteers in the multi-solid incremental dose study (Targacept study TC-5619-238-CLP-002). Subjects in these studies up to 406 mg (free test) The following adverse reactions were reported, and the intensity of these adverse reactions was mild to moderate: rhinorrhea, influenza 'abdominal rash (non-sputum), sensory fever, vagus nerve discomfort, dizziness, upper abdominal pain, low standing position Blood pressure, standing tachycardia, hypertension, abdominal pain, elevated ALT/AST/CK, ECG changes, nausea, headache, and rhinitis. At 609 mg (higher tolerance than defined by the single incremental dose study) At doses of 'dose', reports of discomfort, standing hypotension, and severe adverse events in pale. Potential benefits include new information in the medical and scientific fields from the study on TC-5619 for adults with ADHD Effect. Individual subjects can benefit from research drugs, but this time The extent of benefit is unknown. The theoretical basis for dose selection is based on the SRD study (Targacept study TC-5619-238-CLP-001) and from the MRD study (Targacept study TC-5619-238-CLP-002) As a result, an oral dose of 1 mg, 5 mg, and 25 mg (free base equivalent) of TC-5619 tosylate (TC-5619-238) will be administered. In this range and at a much higher dose (after a single dose to 600 mg tosylate [406 mg free base equivalent]' and after multiple doses to 300 mg tosylate / day [203 mg free Alkali equivalents]) Good tolerance. Preclinical safety and efficacy data support the evaluation of selected doses and in the MRD study at doses of 10 mg (toluene sulfonate, or 6.77 mg free base equivalent) A robust improvement was observed in cognitive measures (CDR). The highest dose used in this study would be a daily dose of 25 mg (free base) to provide at least an 8-fold tolerance limit.

Targacept Company Confidential 163062.doc · 58 -

201244717 im^ACEPT PRO-05619-CRD-002(00) Effective Date: December 22, 2009 1.5. The implementation of the trial will be based on the ICH guidelines for Good Clinical Practice, according to the Declaration of Helsinki (2008 Edition). Implement this study in accordance with applicable regulatory requirements. 1.6. Study Population This study will consider inclusion of male or female subjects aged 18 to 65 years who are eligible for ADHD diagnosis according to the DSM-IV TR guidelines and use the MINI International Neuropsychiatric Interview (MINI) as an adjunct to exclude other Primary DSM-IV TR diagnosis. The patient will score at least 2 out of 6 of the 9 items in at least 1 subscale of CAARS-Inv. The patient will have a CGI-severity rating of moderate (4) or higher. Only non-tobacco users will be eligible, as defined by the use of tobacco for up to 12 months prior to screening. 1.7. Theoretical Basis for Research 1.7.1. Cholinergic Systems Involved in Cognitive Defects in ADHD There are several ways to stimulate the central cholinergic system to have a beneficial effect on cognitive deficits associated with ADHD. For example, methods such as continuous attention and working memory are regulated by the central biliary system (Sarter and Bruno 1997, 1999). Clinical studies have examined the effects of polar nicotine on behavioral inhibition in non-smoking adolescents and young adults with ADHD (Potter and Newhouse 2004, 2008). In one study, the youngster was eager to administer nicotine or thiophene fenida (the normal morning dose of the subject). Nicotine (as well as methyl fentanyl) improves behavioral inhibition, as reflected by the cessation of signal response #SS (SSRT) significantly faster. Data from the second study extended the discovery of the positive effects of nicotine on behavioral inhibition to young adults with ADHD. Importantly, nicotine improved overall in the stop signal task because no significant differences in reaction time or accuracy (more than 9〇% for all doses of all blocks) were found in the Ren-study. The extracorporeal study used the St.Pp Task (the StF〇〇P Task), which measures the effects of cognitive interference control. The results in this test are 4 degrees of the Schuster effect, which inhibits automatic processing (word reading) and slower processing. The time spent responding (color naming) is 2, children and adolescents with ADHD have a greater effect than normal controls (Potter and Newhouse, 2004; Newhouse, 2008). Nicotine instead of A The improvement of the Schug's mission in the Ϊίΐίί faceless youth reflects this:

Targacept Company I63062.doc -59- 201244717 (WRGACEPT PRO'05619*CRD-002(°0) Effective Date: December 22, 2009 1.7.2. A large number of studies on adult ADHD and cholinergic systems indicate that childhood is characterized Cognitive deficits in ADHD are present in adolescents and adults (Seidman 2006, Gualiteri and Johnson 2006). Recent reviews have found that studies comparing ADHD subjects with control subjects have been found in all ages examined. Significant shortcomings in the executive function associated with ADHD (seidman 2006). Larger representative studies found that ADHD subjects had a deficit in set-point transition and Struper performance compared with controls (ages 10-29; Gualtieri and Johnson 2006) This study found that with age, there is a developmental shift in interest in performance. Normal middle-aged people have a faster response than normal adolescents. In contrast, adults with ADHD and ADHD Adolescents have higher accuracy, but the response time is not faster than ADHD adolescents (Gualiteri and Johnson 2006). This is explained along with significant deficits in the potential shift in ADHD to indicate It is difficult for young adults of ADHD to allocate attention resources (Gualiteri and Johnson 2006). The findings associated with persistent defects in the effective allocation of attention to ADHD support the regulation of the cholinergic system to be able to 'see the cognitive deficits in ADHD'. It has been suggested that the effect of nicotine is most obvious for tasks that require conscious processing (Rusted and Warburton 1994). In addition, recent theories have proposed 'in the required tasks (ie, continuous attention, fixed-pot change, etc.; Sarter and Bruno 1997) During this period, the cholinergic system allocates additional attention to resources. Therefore, it is possible that in ADHD, the cholinergic system is low-reactive or underdeveloped and therefore stimulates nicotine receptors via nicotine, especially in tests that require conscious processing. Improving cognitive performance. 1-7.3 Effects of nicotine stimulation on clinical signs of ADHD Recent studies of nicotine agents in ApHD have shown promising improvement in symptoms in both adolescents and adults with ADHD (Levin et al. 1996; Potter and Newhouse 2004, 2008; Shytle 2002, Wilens et al., 1999, Wilens et al., 2006). Levin and his colleagues (1996) are already suffering from ADHD. Among the young people (smokers and non-smokers), the effect of percutaneous cigarettes was examined, and the two subject groups were found to have significant self-assessment vitality, concentration and observer-determined disease severity (CGI). improve. In addition, both smokers and non-smokers should have improved speed and reduced variability in response time for smokers (Levin et al. 1996). In the second study (Connors et al. '1999), long-term (4 weeks) administration of alkaloids was combined with the use of thiophene venida, placebo, and combination of nicotine and thiophene Compared with adults with ADHD. The smoke test significantly reduces the clinical rating of the severity of the symptoms and the self-reported reduction in depressive symptoms and the improved response time to continuous performance tasks. 〇 Other studies have examined the new test in adults with ADHD. The biliary agonist ABT-418, which used a crossover design and used placebo and ABT4i8, received 2 double-blind 3-week treatment periods per subject (Wilens et al, 1999). Reporting after treatment with ABT-418 has a significant improvement in the objective assessment of attention and the severity of the disease as assessed by the observer of the clinical overall impression scale.

Targac Printing Company Confidential 163062.doc £t 201244717

(TARGACEPT PRO-05619-CRD-002(00) Effective Date: December 22, 2009 An updated, more selective agonist that acts at the α4β2 nicotinic receptor subtype ABT-089 is also already Testing in adults with ADHD (Wilens et al., 2006). ABT-089 was administered to adults in a multi-dose, randomized, double-blind, placebo-controlled trial for up to two weeks based on symptom scores, ADHD index hyperactivity/impulsive assessment, and The improvement in clinical overall impression was better than placebo. However, the longer 8-week trial of ABT-089 in adult ADHD did not have a significant effect on symptom scores, ADHD hyperactivity/impulsive assessment, or clinical overall impression (Bain et al. , 2〇〇9). Therefore 'although some studies such as these provide a stimulus to select a smoke test to relieve some of the dominant behavioral symptoms of ADHD (as measured by self-reporting and observer assessment) 'However, it is uncertain how long the positive effect lasts. Moreover, these studies do not specifically address the cognitive field in which nicotine can affect individuals with ADHD. Recently, the α4β2 NNR agonist AZD3480 (TC-1734) was examined. ADHD core disease in adult subjects The effect of the test using the Conor adult adhd scale (CAARS-Irw) on the total I and over/impact and attention deficit subscales found statistically significant monthly b. A statistically significant effect was also identified in a behavioral inhibition test (Targacept study TC-1734-226-CRD-005). Together with administration (X7NNR agonist TC-5619 to normal volunteers (TC-5619-238-CLP) -002) After cognitive improvement, these data provide the basis for the study of a7NNR agonists in adult adhd. 2. Research purposes 2.1. Main purpose The main purpose of this study was to evaluate TC-5 619 in adulthood with ADHD. Efficacy in improving the core symptoms of ADHD in humans. 2·2· Secondary purpose • Evaluate the safety and tolerability of TC-5619 in adults with ADHD • Record TC-5619 plasma exposure by sparse sampling. 3. Research Design Overview 3.1. Study Design This is a multicenter, double-blind, randomized, placebo-to-dose, dose escalation study conducted at multiple centers in the US. At least 125 subjects will be recruited in this study ( To ensure 100 yuan.) All subjects should be in the sieve No tobacco has been used for at least 丨 ΐ ΐ ΐ ϊϊ ϊϊ : : : : : : : : : : : : : ΐ ΐ 第 ΐ 第 第 第 第 第 第 第 ΐ 第 第 第 ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ The TR guidelines are for the evaluation of adult AADHD. The other (4) subjects will be classified according to the following chapters.

Targacept Company 163062.doc 201244717 (T^lRGACEPT PR〇-〇5619-CRD-〇02(00) Effective Date: December 22, 2009 受试者 For subjects meeting all eligibility criteria, will be at baseline (Day 1) Start oral administration of TC-5619-238 or placebo once a day. The study drug will increase every 4 weeks, starting with a starting dose of 1 mg qd for 4 weeks (Day 1 - Week 4); then 5 mg The second dose of qd lasted 4 weeks (Day 5 - Week 8); and finally lasted for 4 weeks at 25 mg qd (Day 9 - Week 12; see the following study diagram). All doses are expressed as Free base equivalent. Double-blind treatment 25 mg QO 5 mg QD 1 mgQD comfort cut. J3 1st 1st 4th 8th 12th 14th week, week, week, week, week and week based on the following, each dose lasts 4 weeks (total 12 weeks) should be sufficient to detect a positive effect on the core symptoms of ADHD: administration of (10) mouth in subjects with age-related memory impairment] ACT effect of cytokine TC-1734 after 8 weeks (procognitive effect) (Study: -^ each 112-CRD-004); Effect of AZD3480 (TC-1734) on the core symptoms of adult ADHD after 2 weeks of treatment TC-1734-226-CRD-005); and cognitive improvement (TC-5619-238-CLP-002) after 1 day and 10 days of administration of TC-5619 to normal volunteers in the MRD study. If the trial interrupts the study early between baseline and week 12 for any reason, the trial host will make every effort to implement the 12th week assessment. These assessments should be implemented as soon as possible within 2 weeks of the interruption. Blood samples for pharmacokinetic assessment were collected from subjects. They will be on day 1 (1 mg single dose), week 4 (1 mg qd, in steady state), week 8 (5 mg qd, in steady state) Sparse samples were collected at the 12th week (25 mg qd 'at steady state). These samples will be collected before, 3 and 6 hours after administration of each of the visits. For subjects who completed the treatment phase, a follow-up visit will be conducted at week 14 (2 weeks after the last dose of the test agent). At this time, any signs or symptoms of recurrence will be assessed. Assume that TC-5619 is in humans. The half-life in the subject is about 2 hours, and the follow-up visit is appropriate 2 weeks after the last study dose (week 12). 3.1.1. Point 3.1.1.1. Primary endpoint The primary efficacy endpoint was the CAARS-INV total score, obtained 7 times: weeks -3, 1st, 1st, 4th (assessment of 1 mg dose); week 8 (evaluation) 5 mg dose); Week 12 (evaluation of 25 mg dose); and Week 14. The primary efficacy comparison would be from Day 3 to Week 4; Day 1 to Week 8; and 3 CAARS-INV endpoints from Day 1 to Week 12.

Targacept Company Confidential 163062.doc PRO-05619-CRD-002(00) 201244717

(TARGACEPT Effective Date: December 22, 2009 3.1.1.2. Secondary Endpoint Performance Endpoint: CAARS-INV Subscale: Attention Deficit, Overactivity_Impact and ADHD Index, (Part: 3k Days Week 1) , 4th week, 8th week, 12th week or early exit

CogState ADHD Test Kit (CATB), on the 3rd week, the 1st day, the first! Week, flute 4 weeks, 8th week, 12th week or EW and 14th week. ^

The CogState stop signal task score was obtained on week 3, day 1, week, week 4, week 8, week 12 or EW and week 14. The CAARS-S total score was obtained on the -3rd, 1st, 1st, 4th, 8th, 12th, or EW and 14th weeks. No w spear Clinical overall severity impression (CGI-S); at week -3, day 1, week, week 4, week 8, and week 12 or EW. Clinical overall impression - overall improvement (CGI-I); at week 1, week 4, week 8 week 12 or EW and week 14. And • Emotional Status Scale (POMS) scores; at Weeks-3, 1st, 4th, 8th, and 12th or EW. Safety endpoint: Physical examination (including neurological examination), at week -3, day 1, week 1, week 4, week 8, week 12 or EW and week 14 (tracking visit). AE evaluation, EW and Week 14 were consulted on the 3rd, 1st, 1st, 4th, 8th, and 12th week. Completion of the Colombian Suicide Severity Rating Scale (CSSRS) at weeks -3, 1st, 1st, 4th, 8th, 12th or EW and 14th. Sitting and standing vital signs, on the 3rd, 1st, 1st, 4th, 8th, 12th or EW and 14th week; these are on the 1st, 4th week At the 8th week and the 12th week or EW, it was carried out before and after the administration of the drug, +3 hours after administration and +6 hours after administration. When collecting sitting vital signs, BP and heart rate will be recorded after the subject has been sitting for at least a minute. When collecting standing vital signs, BP and heart rate will be recorded when standing for at least 2 minutes and no more than 3 minutes. • 12-lead digital ECGs implemented in triplicate, at weeks -3, 1st, 1st, 4th, 8th, 12th or EW, and 14th week; On the first day, the fourth week, the eighth week, and the twelfth week or EW, it was carried out before administration and at 3 hours and 6 hours after administration. • Clinical laboratory tests (hematology, plasma biochemistry, liver function tests [LFT], bilirubin, and urinalysis) at weeks -3, 1st, 1st, 4th, 8th, And Week 12 or EW 'and Week 14" will be performed on an empty stomach at screening, week 12 and week 14; and the fasting lipid group will be added to the test columns obtained from such visits

Targacept Confidential 163062.doc 201244717 (i^RGACEfT PR〇-〇5619-CRD 〇〇2(00) Effective period: 2〇09月22 曰• Urine drug screening, at week -3, 1st Days, Week 4, Week 8 and Week 12 • Urine cannin content at weeks -3, 4 and 8 • Urine pregnancy test for premenopausal women, week -3 , Day 1 and Week 12 or EW. PK Endpoint: Sparse blood samples used to document plasma exposure of TC-5619 will be administered on Days 1, 4, 8 and 12 before and Collected 3 hours after dosing and 6 hours after dosing 3.2. Theoretical basis for study design Random, parallel, forced-incremental design was used to evaluate the effect of TC-5619 on placebo for efficacy. Parallel set design allowed for clear establishment of TC The effect of -5619, and the randomized nature of the design minimizes the deviation between the observer and the subject. Since the forced dose escalation design will be used, the effect of the individual dose will be preliminary, as the design will make the dose Confusion over time. Based on preclinical extrapolation to humans and based on MRD studies (Targacept research) TC-5619-238-CLP-002) The cognitive effect of TC-5619 identified by the CDRs, the selected dose (1 mg, 5 mg, and 25 mg) is reflected in the expected effective dose (3_1 〇 mg) Scope All subjects will be non-tobacco users. Tobacco (smoke) may interfere with a7NNR-mediated effects. 3.3. Time and event schedules after the summary of the study procedure summarize efficacy, safety, pharmacokinetics and The approximate volume of blood of other measurements, frequency and timing

Sample type Body volume per sample Number of samples per subject Total volume of blood a Safety (including screening, double-blind period and follow-up evaluation) -jk liquefaction 5 mL 7 35 mL - serum chemistry 10 mT. 7 70 mL -HbAlC 10 mT. 1 10 mL Pharmacokinetic sample 6mL 12 72 mL Total 187 mL Confidential-64 *

Targacept Company 163062.doc 201244717 _ um^ACEPT pr〇-〇5619-crd-〇〇2(〇0) Effective Date: 2009 I2 Month 22 数量 The amount of bribes sampled to the amount of money. The amount of blood will not exceed ^ ^ 3.3.1. The screening procedure for each visit is pre-" 'sex 3.3.1.1. Screening (week 3) Informed Consent: 2 The eligibility criteria will be verified. 4 ^^^准^^ and psychiatric history (10) If you use bribe evaluation, you will record past medication history and any combined medication. Ϊίί ί(3) Begin to remove any medication that affects cognition (Appendix 3). This removal will verify that tobacco has not been used for 12 months prior to screening. The CAARS-INV and CAARS-S scales will be executed. POMS will be executed. 9. Train the ^gSta^^DHD test set (CATB) and complete two €, '2; ^ test period will be used to average 2 to get the baseline score (: ^ D 32 will implement CGI-S Evaluation. ι〇· Defective adverse events; Completion of the Colombian Suicide Severity Rating Scale (CSSRS) ° 11. The physical examination will be performed. 12. Three copies of the 12-lead digital ECG will be obtained. Vital signs (including contraction and diastolic blood pressure (BP) and heart rate (HR)) in sitting position (5 minutes) and standing position (at least 2 minutes and less than 3 minutes) will measure height, weight and oral temperature. Fasting blood samples for safety laboratory assessment (composed of hematology, clinical chemistry, bilirubin, liver function test (LFT), and lipid groups) will be drawn and processed and sent for analysis. These will also be used. The blood sample obtained HbAlC content.

