EA039995B1 - USE OF PRIDOPIDINE FOR THE TREATMENT OF HUNTINGTON'S DISEASE - Google Patents

Description

This application claims priority from U.S. Provisional Application No. 61/837,928, filed June 21, 2013, and U.S. Provisional Application No. 61/877,832, filed September 13, 2013, the entire contents of which are incorporated herein by reference.

Throughout this application, references to various publications are made by indicating the name of the first author and the year of publication. The full titles of these publications are given in the References section immediately before the claims. Thus, the descriptions of the publications cited in the reference section are incorporated by reference in their entirety into this application in order to more fully describe the state of the art at the time of the filing date of the invention described here.

State of the art

Huntington's disease.

Huntington's disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant mode of inheritance. The disease is characterized by a triad of motor, behavioral and cognitive symptoms. Movement disorders are the defining feature of the disease, with chorea being the most obvious movement symptom. While useful for diagnosis, chorea is a poor marker of disease severity. Rather, disability and disease severity are correlated with negative motor signs, such as impairments in fine motor skills, bradykinesia, and gross motor-coordination skills, including difficulty speaking, gait, and posture (Mahant 2003).

Dopamine is widely recognized as an important neurotransmitter that modulates several aspects of brain function, including motor function. (Nieoullon 2003). Disruption of the dopaminergic signaling pathway is implicated in a number of neurological and psychiatric diseases (Zhan 2011, Dunlop 2007), and there is a significant amount of clinical and preclinical evidence that disruption of dopaminergic functions is also observed in HD. (Kung 2007, Huot 2007).

There are a number of medications that are prescribed to improve the motor and emotional problems associated with HD; however, scientific data on the usefulness of different drugs in HD are lacking. (Mestre 2009 CD006455, Mestre 2009 CD006456). Only 1 drug, tetrabenazine, which reduces the availability and transmission of dopamine, is registered specifically for the treatment of chorea in patients with HD. There are no registered drugs for the treatment of complex motor symptoms. Thus, there is an urgent unmet need in medicine to develop drugs that can improve the symptoms of HD.

pridopidin.

Pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine) (formerly known as ACR16) is a drug under development in a new class of pharmaceuticals, dopidins, that are suspected to have dopaminergic stabilizing properties. Dopaminergic stabilizers are compounds that can either enhance or suppress dopamine-dependent functions of the central nervous system (CNS), depending on the initial level of dopaminergic activity. Dopaminergic stabilizers suppress hyperactive behavior caused by stimulants such as amphetamines. Conversely, at low levels of dopamine function, dopamine stabilizers increase behavioral activity. Thus, the main effect of pridopidine on motor symptoms associated with HD is presumably due to the ability of pridopidine to modulate dopamine transmission. (Ponten 2010).

The essence of the invention

The present invention relates to the use of a pharmaceutical composition containing pridopidine or a pharmaceutically acceptable salt thereof and a method for reducing functional impairment in a human patient suffering from Huntington's disease, wherein the composition is administered at a daily dose of 90 mg, 135 mg, 180 mg or 225 mg of pridopidine or its pharmaceutically acceptable salt and, where the reduction in impairment of functional ability is measured by the assessment of the general ability to function (TFC) in accordance with the Unified Huntington's Disease Rating Scale (UHDRS).

Brief description of the figures of the drawings

The present invention is further illustrated by means of the accompanying drawings.

Fig. 1 - the general scheme of the study of example 1.

Fig. 2 - the general scheme of the study of example 2.

Detailed description of the invention

The present invention relates to the use of a pharmaceutical composition containing pridopidine or a pharmaceutically acceptable salt thereof for the reduction of functional impairment in a human patient suffering from Huntington's disease, wherein the composition is administered in a daily dose of 90, 135, 180 or 225 mg of pridopidine or a pharmaceutically acceptable salt thereof and , where the reduction in impairment of functional ability is measured by the assessment of the general ability to function (TFC) in accordance with the uniform evaluation scale of Huntington's disease (UHDRS).

In one embodiment, the patient is administered 180 or 225 mg of pridopidin daily. In another embodiment, the patient is administered daily 135, 180 or 225 mg of pridopidine.

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In one embodiment, a single dose of the pharmaceutical composition contains 90 mg of pridopidine.

The present invention also relates to a method for reducing functional impairment in a human patient suffering from Huntington's disease, where the method comprises administering a pharmaceutical composition containing pridopidine or a pharmaceutically acceptable salt thereof to said human patient, where the composition is administered at a daily dose of 90, 135, 180 or 225 mg of pridopidine, or a pharmaceutically acceptable salt thereof, and where the reduction in functional impairment is measured by the Huntington's Disease Uniform Assessment Scale (UHDRS) General Functioning Assessment (TFC).

In one of the embodiments of the methods of the present invention, the pharmaceutical composition is administered twice a day.

In one of the embodiments of the methods of the present invention, an equal amount of the pharmaceutical composition is administered at each dose.

In one embodiment of the methods of the present invention, the pharmaceutical composition is administered for at least 12 weeks. In another embodiment of the methods of the present invention, the pharmaceutical composition is administered for at least 26 weeks.

In one embodiment, the methods of the present invention, treatment includes the reduction of one or more symptoms of Huntington's disease. In one embodiment, one or more symptoms are selected from the group consisting of depression, anxiety, impaired motor function, cognitive impairment, physical symptom, mental symptom, emotional symptom, behavioral symptom, impairment of the patient's functional state, and reduced life expectancy.

In one embodiment, the Huntington's Disease Unified Rating Scale (TFC), Huntington's Disease Unified Rating Scale (UHDRS) Independence Score (IS) is used to measure one or more symptoms.