Targacept company 擤 163062.doc « 201244717 (WRGACEPT pr〇-〇5619-crd-〇〇2 (〇〇) Effective date: December 22, 2009, urinalysis and cotinine / creatine needle measurement. $ ff Age-aged women (W0CBP) perform a urine pregnancy test. I7. Advise WOCBP and men 4 with appropriate contraception 3.3.1.2. Baseline evaluation (Day 1) White for about 21 days and a baseline visit in the range of +/_3 days According to the needs of the external EC〇f ί, the results. If the screening visit is abnormal, you can get 1 additional amount ^, these measurements must be normal before the first day of visit 2 I. Breaking the eligibility criteria (see Section 4.1) Completing the Social Habits Questionnaire 4 Evaluating the combined medications. Adverse events will be evaluated; CSSRS will be completed. W0CBP and men will be advised to use appropriate contraception. And 3 hours and 6 hours of life 8. If 5 selected gas and abnormal value 'will be repeated hematology, before delivery, red pigment, lft or urine analysis. Fresh results must be randomized! Drug Screening and Pregnancy Test (for w〇cBp) • II. Implementation of CAARS-INV and CAARS^M Baseline C·number of knives 12. Evaluation of CGI-S 13. Perform POMS » Clinical dose study drug (1 mg study drug). Gas collection for sparse blood samples from drug power workers. Re-implementation. After +3 hours and +6 hours, the blood samples of 17檑乂戈 and ^ΡΚ are sampled, no more than 30 minutes apart. After the assessment of the financial value of the towel, the county issued a supply of research drug for 1 week. To cover the 4th week of the lost material. The study drug will be brought to the confidentiality during the first week of visit. 66 -

Targacept Company 163062.doc 701244717 ^ im^ACEPT pr〇-〇5619-crd-〇〇2(〇〇) Effective Date: December 22, 2009 3.3.1.3· Week 1 Efforts will be made to evaluate on the day indicated. Permitted +/_3 days of gluten is also gambling monitoring, and in the evaluation of research drug compliance " & evaluation of combined drugs. Adverse events will be evaluated; CSSRS will be completed. Appropriate contraception will be advised to use WOCBP and men. Complete the CATB and stop signal tasks. The CAARS-INV and CAARS-S will be evaluated. CGI-S and CGI-I will be evaluated. - A physical examination will be performed. 10. Will obtain vital signs (including standing position β) β 11, will get triplicate 12-lead digit ecg. 12. Blood samples will be obtained for chemistry, hematology, and biliary sounds. 13. Urinary vesicles will be analyzed. Heart H and LFT. 14. Subject's study medication will be reissued upon completion of the visit. 3.3.1.4. Week 4 'Efforts will be made to evaluate on the day indicated. Allow a range of +/_3 days. Dereliction of duty will not be used again" Evaluation of combined medication. Adverse events will be evaluated; CSSRS will be completed. Appropriate contraception will be advised to use WOCBP and men. Complete the CATB and stop signal tasks. Complete CAARS-INV and CAARS-S. Complete POMS. Evaluation of CGI-Ι and CGI-S. 10. Perform a physical examination. η·hours of birth 12· Will charge blood samples for hematology, clinical chemistry, bilirubin 13. Collect urine for urine analysis 'drug screening and cotinine'. 14. Will be administered clinical dose Study drug (5mg study drug I 15 · According to the time and event table, the sparse blood sample collected in the pharmacokinetic evaluation 16. 〒凫赘, before the application of triplicate 12-lead digital ECG record, hours and 6 hours ( About Tmax) should be implemented again. ECG drawing and blood sampling for PK should be applied after administration, separated by hours 2 4 6 9 2 4 6 9

Taigacept Confidential 163062.doc 201244717 (TMGACEPT PR〇-°5619-CRD-〇〇2(〇〇) Effective Date: December 22, 2009 17· Xuan?, Research Drugs for Industry. Additional 1 week of research will be provided The remaining 3 visits or m doses. All remaining 3.3.1.5 · Week 8 ... will try to evaluate on the day indicated. Allow +/_3 days range. h isstssr The drugs will be returned and will not be used again. Concomitant medication. 4 Adverse events will be evaluated; CSSRS will be completed. WOCBP and men will be advised to use appropriate contraception. Complete CATB and stop signal tasks. 9 Complete CAARS-INV and CAARS-S. Complete POMS. 10. Evaluate CGM and CGI-S 11. Perform a physical examination 12. Use 5 SSSSi liquid and LFT for 3 hours and 6 hours of gambling and sputum 15. The clinical dose of the study drug (25 mg of study drug) will be administered. _ and event table collection of drugs (4) mechanical assessment of sparse blood samples 17_ before? Apply three copies of 12-lead digital ECG records, and about 3 (about Tmax) after administration, should be +3 hours after administration and +6 small ai tube 〇 drawing and blood sampling for PK, no more than 3 minutes apart. For 4 weeks of study drug. An additional 1 week of research will be provided to cover the abnormality of the next visit or the loss of the drug. The remaining research drugs will be returned to the clinic at the next visit*. _All remaining 3·3·1·6· Week 12 or early exit visit will try to evaluate on the day indicated. Permitted for +/·3 days. 1. All remaining research drugs for previous visits will be returned Will not be used again. 2. Evaluation of research drug compliance. Confidential.68·

Targacept Company 163062.doc 201244717 c imoACEPT pr〇-〇5619-crd-〇〇2(〇〇) Effective Date: December 22, 2009 Complete the Social Habits Questionnaire. Evaluation of the combined medication. Adverse events will be evaluated; CSSRS will be completed. Appropriate contraception will be advised to use WOCBP and men. Complete the CATB and stop signal tasks. Complete CAARS-INV and CAARS-S. Complete POMS. 10. Evaluate CGI-Ι and CGI-S. 11. Perform a physical examination. 12· The right to correct the 6-hour life 13. ^ ü machine blood samples for hematology, clinical chemistry, bilirubin, LFT and fasting blood 14. The urine will be collected for urine analysis, pregnancy testing and drug screening . Airbed dose study drug (25_, except for subjects who withdrew early. Academic review sparse blood samples 17. Trial of 12-lead digital ECG records will be performed prior to dosing, and small and 6 hours after drug administration (Approx. Tmax) Re-implemented, except for subjects who quit early. ίίίί hour ECG mapping and blood sampling for PK, 'phase 3.3.1.7 · follow-up visit, week 14 allowed +/- 3 days Scope. Evaluation of combined medication. Adverse events will be evaluated; CSSRS will be completed. WOCBP and men will be advised to use appropriate contraception. Complete CATB test and stop signal tasks. CAARS-INV and CAARS-S will be evaluated. CGI-S and CGI will be evaluated. - Ι. A physical examination will be performed. Vital signs will be obtained (including standing position ΒΡ). Triodes of 12-lead digit ECG will be obtained. 10. If only the 12th week visit identifies an abnormality, a blood sample will be obtained. Contributing hematology, bilirubin, LFT, and urinalysis. ', 11. Blood samples for the fasting lipid group will be obtained. β3·4·Restrictions h Green secret in the test period 4 6 9 2 4 6 9

Targacept Company 163062.doc Confidential-69. 201244717 CTMGACEPT PRO'0561 9-crd-002(00) Effective Date: December 22, 2009 2. During the entire study period 'except for acetaminophen (no more than i, 5 gm /day) Two subjects outside the soil cannot use any new prescription or over-the-counter pharmaceutics and herbal aids). Use new prescription or over-the-counter medications. 3. 4. 4. Inquire about the Targacept medical monitor to interrupt the trial. A thing again. Subjects will be discontinued unless the prescription drug (eg, benzodiazepine for sleep) is properly used and after discussion with the Targacept medical monitor, subjects who are positive for urine music screening will discontinue the test. i subjects who did not complete the study were less likely to participate in the R&D drug study at least 1 month after completing the study. After the study of the nine drugs, the drug was not used until 7 days after the completion of the study. The following contraceptive methods were used until the study a. Abstinence; b. Men who underwent vasectomy were condoms; Male subjects must use condoms, and thousands of other contraceptive forms should be used, such as mD, spermicide: mouth, 6. Women of childbearing age must: a. urine pregnancy test is negative b. not breastfeeding c. ^ It is intended to use 3 5 dietary methods (such as IUD, spermicide, oral contraceptives) throughout the study period and 7 days after the completion of the financial period. There are 2 restrictions on diet: # No grapefruit or grapefruit juice; • Front; dying, pre-day-night from midnight This fasting phase will be ϋίίί to get fasting lipid content. Subjects are at 3.6. Minimization of bias 3.6.1. Randomization Subjects will be assigned to study treatment based on the group according to a predetermined randomized schedule. The knife is assigned to the area of 4 blind sets of the mother's location.

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(TMGACEPT PRO-05619-CRD-〇〇2(〇〇) Effective Date: December 22, 2009 3.6.2 Blind Consolation to Blind The test will use TC-5619-238 capsules in blister packs Matching security and research staff. All research staff will remain blind throughout the study period. Unless (10) is required, if there is no permission from the test donor medical monitor, no T. 3.7. Research treatment and clinical trial supply § $ The study drug will be delivered to the pharmacist or other qualified person in each location in a blinded kit to be distributed to the randomized patient at each study visit (see below). 3.7.1. Physicals of the study drug The drug TC-5619-238 (TC-5619 benzoate) will be provided based on the strength of the free test, 5 mg or 25 mg. The drug is stored in white opaque gelatin capsules with Αρϊ and excipients. (_ and the blend of dioxide (6) towel - silk supply ^ used excipients are microcrystalline cellulose, colloidal bismuth bismuth, croscarmellose sodium and magnesium stearate. Placebo formulation by Microcrystalline cellulose in white opaque gelatin capsules (gelatin and titanium dioxide) It is composed of croscarmellose sodium, colloidal cerium oxide and magnesium stearate. The shape, color and size of the placebo capsule are exactly the same as those of TC--5019 capsule. 'Other research and development products will not be used in this study. 3.7.2. Drug Packaging and Standardization Two study drugs (TC-5619-238 and placebo) were packaged in blister packs and placed in a blister card suitable for the dosing regimen of each randomized subject. ' Research supply will be maintained under controlled conditions on site and distributed by on-site pharmacists or other qualified personnel. Will be distributed on Day 1 and Week 1 (redistribution after visit), Week 4 and Week 8 Providing each subject with a randomized blister card dedicated to the subject. Each set of blister cards will contain a study drug sufficient to continue until the next visit to dispense a new blister card, with additional 1 week supply to cover abnormal scheduling or loss of medication. The study drug label will contain information that meets applicable regulatory requirements. 3·7·3·Dose and Dosage Protocol All doses in this study are expressed as free base equivalent.TC- 5619 or matching placebo will be white impermeable Gelatin capsules are available in strengths of 1 mg, 5 mg and 25 mg. Confidential • 71 ·

Targacept Company 163062.doc 201244717 (T^RGACEPT PRO'056I9'CRD-〇02(〇〇) Effective Date: December 22, 2009 3·7·4· Drug Storage Research Drugs must be stored at a controlled room temperature of 15〇 c to the button force ^^ factory secrets are properly sealed. The temperature will be continuously monitored and recorded by the appropriate research center 1 for the duration of the ongoing study. = The product must be in accordance with the procedures described in this article and the study drug procedure manual. All applicable regulations require that only those recruited in the study can receive R&D products. Only authorized field staff can supply or invest in R&D products. 3·7·5· Drug distribution will be performed each time At the time of the visit, a dose sufficient to cover each dose escalation (4 weeks after the third day; 4 weeks after the 4th week, and 4 weeks after the 8th week) was distributed. A sufficient amount of blister will be provided to each subject. Card f and other blister cards contain doses of diced (10) 19 (1 call, 5 ridge cut mg) or comfort Qi; capsules (which will look the same as TC-5619 capsules) and additional 丨 weeks of supply, ^^ 欠^ The schedule is outside the specified timeline or the study drug is lost. The blister card will be designated as: "Α巧The first therapeutic dose level of the study drug; "Β" for the second therapeutic dose level &drug; and "C" for the third therapeutic dose level of the study drug. (1 mg, 5 mg Or 25 mg po qd) subject the subject to a single capsule of corresponding strength orally per day. Labels indicating the study identifier, subject identifier, blind dose, start and stop instructions to the subject On study drug containers. 3.8. Study duration and follow-up subjects who will be in the study for up to 12 weeks after the 3-week screening period will receive a single 2 weeks after completing the double-blind treatment period. Tracking visits. ', 3.9. Interrupt criteria test The commissioner reserves the right to temporarily interrupt this at any time, at a single location or at all locations, but not limited to security or ethical issues or serious non-compliance. The right to study. If the trial client determines that the action is required, the trustee will discuss it with the trial host (including the original action of the action 1 2 'The trial client will give an early notice before the actual action. j If the study is suspended or terminated for safety reasons, the trial client will inform the moderator and/or the research implementation agency, and inform the organization and the applicable requirements of the action, the service audit; ^ IEC /IRB and provide reasons for suspension or termination.

Targacept 163062.doc -72- 20 124^^ACEpj PRO-05619-CRD-002(00) Effective Date: December 22, 2009 曰 If the study is interrupted in advance, all research data must be returned to the trial client. In addition, all unused R&D products to be destroyed or returned will be configured in accordance with the Applicant's Applicant's Procedure for Research. @3·1〇. Research drug responsibilities The test host is responsible for the research and development of product responsibilities, mediation and record maintenance. 3.10.1. Inventory Records The test host or designated field staff must maintain a development product accountability record throughout the study process, as required by all applicable regulations. This person will record the amount and supply of the R&D product from the trial client and/or the amount of the subject and the amount returned by the subject. 3.10.2. Disposal of Unused Supplies Unused supplies will be disposed of using appropriate documentation and in accordance with ICH-GCP, local requirements and Targacept Standard Operating Procedures (SOPs). 3.11. Procedures for Revealing Randomized Codes Only if the knowledge of the test product is inevitable for the clinical management or well-being of the subject, the test moderator will be able to approve the approval of the Targac Medical Director or the designee. The Subject's Treatment Dispensal/Test Host will report the period and cause of the subject's blind treatment assignment on the appropriate source document and eCRF page. If a major adverse event (SAE; as defined in Section 8213) is reported to the trial client, the clinical study of the trial client and the staff member of the job-oriented Lin M may unbundle the treatment of the individual subject. . If you turn to “or the agency to report the management of the Lai Duan”, then the newspaper (4) is more subject to the treatment of the subject. According to the relevant regulations, the trial client/the reporter will report the drip line test host. Requires the trial host Lai, the history of the transfer and the accuracy, its video recordings for all the observations of the study participants and other research ugly according to M has been recorded on the deduction of this research = the financial Wei _ It’s the same as the one that touches the money. The person ~ not rJt'I treatment book under the birth data data set on the subject case record and then entered into the eCRF. The trial client will provide the study site with a study manual that will be summarized (10). The test moderator is responsible for the accuracy of the data transcribed from all source documents. °

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201244717 (f^tRGACEPT PRO-05619-CRD-002(00) Effective Date: December 22, 2009 All eCRF entries should be made within 3 working days from the visit time of the subject. The completed test The health record book, its lion file and eC:RF are ready for use in the final study of the money and can be used for on-site review by the trial client or its designated representative. The steps to ensure accurate, complete and reliable data will begin with The trial moderator and the 35 design and procedure research «review, after which it will be reviewed with its I staff. 4. The research community 4.1. Inclusion criteria for participating in the study' subjects must meet all of the following criteria:

1. Diagnosis of ADHD according to DSM-IV TR criteria 2. 3. 4. 5. At least 6 of 9 items in at least 1 subscale of CAARS-INV 2 2 Clinical overall impression - severity (CGI-S ) Index score ^ 4 (at least moderate) Age 18-65 years old, male or female non-endocytic users, if not used in grass and negative within 12 months before screening 6. Cantinine content (such as after quantification) <50 ng/mL as defined) indicates that informed consent can be understood and signed. 4.2. Exclusion criteria for participating in the study, the subject cannot meet any of the following criteria: 2. 3. 4. 5. 6. = before DSM-W spindle! Psychiatric disorders other than ADHD; use the Mini International Neuropsychiatry Questionnaire (MINI) to rule out other major DSM_IVTR psychiatric diagnoses according to the above definition (inclusion criteria), current use of tobacco ^ known or suspected for 6 months prior to screening Intra-drug abuse, screening for urine drug screening for illegal or over-the-counter drugs. The test host judges drugs that affect cognitive function by using suicide or threatening the risk of oneself or other people within 3 weeks before the first day. This includes the use of any two =, ADHD combined medication ADHD (Appendix 3, proposal). Any drug clearance must be completed during the 3 weeks between screening and day 1. Use any other restricted or banned drugs (Appendix 3). Any other concomitant medication that has changed within 4 weeks prior to screening 8. Effective date: December 22, 2009 201244717 “EPT PR〇-05619-CRD_002(00) 9. The research procedure cannot be followed in accordance with the opinion of the trial host (including CogState ADHD Complete Test) 10. Important other major or unstable neurological, metabolic, liver, renal, hematologic, pulmonary, CV, GI or urological history, or diagnosis of major depression 11. Myocardial infarction in the past year. In the past year, there was epilepsy type 13.1 type diabetes (dm); type 2 dm requiring medication (allowing diet control) 14. HbAlC at screening 7.4 15. BMI <15 or >33; male body weight <1〇〇 Lbs; female body weight < 80 ibse. 16. Current TB or known systemic infections (HBV, HCV, ΗΓ 〇Η 临床. Clinically significant findings in physical examination 忐 can clinically cause safety problems in the study Significant laboratory or ECG

Often 'includes QTcF>450 (male) or QTcF>480 msec (female) and includes LFT greater than 3 times the upper limit of normal. 19 Women of reproductive age who are unwilling or unable to use recognized contraceptive methods and men 20. Positive pregnancy test or Females in breastfeeding 21' participated in another clinical trial in the last 3 months before screening^, 22 Λ On-site staff or trial entrusted staff 2 3-4. Completion and withdrawal of the tester 4.3.1. Subjects Completion is double, at the end of the period (week 12) has completed all the requirements of the evaluation, then it will be regarded as the second respondent will be two; Ren " 'cause before the completion of the double f treatment period to interrupt the study treatment in advance It is said to be handled as outlined in the next section. · 2 · Patient withdrawal (early interruption study) ===== can return = make necessary visits or withdraw from the study' and must withdraw from the study or be investigated for reasons. The subject may be for any of the following reasons: • Subject request (for any reason) to continue the study in the best interests of the subject, as determined by the ',,, trial host's opinion.