In one embodiment, the methods of the present invention, the treatment includes improving the symptoms of motor impairment in the patient, which is measured using the general assessment of motor ability (TMS) in accordance with the Huntington's disease uniform rating scale (UHDRS).

In one embodiment, the methods of the present invention, the treatment includes improving the patient's symptoms of motor impairment, as measured using the Huntington's Disease Uniform Rating Scale (UHDRS) chorea score.

In one embodiment, the methods of the present invention, the treatment includes improving the patient's symptoms of motor impairment, as measured using the Huntington's Disease Uniform Rating Scale (UHDRS) dystonia score.

In one of the embodiments of the methods of the present invention, the age of the patient is at least 21 years. In another embodiment of the methods of the present invention, the age of the patient is less than 30 years.

In one embodiment, the methods further include the step of determining if the patient is indeed at least 21 years of age and the step of periodically oral administration of the pharmaceutical composition to the patient if the patient is at least 21 years of age. In another embodiment, the methods further include the step of determining if the patient is indeed less than 30 years of age and the step of periodically oral administration of the pharmaceutical composition to the patient if the patient is less than 30 years of age.

In one embodiment, the methods further include the step of determining if the patient is indeed at least 21 years old and less than 30 years old, and the step of periodically oral administration of the pharmaceutical composition to the patient if the patient is at least 21 years old and less than 30 years old.

In one embodiment of the methods of the present invention, the patient has a UHDRS-TMS score of >25 before starting treatment.

In one embodiment of the methods of the present invention, the patient has an UHDRS-IS below 90% before starting treatment.

In one embodiment of the methods of the present invention, the patient contains >36 CAG repeats in the huntingtin gene.

In one embodiment, pridopidine, or a pharmaceutically acceptable salt thereof, is in the form of pridopidine hydrochloride. In another embodiment, pridopidine, or a pharmaceutically acceptable salt thereof, is pridopidine hydrobromide.

In one embodiment, the pharmaceutical composition contains silicified microcrystalline cellulose and magnesium stearate as excipients.

In one embodiment, the patient is administered 180 or 225 mg of pridopidin daily.

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In one embodiment, a single dose of the pharmaceutical composition contains 90 mg of pridopidine.

In one embodiment, the patient is administered 135, 180, or 225 mg daily.

In one embodiment, a single dose of the pharmaceutical composition contains 90 mg of pridopidine.

In one embodiment, the pharmaceutical composition is for administration twice a day.

In one embodiment, the same amount of pharmaceutical composition is administered each time.

In one embodiment, the pharmaceutical composition is formally administered for at least 12 weeks. In another embodiment, the pharmaceutical composition is formally administered for at least 26 weeks.

In one embodiment, the treatment includes the reduction of one or more symptoms of Huntington's disease.

In one embodiment, one or more symptoms are selected from the group consisting of depression, anxiety, motor impairment, cognitive impairment, physical symptom, mental symptom, emotional symptom, behavioral symptom, impairment of the patient's functional ability, and reduced life expectancy.

In one embodiment, the Huntington's Disease Unified Rating Scale (TFC), Huntington's Disease Unified Rating Scale (UHDRS) Independence Score (IS) is used to measure one or more symptoms.

In one embodiment, the methods of the present invention, the treatment includes improving the symptoms of motor impairment in the patient, which is measured using the general assessment of motor ability (TMS) in accordance with the Huntington's disease uniform rating scale (UHDRS).

In one embodiment of the methods of the present invention, the treatment includes improvement in the patient's symptoms of motor impairment, as measured using the Modified Huntington's Disease Uniform Rating Scale (UHDRS) motor ability score (mMS).

In one embodiment, the methods of the present invention, the treatment includes improving the patient's symptoms of motor impairment, as measured using the Huntington's Disease Uniform Rating Scale (UHDRS) chorea score.

In one embodiment, the methods of the present invention, the treatment includes improving the patient's symptoms of motor impairment, as measured using the Huntington's Disease Uniform Rating Scale (UHDRS) dystonia score.

In one embodiment, the pharmaceutical composition is for administration to a patient who is at least 21 years of age. In another embodiment, the pharmaceutical composition is for administration to a patient who is less than 30 years of age.

In one embodiment, the pharmaceutical composition is for administration to a patient whose UHDRS-TMS score is >25 prior to treatment.

In one embodiment, the pharmaceutical composition is for administration to a patient whose UHDRS-IS score is less than 90% prior to treatment.

In one embodiment, the pharmaceutical composition is for administration to a patient in whom the number of CAG repeats in the huntingtin gene is >36.

In addition, the invention relates to the use of an amount of pridopidine or a pharmaceutically acceptable salt thereof in a process for the preparation of a medicament for the treatment of a human suffering from Huntington's disease, wherein the medicament is to be administered intermittently orally to a patient such that the patient receives more than 135 mg of pridopidine per day.

In one embodiment, the drug is for intermittent oral administration to a patient such that the patient receives 180 or 225 mg of pridopidine per day.

In one embodiment, the drug contains 90 or 112.5 mg of pridopidine.

In addition, the invention relates to the use of an amount of pridopidine hydrochloride in a process for the preparation of a medicament for the treatment of a human patient suffering from Huntington's disease, wherein the medicament is for intermittent oral administration to the patient such that the patient receives more than 90 mg of pridopidine per day.

In one embodiment, the drug is for intermittent oral administration to a patient such that the patient receives 135, 180, or 225 mg of pridopidine per day.

In one embodiment, the drug contains 67.5, 90 or 112.5 mg of pridopidine.

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In one embodiment, the drug is for administration twice a day.

In one embodiment, the treatment includes the reduction of one or more symptoms of Huntington's disease.