TargacepT^i' 163062.doc •75- 201244717 (T^tRGACEPT PR〇-05619_CRD'002(00) Effective Date: December 22, 2009 • Major or unexpected adverse events, making it unsuitable for continued research • Lack of efficacy (if this poses a risk to the subject). The subject will be considered appropriate for the trial host. If the subject discontinues participation in the study for any reason, the trial moderator It must be assumed that the subject has reached the end of the treatment period and that all assessments are performed in accordance with the plan, which will be implemented as soon as possible within 2 weeks of interruption. Similarly, the trial moderator will: • All ongoing adverse events ( • If present; • Collect all unused study agents. These data should be recorded as they contain the necessary assessments that should be performed before any subject leaves the study. To avoid the subject being at any time due to AE (eg, The interruption of the study in advance of the SAE (as defined in 8.2.1.1) or the SAE (as defined in 8.2.1.3) must follow the procedure set out in Section 8.2. 4.3.3. Reporting the interruption must be in the source file and in the eCRF Record Reasons for the study. The study drug assigned to the subject who has withdrawn from the subject cannot be assigned to another subject. 4.3.4. The replacement of the patient will replace the failed player. Will not replace the double-blind who entered the study after randomization. Subjects who withdrew from the study during the mid-term ("halfway exit"). 5. Treatment of the subject 5.1. Dosage and administration TC-5619-238 will start at a dose of 1 mg; increase at week 4 Up to 5 mg; and up to 25 mg at week 8, or a matched placebo. The dose is expressed as the free base equivalent. If the subject experiences intolerance to the study agent, the subject will withdraw from the study. All doses (TC-5619 and placebo) will be administered orally once a day in the morning. Except for clinical visits at weeks 4, 8 and 12, all subjects will be as awake as possible Taking the study drug quickly. On the day of the 4th, 8th, and ηth week visits, all subjects will avoid taking the study drug during the visit until the indication is taken.

163062.doc ^ /^KbACEPT PR〇'05619-CRD-°02 (0°) Effective period: December 22, 2009 5.2 Treatment allocation will recruit at least 125 subjects to ensure at least each cohort 5 受试者 subjects completed. One cohort will be administered to TC-5619 and the other cohort will be administered to match the placebo. 5.3. Concomitant Therapy '5·3·1· Permitted Agents All concomitant medications taken during the study period will be recorded on the source document and in the eCRF along with the indications, dose information and administration period. Short-acting sleeping pills will be permitted until 2 nights before the neuropsychological evaluation. 5.3.2. Prohibited or restricted agents Several agents are prohibited or restricted and are summarized in Appendix 3. 5·3·3. Non-pharmacological therapy Subjects prohibited psychotherapy (analytical, cognitive, or behavioral) during their participation in the trial because they may interfere with efficacy evaluation. 5.4 Compliance Subjects who consume at least 8% of the prescribed daily dose during the treatment phase are considered to be compliant in the context of this proposal. 6. Evaluation of pharmacokinetics 6.1. Sample collection and treatment will be on day 1 (1 mg) and on week 4 (1 mg at steady state), 8th mg, in steady state = s Sparse blood samples (6 mL each) were collected at 12 weeks (25 mg 'at steady state) visits at approximately the following time points: approximately 3 hours and 6 hours after administration and after administration. The exact date and time of blood sample collection must be recorded on the source document and on the laboratory application form. The concentration of TC·5619 in all the gold-concentrated samples. The date and time of the study drug (TC-238 or *Consolation) will be recorded on the source document and in the eCRF. Blood samples will be prepared according to the tester's instructions and stored at -20 ° C (or lower). The study is over. Appendix 1 details other resources for collecting, processing and transporting blood samples

Targacept Company' ------- 163062.doc Confidential-77· 201244717 (l^RGACEPT PR〇-〇5619-CRI>-〇〇2(〇〇) Effective Date: December 22, 2009 6.2. Analysis The program will, under the supervision of the trial client, analyze all plasma samples in a trusted bioanalytical laboratory using a validated, proprietary, and sensitive LC-MS/MS method to determine the TC-5619 wave. If necessary, use There are qualified research methods to analyze selected plasma samples to document the presence of circulating metabolites. Additionally, plasma sputum samples can be stored for later analysis of metabolite profiles. 6.3. Pharmacokinetic parameters will be administered under the supervision of the trial client. The pharmacokinetic data collected under the sparse sampling paradigm will be aggregated using dose statistics and schedule collection time. Cross-sectional studies can be performed on the pharmacokinetic data collected in this study on subsequent dates. "The results will be presented in a separate report. 7. Performance evaluation 7.1. Effectiveness 7.1.1. Conor Adult ADHD Rating Table - Trial Host Version (CAARS-INV) and Subject Edition (CAARS-S) These scales evaluate various cognitive traits and behaviors. The CAARS-S is completed by the subject prior to interviewing the trial host. Then, after the interview of the subject, the trial host performs CAARS-INV ° 7.1.2. CogStateADHD test set and stop signal task (CogState webpage: http://www.cogstate.com/go/clinicaltrials). It includes multiple factors for evaluating specific cognitive areas, including speed of action, processing speed, working memory. Subjects perform functional and episodic memory. Subjects will be trained on the tool during their screening visit. The Stop Signal task is a computerized behavioral inhibition test as part of the CogState ADHD suite of tests. Sensitivity measure 7.1.3·Clinical Global Impression (CGI) Scale CGI is a three-part scale consisting of: (1) CGI-disease severity [CGI-S], 〇CGI-overall improvement [CGI- Ι] and CGI-effectiveness (or treatment) index [CGI-E]. In this study, only CGI-S and CGI-Ι were used. CGI-disease severity (CGI-S) scores ranged from 0-7^ CGI-S is evaluated according to the overall clinical experience of the trial host The possible value of the degree of illness is: 〇 = not evaluated, 1 == 士常, no disease at all, 2 = near mental dysfunction ' 3 = mild rickets, 4 = moderate rickets, 5 = significant rickets, 6 = severe rickets and 7 = subjects with the most serious rickets

Targac India company secret 163062.doc -78-月22日2〇l2\VmuACEPT ρ^^^-〇〇2(〇0) New Zealand f 9 years 12 price, w obviously 4, (242 ϊ ff micro-deterioration, 6=Significantly worsened, and 7=^ is obviously obviously f-improved '4=no change, 5=very 7.1·4·Emotional Status Scale (POMS)~. €ΈΈΒ"ίι1%^ - Last comparison (See the end of the study for details, number of knives in the third week (4) · Others with placebo 8. Safety evaluation 8.1. Safety parameters • Adverse events SSiiS generation (or, where appropriate, reported by adverse caregiver, substitute f) The duration of the study is defined as the time until the end of the interview (week 14) (see Section 8.2, the physical examination is not performed at the time indicated in the physical examination event schedule. All physical examinations should be completed. • Vital signs, assess blood pressure, pulse and respiration rate at the time indicated in the time and event schedule. Blood pressure and heart rate will be recorded after at least 5 minutes of rest in the sitting position and at least 2 minutes and no more than 3 minutes after standing. .

• The ECG will record a digital twelve-lead ECG at a paper speed of 25 mm/sec, allowing manual measurement of different ECG intervals (RR, pr, qRS, qT). These ECGs will be recorded in triplicate at each visit (unless an abnormality is detected at week 12, except for follow-up visits). The ECG of the subject in the sitting position will be recorded after at least 5 minutes of rest until 4 regular continuous complexes are available. The ECG interval estimate from the ECG recorder will be recorded' and the central ECG reader will verify all values and readings. QTcB and QTcF will be calculated from each ECG trace; the average QTc will be calculated when triplicate ECG is obtained » Confidential -79· T Targacept 163062.doc 201244717 (TARGACEPT pro'05619-crd-〇〇2(〇〇) Effective Date: December 22, 2009 • The clinical laboratory test summary is included in Appendix 4 for the β A type of 8·ι·ι. Blood samples will be screened (if specified 'and baseline'), (10), =血液 and biochemical blood samples. Samples and 12th week and Χί ΪΪ: ^ will be available for other hematology and biochemical laboratory tests. Any value in the week is clinically abnormal, and the sputum is visited and/or until the foreign body is withdrawn from other materials. (4) The job is chased in the 14th week. 8.1·2. Urine analysis except the baseline (Day 1) Urine analysis will be performed at each visit. 8.1.3. Adverse events to ί ίίί 主动 主动 主动 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在= year. Any early termination of pregnancy will be reported. Continued after the knife-cut date 1 Always treat spontaneous abortion as SAE Reports, such as 筮 士士必,+. Report any SAE that is moderately related to J due to post-study pregnancy. Although the trial host did not seek this information, it can use the spontaneous report to learn that椹 Research participants are closely related

Targacept Company 163062.doc -80 - PRO-05619-CRD-002(00) 201244717

c imGACEPT Effective Date: December 22, 2009 8.1.5. Security Parameter Analysis A full-featured analysis will be conducted on the full-fledged data set. Narrative statistics will be implemented based on the evaluation time. • Physical examination at the end of treatment (or at the termination if the subject withdraws from the study): Clinically significant changes from screening will be presented; the frequency table will be calculated. • Life test: blood pressure and conversion and stagnation rate: Narrative statistics will be calculated based on actual values and changes from baseline values. The value outside the reference range will be counted and also explained using the transition table. A graph of the mean and standard error will be provided. • Oral temperature: Descriptive statistics will be calculated for each cohort. • Laboratory parameters: Narrative statistics will be calculated based on actual values and changes in all laboratory parameters relative to the screening values. The values outside the reference range will be listed and the transition table will also be used to form the table. • Bad experience: AEs and SAEs will be coded by MedDRA and summed by dose, organ type and priority terms (number of events, number and % of subjects with or undergoing at least one event). • The Colombian Suicide Severity Rating Scale score will be tabulated and a summary statistic will be displayed. • The combined use of the WHO Pharmacopoeia code will be listed. • ECG: The narrative statistics based on heart rate, PQ interval, QRS duration, qT, and qTc interval (qTcB&qTcF) will be calculated based on actual values and changes from baseline values. The value outside the reference range will be counted. A chart of the mean and standard error will be provided. 8.2. Report of adverse events – The test moderator is responsible for the detection and documentation of the events in the plan that are in compliance with the criteria and definitions of non-significant AEs or SAEs. During the study period, from the time of informed consent until the end of the follow-up visit (week 14), the trial host or field staff will be responsible for detecting and tracking AEs and SAEs as detailed in this section of the plan. 8.2·1·Definition 8.2.U. Adverse events Adverse events (ΑΕ) are administered to pharmaceutical products and do not necessarily have a causal relationship with this treatment 201244717 (f^tRGACEPT PRO_05619'CRD_002(〇°) Effective Date: December 2009 Any adverse medical event in a 22-day subject or clinically developed subject. Therefore, adverse events can be any adverse and unexpected signs (including abnormal laboratory findings), symptoms, or temporary and medical (R&D) products. Use of related diseases (whether or not related to medical (R&D) products.) 8.2.1.2·Unexpected adverse drug reactions Unexpected adverse drug reactions are adverse reactions, the nature or severity of which is related to the applicable product sK (for example, unapproved products) Inconsistent in the test host's manual or the packaged instructions/outline of the product characteristics of the approved product. 8.2.1.3. Major adverse events Major adverse events (SAE) are those that occur at any dose that meet one of the following criteria. Any unfortunate medical event: causing death; life-threatening; requiring hospitalization for hospitalization or extension of hospitalization; resulting in permanent or significant disability or incompetence; or if The item is a congenital anomaly or a natural defect... 〆8·2·1·4· Special attention to the adverse events The special concern includes any of the following items: QTcF prolonged LFT abnormal delayed movement can not be tonic or exercise Delayed dose over-pregnancy 8.2.2. The adverse event report will encourage the subject to spontaneously report baseline health from any change from the subject's entry into the study. The research staff will also be present in the study at each visit. In the center, ask for adverse events. All AEs will be recorded in the source file and eCRF. In addition, special attention will be reported to the trial client and CR〇 within 24 hours after reporting or determining at the clinical site » 8.2.3. The laboratory abnormality of the event is met by the test host's female clinically significant abnormal laboratory findings (eg, clinical chemistry, hematology, urinalysis) or other abnormal evaluations (eg, ECG, vital signs, etc.). The definition of SAE (as defined in 8.2.1.1) or SAE (as defined in Section 8213) will be recorded as AE or SAE. It is detected during the study or exists at the time of screening and After the study began

163062.doc •82· 201 24, 1^JaC£/T age. 5619 gamma (°°) Effective date: 2 () G9 December 22 The laboratory found that it was evaluated as _ or from SAE. However, related to the disease under study (unless the trial host is serious), the rest of the study started a deposit check _ and the clinically significant abnormal laboratory findings or their regular assessments are not reported as . Ίί用学H laboratory findings or other abnormal evaluations are clinically obvious. 8-2.4. Intensity evaluation test moderator Lai research (4) report every time and _ strong price will be based on the clinical judgment of the trial host ^ and (10) Medium record = degree assigned to one of the following categories: and E strong • ^ degree: event that the subject is prone to tolerate, causing minimal discomfort and treacherous daily activities 0 • Moderate: uncomfortable enough to interfere Events of normal daily activities. • Severe: An event that hinders normal abnormal activity. A AE rated as severe should not be confused with SAE. Severity is used to assess event intensity categories; and both AE and SAE can be evaluated as severe. 8.2.5. Causality evaluation The trial host is obliged to evaluate the relationship between the R&D product and the occurrence of each AE/SAE. The moderator will use clinical judgment to determine the relationship. Alternative reasons, such as the natural history of underlying disease, combined therapies, other risk factors and events, and the production of R&D products, will be considered and studied. The holder will also review the trial host's manual and/or market availability when determining their evaluation. The trial host will determine the relationship between study treatment and AE based on the following definitions: • Not relevant (AEs are more likely to be explained by reasons other than study treatment). • Relevance (Study treatment is closely related to AE in time and AE can be explained by exposure to the study product: for example, known pharmacological effects or relapse based on re-stimulation). There may be situations where SAE has occurred and the trial host has very little information to include in the initial report to the trial client or CR〇. However, it is extremely important that the trial host transmits the SAE Medwatch to the trial. The commissioner or CRO always conducts a causal relationship evaluation for each event. The test host can change his opinion on causality based on the tracking information and change the eCRF and SAEMedwatch tables accordingly. Causality evaluation is one of the criteria used in determining management reporting requirements. Confidential • 83·

Targacept Company 163062.doc 201244717 (T^RGACEPT PR〇-〇5619-CRD-〇〇2(00) Effective Date: December 22, 2009 The trial host will provide a causal relationship evaluation. _Evaluation should also be recorded as the source of the medical record of the subject. 8·2·6. Record of adverse events. When the cockroach occurs, the responsibility of the test host is to review all documents related to the event—for example, Wei The course record, laboratory and series report. The money test moderator will; ^ eCRF has recorded all relevant information about αε. The test host sends a photocopy of the subject's medical record to the trial client to replace Completion of the appropriate Ae eCRp entry is not acceptable for a 0. However, there may be a copy of the medical record required for the transfer of the medical record. In this case, all subject identifiers will be blinded on the copy of the test record submitted to the trial client. ▲The trial host will attempt to diagnose the incident by attempting to classify the ship, record and/or its mitigation. In such cases, the diagnosis is documented as AE/SAE rather than individual signs/symptoms. 8.2.7. Leading out adverse event reports At each visit, the subject will be asked eight questions with non-inductive questions, such as “How do you feel since the last visit?” or “How about the medication?” In this way, the potentially minor but clinically important side of the pharmacy can be detected. Once the trial host determines that the event meets the SAE's definition of the plan, it will report the SAR to the trial client or (10) as described below. 〇8·2·8· SAE Reporting Procedure - Once the trial host knows that _ has occurred in the study subject, it will report the m to the trial client or CRO within Μ hours for the report Always as much as possible, all the details of the event can be completed 'transferred to the trial client by the trial host (or designated person) = ^^ time range or (10). If the trial host has not yet = all about SAE Information' will not wait to receive other information until the trial client or cr〇 event is completed and completed. When the other information is received, the form will be updated. 0 Confidential • 84·

Targacept Company 163062.doc 201244717

^ //\K(jACEPT PR〇'05619-CRD-°〇2(00) Effective Date: December 22, 2009 Table 1. Submit to the test consignor or CRO SAF ▲ 奂 貉 HSR φ. • J Τ ;ί r - ^ l ι, ί;- a r --- . - __ _ * ! ί . ^.•/ί'ιΐηι,.& ί, . it . II.杧. Updated Medwatch Table

Medwatch Table 24 hours 24 hours _ Li - Medwatch Table [The trial host will always provide a causal relationship evaluation at the initial report'. The fax transmission SAE form as described in Section 8.2.5 transmits this information to the responsible SAE recipient. The preferred party for the project contact. In rare cases and when there is no fax device, it is acceptable by telephone notification and a copy of the hall's shouting is sent by the next day's delivery. Initial notification via telephone does not replace the need for the trial host to complete and sign the SAE form within 24 hours. Trustee, a list of project contacts, fax numbers and mailing addresses for receiving SAE. u ^ 8.2.8.1. Management Report Requirements for SAE The trial client or CRO has the legal responsibility to notify the local authorities and others, as appropriate, about the safety of the products under clinical development. It is up to the test leader to promptly notify SAE of the appropriate project contact person to receive the necessary legal obligations and ethical responsibilities for the safety of other subjects. 8.2.9. Management of overdose Any single dose τ n = greater than 25 mg taken from an attempt or gesture will be considered a dose Μ. In the study subjects take the dose = the identity of the transmitter (4). A detailed description of the clinical course of the ϋίί therapy and the subject will be recorded in the provided * If the overdose medical treatment is #, the subject should be qualified to determine the clinical condition of the subject without hospitalization. Then let the towel be wrapped, in the tune, _ use the (four) degree of the details of the limbs (including the ship, the money, the service

201244717 (T^lRGACEPT PRa〇5619-CRr>-〇02(〇〇) Effective Date: December 22 of the earthquake year 曰• Immediately, 1 hour later, 4 hours later and then every 8 hours in the shortest 24 hours, take 10 Ml plasma sputum is used for TC-5619 analysis and until all signs and symptoms of overdose have subsided. If possible, additional plasma should be obtained in the event of any significant clinical event (eg, neoplasia or hypotension) Samples • Immediate drug screening to detect other drugs taken during overdose. • Detailed clinical signs and symptoms, such as anti-parasympathetic effects (eg, urinary retention, intestinal congestion, etc.), arrhythmia, Epilepsy, respiratory depression, and disturbance of consciousness. • Frequent measurement of vital signs (initially hourly, or more frequently measured by clinical indications) 'includes supine blood, standing blood pressure (if possible), supine pulse, body temperature, and respiratory rate • Perform ECG every 8 hours immediately and thereafter until 3 consecutive ECGs are normal or the same as the pre-study ECG obtained. Special attention should be paid to the pr, qRS and qTc intervals. • Continuous monitoring of heart rhythm And any representative drawing of arrhythmia until 24 hours of heart rhythm abnormality is observed (so the minimum cardiac monitoring time should be 24 hours). • Hematology and blood chemistry tests and urinalysis are performed once a day and in the shortest 48 hours. Physicians who manage overdose may arrange for additional tests to be considered to be responsible for managing the safety of the subject. 8.2.10. Reporting safety information to the IRB The test host or responsible person meeting local requirements will comply with the human body. The Test Board (IRB) / Institutional Ethics Committee (Positive C) reports applicable local regulatory requirements for SAE. If a given SAE is attributable to both R&D products and accidents, the SAE may be eligible for full reporting. In this case, all trials participating in the study using this drug 'received a copy of the safety report. Receive an initial or trace safety report or other safety information from Targacept at a location (eg 'Revised Clinical Trial Host Manual / Trial Host Manual): 杳: The required person is promptly notified of the IRB. Putian 8^2.11·Proposal due to emergency or adverse events Poorly attending any of the subject matter of an emergency or adverse event requiring immediate medical attention and appropriate medical management of the medical staff at other indicated clinical locations. ^ Can report this to the medical monitor of the trial client quickly If the medical management is on the research plan, the medical monitor will be responsible for returning the compliance in time to the subject, authorizing the subject to continue the trial. If the subject fails to return to the research plan in time, the test will be interrupted. Research. Confidential -86 -

Targacept Company 163062.doc 201244717

^ tmuACEPT PRO-05619-CRD-002(00) Effective Date: December 22, 2009 8.3. Tracking of Adverse Events After the initial AE/SAE report, the trial host is required to actively follow each subject and The trial client provides further information about the condition of the subject. All AE&SAEs recorded during the previous visit/contact and designated as ongoing will be reviewed in subsequent visits/contacts. All AEs and SAEs will be tracked until they resolve until the condition is stable until the event is otherwise resolved' or until the subject loses track. Once it has faded, the #eCRp entry and the Medwatch table will be updated. The trial moderator will ensure that the tracking includes any __ investigation studies that may clarify the nature of the £8 or 3^ and/or the cause. This may include other experimental trials or investigations, histopathological examinations, or consultation with other health care professionals^, and the trial client may request the trial host to perform or configure for ancillary measurements and/or assessments to be as comprehensive as possible. The nature and/or causal relationship of AE or SAE. The trial host is obligated to help. If the subject dies during the study period or during the approved follow-up phase, the trial client will be provided with a copy of any post-mortem findings (including histopathology). New or updated information will be recorded on the originally completed Medwatch form, and all changes will be signed and dated by the trial host. This information will also be entered into eCRF*. The trial host is not obligated to actively seek for eight or § in the previous study participants. However, if the trial continuation is aware of any (including death) at any time after the subject has left the study and believes that the incident is reasonably detailed with the R&D product, the trial host will promptly notify the trial client. SAE, which is related to the participation in research, procedures, invasive duties, and changes in wealth, is reported to the trial client even if it occurs in the pre-secret stage or in the training section. 〇 9. Statistics 9.1. Statistical Methods Description 9.1.1. Quantitative parameters are calculated statistically (standard values of mean, median, and mean values; and the treatment ANCOVA model using the chi-square test performance is used to analyze all continuous measures. In addition, all statistical tests indicating the degree are unilateral and will be (4) Conghui water

Targacept Confidential 163062.doc 〇. 201244717 (TARGACEPT PR〇-〇5619_CRD'002(0°) Effective Date: December 22, 2009 9.1.2. Qualitative parameters The 参数-parameter parameters will be aggregated according to the frequency and percentage of the category. The chi-square test was used to examine the difference between treatment and placebo. 9.1.3. Baseline data analysis will use narrative statistics to present and summarize demographic data and subject characteristics at screening. Medical history (by disease) Type classification) will be tabulated by group and subject. Any deviation from inclusion/exclusion criteria will be listed. 9.1.4. Primary efficacy endpoint analysis from baseline (Day 1) to Week 4, At 8 weeks and 2 weeks, the primary endpoint will vary in the total score. This change from baseline will be analyzed using ANCOVA technique at 0.10 alpha (unilateral) to examine TC-5619 versus placebo treatment. Differences between groups The ANCOVA model will include treatment as the primary factor with baseline values and loci as covariates. Other covariates may be used as appropriate, and these covariates will be presented in the statistical analysis plan. Week 4 [1 Mg]; Week 8 [5 mg]; and Week 12 [25 mg]), which may lead to rejection of the null hypothesis, so the H〇chberg method will be used to control multiple comparisons. To ensure the significance of the two independent tests 10%, if the first p value is higher than 10. /. Significance level ' will use the 5% significance level to evaluate the second p value. If the second p value is higher than 5% significance level 'will use The 3.3% significance level is used to evaluate the third p-value. For the intended treatment (ITT) population and the plan-based (pp) population, the primary efficacy endpoint will be used to perform the primary efficacy analysis. To account for the missing data, the final observation will be used. The estimated (L〇CF) method 'ie' will use the observations obtained in the last available treatment of the subject to estimate subsequent missing data points. If in the intended treatment (ITT) population, 3 doses to the placebo The primary endpoint of the comparison is statistically significant, then the primary efficacy endpoint will be considered positive. 9·1·5 Pharmacokinetic Analysis For TC-5619, plasma will be presented by visit/dose value Plasma concentration data for all individual subjects at which concentration is available" All below the limit of quantitation The concentration or missing data of (L〇Q) will be as the actual data in the list of data. In the summary statistics and the calculation of pharmacokinetic parameters as appropriate, concentrations below LOQ will be treated as zero. All subjects and samples excluded from this analysis will be clearly documented in the study. Confidential-88 -

Targacept Company I63062.doc 2011PR〇-05619-CRD-〇〇2(0〇) Effective Date: December 22, 2009 曰 For each dose value, the narrative statistics will be calculated for each sampling time. Includes arithmetic mean, standard deviation, coefficient of variation, median, minimum, and maximum). A cross-disciplinary PK analysis was performed on the pharmacokinetic data collected in this study on subsequent dates. Their results will be presented in a separate report. 9.2. Sample size At least 125 subjects will be randomized into 2 cohorts to ensure that at least 1 subject is completed. This assumes a 20% midway exit rate. ° This is based on the following sample size calculations. This study has the ability to show a placebo from placebo (Day 1) to 4 weeks at the end of the treatment period for each dose (1 m day to week 4 '5 mg. Day 1 to Week 8; and 25 Mg: Day! Day 12 to Week 12) Statistically significant difference in the change in the CAARS-INV total score. The number of testers required for each cohort is 50 'to use the unilateral test to detect the difference of 4.0 points with the 8G% test power and the overall score of the secret (?<0.!0), assuming standard deviation ( 31)) is 75, ^Khberg to adjust multiplicity, assuming only one dose is positive, and assuming a normal difference. 9.3. Significance level For the effective money #reading the sexual forest will be determined at the end of the test for the main efficacy end point because of the three dose comparisons, this weight comparison. To ensure that two independent tests are performed * ^^^3.330/0 9·4· to account for missing, unused, and false data, the value is calculated using the L0CF method. The details of the procedures for taking care of omissions and failures to make data will be detailed in the study of specific data management and 9.5. Analysis of patients who withdraw from the study early " price-tested gas testers should complete all necessary in early termination visits坪• The total interruption caused by the ping. All information about the withdrawal from the subject will be 9.6. Selection of the patient to be included in the analysis The randomized data set will contain all randomized subjects. Entering the thief An Zheng confidential • 89.

Targacept Company 163062.doc 201244717 CT^RGACEPT PR〇-〇56I9-CRD-〇〇2(00) Effective Period: December 22, 2009 According to § 10, the book (PP) data set will only include the plan All the aspects (including 8〇% according to the research and development of the drug) Yuancheng study randomized subjects. A secondary performance analysis will be based on the data set according to the plan. The Intent Therapy (ITT) data set will include all randomized subjects who receive at least one dose of the study agent and perform at least one post-administration efficacy evaluation. For those subjects who withdraw from the study in advance, the final value of Treatment ♦ will be used for all subsequent (missing) visits (ie LOCF calculations). The primary performance analysis will be implemented based on the ITT data set. 10. Directly review source data/documents 10.1. Monitoring According to applicable regulations, ICH-GCP and trial client procedures, the trial client or CR〇 monitor will contact the site prior to the recruitment of the participants to review the proposal with the field staff. And data collection procedures. In addition, the tester will contact the site on a regular basis, including conducting on-site visits at the appropriate frequency. During these liaisons, the monitor will: 1. Check the progress of the study. 2. Review the research data collected. 3. Implement source file verification and eCRF data entry. 4. Identify any problems and document their solutions. This will be implemented to verify: 1. The data is true, accurate and complete. 2. The safety and rights of the subject are protected. 3. The research is carried out in accordance with the currently approved plan (and any changes), ICH_Gcp and all applicable regulatory requirements. The trial host agreed to allow the monitor to review all relevant documents directly and agreed to assign the monitors their time and their staff time to discuss the findings and any related issues. At the end of the study, the monitor will also implement all of the activities described in Section 13.3. 10.2. Review of original subject records During the monitoring process, the original subject records (source files and subject case records) will be audited or reviewed to verify the accuracy of the data entered into the eCRF. This audit or review will be carried out in accordance with the standard operating procedures and monitoring plans of the tester. °

163062.doc (TARGACEPT PRO_05619_CRD-002(00) Effective Date: December 22, 2009 11. Quality Control and Quality Assurance 11.1. Regulatory Approvals The trial client will be unique to the country before starting the study at one of the countries. All applicable regulatory requirements are approved by the appropriate regulatory agency for implementation studies. To ensure that Targacept can implement quality assurance audits in accordance with ICH-GCP and all applicable regulatory requirements, the regulatory body may also conduct regulatory review of this study. Such audits/checks It may be conducted during the study or at any time after the completion of the study. If an audit or check is conducted, the test host and the agency agree to allow the auditor/auditor to directly review all relevant documents and agree to assign the time to the auditor/auditor The time of the staff member and the staff to discuss the findings and any related issues. 11·2·Modification of the plan Before the change is implemented, all plan changes must be signed and dated by the test host and approved by the IRB. Submit all plan modifications to the IRB or applicable local authority. Test consignor or The designee will submit a proposal revision to the FDA and other national regulatory agencies. In the event of an emergency, the 'Da's plan will be determined to be tolerable on a case-by-case basis. The trial host or other on-duty Physicians must contact the medical monitor (test client or CRO) as soon as possible to discuss the emergency. The medical monitor will work with the trial host to determine if the patient should continue to participate in the study. All program deviations and the reasons for such deviations Must be noted on the source document and in eCRF and reported to irb/iec as appropriate. 12. 俭12.1. Ethical Principles This study will be based on the International Coordination Meeting, Good Clinical Practices and all applicable regulatory requirements (if applicable) The Helsinki Declaration 2〇〇8) is implemented. The trial host (if appropriate, or the trial client) is responsible for ensuring that the appropriate IRB/IEC review and approval of the proposal, the informed consent of the site, and the potential test will be conducted. Any other information presented (eg, advertising or information that supports or supplements informed consent). The trial host agrees to allow IR^/IEC to directly view all relevant documents. The IRB/IEC must be prepared in accordance with all applicable regulatory requirements. The test entruster or CRO will provide the test host with a review and approval study = relevant documents/data required. The R&D products and other research materials can be shipped to the site. Previously, the trial client or CRO must receive a copy of the IRB/IEC approval, the approved informed consent, and any other information that the IRB/IEC has approved for presentation to potential subjects. Confidential-91 -

Targacept Company 163062.doc 201244717 (T^tRGACEPT PR〇-〇5619-CRD-〇02(〇°) Effective Date: December 22, 2009 If the proposal, informed consent or IRB/IEC has been approved for use If any other information presented by the potential subject changes during the study period, the trial moderator is responsible for ensuring that the IRB/IEC reviews and approves (if appropriate) the special document 4 the tester _ the consent of this version ^ and the study before the test The moderator must comply with all applicable regulatory requirements of the book (4), including obtaining IRB/IEC approval for change consent. IRB/IEC approval and change of informed consent for change of informed consent/other information must be obtained. The publication of the book/other information to the trial client 12.2. Informed consent will be obtained before the subject can participate in the study. The process of consent and understanding will meet all applicable regulatory requirements. β " This study will be complete 21 CFR5 wipes are implemented by the rules of knowledge. The consent form must be reviewed and approved by the trial client before being submitted to the IRB/IEC. The consent form must be approved by the IEC before starting the study. There is a comprehensive interpretation of the possible advantages, risks, alternative treatment options, and treatment in the event of damage under Section 21 of the Federal Regulations. The consent should also refer to *, by the patient or (if appropriate) The signature of the supervisor is to permit the trial client and the representative of the FDA to review the relevant medical records. The moderator is responsible for the implementation of any test positions or evaluations required by the implementation of the test. A copy of the signed consent document will be returned to the patient and the original and the case report form on site. The trial host will keep it together. The non-experimental reader has already had the dissatisfaction of the person or the money. The moderator cannot allow the person to participate in the study as a subject. Test ^==, and make forced or inappropriate influence The possibility is minimized. Giving ϊίί JJ ^ information must be paid by the person or representative of the language that can be transferred. Knowing the system (transfer of ^ written) can not include any exemption statement, through which the statement will ^ ί or = give up the test Any legal rights of the person may be exempted or appear to be the 'institution, the tester or the person who is degrading (10). The green sister is responsible for the table redundancy = the legal study of each prospective subject does not affect the progress Treatment = Exemption He agreed to withdraw the requirement of the time. 21CRF 50.23 column is not in the United States informed

Targacept Company I63062.doc •92· 201244717

Um^ACEPT PR〇-〇5619-CRD-〇〇2(〇〇) Effective Date: December 22, 2009 Before the start of any screening evaluation for this study, the consent form. Subjects who are unable to write are allowed to use the subject's m-shot and the representative of the tender test surface = the photo of the Human Test Committee (mB) regulations and applicable local regulations in 21 cfr 56, according to the Helsinki Declaration (2008) Implementation. This plan will not be started unless the plan has been reviewed by the IEC to comply with the requirements of 21 CFR 56 and approved for the second level.丽ec should review the stipulations, request a modification _ to ensure approval) or not approve the plan to inform the trial host and the agency of its decision. 1 wake up should be required for CFR 50·25 ° irb/ie«^^ The degree of risk is appropriate but not less than once a year to continuously review the plan. It is necessary to have a copy of all the needle test host's report and the test host and bribe 1ECi. In addition, the IRB/IECit line is the purest at the completion of the test or early termination. Any significant scientific impact on patient safety, R&D scope, or trial quality in the plan must be determined by the trial client and the decapital prior to implementation. However, if the trial client subsequently informs the FDA or the local regulatory agency of the change and the trial host informs the deletion, then the intention = any change to the plan that is directly harmful to the subject can be immediately implemented. ^ The test host is obliged to transfer the IEC communication reading, and the money is tested by the representative of the trustee (as part of the test monitoring process). 12.4. The test moderator's report requires that the test moderator (if appropriate, or the test client or c) report to the IRB/IEC gSAEe in accordance with all applicable regulations, as required by Section 8.2, may request a study at its location. • Safety updates and bribes. These periodic safety updates and notices are the responsibility of the test moderator and not the responsibility of the test client. Any changes in the study implementation (including exceptions to the inclusion/exclusion criteria, research) The test host is also responsible for notifying the IRB/IEc and accepting the MRMEC at the completion of the study at its location. The final report of the IRB/IEC must also be submitted to the test host. Test provided confidentiality-93-