In one embodiment, one or more symptoms are selected from the group consisting of depression, anxiety, impaired motor function, cognitive impairment, physical symptom, mental symptom, emotional symptom, behavioral symptom, impairment of the patient's functional state, and reduced life expectancy.

In one embodiment, the Physician and Caregiver Impressions Patient Rating Scale (CIBIC-Plus), Physical Disability Rating Scale (PDS), Functioning Assessment (FA) according to the Uniform Disease Rating Scale is used to measure one or more symptoms. Huntington's Disease Rating Scale (UHDRS), Overall Clinical Impression Scale (CGI-C) change score, Huntington's Disease Unified Rating Scale (TFC), General Functioning Ability (TFC), Unified Disease Rating Scale (IS), Independence Score (IS) Huntington Scale (UHDRS), HD Quality of Life Scale (HD-QoL), Multiple Sclerosis Walking Ability Assessment (MSWS-12), Physical Performance Test (PPT), Hand Movement Assessment, Gait and Balance Assessment, Quantification motor function test (Q-Motor), stand up and walk test (TUG), test for the analysis of cognitive batteries (CAB), test for Symbol and Numeric Test (SDMT), Stroop Word Reading Test, Short Montreal Cognitive Assessment (MoCA), Path B Test, or Problem Behavior Analysis - Short Form (PBA-s). In another embodiment, one or more symptoms are measured using EQ5D-5L, Walk-12, or a modified physical performance test (mPPT).

In one embodiment, the methods of the present invention, the treatment includes improving the symptoms of motor impairment in the patient, which is measured using the general assessment of motor ability (TMS) in accordance with the Huntington's disease uniform rating scale (UHDRS).

In one embodiment of the methods of the present invention, the treatment includes improvement in the patient's symptoms of motor impairment, as measured using the Modified Huntington's Disease Uniform Rating Scale (UHDRS) motor ability score (mMS).

In one embodiment, the methods of the present invention, the treatment includes improving the patient's symptoms of motor impairment, as measured using the Huntington's Disease Uniform Rating Scale (UHDRS) chorea score.

In one embodiment, the methods of the present invention, the treatment includes improving the patient's symptoms of motor impairment, as measured using the Huntington's Disease Uniform Rating Scale (UHDRS) dystonia score.

In one embodiment, the drug is for administration to a patient who is at least 21 years of age. In another embodiment, the drug is for administration to a patient who is less than 30 years of age.

In one embodiment, the drug is for administration to a patient whose UHDRS-TMS score is >25 prior to treatment.

In one embodiment, the drug is for administration to a patient whose UHDRS-IS score is less than 90% prior to treatment.

In one embodiment, the drug is for administration to a patient in whom the number of CAG repeats in the huntingtin gene is >36.

Combinations of the above embodiments are also within the scope of the present invention.

Pharmaceutically acceptable salts.

The active compounds for use in accordance with the present invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (ie, physiologically) acceptable salts, as well as pre- or prodrug forms of the compounds of the present invention.

Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic inorganic and organic acid addition salts such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate , embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-psulfonate, etc. Such salts can be prepared using methods well known and described in the art.

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pharmaceutical compositions.

Although the compounds for use in accordance with the present invention may be administered as crude compounds, preferably the active ingredients, optionally as their physiologically acceptable salts, are administered in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical auxiliaries.

In one embodiment, the present invention provides pharmaceutical compositions comprising the active compounds, or pharmaceutically acceptable salts or derivatives thereof, along with one or more pharmaceutically acceptable carriers and optionally other therapeutic and/or prophylactic ingredients known and used in the art. The carrier(s) must be acceptable, ie. it must be compatible with the other ingredients of the composition and not adversely affect the recipient.

The pharmaceutical composition of the present invention may be administered by any convenient route that is appropriate for the therapy being used. Preferred routes of administration include oral administration, for example, in the form of a tablet, capsule, dragee, powder or liquid form, and parenteral administration, including dermal, subcutaneous, intramuscular or intravenous injections. A person skilled in the art can prepare the pharmaceutical composition of the present invention using standard methods and conventional techniques appropriate to the desired formulation. If desired, compositions having a sustained release of the active ingredient can be used.

More detailed information on how to prepare and administer the compositions can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

As used herein, the term effective, when applied to an amount effective to achieve a result, means an amount of a component that, when used in the method of the present invention, is sufficient to produce the indicated therapeutic result in the absence of undue undesirable side effects (such as toxicity, irritation, or allergic reaction) and has a reasonable benefit/risk ratio. For example, an amount effective to treat a movement disorder. The specific effective amount will vary depending on factors such as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of treatment, the nature of the concomitant therapy (if any) and the specific drugs used, as well as the structure of the compounds or their derivatives.

As used herein, the amount of pridopidine, measured in milligrams, refers to the number of milligrams of pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine) present in the formulation, regardless of the form of the formulation. For example, the expression unit dose containing 90 mg of pridopidine means that the amount of pridopidine in the preparation is 90 mg, regardless of the form of the preparation. Thus, if pridopidin is present in a salt form, such as pridopidine hydrochloride, the weight of the salt form required to provide a 90 mg dose of pridopidine will be in excess of 90 mg.

As used herein, the term treat or treat encompasses, for example, symptom reduction, inhibition, regression, or delay in the development of a disorder and/or disease. As used herein, the term inhibiting disease progression or disease complication in a subject means preventing or reducing disease progression and/or disease complication in a subject.

List of abbreviated names and definitions of terms.

The following abbreviations are used in this application: AE: adverse event; ALT: alanine aminotransferase; AR: autoregressive; Arc mRNA: cytoskeletal-associated protein messenger ribonucleic acid with regulated activity; ARH: heterogeneous autoregression; ACT: aspartate aminotransferase; AUC: area under the concentration-time curve; Bid: twice a day; BL=background line; CAB: test for the analysis of batteries of cognitive abilities; CAG: cytosinguanine-adenosine; CDMS: clinical data management system; CFR: Code of Federal Regulations; CGI-C: assessment of change on the overall clinical impression scale; CGI-S: assessment of the severity of the disease on a scale of general clinical impression; CI: confidence interval; CIBIC-Plus: a scale for assessing the patient's condition based on the impression of the doctor and caregivers; CIBIS: clinician's impression of severity based on interview; CIOMS: International Council of Medical Scientific Societies; Cmax: maximum drug concentration observed in plasma; CNS: central nervous system; CRF: individual registration card; CRO: contract research organization; CS: compound symmetry; CSH: heterogeneous compound symmetry; C-SSRS: Columbia University Suicidal Severity Scale; CYP: cytochrome P450; DSM-IV TR: Diagnostic and Statistical Manual - Fourth Edition, Revised; ECG: electrocardiogram; I eat: fast metabolizers; EU: European Union; FA: performance assessment; FAS: full sample of patients for analysis; FDA: US Food and Drug Administration; Freq: tapping frequency;

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GCP: good clinical practice; GFV-C: static phase grip force variability; GGT: gamma-glutamyl transpeptidase; HART: randomized trial of Huntington's disease ACR16; HCG: human chorionic gonadotropin; HD: Huntington's disease; HD-QoL=quality of life in Huntington's disease; ICH: International Conference on Harmonization; IEC: Independent Ethics Committee; IOI: interval between start times; IPI: interval between peaks; IRB: Institute Review Board; IRT: Interactive Randomization Technology; IS: independence score; ITI: finger strike interval; ITT: in accordance with the prescribed treatment; LSO: local security officer; MAD: multiple incremental dose; MedDRA: Regulatory Medical Dictionary; MermaiHD: ACR16 Transnational European Multicentre Huntington's Disease Study; ML: maximum likelihood; mMS: modified locomotor score; MoCA: Montreal Cognitive Assessment Scale; MS: multiple sclerosis; MSWS-12: Walking Ability Assessment in Multiple Sclerosis; MTD: maximum tolerated dose; NMDA: N-methyl-D-aspartate; NOAEL: no observed level of adverse events; PBA-s: problem behavior analysis - short form; PD: pharmacodynamic characteristics; PDS: Physical Disability Rating Scale; PK: pharmacokinetic characteristics; RM: slow metabolizer; PPT: physical performance test; Qd: once a day; Q-Motor: quantitative assessment of motor function; QoL: quality of life; QTcF: Friederick corrected QT interval; RBC: red blood cells; REML: limited maximum likelihood; SAE: serious adverse event; SD: standard deviation; SDMT: character-number matching test; SOC: class of organ systems; SOP: standard operating procedure; SUSAR: suspected unexpected serious adverse reaction; tV ₂ : half-life; TC=phone call; TD: tapping duration; TF: tapping strength; TFC: assessment of general ability to function; TMS: assessment of general motor ability; TUG: test get up and go; UHDRS: Unified Huntington's Disease Rating Scale; ULN: upper limit of normal range; US: United States of America; WBC: white blood cells; WHO: World Health Organization; WHO: World Health Organization (WHO) drug glossary; AHR: change in heart rate relative to baseline; AQTcF: change in QTcF from the original values; AAHR: placebo-adjusted change in heart rate from baseline; a placebo-controlled study of Huntington's disease; AAQTcF: Placebo-corrected change in QTcF from baseline.

Clinical researches.

Sixteen (16) clinical studies of pridopidine were conducted, including 8 studies in healthy subjects (of which 1 study was conducted in patients suffering from schizophrenia), 1 study in patients with Parkinson's disease, 2 studies in patients with schizophrenia (in including the study mentioned above) and 6 studies in patients with HD (including 1 open-label extension study). In addition, a trial of pridopidine is currently underway in Europe as part of an unregistered severe pathology program in patients with HD, and an open long-term safety study is underway in the United States of America (US) and Canada. Since May 1, 2013, 853 patients with HD have been enrolled in clinical trials of pridopidin, with 621 patients receiving pridopidin at doses ranging from 20 to 90 mg per day.

Three randomized, double-blind, placebo-controlled, parallel-group clinical trials are being conducted to investigate the efficacy and safety of pridopidine in patients with HD. The ACR16C007 study measures the efficacy of 44 mg once daily (QD) pridopidine in 58 patients. The ACR16 Huntington's Disease Randomized Trial (HART) (ACR16C009) is then planned to determine the dose-response relationship for pridopidine at 3 different daily doses (10, 22.5 and 45 mg twice daily [bid]) in 227 patients for 12 weeks of treatment. In parallel, the ACR16 Huntington's Disease (MermaiHD) (ACR16C008) Multinational European Multicentre Huntington's Disease Study (ACR16C008) is being conducted to determine the efficacy and safety of administering 45 mg once daily and twice daily for more than 26 weeks of treatment in 437 patients.