Targacept Company 163062.doc 201244717 (J^RGACEPT pr〇-〇5619-crd-°〇2(〇〇) Effective Date: December 22, 2009 曰13. Data Processing and Recordkeeping 13.1. Documented submission at the beginning of the study The documents that must be provided to the trial client before are as follows: • The FDA 1572 and the latest curriculum vitae signed and dated by the chief test host; • The signed and dated trial host contract; • The IRB/IEC has been in accordance with federal regulations The requirements stated in the Code review and approve the plan's warranty. The required documentation will be made up of the name and address of the IRB/IEC and the current list of members of the 111]8/1 £;;: in the United States, available from Health and The public service guarantee number replaces this list; ^ • A copy of the official written notice of the IRB/IEC approval plan and informed consent given to the test moderator. »Written notice must be signed by the chairman or charteree and must be specified Proposal. If the IRB/IEC member has a known conflict of interest, the individual should not be recorded for voting; the trial host (or co-sponsored pilot) may be an IRB/IEC Members' may not vote on any of the studies they participate in; • A copy of the RB/IEC approved informed consent and other supporting materials (eg, advertisements) to be used in the study, including IRB/IEC approval for such items Documented in writing. In addition to the documents required prior to the study, other documentation may be required during the course of the study. The trial host will promptly report to the IRB/IEC all changes in the research activities and all incidents involving risks, and unless Need to eliminate direct hazards to human subjects, otherwise no changes can be made in the study without IRB/IEC approval. They only involve minor risks or minor changes in previously approved studies need only be changed to 111] 8/正(::Submit. Important changes are required, approved by all IRB committees, and must be submitted to the FDA by the trial client prior to execution in addition to the emergency situation. All documentation of research change activities should be forwarded to the trial. The commissioner must also report the progress of the study to Ι^β/IEc at least once a year. The continuous IRB review should be from IRB/IEC. The letter is recorded and the letter is forwarded to the trial client. The test host must be notified of the irb/iec within 3 months after the completion of the study at the specific research center, termination or Yin. 13.2. Case report form and source documents Subjects who have screened but have chosen not to continue the study or who have found that they are unqualified for the study will be considered “screening failure.” The reason for the failure will be recorded on the source file and in eCRp. Confidential • 94-

Targacept Company 163062.doc 2〇12tSJ/\C£/T PR〇_〇5619-CRD-〇〇2(〇〇) Effective Date: Lions Year 22nd Clinical Research Specialist (CRA) will follow the source of the research center The document verifies the documentation of each patient. The omission or unexplained data will be reported to the trial client's solution to the source document and a copy of the eCRF (ie dvd-ROM containing the .pdf document of eCRF)^ placed in the research paper of the moderator's The original eCRF will be saved by the trial commissioner. eCRF will be the exclusive property of the trial client. η 13·3 · Study site closing At the completion of the study, the monitor will work with the trial host or field staff to perform the following activities as appropriate: ‘See • 1. Return all research data to the trial client. 2 3 4 5 6 7 Analysis of data query. Class, mediation and configuration of unused R&D products. Review the completeness of the field study record. The treatment code is returned to the trial client. Transport the sputum sample to the central laboratory. · Return all research-specific equipment to the trial client. And the trial host established between the trial client to give the trial host 13·4. Research document retention

f After the study is over, the test-age holder must ride the Wei field study record to maintain the place =. Records must be maintained so that when needed (for example, auditing or checking J and promptly retrieving, and whenever feasible, any subsequent review of the facility, support, and data can be combined. If local laws/regulations = For example, the format of the microfilm 'scan type, electronic type' will be used to hold the μ or all; however, 'Before taking this action, you need to be careful = and search criteria, if necessary, including regenerating the hard copy. In addition, the verification of ίϊίί^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Or the stipulations of the stipulations of the stipulations of the stipulations of the stipulations of the stipulations of the stipulations of the new syllabus, including (but not limited to the right to record in the facilities outside the site, transfer the confidentiality when the trial host leaves the site -95·

Targacept Company 163062.doc 201244717 (WRGACEPT pr〇-〇5619-crd-o〇2 (〇〇) Effective Date _· December 22, 2009 13.5. Provide research findings and information findings to the trial host. 7 host; ^ Provide the main data of the study to determine the treatment of the subject's scalpel, so that it can be judged 13.6. Information disclosure and invention 13·6·1· Ownership ί 验 验 委托 委托 委托 委托 委托 委托 委托And therefore assign a written contract between the ίί ΐϊΐ 与 与 与 与 与 与 ( ( 四 四 四 四 舰 舰 舰 舰 舰 舰 舰 舰 舰 舰 舰 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四Confidentiality. The test moderator or other on-site person (4) does not use η for any purpose other than the implementation of the study. These restrictions are not applicable to the evening due to mistakes made by the test host or the on-site guardian. (2) It is necessary to disclose to the 1RB in a confidential manner for research evaluation only. (3) The need to disclose the appropriate medical care for the study subjects. The results of the public research described in the following paragraphs. Executive research The confidentiality clause that is inconsistent with this statement shall be subject to the confidentiality of the contract and not the statement. 13.6.3. In the case of public opinion, the first disclosure or disclosure of the research results shall be conducted by the examinee. Coordination of complete, multi-center joint disclosure or disclosure. Therefore, any one = disclosure will refer to the original disclosure. For disclosure, presentation, for instructional purposes or otherwise revealing the results of the research (collectively referred to as "public") The trial moderator shall provide the trial committee with a copy of the content intended to be disclosed, and allow the trial committee to review the content of the intention to disclose it. The content intended to be disclosed shall include the test client's confidential information or any subject matter. Personal data of the tester (eg name or initials) u^j/\OEFT PR〇-〇5619-CRD.(00) Effective date: December 22, 2009 提交 Should be requested by the trial client, submitted or otherwise The disclosure of the content intended to be disclosed will be delayed for a sufficient period of time to enable the trial client to seek any invention, technical drum or other intellectual or industrial property rights disclosed in the content intended to be disclosed. 13.6.4. Data Management The test host or designee uses the source files in the input eCRF to collect the subject data defined by the trial client. The subject data required for analysis and reporting will be Enter the source file and then enter the validated eCRF system. Clinical data management will be performed according to the applicable trial client criteria and data cleansing procedures. When the data management quality control program is completed, the database will be locked. All eCRF data will be commissioned by the trial. The test host will keep an accurate copy of all source files and eCRF data (ie dvd_r〇m containing the .pdf version of the eCRF) on site. Confidential -97-

Targacept Company 163062.doc

201244717 CWRGACEPT PRO-05619-CRD-002(00) Effective Date: December 22, 2009 14. References

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Targacept Company Confidential 163062.doc -98- PRO-05619-CRD-002(00) 201244717

^ im^ACEPT Effective Date: December 22, 2009

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Levin, ED, Rose, JE (1995): Acute and chiomc mcodnic interactions witii dopamine systems and working toemory performance. In Lajtha, A, Abood, L, eclitots. New Yoik: The New York Academy of Sdences, pp 218-221.

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Moore, L (May 2006a) Lack of inhibitioh of (^-(S^Nicotiae binding to the α4β2 nicotinic acetylcholine receptor by TC-0S619. Targacept Litemal Rqx>rt

Moore, L (May, 2006b) Lack of functional activation of peripheral oicotinic ac^yldioliiie receptors by TC-05619. Tar^cept btemal Report

Newhouse, PA, Potter, AS, Smgb S. (2004). Effects of nicotinic atimulotion on cognitive perfoimance. CurrOpin Phannacol 4:36*46.

Newhouse PA, Sunderiand T, Tariot PN, Blocohardt CL, Wclngartner H, Mellow A, Mwphy DL (1988) Intravenous nicotioe in Alzhdmer's disease: A pilot study. Psydiophanoacology 95:171-175.

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201244717(TARGACEPT PRO-05619-CRD-002(00) Effective Date: December 22, 2009

Nigg JT (1999) The ADHD ie^oose inhibition deficit as measured by the Stop Task: replication with DSM>IV combined type, extension, and qualificatioa. J Abaonn Child Psychol 27: 393-402. Nigg, JT (2001): Is .AHD, JT (2005): Neuropsychological theoiy and findings in Attentioo-Deficit/Hyperactivity Disorder The state of tbe field and saKeot dudlog^s for the coming decade. Biol Psychiatry. 57,11:1424-1435. Oosteriaan, J, Logan» OD, Sergeant, JA (1998): Response inhibition in AD/HD, CD, comorbid AD/HD and CD, aoxioos and control childrcaL* a meta-analysis Of studies with the stop

3): Rjespoi childrcaL* i task. J Child Psychol Psychiatry 39:411-26. E, Kenemans, JL, Verbaten, MN, Kenmer, C, van der Moleo, MW, Van Engeland, (2002): Iiihibiti (> n in childr«i witii attendon-deficit/hyperactivity disorder: A

Overtoom, CCE, H et al. psychophysiological study of the stop task. Biol Psychiatry 51:668-676. Pettersson J, Hindoif U, Persson Bengtsson T, Malmqvist U, Weikstrom V, Ekelund M. ' (2008). Muscular exercise can cause Highly padiological liver function tests in healthy mm Br. J Clin Plonnacol jL 65:253-259

Pomerieau» O. F? Downey, K· Stdsoi^ F. W” and Pomerieau» CS (1995): Cigarette smoking in adult patients diagnosed with attention deficit hyperactivity disorder. J Subst Abuse. 7:373-8. Potter, AS &amp Nev^iouse, PA (2004) E£fects of acute nicotine behavioral inhibition in adolescents with attoition-deficil/Hyperactivity disorder. Psychoj^urmacology 176:182· 194. Potter A, Newbouse P. ¢2008): Acute Nicotine Improves Cognitive Deficits in Young Adults widi Attention>Deficit/Hypcractivity Disorder, niamiacology, Biochonistry aad Behavior 88(4): 407-417. Provost SC, Woodward R (1991) Effects of niccttine gum <m repeated administration of the Stroop test Psychophannacology 104: 536-540. Rapier, C,; Lunt, OG, A. Wcmaco% S (1990): Mcotmic moduladon of [3h]dopamine release from striatal synq>tosames; {Aarmacological charactoisatioa. J NeurocteiiL 54:937-45. Rulna, K, Ovetmeyw, S, Taylor, E ¢ 1999): Hypofronialitjr in attaitioD deficit hyperactiviQr disoider during l^gher*≪n^ler motor control: a study with functional MRI Am J Psychiatry 156:891*6. ··· . Sarter M, Bnmo JP. Cognitive fuoctioos of coiticel acetylcholine: towards a unifyittg hypotiiesis. Brain Res Rev, 1997^23 (1-2): 28<46. Saxter M, Bnmo JP. Cortical cholmetgic inputs mediating aiovsal, attmtiooal processhig aod dreaming: differmiial afifeient regulation of the basal fi brainstenu ^golation ce,2000;! forebraiaby tele 95(4): 933 -52.

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(TARGACEPT Effective Date: December 22, 2009

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Targacept Confidential 163062.doc -102· 201244717 (TMGACEPT PRO-05619-CRD-002(00) Effective Date: December 22, 2009 15. Appendix

Targacept Company Confidential 163062.doc -103- 201244717 (f^tRGACEPT PR〇-〇5619-CRD-〇02(〇°) Effective Date: December 22, 2009 曰Appendix 1. Pharmacokinetic Sample Collection, Handling and Transportation Materials And label: Blood must be collected in a glass or plastic blood collection tube containing KEDTA (for example, ). The blood sample must be leaked into the polypropylene storage tube. It should not be used with the mark = will be marked with a pre-printed label. If appropriate, the pre-printed information will include the investigator identification number (ecRF LD.), the treatment or treatment phase, and the preparation of the plasma pharmacokinetic sample for the ice fiber contributor as specified in the plan: (iv) to _dta Appropriate collection of tubes • Record the exact date and time of sampling on the laboratory application form • Gently flip the tube 8 to 10 times before mixing for mixing. The pepper is placed in the Linsi • After centrifugation) In each of the two storage tubes, each tube contains about 5 points of no frost; the east cold unit (track test - free drug set · 委 ί ίίίί, all pharmacokinetic samples will be sent to the test by multiple shipments The moderator must follow the following instructions·· Instructions to transport the sample collection date, by subject, by K sample households it with the country ⑤ = World Courier (Courier). For the American Express). For domestic use of domestic courier, such as FedEx (Federal), domestic shipments from the United States, will use a reliable domestic speed towel _, which (four) to send. This confidential

Targacept public g 163062.doc

201244717 D (TARCACEPT PR〇-°561 9-crd-o〇2(〇〇) Effective period: December 22, 2009 曰 • Notify the central laboratory and courier at least 24 hours prior to the planned shipment. Courier provides the appropriate account number to use. • Unless otherwise agreed with the trial client, samples will be delivered overnight via Monday to Wednesday (except holidays). • Double-package frozen samples from each subject. Subject to dry ice conditions (eg, low temperature bags) and label the eCRF id number. Fill the frozen sample in a suitable container with sufficient dry ice to maintain a frozen condition for at least 3 days. • By using dry ice resistant materials (eg , newspaper) Separate the sample bag from dry ice to avoid direct contact with the two. For all biological samples, follow the shipping regulations of the Intemati〇nai Air Transport Association (IATA). Observe the transport of biological samples (including all instruments) All courier regulations for work. • Ensure that the total package weight does not exceed 27,2 kg (6 mash). Mark the package with the test consignee's name and research number. The outside of the container includes the return address (which includes the name of the trial host). • Keep all the documents indicating the date of delivery on the study slot. The delivery date and the air waybill are broken, and the site will immediately go to the center. The laboratory calls, sends a fax or email. The number of telephone, fax or e-mail dynamics samples and the time of delivery. April research and nine editions say Le Hui = where the problem of the drug should be sent to the test consignor Contact person. If the trial client approves, the alternative procedure will not cause the change of the proposal. Confidential-10S-T Targacept Company 163062.doc 201244717 CWtRGACEPT PRO_05619_CRD_002(00) Effective period: December 22, 2009 Appendix 2 CogState ADHD Complete Test CogState ADHD Complete Set Test 1. General Description

The CogState ADHD suite of test kits has been developed to provide rapid and accurate testing of cognitive functions specifically for repeated evaluation of children and adults with ADHD. Non-verbal stimuli' Fixed stimuli response requirements and simple instructions mean that the CogState ADHD suite of tests can be used to assess cognitive function in children over the age of 4 and adults from different linguistic, cultural, and socioeconomic backgrounds.

The results of the CogState ADHD test have been shown to be sensitive to cognitive deficits in ADHD and also to the effects of drugs in children and adults with ADHD.

The CogState ADHD suite of tests allows for non-professional execution on standard computer equipment, which reduces cost and makes it easy to integrate into any clinical trial. 2. Attention and Alert Tasks A. Detection Tasks The instructions on the screen before the task ask: “Is the card flipped?” The game card is displayed in the center of the screen. The playing cards will flip and face up. After it has been turned over, the subject must immediately press the "Yes" button. The playing card will go to the back of the deck and the subject must press the "Yes" button and so on immediately after the next playing card is turned over. B. Identifying the task The command on the front of the mission asks: "Is the playing card red?" In the curtain center, there is a bash. The playing cards will flip and face up. After it has been flipped, the subject must immediately decide if the playing card is red. If it is red, the subject should press "Yes". If color, the subject should press "No γ ' 3 · Perform functional task Α. Count down 1 task (〇ne_back Task) with the task before the task on the screen The command asks: "Whether the face-up playing cards are exactly the same as the previous one," the placard is presented upwards. In each playing card, it is still the same as before the test shirt is fresh. If the job is the same as the one in which it appears, the subject touches "Yes". If it is not JSJ, the tester should press "No Confidential -106.

Targacept Company 163062.doc PRO-05619-CRD-002(00) 201244717

crmGACEPT Effective Date: December 22, 2009 B. Grozent Maze Learning Task Shows the subject on the computer touch screen 1〇> . There are 28 possible paths in the 100 possible positions. On the top left side, the starting point is indicated by a blue square, and the end point is Ϊ, =, = the square of the 3 color circle. The subject is instructed to move one step from the starting position and then continue to move toward the end point (bottom right side).