The HART study (ACR16C009) demonstrates the dose-dependent efficacy of pridopidine in the treatment of motor symptoms of HD, as measured using Modified Motor Performance Score (mMS) and Total Motor Performance Score (TMS) according to the Unified Huntington's Disease Rating Scale (UHDRS). The HART and MermaiHD studies (ACR16C008) showed a trend of 45 mg bid dose effect on mMS that did not reach the predefined significance criteria. However, the HART and MermaiHD studies showed statistically significant results for TMS. The observed effect on motor functions is consistent with the proposed mechanism of action of pridopidine. UHDRS-TMS and its subscales are used in clinical studies of the effects of other compounds on HD. An effect of 2.8 to 3 points on the UHDRS-TMS scale (compared to a baseline of

- 6 039995 34 to 43 points in the MermaiHD [ACR16C008] and HART [ACR16COO9] trials), comparable to the effect seen in the pivotal study of tetrabenazine TETPA-HD, which is the only FDA-approved treatment for symptoms of Huntington's disease (especially chorea). In addition, it is comparable to the effect expected to be achieved in other large trials of drugs aimed at alleviating the motor symptoms of HD, namely the RID-HD and TREND-HD studies:

The pivotal study of tetrabenazine (103004/TETRA-HD), the only FDA-approved treatment for symptoms of HD (especially chorea), shows an improvement with a borderline significance of 3.3 points on the UHDRS-TMS scale ( p=0.075; baseline 45 to 47 points). The improvement caused by the administration of tetrabenazine is entirely attributable to the improvement in chorea, and no significant effect on other motor functions is observed. The study was undertaken to find a 2.7 point improvement in overall chorea score (constituting chorea elements on the TMS scale) and a neutral effect on other UHDRS-TMS elements. (Huntington's Disease Research Group 2006).

The riluzole RID-HD study is expected to find an effect of the same magnitude (2.8 points on the total scale of chorea). (Huntington's Disease Research Group 2003).

The TREND-HD ethyl eucosapentaenoic acid study uses a modified version of UHDRS-TMS (TMC-4 covering chorea, dystonia, and visual tracking) as the primary endpoint. The study is undertaken to detect an effect of magnitude from 2.7 to 3.2 (depending on the length of the repeat of the cytosine-adenosine-guanine [CAG]). (Huntington's Disease Research Group 2008).

In placebo-controlled trials of pridopidine (ACR16C007, MermaiHD [ACR16C008] and HART [ACR16C009]), the most common adverse events (AEs) in patients with HD are falling, diarrhea, nausea, nasopharyngitis, and Huntington's chorea. Pridopidin is generally well tolerated and has an AE profile similar to placebo. Apart from a transient increase in pulse rate and plasma prolactin levels, no clinically significant changes or trends in vital signs and/or laboratory parameters are observed. Analysis of the electrocardiogram (ECG), including the analysis of repolarization of cardiac cells, demonstrates the absence of a clinically significant effect of pridopidine on the ECG in patients with HD. Overall, the rates of AE and serious adverse events (SAE) were similar in the placebo group (58.6% vs. 5.2%) and in the pooled active group (61.2% vs. 4.9%). The percentages of patients who discontinued therapy were also similar in the placebo group and in the active drug group (8.2 and 9.2%). Four patients experienced AE with a fatal outcome; 2 patients received placebo and 2 patients received pridopidine. The lethal outcome among patients receiving pridopidine is assessed as not related to the study drug.

Long-term safety is being analyzed in 2 open supplementary studies (completed ACR16C008-OLP and ongoing ACR16C015-open HART). In general, safety profiles in open label supplementary studies are similar to those observed in previous randomized placebo-controlled trials of pridopidine. To date (June 2013), 5 deaths have been reported in open-label MermaiHD and HART supplementary studies. Deaths among patients receiving pridopidine are considered non-pridopidine related (subarachnoid hemorrhage, urosepsis, completed suicide, aspiration pneumonia, death of unknown cause, and myocardial infarction).

Clinical pharmacological studies.

Pridopidin is relatively rapidly and almost completely absorbed after oral administration, with the individual maximum concentration (Cmax) being reached in the range of 0.5 to 4 hours after administration (average 1.25 to 2 hours). Food intake does not affect the degree of absorption of pridopidine.

After absorption, pridopidine is eliminated partly in the urine and partly by hepatic metabolism (mainly via the cytochrome P450 [CYP] 2D6 pathway), with an average half-life (t ¹ / ₂ ) of approximately 10 hours at steady state. Among the rapid metabolizers (EMs), pridopidine is metabolized by CYP2D6 to 1 major metabolite (TV-45065, formerly known as ACR30); the contribution of other enzymatic pathways does not appear to be significant. Conversely, slow metabolizers (PM) are involved in renal excretion as the main route of elimination.

In special PK studies, Cmax and AUC values are determined, which, after administration of a single dose of bid, are approximately 1.6 and 2.8 times higher for RM than for EM, respectively. However, at steady state, this difference decreases to 1.3 for both Cmax and AUC. The population PK model confirms that due to autoinhibition of CYP2D6 in an EM-mediated mechanism, the clearance values by EM and PM approach each other at steady state, however, they still differ significantly (9.22 l/h or 6.30 l/h at typical EM or PM individual weighing 60 kg). Due to this auto-inhibition of CYP2D6, the proportion of the metabolized compound decreases after multiple doses and renal elimination becomes a more important mechanism than the polymorphic metabolism of CYP2D6. Renal clearance of pridopidine at steady state varies from 90 to 116 ml/min, which also corresponds to the glomerular filtration rate.

In special PK studies, Cmax and AUC values are determined, which, after administration of a single dose of bid, are approximately 1.6 and 2.8 times higher for RM than for EM, respectively. However, at steady state, this difference decreases to 1.3 for both Cmax and AUC.

The population PK model confirms that due to autoinhibition of CYP2D6 in an EM-mediated mechanism, the clearance values by EM and PM approach each other at steady state, however, they still differ significantly (9.22 or 6.30 l/h in a typical EM or RM-individual with a body weight of 60 kg). (Study population 2012). Due to this auto-inhibition of CYP2D6, the proportion of the metabolized compound decreases after multiple doses and renal elimination becomes a more important mechanism than the polymorphic metabolism of CYP2D6. Renal clearance of pridopidine at steady state ranges from 90 to 116 ml/min, which also corresponds to the glomerular filtration rate.