-107- 201244717 (filRGACEPT PR〇-〇5619-CRD_002(00) Effective date: December 22, 2009 Appendix 3. Prohibited and restricted combination drugs affecting cognitive function: Memantine Methylfeni Rivatigmine, Tacrine, Amphetamine, Tonepezil, Duloxetine, Duloxetine, Galantamine, Ginkgo biloba, Ginkgo biloba, Ginkgo biloba, Ginkgo biloba, Ginkgo biloba, Ginkgo biloba, Ginkgo biloba, Ginkgo biloba, Ginkgo biloba, Ginkgo biloba, Ginkgo biloba, Ginkgo biloba Therapeutic range and banned drugs ·· Within 10 weeks before the first day and during the study period: Amiodarone From the first day and during the study: Antiarrhythmic drugs (eg diisopropyl isopropyl than amine) (dis〇pyramide), dofetilide, flecainidej, ibutilidej, procainamide, propafenone, quinidine, Tocainide, verapamil anticoagulant [eg acenocoumarol, heparin (except for topical use), warfarin] anti-skinning agent: Barbie Barbiturate (for example, phenobarbital) Amine derivatives (eg, carbamazepine, oxcarbazepine) fatty acid derivatives (eg, valproic acid); beta glutamate derivatives (eg, phenytoin) Anti-inhibitory drug; Moclobemide. Tricyclic anti-repressive drugs (Τ0Α) (for example, amitriptyline, clomipramine, imipramine, Lofepramine, maprotinline, nortriptyline, trimipramine; the largest dose allowed is based on the lowest therapeutic dose of the US label. Astemizole, terfenadine antipsychotic; clozapine cytostatic (eg, nietotrexate) digoxigenin (Digitalis glycoside) ): Digitoxin, Digoxin, immunization preparation (for example, cyclosporine, sirolimus, tacrolimus) HIV protease 4 preparation / Antiretroviral drugs (for example, zid〇Vudine) 10 weeks from day 1 Internal and during the study: amiodarone hypoglycemic agents (eg, glibenclamide, glimepiride, glipizide, insulin, metformin (metform(8), tolbutamide) Tolbutamide)) Emotional Stabilizer: A drug with a narrow therapeutic range and limited use of lithium: Confidential-108 _

Targacept Company 163062.doc 201244717

(TARGACEPT PRO-05619-CRD-002(00) Effective date: December 1, 2009 from the first day and during the study period: acetaminophen, maximum dose 0.5 gx3 / day acetaminosalicylic acid, maximum Dosage: 0.5 gx3/day Exclude the use of these drugs: Antipsychotics (eg 'chl〇Ipromazine, chlorprothixene, flu π 嗟 ( (flUpentix〇i), said Fen Nai Static (1) Uphenazine), haloperidol, 丨evomepromazjne, meiper〇ne, perphenazine, pimozide, proplopenin Prochlorperazine), sertindole, thioridazine, ziprasidone, zuclopenthixol Note: use quetiapine or risperidone Patients treated with antipsychotics other than (risperidone) were unqualified for the study and could not be recruited or randomized. If the agent is needed after randomization, the patient must withdraw from the treatment. Drugs that are restricted for 4 weeks before Day 1 and during the study period: Anti-parasympathetic antispasmodic drugs: (eg, hyoscyamine) Anti-Parkinson drug (eg Benztropine) , biperiden, trihexyphenidyl antihistamines (eg Alimemazine, Cygon eptept (jine), dexchlorpheniramine ), dimenhydrinate, diphenhydramine, promethazine tricyclic antidepressants (TCA) (eg, amitriptyline, imipramine, imi Pamin, lofiparin, maprotiline, nortriptyline, trimipramine) Confidential-109-

Targac Printing Company 163062.doc Effective Date: December 22, 2009 201244717 _GACEPr _5619-C_2(〇〇)

Appendix 4. Clinical Laboratory Testing of Heme A1C Clinical Chemistry (Sodium, Potassium, Chloride, Bicarbonate, Glucose, Creatinine, BUN, Bilirubin, Liver Function Test [LFT; ALT, AST, Alkaline Phosphatase, LDH]) Hematology (white blood cell count, white blood cell differentiation, red blood cell count, red blood cell MCV, red blood cell MCHC, hematocrit, heme, platelet count) Blood lipid group (total cholesterol, HDL, LDL, VLDL, triglyceride, HDL/LDL) Ratio) urinalysis (glucose, protein, bilirubin, blood, ketone, pH, specific gravity) urine pregnancy test urine drug screening urine cotinine content urine creatinine

Targacept Company Confidential 163062.doc .n

201244717(TARGACEPT PRO-05619-CRD-002(00) Effective Date: December 22, 2009 Appendix S. Conor Adult ADHD Rating Form - Trial Host Version (CAARS-INV) These scales are subject to copyright The scale of protection is therefore not re-stated here. The field staff will receive a copy and the scale will be included in the research manual.

Targacept Confidential 163062.doc _111_ 201244717 CTARGACEPT PRO'05619'CRD'002(°0) Effective Date: December 22, 2009 Appendix 6. Conor Adult ADHD Rating Form - Subject Version (CAARS-S) The scales are copyright protected scales and therefore cannot be repeated here. The site worker will receive a copy and the scale will be included in the research manual.

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201244717(TARGACEPT PRO-05619-CRD-002(00) Effective Date: December 22, 2009 Appendix 7. Clinical Overall Impression Scale (a) Clinical Overall Impression - Overall Improvement (CGI-I) Assessment of overall improvement, whether it is Completely due to drug treatment. Consider the time when the subject entered the study and observe it. □ Not evaluated □ Very significant improvement □ Significant improvement □ Very slight improvement □ No change □ Very slight deterioration □ Significant deterioration □ Very obvious deterioration

Targacept Confidential 163062.doc - 113- 201244717 PR〇_〇5619 CRD_〇〇2(〇〇) Effective Period: December 22, 2009 曰(b) Clinical Overall Impression - Severity of Disease (CGI-S) Tester No. Subject Name First Letter Visiting Visiting Period Targacept Company 1 1 II I-- L-1 L 1 1 | 1 1 II t 1 -11- 1 1 1 1 dd MMM ww TC*» DQ («yyy-CFO-az At this time, the patient's mental illness has a clinical overall impression - the severity of the disease is serious and your overall clinical experience for this particular group is heavy, □ not evaluated □ normal 'completely unaffected □ yan Abnormal heart □ mild rickets □ moderate rickets □ significant rickets □ serious rickets □ most serious patients confidential --114-

Targacept Company 163062.doc 201244717 (T^lRGACEPT PRO'05619_CRI) '002(00) Effective Date: December 22, 2009 Appendix 8 · Emotional Status Scale (POMS) These scales are copyright protected scales And therefore cannot be repeated here. The field staff will receive a copy and the scale will be included in the research manual.

Targacept Confidential 163062.doc -115- 201244717 (f^tRGACEPT PRO'05619'CRD'002(00) Effective Period: December 22, 2009 Appendix 9. Colombia Suicide Severity Rating Scale A. Colombia Suicide Severity Rating scale: baseline visit form, baseline CSSRSB, if the two parties are negative, then proceed to the “suicide behavior” section. The rabbit’s question is “yes” and ask questions 3, 4 and 5. If the answer to question 1 and / or 2 - is "yes", then the following "intentional intensity 1 is divided. Lifetime: the time when you want to commit suicide. 1. Hope to die, try, back f. Strong or strong; 1; The idea of living, or the idea of sleeping light and not waking up. You had hoped to die or hope to sleep and not wake up if it was 'declared: CSI1DESC' is □, □ 〇 ID CSIDEAT1 2. Non-specific active suicidal thoughts - I don't want to end my life/suicide. (For example, "I'm not thinking about suicide methods/related methods, intentions or plans. ^ Have you ever thought of killing yourself?" If yes, explain: CSI2DESC □ 1 □ 〇CSIDEAT2 3. Have any tools still __ Subject endorsement suicidal thoughts and in the evaluation _ thought at least = from the heart to develop the time, place or method details and the body 'different from the law, but not specific plans Including the following words: % of the following suicide doses, but never made up when and how to actually do it. I took too much wisdom to go to jealousy. You have thought about how you might commit suicide ^ .... and I will never , then elaborate: CSI3DESC MA. Whether □ 1 〇 0 CSIDEAT3 4. Has a certain intention of action but does not have _______ There is suicidal active suicidal idea and the subject reported killing and mourning I have an idea but I am sure that Shi will not act Huan Zengzi’s situation has something to do with the idea of greed. “It’s similar to the following: Is CSI4DESC iT moving? Is it □1 □0 CSIDEAT4 5·The initiative with specific plans and intentions---_______ suicide Ideas and intentions have been fully or partially formulated. Phases, and the person with the mitigation has the details that you have begun to formulate or have developed how to commit suicide. If yes, explain: CSI5DESC '' · If you want to implement this plan?Whether □1 □〇 CSIDEAT5 ^~~S, ______

Targacept Company 163062.doc Confidential -116- ^----

201244717^ imQACEPT PRO-05619-CRD-002(00) Effective date: _ year! February 22 Lumibia Suicide Severity Rating Scale. Baseline Intentional Strength ___ Face is 1-5_ above, and it is heavy] 'Xu Ding y y yue' asked why he most wanted to commit suicide. For the most serious idea: CSMSI ~ 丨一 ------ - type number (1-5) description of the idea

CSSRSB Most severe frequency How many times have you had such thoughts? muf1—*(3) 2_5 times per week (4) Daily—times or times Duration How long does it last when you have such an idea? (1) Short-seconds or minutes (4) 4-8 hours/day most of the time (2) less than 1 hour/sometimes (5) more than 8 hours/lasting or lasting (3) 1-4 hours/ A lot of time to study controllability If you want 'can you stop thinking about suicide or want to die? 3, easy to control think * (4) can control ideas but hard (2) can control ideas but slightly difficult (5) can not control Thoughts are empty ideas but there is a certain difficulty (Ό) Go to the cobalt map to control the idea to retain " '~~ - —— What is bribery or bribery (such as family, 帛健仰止你要死 or commit suicide thoughts) (1) Retaining does prevent you from attempting to commit suicide (4) Retaining is very good (2) Retaining may prevent you (5) £1^_Retention can stop you (〇) Reasons for your thoughts ___ You think What is the reason for wanting to die or commit suicide? Is it a feeling? (Shooting, Charm (4) This axis ends when you are currently from other people (4), listen to him or to inspire, react or retaliate against others. Can not bring this (3) = raw (7) mainly to cause others to notice, react or retaliate against others. ^ Wang Hao in order to terminate or end the pain (you (3) In order to arouse the attention of others, the anti-defense method continues to succumb to other people with such pain or feeling, and the same '}° is to end/end the pain.

Targacept Company 163062.doc

CSMS1FRQ

CSMS1DUR

CSMS1CTL

CSMS1DTR

CSMS1REA -117- 201244717 (T^RGACEPT pr〇-〇5619-crd-°〇2(〇〇) Effective date: December 22, 2009 β post-worm suicide is seriously planted Zen Zensin

Real picture: ----------.____ Write the action, ί fruit at least - some behaviors want to die. Line infant "ί亨|/| order to prove S. ° Cover case 苎 listen to 1 miscellaneous S|l Lu and fIf#, when the gun is in the mouth (four) buckle trigger ‘ : |歆? No|'Hurry up, on the self or the situation to infer ^: 4 map (1 gas green wear, Xiqi; then in addition to self, do you hurt yourself? The dangerous things that may make you die έ — - Is t the way to blame your life? Wrapped iHSF following, if it is, then elaborate: J CSACTDES: Intent (such as releasing pressure 3 broken attempts: --__ ___ in the external situation, may start self-injury Linbi is heavier than any pill, so it is going to climb. The ambition is said to be: (4) Say: On the hang: Has the individual stopped the situation on the moon? 肀 '朿的朿, someone or something is If you actually do anything right, explain: If yes, explain CSINTDES to give up _ attempt: 'corpse; ^ stop-solid. ----------- stupid every r Qing tried her one (10) fine := CSABTDES > Preparation Action or Behavior:

For the implementation of the i killing attempt ^ " -113⁄4 test 黯) 3⁄4 - suicide (such as collecting pills, getting grab CSPRPDES

Targacept Company 163062.doc _ Suicidal behavior: — _ There is suicide in the evaluation stage?

CSSUICID

CSSRSB female

Whether [3i 〇 CSACTAT

Total number of attempts CSACTN CSNSSI Whether □ 1 port 〇

Whether □ 1 □〇 CSINTATT

Total number of interrupts CSINTN

Whether □ . □〇 CSABTATT

Total Abandonment CSABTN

Whether □ iD〇 CSPREP □ iCfo PRO-05619-CRD-002(00) 201244717

(TARGACEPT Effective Date: December 22, 2009

Colombia since _^ Severity Rating Scale, Baseline, Continued CSSRSB Only answers to actual attempts V 'ft . -* Actual lethality / medical injury: 0. No physical injury or minimal physical injury (eg surface rubbing code) Enter the code to enter the code to hurt). 1. Minor body damage (such as lethargy speech; first-degree burns; mild bleeding; sprain). 2. Moderate physical injury requires medical care (eg conscious but drowsy 'slightly reactive; secondary burns; major vascular bleeding) 〇 CSMRAAL CSMLAAL CSIFAAL 3. Moderately serious physical injury; hospitalization and may require priority care ( For example, coma but complete reflex; less than 2% of the body's tertiary burns; a large number of blood loss but recoverable; major fractures). 4. Severe physical injury; hospitalization and need for critical care (eg fainting and no reflex; tertiary burns of more than 20°/body; massive blood loss and unstable vital signs; major injuries in important areas). 5. Potential fatality of death. Only in the case of actual lethality = 回答, the actual attempt may be fatal if there is no medical injury (although the input code input code input code below does not cause actual medical damage, it may be extremely significant Lethality: Will grab the entrance and pull the trigger but grab the fire, so there is no medical damage; lying on the train track when the train is approaching, but being pulled away before being crushed). 〇=Behavior is unlikely to cause harm CSMRAPL CSMLAPL CSIFAPL Act may cause injury but cannot cause death Medical care ‘but behavior can lead to death

Targacept Company 163062.doc Confidential-119- 201244717 O^RGACE/T PR〇-〇5619-CRD_〇〇2(〇〇) Effective Date: December 22, 2009 B. Colombia Suicide Severity Rating Scale - Last This scale is almost identical to the scale used for baseline visits after a visit and is not repeated here.

Targacept Confidential 163062.doc - 120- Effective Date: December 22, 2009 20124=Which-- Appendix 10: Mini International Neuropsychiatric Interview M.I.N.I. Mini International Neuropsychiatric Interview English Version 5.0.0

DSM-IV United States: D. Sheehan, J. Janavs, R. Baker, K. Hamett-Sheehan, E.

Knapp, M. Sheehan University of South Florida-Tampa France: Y. Lecrubier, E. Weiller, T. Hergueta, P. Amorim, L. I.

Bonora > J. P. Lepine Hopital de la Salpetriere - Paris © Copyright 1992, 1994, 1998 '2000, 2001, 2002, 2003 Sheehan

DV & Lecrubier Y All rights reserved. No part of this document may be used without the written permission of Dr. Sheehan or in part - in the form or by any means - (electronic or mechanical, including photocopying) or by means of - . A copy of the M.I.KL tool is available for its own clinical and research applications in the case of the General Planner or the Public School, the Non-Compliant Hospital and the Government Lin. ^^1.5.0.0 (July 1, 2003)

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1P' 蓦 & quot 时 时 时 时 & 时 时 时 之一 之一 之一 之一 之一 之一 之一 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 严重 严重 严重 严重 严重 严重 严重 严重 严重 严重 严重 严重 严重 严重The episode of mild manic episodes is currently (2 weeks) recurrence (2 weeks) E panic disorder F market fears G social fear (social anxiety disorder) Η obsessive-compulsive disorder 1 post-traumatic stress disorder (optional) J Alcohol dependence Alcohol abuse Κ Substance dependence (non-alcohol) Substance abuse (non-alcohol) \ Ur \J \J \J ) / t PT^ ^ A number of 2 2t 1i nnn 3W Go to 3i to go The cerebral palsy has passed: Q has passed 21222 -·-, is 5; _ before going to go before and after going to life before going to go to the eyes of the eyes and eyes Exceeding high standards DSM-IV ICD-10 □ □ 296.20-296.26 Single F32.X 296.30-296.36 Recurrence F33.XD 296.20-296.26 Single F32.X 296.30-296.36 Recurrence F33.X □ 300.4 F34.1 □ D 296.00-296.06 F30.X-F31.9 □ 296.80-296.89 F31.8-F31.9/ □ F34.0 α □ 300.01/300.21 F40.01-F41.0 □ □ 300.2 2 F40.00 □ 300.23 F40.1 □ 300.3 F42.8 □ 309.81 F43.1 □ 303.9 F10.2X □ , 305.00 F10.1 □ 304.00-.90/305.20-.90 F11.1-F19.1 D 304· 00·.90/305.20·.90 F11.1-F19.1 L Mental illness for life □ 295.10-295.90/297.1/ F20.xx-F29 Present □ 297.3/293.81/293.82/ 293.89/298.8/298.9 Affective with psychotic characteristics The current condition □ 296.24 F32.3/F33.3 Μ Anorexia nervosa (current 3 months) □ 307.1 F50.0 Ν Nervous bulimia (currently 3 months) □ 307.51 F50.2 Anorexia nervosa, Gluttony/Clearing Type α 307.1 F50.0 0 Generalized Anxiety Disorder (currently 6 months) □ 300.02 F41.1 Ρ Antisocial Personality Abnormal Optional Lifetime 1.7301.7 F60.2 Μ,Ι.Ν.Ι_5.0.0 (July 1, 2003) 2

Targacept Company 163062.doc Confidential-122- 201244717 22nd d^RGACEPT pro'05619-crd-002(00) Effective Date: December 2009 Appendix 10. Mini International Neuropsychiatric Interview, Continued ____ General Description Implement a clinical interview that is more structured than usual, and with regard to the general format of psychology: "-" MINI is divided into groups of questions identified by letters, each question group corresponding to a diagnostic category. When the working group (except the psychiatric group) begins, at the end of each question group that presents the main criteria for the condition in the gray box, the diagnostic box allows the clinician to indicate compliance with the diagnostic criteria. Accurate reading, this is because it is written to the patient with the evaluation of standardized diagnostic criteria β 冩 (4) written by the child. It is used for the time range studied by the interviewer's (4) 4 Lin Lai algorithm. Interviewers should read these sentences as often as needed. Symptoms that occur only during the indicated time frame should be taken into account when scoring the response. The answer to Zhai Guang (*) indicates that one of the criteria required for diagnosis is not satisfied. In this case, the interviewer should go to the end of the question group. Circle "No" in all diagnostic boxes and move to the next question group. ^ Multiple items are slanted by lines (ο _ _ when the interviewer should only read the symptoms of their known patients (eg, question Η 6) β clinical examples of the symptoms of the film you are throwing. Can be read out to the patient These phrases are used to clarify the problem. Assessment instructions: = All questions must be assessed. The assessment is done by circled "Yes" or "No" on the right side of each question. ^ The clinical value of the rater should be used in the response coding. Judgment. The assessor should ask for examples to ensure accurate coding when needed. Patients should be encouraged to ask questions to clarify any issues that are not fully understood. The clinician should ensure that the patient takes into account every dimension of the problem (eg, time, frequency, Severity and/or another option. In Μ.Ι.Ν.Ι·, symptoms due to organ or due to the use of alcohol or drugs should not be coded as positive βΝ1·ΐ.Ν.Ι· Plus has questions to study these arguments. _ For any questions, suggestions, needs for training sessions or information about M.LN.I. updates, please contact:

David V Sheeban, M.D., M.B.A. Yves Lecrabier, MD. / Thierry Hergueta, M.S.

University of South Florida INSERM U302

Institute for Research in Psychiatry HOpital de la Salp6tri6re 3515 East Fletcher Avenue 47, boulevard de 1'HOpital

Tampa, FL USA 33613-4788 F. 75651 PARIS, FRANCE Tel: +1 813 974 4344; Fax: +1813 974 4575 Telephone: +33 (9) 142 16 16 59; Fax: +33 (9) 145 85 28 C Email · dsheehan @hsc.usf.edu Email: hergueta@ext.jussieu.fr Μ.Ι.Ν.Ι. 5.0.0 (July 1, 2003) 3 Confidential-123-

Targacept Company 163062.doc 201244717 (TARGACEPT PRO'05619'CRD-002 (00) Effective Date: December 22, 2009 Appendix 10. Mini International Neuropsychiatric Interview, Continued A. Major Depressive Episodes (♦ Means: Go to Diagnose box, circle "No in all diagnostic boxes, and move to the next one is Λ: go to two U in S.", hi big H 卞 不 t:, Xingbian or this is no better than 丨 ί · Can you enjoy the eternal love? · Is Λ1' or Λ2 coded "Yes"?

Aj has been depressed or not interested in the past two weeks: Does your appetite decrease or increase almost every day? Does your weight decrease or increase without deliberate effort (ie for 160 lb./70 kg. Individuals, within 1 month, change body weight by ±5% or ±8 lb or ±3.5 kg)? If any one is met, the code is "Yes". Do you have sleep disorders almost every night (difficult to fall asleep, wake up at midnight, wake up too early or sleep too much)? 'Do you speak or move slower than usual, or are you almost irritated, restless, or difficult to sit still? Are you feeling tired or not energized almost every day? Do you feel worthless or guilty almost every day? Are you hard to concentrate or make decisions almost every day? Do you think about hurting yourself, want to commit suicide or hope that you are dead? * Yes Yes 氺 Yes Yes Is there 5 or more answers (A1_A3) coded as "Yes"? No No No No Yes Yes Yes Yes Severe Suppressed Attacks Currently: 3⁄4 patients currently have a major depressive episode, continue to A4, otherwise move to question group b A4 a During your life, you have two weeks or longer Other times I feel depressed or not interested in most things, and have most of the questions I just talked about. Have you had any depression and any loss of interest at least 2 months between the two depressive episodes? Yes No Yes Major depressive episodes Recurrence * If the patient currently has a major depressive episode, code "yes" on the corresponding question on page 5. M.I.N.I. 5.0.0 (July 1, 2003) 4 Confidential -124.

Targacept Company 163062.doc 201244717 (l^RGACEPT PR〇〇5619_CRD-〇〇2(〇〇) Effective Date: December 22, 2009 Appendix 10· Mini International Neuropsychiatric Interview, Continued Major Depressive Episodes with Depression Characteristics (Optional) ^ means: go to the diagnosis box, circle "No", and move to the next-question group) for Lang (5) = foot), the daughter said to the factory that several households have the winter ability? Temporary; Is A5a or A5b coded "Yes"? If today: When something good happens, can't you feel better? Or is it A6? In the past two weeks, when you feel hip and have no interest: a. You feel depressed and the person close to you. Is the feeling you experienced when you die, is b different? *f small almost mother-in-law always feel unhappy in the morning? No Yes C You are almost every day than you can do with _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Is the A3C code "Yes" (mental exercise retardation or excitement)? No Yes e For anorexia or weight loss, No Yes f Do you feel excessive guilt or guilt that is not commensurate with the actual situation? Is there a 3 or more A6 answer coded as "Yes"? 7 No is a severe depressive episode with a symptom of anxiety. Currently, Ι.Ν.Ι· 5_0·0 (July 1, 2003) 5 Confidential-125-

Targacept Company 163062.doc 201244717 (f^RGACEPT PRO'05619'CRD'002(00) Effective Date: December 22, 2009 Appendix 10. Mini International Neuropsychiatric Interview, continued B. Mild depression (♦ means: turn To the diagnosis box, circle "No" and move to the next question group). The team of the former team A and the defender of the 发作 不 不 不 此 此 此 此 此 此 此 : : : : : : : 此 此 此 此 此 此 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在Is it time to grief, depression, or depression? ^ B2 B3 B4 Is this stage interrupted for two months or more because you feel good? In this stage of depression, most of the time: a you Does your appetite change significantly? b Do you have sleep disorders or excessive sleep? c Do you feel tired or not energized? d Are you losing your confidence? e Do you have difficulty concentrating or making decisions? f Are you feeling desperate? Is 2 or more B3 answers coded as "yes"? Depressive symptoms make you very painful or at work "in the society or in some other important way to impair your ability to function? No whether or not whether or not Is the peak No, the peak is B4? "Do? 1 ^ [. 1_ from 1.5.0.0 (July 1, 2003) 6

Targacept Company 163062.doc Confidential-126- No is a mild depression at present 201244717 (f^RGACEPT PRO'05619'CRD'002(00) Effective Date: December 22, 2009 Appendix 10. Mini International Neuropsychiatric Interview, Achievement C Suicide tendency In the past month, you: Score C1 C2 C3 C4 C5 C6 Think you are better or want you to die? Want to hurt yourself? Have you ever thought about suicide? Is there a suicide plan? In your life: Have you ever committed suicide attempts? Is there at least one code for the above question as "yes"? If yes, increase the total number of points in the answer (C1-C6) and check "yes" as follows. Describe in detail the degree of suicide risk: No Yes 1 No Yes 2 No Yes 6 No Yes 10 No Yes 10 No Yes 4 No Suicide wind test · Currently 1-5 points low 0 6-9 points Medium □ More 10 points ik a MINI 5.0, 0 (July 1, 2003) 7

Targacept company secret 163062.doc - 127- 201244717 PR (10) MW collar GG) New date: Linnian 22nd month appendix 10 · Mini International Neuropsychiatric interview, continued D · (light) manic episode (► means: turn to diagnosis Box, circle "No," and move to the next question group in all diagnostic boxes.

, Dlb or f Dlb and D2b=No: Explore the most obvious episodes of past symptoms. In the time when you feel excited, energetic or irritable, you: You feel able to _ others do not _ wrong, silk you are important copper Ξΐΐΐΐί ( (For example, 'I feel energetic after only a few hours of sleep?'), 'A appears grunting, or is it too fast to make people difficult to understand? '; makes any small disturbances distract you? g Worried about you? Crazy, reckless driving or you ignore the risk or consequences (for example, spending $3^ more D3 answers coded as "when going to attack" or if (10) silk (in assessing the current episode of MINI 5.0.0 (2003^-7^ la) 8

C No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes

Targacept Company 163062.doc Confidential-128- 201244717 (f^RGACEPT PRO_05619'CRD"002(00) Effective Date: December 22, 2009 Appendix 10. Mini International Neuropsychiatric Interview, Continued No 1 1 □ □ More Manic episodes D4 These symptoms last for at least a week and cause significant problems at home, at work, in the community, or at school, or are you hospitalized for these problems? Discovered as: D4 coded as "No Details? The episode is current or past. Is the D4 code "Yes"? Details the current or past episode. MINI 5.0.0 (July 1, 2003) 9

Targacept Confidential 163062.doc - 129- No Yes Manic episodes Currently □ Over "Ϊ· □ No Yes Manic episodes Currently α over □ 201244717

(T^RGACEPT PRO-05619-CRD-〇〇2(〇〇) Effective Date: December 22, 2009 Appendix 10. Mini International Neuropsychiatric Interview, continued E. Panic disorder (♦ means: at E5, E6 Circle "No" in E7 and jump to FI) μ X ^1"'............................... ............................... ^ 糊一音1 任任—Time 'These attacks (spell or attack) have Does any occurrence occur in a mode or in an unpredictable or unreasonable manner? Otherwise 过 3 times - such episodes, after 1 month or more, there is always a recurrence of ten whites, or fear of a seizure Ε4, the most severe episode you remember: t Heart leak, rapid heartbeat or heart beat? b Have you ever sweated or wet hands? c Do you tremble or tremble? d You breathe or breathe Is it difficult? e You are angry. Do you feel more or swallow? f Have you had chest pain, pressure or discomfort? f 嗔?, stomach upset or overfill? i Unstable ' dizziness or fainting? No Is it strange, unreal, detached or unfamiliar? Or are you not afraid that you will die? Tingling or numbness in it? In case of hot flashes or chills it? More E4m coded as "yes" right? No fine was

Yes No No No No No No No No E5 E6 E7 m No No No No ^ Is there any E4 answer coded as "Yes"? Then jump to F1. If the attack occurs (2 or more times) and Μ·Ι.Ν.Ι·5·0·() (July 1, 2003) 10 No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Is panic disorder life is limited symptoms episodes are life-threatening panic disorder

Targacept Company 163062.doc Confidential -130- PRO-05619-CRD-002(00) 201244717

c iakuACEPT Effective period: December 22, 2009 Appendix 10. Mini International Neuropsychiatric interview, continued F. Market fears - Standing into. Smoke: 3⁄4 minus

If F1=N0, circle "No" in F2. F2 Are you so afraid of these situations that you evade these situations, or have you survived these situations, or do you need your peers to face them? Market Fears Currently F2 (Current Market Fear) is coded as "No" and E7 (Current Panic) is coded as "Yes"? F2 (Current Market Fear) is coded as "Yes" and E7 (Current Panic) is coded as "Yes"? F2 (Current Market Fear) is coded as "Yes" and E5 (Lifetime Panic) is coded as "No"? ^1 and 1.5.0.0 (July 1, 2003)11 No Yes Phobias No market fears Currently No Yes Panic disorder Market fears ‘Current no Yes Market fear, no history of panic disorder

Targacept Confidential 163062.doc - 131 - 201244717 (T^RGACEPT PR〇-〇5619-CRD-〇02W Effective Date: _ December 22, Appendix ίο. Mini International Neuropsychiatric Interview, Continued G Social Fear (Social anxiety)

G2 Is this fear excessive or unreasonable? No Yes G3 Are you so afraid of these situations that you evade these situations or have passed through these situations? no Yes

G 4 Does this fear make you work or socially confusing or make you very painful? From 1.>1.1 '5.0_0 (July 1, 2003) 12 Confidential -132-

Targacept Company 163062.doc 201244717 CrMGACEPT PRO'05619-crd-〇〇2(〇〇) Effective Date: December 22, 2009 Appendix 10. MINI International Neuropsychiatric Interview, performance H. Obsessive-compulsive disorder _ (· above and Means: Go to the diagnosis, circle "No", and move to the next question group) ΰ去1 月月中' often ^zy\; -u~~ Qiao, interference, a person, ...f · iviVA'『]+3⁄4气气气,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , or fear or fascination · ' 〇 j. 馋冇 馋冇 艾 艾 也 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、灼 汴 汴 吱 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ Want to get green -..... τ ;~; :~:------- - , ', - _______________________

HI 112 - even if you are diligent, t, slightly τ£, starting #钱念%?-

The concept of obstination such as H3 is due to your own thoughts and it is not the outside of the positive $ to |4 ΐ -., f>; ρ, ί, , -c. p ]► ij « ^<.1t-fbiK hi "ii Λ I H5 H6 H3^H4 is coded as "Yes"? ^-二乂'' ---- Do you admit that such strong ideas or such compulsive behaviors are unreasonable? Forced or forced behavior significantly interferes with your daily work, job!; force this, daily social activities or contact, or its daily occupation exceeds Ά Ι.Ι.Ν·Ι_ 5·0.0 (July 1, 2003) 13

Targacept Company 163062.doc Confidential -133- ~~~-

201244717 (ThRGACEPT PR〇-05619-CRD-002 (00) Effective Date: December 22, 2009 Appendix 10. Mini International Neuropsychiatric Interview, continued I. Post-traumatic stress disorder (optional) ____ (♦ means: Go to the diagnostic box and circle "Φ Rr Ding -. IS Guan Yu, 12' ν-, 'Λ Your reaction with strong maternal fear: no help, disgust?, - Thieves along the f, Shao, strong (d) ~ In the past month, f----- Have you escaped thinking or talking about the incident? You have escaped to remind you of this: ί; the activity, place or person you have difficulty remembering what happened An important part? ...· Have you become less interested in hobbies or social activities? Do you feel separated or alienated from others? Do you notice that your feelings become numb? You feel that your life will be shortened or you Will there be 3 or more 14 answers than others? If yes, Λ·. No is 13 abcd No No No No No No No Yes Yes Yes Yes Yes 15 ab 16 In the past Η Gu Yuezhong: Do you have difficulty sleeping? Are you particularly irritable or have you ever experienced anger? Are you hard to concentrate? You Are you nervous or always on the police? Are you frightened? Is there 2 or more 15 answers coded as "Yes"? Significant interference with your work or Μ_Ι·Ν_Ι· 5.0.0 (July 1, 2003) no Yes

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201244717 (MRGACE/T PR〇_〇5619'CRD-〇02(00) Effective date: December 22, 2009

Appendix 10. MINI International Neuropsychiatric Interview, continued J. Alcohol abuse and dependence (♦ means: go to the diagnostic box, circle in two diagnostic boxes -Uli^ ^ιι1",Τ[|^Τ·ΓΤ^ ,ΐ·Ιίϊ1ΠΓιΤ,' 11 III III I ι·ι II ί 11 ii— , fcM

J2 In the past 12 months, do you need to drink more wine to get the same effect as when you first started drinking? No 汗 Is it caused by sweat? During your drinking, did you drink more at the end than planned at the beginning? No, have you tried to reduce or stop drinking but failed? In the days of 7 a 6 mS9, you spend a lot of time getting wine, drinking or self-drinking. Otherwise, you spend less time because of I wine. Work, enjoy hobbies or get along with others? No Yes g Even if you know that drinking will make your health or mental problems continue to drink? No Yes There are 3 or more J2 answer codes as "Yes? H SS is used in the middle of the circle _ and moves to the next b

J3 is in the past 12 months: u (only when the problem is caused by coding ϋ ??? (such as driving, riding a motorcycle, using machinery, Ge, ι is C, you have been drinking because of the time - the second ▲Do you have legal questions (such as detention or nuisance)? Is it d that you continue to drink even if you have problems with your family or other people? Is there one or more J3 answers coded as "Yes"? MINI 5.0.0 (July 1, 2003) 15

Tafgacept Company 163062.doc Confidential-135 - No N/A is Alcohol Abuse Current 201244717 (l^lRGACEPT PR〇'05619'CRD'002(°〇) Effective Date: December 22, 2009 Appendix 10. Mini International Neuropsychology Section interview, continuation, establishment of alcoholism, substance abuse, and abuse of the mouth. #巧.^率ed eed)", crystal 甲安 (cryStai meth), "happy water (rush)", dexamethasone (Dexedrine) Ritalin, diet pills. fpieSr"a:ne): direct nasal inhalation, intravenous injection, free base: Creck, "fast ball Yanxixin: tH (l^roin), morphine, (morphine), dihydrogen. (Dilaudid), Hong film SPmni]: 矣沙 deleting methadone), codeine (codeine), after the test

Jerc^dan) ^ Erbai (D^v〇n), OxyContin (〇xyC〇ntin). Thai P' fans ii? (a?d) / ), mescaline (mescaline), Pey〇te, Qiao ("天(吏^^ngelipust:»", "peacepm" "), Umbrella 簟', ST?, Psychedelic mushroom (mUShr〇〇mS) J, Ecstasy (eCStaSy), MDA or rival %te) "",: 乙乙烧, nitrous oxide ("笑气 ( Iau ale (4)"], isoamyl or butyl nitrate ("P叩per"). & 6 λ out of Marijuana): J-degree marijuana (hashishX "hash"), THC, "pot", "weed", "marijuana cigarette (both (four)". Agent * * sleep ^ ^ aalude), sicabarbital (Seconal, "red (red)"), two Nitrogen galmm) ', Librium, fatty algae (eight plus (10)), sleep more: barbiturate salt, Milton (Miltown) ° test miscellaneous 1 most expensive, medicine or weight loss Medicine, GHB. Any other drugs? Use only one drug/drug type Check box 1 Only the most used drug types are studied. ^ ^ Each drug type used for independent examination (photocopying K2 & K3 as needed) mouth b 5 read ^? Wei Xu? The substance gamma' detailed description will be explored in the following discussion: the use of the drug / Κ2 i and the name of the miscellaneous / drug _ class: a name of the species) to obtain or not is '铋鍫: 锱所| Is the medicine fF33壬• Anxiety: Is it irritating 2?# If it meets the requirements of the record) or makes you feel better? : When the quantity of the substance is the name of „, is it OK? 4f force is reduced or stopped (the name of the drug/drug type) but the value is e 1 (3⁄43⁄43⁄43⁄43⁄4 thing, you will be MINI if you are a lot of time) 5·〇·〇(2〇〇&July music^Do you want to recover or think about drugs? Confidential-136·

Targacept Company 163062.doc PRO-05619-CRD-002(00) 201244717

(TARGACEPT Effective Period: December 22, 2009 Appendix 10. Mini International Neuropsychiatric Interview, Continued f You spend less time working, enjoying hobbies or being with your family or friends because of medications? (the name of the selected drug/drug type) makes your health or spirit appear.