In a multiple incremental dose (MAD) study (ACR16C018), the tolerability and safety of pridopidine administered at a dose of 45 to 90 mg bid for 9 days was determined in 36 healthy subjects. The safety profile of pridopidine in the 45 and 67.5 mg bid dose groups is similar to that observed in larger clinical trials. In general, the most common AEs belong to the systemic and organ damage (SOC) classes, which include nervous system disorders, gastrointestinal disorders, and psychiatric disorders. Mental symptoms and signs such as nightmare, aggression, depressed mood, anxiety and sleep disturbances are only reported at the 90 mg bid dose level and are all considered treatment related. The incidence of dizziness increases markedly with increasing dose of pridopidine (50 and 35% in the groups of individuals receiving 90 and 67.5 mg bid, respectively, compared with 11 and 14% in the groups receiving 45 mg bid and placebo, respectively). In a multiple incremental dose (MAD) study, a dose of 90 mg bid is considered the maximum tolerated dose (MTD).

The effect of pridopidine on QT interval duration, which may be of clinical significance, is observed in healthy subjects. The results of the ACR16C018 study demonstrate a dose-dependent increase in Friederick-corrected QT interval (QTcF), with a mean placebo-adjusted change at day 9 from baseline in QTcF (AAQTcF) of up to 24.8 ms in the 90 mg bid dose group observed 1 hour after receiving the morning dose of the study drug, which corresponds to the time required to reach Cmax.

After repeated administration of 45, 67.5 and 90 mg bid to healthy subjects, it can be seen that the area under the curve (AUC), concentration-time and Cmax are proportional to the dose. Information on higher doses is not available, but linear pharmacokinetics (PK) are expected due to the low probability of absorption saturation upon oral administration (mean 98% absolute bioavailability) and the low probability of the main route of elimination at steady state (passive renal excretion of unchanged drug).

In a study in healthy volunteers with mild or moderate renal insufficiency, it was shown that mild renal insufficiency does not affect the pharmacokinetics of pridopidine at steady state; however, individuals with moderate renal insufficiency exhibit higher AUC and Cmax at steady state than healthy individuals. Studies in patients with liver failure have not been conducted, and RM represents the worst-case scenario for liver failure.

Pridopidine is a CYP2D6 substrate and therefore PK interactions with drugs that inhibit CYP2D6 can be expected, although not more than expected from RM. Since pridopidine is also a strong inhibitor of CYP2D6, drug-drug interactions with co-administered CYP2D6 substrates may be expected.

Medicines and doses.

The MermaiHD (ACR16C008) and HART (ACR16C009) studies demonstrate that the pridopidine 45 mg bid dose is associated with an improvement in UHDRS-TMS (approximately 3 points compared to placebo) and its motor subscales, in the absence of worsening of other disease features (cognition, behavior and performance). However, by defining functional and global criteria, it cannot be shown that the magnitude of the effect of pridopidine on motor symptoms is of clinical significance to the patient. In general, pridopidine is generally safe and tolerable in patients with HD at study doses up to 45 mg bid.

Of note, the MAD study (ACR16C018) showed that in addition to an increase in QT duration, which may be of clinical significance, the 90 mg bid dose is associated with more frequent AEs, in particular dizziness and psychiatric events. Psychiatric events include nightmares, aggression, depressed mood, anxiety, and sleep disturbances. The 112.5 mg dose was not used in the MAD study.

tolerance and adverse events.

In the MAD study (ACR16C018), the tolerability and safety of pridopidine at a dose of 45 to 90 mg bid administered over 9 days was studied in 36 healthy subjects. The safety profile of pridopidine in the 45 and 67.5 mg bid dose groups is similar to that observed in larger clinical trials. In general, the most commonly reported AEs are SOCs, including nervous system disorders, gastrointestinal disorders, and psychiatric disorders. Most AEs are defined as mild. In the MAD study, a dose of 90 mg bid is considered MTD.

Example 1: Phase 11 Randomized, double-blind, placebo-controlled, parallel-group study to determine the safety and efficacy of 45, 67.5, 90, and 112.5 mg pridopidine administered twice daily for symptomatic treatment patients with Huntington's disease compared with placebo.

Purpose and objectives of the study.

The present study determines the effect of 4 doses of pridopidine (45, 67.5, 90 and 112.5 mg bid) on improvement in motor function in HD patients after 12 weeks of treatment compared with placebo, as well as the dose-response relationship. In this study, the efficacy and dose response of pridopidine 45 to 112.5 mg bid in improving motor function in HD patients after 12 weeks of treatment was determined using UHDRS-TMS.

The study also measures the effect and dose response after 12 weeks of treatment with pridopidine on different functional scales, including:

Physician and Caregiver Impression Scale (CIBIC-Plus), Physical Disability Scale (PDS), Functional Assessment (FA) UHDRS.

Other goals include:

determination of the safety and tolerability of the dose range of pridopidine in patients with HD over 12 weeks of treatment, analysis of the PK of pridopidine in the studied patient population, investigation of the relationship between pridopidine exposure and outcome measures (such as clinical efficacy and toxicity indicators).

Study design.

General design and scheme of the study.

A multicenter, multinational, randomized, double-blind, placebo-controlled, parallel-group trial is being conducted to compare the efficacy and safety of 45, 67.5, 90, and 112.5 mg bid of pridopidine bid versus placebo in the treatment of movement disorders in patients with HD.

Patients are randomized into equal groups (1:1:1:1:1) receiving pridopidine 45, 67.5, 90, or 112.5 mg or placebo bid for 12 weeks, including a 4-week progressive titration period. .