Question, do you continue to use the drug? Is there 3 or more K2 answers encoded as "yes"? Explain the drug in detail: _ Consider the use of (the name of the selected drug type) in the past 12 months: K3 a When you have other responsibilities at school, at work or at home, you have been more than once Intoxicated, excited or hangover because of the name of the selected drug/drug type? Does this cause any problems? (Coded as "Yes" only if this causes problems.) b You are in any situation where the body is at risk (for example, driving, riding a motorcycle, using a machine, or boating, etc.) (Selected drug/drug type) The name) and excited or intoxicated more than once? c Have you ever caused legal problems (such as detention or nuisance) because of the use of drugs more than once? d Even if the name of the selected drug/drug type causes problems with your family or other people, do you continue to use the drug? Yes Material Dependence Is there currently one or more K3 answers coded as "yes"? Detailed description of the drug: M.I.N.I. 5.0.0 (July 1, 2003) 17 Confidential • 137-

Targacept Company 163062.doc

201244717(J^RGACEPT PRQ-05619-CRD-002(00) Effective Date: December 2009 & 曰 Appendix 10. Mini International Neuropsychiatric Interview, continued L. Examples of each question in which the psychiatric inquiry answers are positive. It is only coded as "yes" when these examples clearly show that the thoughts or saltiness are culturally uncomfortable. Before the coding, the study of delusions can be definite or different. If it is obviously unbelievable, it is incomprehensible and cannot Ordinary life experiences are i.., prostitutes want to blame LI a If there is a voice commenting on the individual's thoughts or behaviors, or having two or more voices talking to each other, the hallucinations are called "weird." ° Now I will You ask about unusual experiences about some people. Have you ever believed that someone is monitoring you, or someone is planning to oppose you, or want to hurt you? Note: Ask an instance to rule out the real tracking. If it is: You believe it now |Things? No b L2 ab L3 ab L4 ab L5 ab L6 a S? You are reading your mind or can hear your thoughts, or can you truly read someone’s thinking or hear what others are thinking What? If it is: Do you currently believe in such things? No S'SilSirS Something in your body will not be your own idea, or will you act in an unusual way? You felt that you were controlled Trampoline Physician: Ask for an example and don't count for anything that is not psychotic. If yes, do you currently believe in such things? No TV, radio or newspaper sends you a special message or a person you don't know yourself. Are you particularly interested in it? If yes, do you currently believe in such things? No, do you think that any of your beliefs are strange or unusual? No. Only in these case studies L1 to L4 are not explored? The code is r, for example, body or religion, 妄 妄 、 妒妄 妒妄 妒妄 妒妄 妒妄 妒妄 妒妄 妒妄 妒妄 妒妄 妒妄 妄 妄 妄 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁 萁? No, the answer to the following question is ", the illusion was rated as "the thought or behavior of the strange snow fiSfSSSSIf or you heard two or one if you have heard of it in the past ί months? No Μ.Ι.Ν.Ι. 5. 0.0 (2003^7^ 1 a) 18 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Targacept Company 163062.doc Confidential-138- 2〇124ff^EPT _Inquiry Effective Date: Recommended Year (D) Day Appendix 10. Mini International Neuropsychiatric Interview, Continued No Whether it is L7 a When waking up, there is illusion or you See things that others can't see? • Clinician: Check to see if these things are culturally appropriate. b If yes, have you seen such things in the past month? Judgment by Clinicians Is L8 b patient currently showing unorganized, deconstructed language or significant association relaxation? Does L9 b patient currently exhibit deconstruction or stiffness behavior? U°b SSsStS repeatedly or no

L11 or more "b» questions are coded as "yes, weird"? More <&lt;b&gt;&gt; questions are coded as "yes" (rather than "yes, blame JJ horse / L12 $1 or more "a» question coded as "yes, weird")? ? l) 2, Af multiple &lt;&lt;a&gt;&gt; The problem is compiled as "Yes" (not "Yes, blame SfiiH pan? Time depends on "occurrence. LI3a | Heavy 4 more and more (Win 1啦71^》_Zhu Ma is "Yes" and just stated the beliefs and experiences "Easy Voice". Is it only for you to feel "depressed/excited/irritated time?"

Ψι%% Sexual Disorders Μ.Ι.Ν.Ι· 5.0.0 (July 1, 2003) 1919

201244717 (T^lRGACEPT PRO'05619'CRD'002(00) Effective period: December 22, 2009 附录 Appendix 10. Mini International Neuropsychiatric Interview, Continued M. Anorexia nervosa

In the past 3 months: No M2 M3 M4 M5 M6 Luxury No Yes Peak No Yes No Yes No Yes No Yes Peak No Yes No Yes Despite this low weight, are you still trying not to gain weight? Even if you are underweight, are you afraid of gaining weight or getting fat? a Do you think you are obese or a part of your body is too fat? b Does your weight or body significantly affect how you feel about yourself? c Do you think your current low weight is normal or excessive? Is there 1 or more items from M4 coded as "Yes"? For women only: During the past 3 months, no menstruation occurred when menstruation was expected (when you were not pregnant)?

For women: Is the M5 and M6 coded "Yes"? For men: Is the M5 code "yes"? Table height/weight threshold (no shoes height; no clothing weight) Female height (Zhao Chongxi λ 2b« 94 143 38 氺10 95 147 39 411 t6 150 39 192 40 51 S9 41 53⁄4 n 138 42 n 160 43 54 97 says 59 antelope 165 43 V6 m ια 46 yj 104 170 47 59 m xn 49 39 1 cut ITS 50 no 112 17« 31 male height / body complex ftr» 5*1 53⁄4 ft 33⁄4 Ϋ7 JTI 510 3*11 CO si Tn ¢3 na 103 1IK 1C8 no ui ΙΌ 115 U€ 119 mm ns 127 130 in et&amp; 135 13« 1仞m 1 (5 m 170 173 173 mmm M mm hi* 47 4« 49 59 n 31 32 S3 54 S3 H 57 H 59 61 As stated by DSM-IV, the above-mentioned body weight threshold is calculated as the patient's height and sex are reduced by I5% from the normal range. This table reflects the normal distribution range in the MetLife Insurance Weight Scale. The lower limit is 15% lower. _ MINI 5.0.0 (July 1, 2003) 20

Targacept Confidential 163062.doc - 140 - 20124SLePT — Effective Date: Recommendation Date 22 Appendix 10 Mini International Neuropsychiatric Interview, continued N. Neurological bulimia (♦ means: go to the diagnostic box, in all diagnostic boxes Circle "No" and move to the next question group)

No Yes N4 Have you done anything to compensate or prevent weight gain due to such binge eating, such as vomiting, fasting, exercise or taking laxatives, enema, diuretics (fluid pills) or other medications? • No Yes N5 Does your weight or body significantly affect how you feel about yourself? • No Yes Is the symptom of N6 patient consistent with the criteria for anorexia nervosa? No 丄 Yes Jump to N8 N7 These gluttons only happen when you are below i lb/ks)? No Yes Interviewer: The weight limit for the height of the patient in the height/weight table of the anorexia nervosa group in the above brackets. Is it a neurological bulimia? Is N8 N5 coded as "yes" and N7 is "No" or skipped? Is N7 coded "yes"? No is anorexia eclipse eclipse/clear type MINI 5.0.0 (July 1, 2003) 21

Targacept Confidential 163062.doc - 141 - 201244717 (T^lRGACEPT PRO_05619&quot;CRD_002(00) Effective Date: December 22, 2009 曰Appendix 10. Mini International Neuropsychiatric Interview, Continued. Generalized Anxiety Disorder (♦ : Arrive at the diagnosis box and circle "No I and Jiang Xia---

03 No Yes No Yes No Yes No Yes No Yes No Yes No Yes gsssmif I,. Exploring before this point in time f In the past 6 months, when you were anxious, most of you felt uneasy, excited or upset? Are you nervous? Feeling tired, weak or exhausted? Is it difficult to concentrate or find out? (Is it difficult to call __, __ too much)? Is there 3 or more 03 answers coded as "Yes"? Extensive* disease confidentiality-142-

Μ·Ι·Ν'Ι. 5·0.〇ρ〇〇3年July 1 曰)22 T Targacept Company 163062,doc 201244717(Wrgacept PRO-05619-CRD-002(00) Effective Date: December 2009 Month 22 曰P1 P2 Appendix 10. Mini International Neuropsychiatric Interview, continued P. Antisocial Personality Disorder (optional) (♦ means: Go to the diagnostic box and circle “No”.) Before you were 15 years old, You: a. Repeatedly skipping school or running away from home for the night? b Repeat to lie, deceive, "cheat" other people or steal? c Start fighting or bullying, threatening or intimidating others? d Deliberately destroy or start arson? Deliberately hurt animals or people? fForcing someone to have sex with you? Is there 2 or more P1 answers coded as "yes"? If the following behavior is only political or religious, it is not coded as "Yes" Since you were 15 years old, you have: a repeated behaviors that others would consider irresponsible, such as not paying for payment, intentional # intentional or deliberate not working, including, b Arrested (_ 'destroy property, store c repeatedly involved in physical struggles (including with spouse Child physical struggle)? d Feng Nian Punish? * "Edit" other people to get money or fun, or simply because of fun and micro-building / e. Make others exposed to danger and indifferent? After saying or stealing other people, or not feeling that 3 or more P2 questions are coded as "yes" after damage to the property? No whether i is whether or not it is

Talking about this end Μ.Ι·Ν_Ι_ 5.0.0 (July 1, 2003) 23

Targacept Company 163062.doc Confidential-143- 201244717 (^RGACEPT PR〇-〇5619 CRD_〇〇2(〇〇) Effective Date: December 22, 2009 Appendix ίο. Mini International Neuropsychiatric Interview, Continued References Tebfatviifv and Z|U){Ac^r4b|te6tiaM· Beep·· fcytiteby. 19»7i mw,m· XMubi«T#a^MAIV«a)«rl»AflMrfAP&gt;BMM»iaiateoX,ter«lrlMtfa IkMNftMMtMltanpfHMitenU»

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Targacept Company I63062.doc 201244717

(TMGACEPT PRO-05619-CRD-002(00) Effective Date: December 22, 2009 Appendix 11. Signed and Dated Trial Host Agreement Agreement Page

Targacept Confidential 163062.doc -145- 201244717 Main results measure (Connor adult ADHD scale test host [CAARS plus] total illusion not shown in week 4, week 8 sgo 12th week (2S, 3R )-N-(2-((3-Tangyl)methyl M•heterobicyclo[2 2 2]octyl)-benzofuran-2-decylamine or a pharmaceutically acceptable salt thereof Statistically significant benefit (Ρ&lt;〇·1〇); and therefore the study did not meet the pre-defined success criteria. However, CAARS-Inv showed support (2S 3R)-N (2 (3 〇) at week 1 Specific benefit of thiol)-1-azabicyclo[2.2.2]octyl-3-yl) benzofuran-2-imamide or its pharmaceutically acceptable salt (p=〇0191) 〇in the secondary result measure, (2S,3R)-N-(2-((3-)-pyridyl)methyl)-azabicyclo[2 2 2]octyl)benzofuran -2-carboxamide or a pharmaceutically acceptable salt thereof showed statistically significant benefits at different times on the following scale: CAARS-Inv Hyperactivity-Impact Scale 'CAARS-Subject (CAARS-S) ADHD Index , over-movement scale, attention deficit scale, and self-concept problem scale; CogState ADHD Objective measures in the test [CATB: Stop signal reaction time (behavioral inhibition test), Groton labyrinth learning test (GMLT), test task (psychological action history test) and international shopping list task (Chinese learning test overall clinical overall impression ( CGI), CGI-Severity (CGI-S) and CGI-Improvement (CGI-Ι) scales; and behavioral items, on anger-hostility and confusion-confused emotional condition scale (POMS). In the post-analysis, it was found that attention deficit (n=30) not only drives the support of (2S,3R)-N-(2-((3-)pyridyl)indolyl)-1-azabicyclo[2.2 .2] a significant benefit of oct-3-yl)benzofuran-2-carbamide or a pharmaceutically acceptable salt thereof, and also a significant improvement in the CAARS-In total score. Thus, although the primary outcome measure is at week 4 , 8th week or 12th week did not show 163062.doc -146- 201244717 shows support (2 8,3 feet)-]^-(2-((3-)-pyridyl)methyl)_1_aza Benefits of bicyclo [2.2.2] octyl-3-yl)benzofuran-2-carbamide or a pharmaceutically acceptable salt thereof, but in various CAARS-Inv and CAARS-S scales, CATB projects, CGI- S, CGI- The positive benefits of supporting this compound were observed in the Ι and POMS programs. And in the post hoc analysis of patients with predominantly under-focused ADHD, not only the primary outcome measure (CAARS-In total score) but also various secondary outcome measures Both support (28,311)氺-(2-((3-&quot;pyridyl)methyl))azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carbamide or its A statistically significant benefit of a pharmaceutically acceptable salt. In summary, these results indicate that (2s, 3r)_n_(2_((3_.) is more than dimethyl)-1) azabicyclo[2 2 2]octyl-3-yl) benzofuran 2 Indoleamine or a pharmaceutically acceptable salt thereof produces cognitive and clinical benefits in adults with ADHD. The results of the performance are shown in Tables 1 to 1. 163062.doc 147· 201244717 ZO0·inchε=Η* 〇 inch·be=PH*_1f : ιϊ^^ϊ舞碱令绰锑^i^^aHavAMI-sevvu:^^^^-!^ ο#, «·χ

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Claims (1)

201244717 VII. Scope of Application: 1. A method for treating ADHD comprising administering a therapeutically effective amount of (2S, 3 ana)-;^-(2-((3-0)pyridyl) fluorenyl)-1 -Azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carbamide or a pharmaceutically acceptable salt thereof. 2. A method of treating atattentive subtype ADHD comprising administering a therapeutically effective amount of (2S,3R)-N-(2-((3-pyridyl)indolyl)-1-aza Bicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof. 3. A method for improving the attention of an individual in need thereof, comprising administering a therapeutically effective amount of (2S,3R)-N-(2-((3-&quot; 咬)))))) Heterobicyclo[2.2.2]oct-3-yl)benzofurancarbamide or a pharmaceutically acceptable salt thereof. A method for treating insufficient attention comprising administering a therapeutically effective amount of (2S'3R)-N-(2-((3.pyridyl)methylbubuazabicyclo[2 2 2]xin_ a benzoyl-2-pyramine or a pharmaceutically acceptable salt thereof 5. A method of treating one or more symptoms associated with ADHD which comprises bismuth and (2S, 3R)-N- (2-((3·pyridyl)methyl)_ι_azabicyclo[2 2 2]oct-3-yl)benzofuran-2-amine or a pharmaceutically acceptable salt thereof. The method of claim 5, wherein the one or more symptoms are selected from the overall performance, hyperactivity, impulsivity, and adhd index subscales of the Conners Adult ADHD Rating Scale (CAARS) (sub- Scales). The method of claim 6 wherein the treatment provides an early effect. 8. The method of claim 5, wherein the one or more symptoms are selected from I63062.doc 201244717 A group consisting of movement, lack of attention, self-concept, anger, hostility, confusion, and bewilderment. 9. 10. 11. 12. 13. 14. 15. 16. The method of claim 8, wherein the treatment Provides continuous acne. One (2S,3R)-N-(2_((3-)-pyridyl)indolyl)-azabicyclo[2.2.2]oct-3-yl)benzofurancarbamide or A pharmaceutically acceptable salt thereof or a combination of another ct7 agonist and one or more stimulating agents for treating a combination as claimed in claim 10, wherein the ADHD is a combined attention deficit or overactive/impulsive type. -(2S,3R)-N-(2.((3.. than dimethyl)methyl)]-azabicyclo[2 2 2]oct-3-yl)benzofuran·2·decylamine Or a pharmaceutically acceptable salt thereof, or a combination of another alpha 7 agonist and one or more antidepressants, for treating ADHD. The combination of claim 12, wherein the ADHD is a combined, under-focused or Over-acting/impulsive type β (2S'3R)-N-(2_((3k))methyl)azaabicyclo[2 2 2]oct-3-yl)benzofuran-2-indole or A pharmaceutically acceptable salt thereof, or a combination of another alpha 7 agonist and one or more antihypertensive agents, for use in the treatment of ADHD. As in the combination of claim 14, wherein the ADHD is in combination with insufficient attention or Dynamic/impulsive type. Species (2S, 3R)-N-(2_ ((3_n ratio) methyl) small azabicyclo[2 2 2]oct-3-yl)benzofuran-2·carbamamine or a pharmaceutically acceptable salt thereof, or another α7 agonist Combination of one or more irritants, one or more antidepressants I63062.doc 201244717, and one or more antihypertensive agents for the treatment of combined, underpowered or overactive/impulsive ADHD. 17. —(2S,3R)-N-(2-((3-Pyridyl)indolyl)azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carbamide or A combination of a pharmaceutically acceptable salt thereof and another therapeutic agent for the treatment of ADHD. I8. The combination of claim 17, wherein the ADHD is a combined, under-focused or overactive/impulsive type. 163062.doc