Patients are screened for up to 2 weeks to determine if they are eligible to participate in the study. The screening period includes a detailed medical and psychiatric history, Columbia University Suicide Severity Scale (C-SSRS), registration of previous medications, a complete physical and neurological examination, measurement of vital signs, routine clinical laboratory tests (hematology , biochemistry, urinalysis), serum pregnancy tests (in women of childbearing age) and one 12-lead ECG. The diagnosis of HD is based on clinical symptoms and the presence of >36 CAG repeats in the huntingtin gene. Define UHDRSTMC and UHDRS-IS. In addition, the screening examination includes a quantitative assessment of motor function (Q-Motor) and a test for analyzing cognitive batteries (short CAB) (character and number matching test [SDMT], Stroop word reading test, short Montreal cognitive function assessment). the [MoCA] scale and route building test B) in order to familiarize test participants with them in advance before measuring baseline indicators (and thus reduce practical effects). Eligible patients are randomly allocated to either active drug or placebo and titrated for the first 4 weeks using pridopidine at a dose of 22.5 mg bid to a final dose of 45, 67.5, 90 or 112.5 mg bid, depending on the experimental group to which they are allocated, as detailed below.

During titration (days 0 to 27), patients make 2 visits to the study site: on day 0 (baseline) and on day 14. In addition, they participate in telephone conversations on days 6 and 20.

At the first visit, prior to receiving the first dose of study drug, an independent assessor compiles the Clinician's Interview-Based Severity Impression (CIBIS), while the participating clinician assesses disease severity using the Global Clinical Impression Scale (CGI-S), get up and walk (TUG) test results, PDS, physical performance test (PPT) results, UHDRS-TMS, UHDRS-FA, UHDRS-IS, UHDRS Total Functioning Ability (TFC), CAB Brief, and Problematic Behavior Analysis Brief forms (PBA-s). The patient scores on the Multiple Sclerosis Walking Rating Scale (MSWS-12) and the HD Quality of Life Rating Scale (HD-QoL), and also determines Q-Motor. The determination of CIBIS, UHDRS-TMC, UHDRS-TFC and PDS should be carried out before the determination of scores on other scales. Before the first dose and 1-2 hours after the dose, a 12-lead triple ECG is recorded and samples are taken for PK analysis, which determine the levels of pridopidine and its main metabolite (TV-45065, formerly called ACR30). Samples for PK are collected after ECG registration.

Phone calls on days 6 and 20 are made to inquire about AEs and concomitant medications and to allow weekly dose increases the following day. During the study site visit on day 14, a 12-lead triple ECG is recorded and blood samples are taken for PK analysis and electrolyte monitoring prior to study drug administration; if hypokalemia is observed, the administration of the drug is stopped until a normal electrolyte level is reached, maintained for 7 days. In addition to obtaining information about AE and concomitant drugs, vital signs are determined. 1-2 hours post-dose, a 12-lead triplicate ECG is recorded again and samples are collected for PK analysis.

During the full dose period (days 28 to 84), patients made a total of 4 study site visits on days 28, 42, 56, and 84 (or at the time of early termination) and a phone call on day 35. During a telephone conversation on day 35, they ask about AE and concomitant treatment. At each visit to the study site, safety variables are determined, including ECG analysis in triplicate before dosing and 1-2 hours after dosing (ECG is optional at day 56) and clinical laboratory tests. In addition, PK samples are taken at days 28, 42, and 84, in which pridopidine and TV-45065 levels are determined before the first dose, 1-2 hours after dosing at the study center, and at days 42 and 84 also before the patient leaves the center. If PK specimen collection and ECG recording are performed on the same day, PK specimens are collected after the ECG recording.

Additional 12-lead ECG analyzes are performed at the study site, at the discretion of the investigator, 1-2 hours after the daily daily dose for patients who experience an increase in QTcF > 50 ms from baseline after the morning dose. This additional afternoon ECG measurement is performed for safety reasons, as the concentration of the study drug may be higher in the afternoon than in the morning.

At days 28, 56, and 84, in addition to safety analysis, an independent evaluator determines CIBIC-Plus, while a participating specialist evaluates UHDRS-TMS, PDS, change in clinical global impression scale (CGI-C), TUG, PPT , UHDRS-FA, UHDRS-TFC, UHDRS-IS, short CAB and PBA-s. The patient puts scores on the MSWS-12 and HD-QoL scales, and also determines the Q-Motor.

Patients who have completed all planned visits undergo final procedures and analyzes during the last visit (day 84). Patients who wish to withdraw from the study prior to its completion undergo procedures and tests scheduled for Day 84 at their last visit.

To assess safety, a follow-up visit is performed 2 weeks after the last dose of study drug, during which a triplicate ECG analysis (optional) and collection of samples for PK are performed. UHDRS-TMS and Q-Motor are also evaluated during this visit.

The study scheme is shown in Fig. 1.

Primary and secondary variables and endpoints.

The primary variable and endpoint of efficacy in this study is the change in UHDRS-TMS score (defined as the sum of scores from all motor function sections of the UHDRS) at week 12 from baseline.

Secondary functional variables indicators and final performance criteria.

In this study, the following secondary functional variables and endpoints of performance are used:

overall CIBIC-Plus score at week 12 from baseline (as determined by an independent investigator), change in PDS score at week 12 from baseline, change in UHDRS-FA at week 12 from baseline, other functional variables and end points performance criteria.

Other functional variables and endpoints of performance are also used in this study, such as:

CGI-C score at week 12 from baseline (as determined by study professional and patient), change in UHDRS-TFC at week 12 from baseline, change in UHDRS-IS at week 12 from baseline, exploratory/ other variables and endpoints of performance.

In this study, the following exploratory/other variables and endpoints of efficacy are used.

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General/functional scales:

change in HD-QoL at week 12 from baseline, change in MSWS-12 at week 12 from baseline, change in PPT at week 12 from baseline.

TMS subscales:

change in hand motor ability score (defined as the sum of UHDRS subsection scores related to finger tapping, hand pronation-supination, and the Luria technique [fist-hand-palm test]) at week 12 from baseline, change in gait and balance score ( defined as the sum of the scores of the UHDRS sections associated with gait, tandem walking, and the retropulsion stability test) at week 12 from baseline, change in UHDRS-mMS (defined as the sum of the scores of the UHDRS sections associated with dysarthria, protruding tongue, tapping fingers , pronation-supination of the hands, Luria technique, rigidity, bradykinesia, gait, tandem walking and retropulsion stability test) at 12 weeks from baseline, percentage of respondents defined as patients with change in TMS from baseline <0 at 12 weeks.

Other assessments of motor functions:

change from baseline at week 12 in Q-Motor scores including digitomotography (rapid index finger tapping), dysdiadochomotography (pronation/supination tapping of the hand), manumotography and choreomotography (grip force and chorea analysis), and paedomotography ( accelerated foot tapping), change in TUG test result at week 12 from baseline.

Assessments of cognitive/psychiatric indicators:

change in short CAB at week 12 from baseline: SDMT, Stroop word reading test, reduced MoCA scale and route building test B, change in PBA-s at week 12 from baseline, investigational drugs and dosage, the study drug (pridopidine and the corresponding placebo) is administered as described below and given in table. 1 scheme.

Study product and dosage.

Pridopidin (as pridopidine hydrochloride) is administered in a size 2 white hard gelatin capsule containing 45 mg of pridopidin and a size 4 white hard gelatin capsule containing 22.5 mg of pridopidine.

Weeks 1-4: titration period.

Patients randomly assigned to the treatment group receiving pridopidine 45 mg bid.

Patients receive 1 capsule containing pridopidine 22.5 mg, 1 capsule containing 22.5 mg placebo, and 1 capsule containing 45 mg placebo bid (22.5 mg bid means a total daily dose of pridopidin is 45 mg).

Patients randomly assigned to the treatment group receiving pridopidine 67.5 mg bid.

Weeks 1 and 2: Patients receive 1 capsule containing pridopidine 22.5 mg, 1 capsule containing 22.5 mg placebo, and 1 capsule containing 45 mg placebo bid (22.5 mg bid means the total daily dose of pridopidine is 45 mg).

Weeks 3 and 4: Patients receive 1 capsule containing 45 mg of pridopidine and 2 capsules containing 22.5 mg of placebo bid (45 mg bid means a total daily dose of pridopidine of 90 mg).

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Table 1. Dose Administration (capsules are administered twice a day, ______ to reach the total daily dose) _______

Treatment Titration period Full dose period 1 Week 2 weeks 3 week 4 week 5-12 weeks Pridopidin, 45 mg bid 1x22.5mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 1x22.5mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 1x22.5mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 1x22.5mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 1x45 mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=90mg) Pridopidin, 67.5 mg bid Pridopidin, 90 mg bid Pridopidin, 112.5 mg bid placebo 1x22.5 mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 1x22.5 mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 1x22.5 mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 2x22.5mg placebo 1x45mg placebo 1x22.5mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 1x45mg pridopidine 2x22.5mg placebo (TDD=90mg) 1x45mg pridopidine 2x22.5mg placebo (TDD=90mg) 2x22.5mg placebo 1x45mg placebo 1x45 mg pridopidine 2x22.5 mg placebo (TDD=90 mg) 1хх45 mg of pridopidine 1x22.5 mg pridopidine 1x22.5mg placebo (TDD=135mg) 1x45mg pridopidine 1x22.5 mg pridopidine 1x22.5mg placebo (TDD=135mg) 2x22.5mg placebo 1x45mg placebo 1x45 mg pridopidine 2xx22.5 mg placebo (TDD=90 mg) 1x45 mg pridopidine 1x22.5 mg pridopidine 1x22.5mg placebo (TDD=135mg) 1x45 mg pridopidine 2x22.5 mg pridopidine (TDD=180 mg) 2x22.5mg placebo 1x45mg placebo 1x22.5 mg pridopidine 1x45 mg pridopidine 1x45 mg placebo (TDD=135 mg) 2x45 mg pridopidine 1x 22.5 mg placebo (TDD=180 mg) 1x22.5 mg pridopidine 2x45 mg pridopidine (TDD=225 mg) 1x22.5mg placebo 2x45mg placebo

Patients randomly assigned to the treatment group receiving pridopidine 90 mg bid.

Week 1: Patients receive 1 capsule containing pridopidine 22.5 mg, 1 capsule containing 22.5 mg placebo, and 1 capsule containing 45 mg placebo bid (22.5 mg bid means total daily dose of pridopidine is 45 mg ).

Week 2: Patients receive 1 capsule containing 45 mg of pridopidine and 2 capsules containing 22.5 mg of placebo bid (45 mg bid means a total daily dose of pridopidine of 90 mg).

Weeks 3 and 4: Patients receive 1 capsule containing 45 mg of pridopidine, 1 capsule containing 22.5 mg of pridopidine, and 1 capsule containing 22.5 mg of placebo bid (67.5 mg bid means that the total daily dose of pridopidine is 135 mg).

Patients randomly assigned to the treatment group receiving 112.5 mg pridopidine bid.

Week 1: Patients receive 1 capsule containing pridopidine 22.5 mg, 1 capsule containing 22.5 mg placebo, and 1 capsule containing 45 mg placebo bid (22.5 mg bid means total daily dose of pridopidine is 45 mg ).

Week 2: Patients receive 1 capsule containing 45 mg of pridopidine and 2 capsules containing 22.5 mg of placebo bid (45 mg bid means a total daily dose of pridopidine of 90 mg).

Week 3: Patients receive 1 capsule containing 45 mg pridopidin, 1 capsule containing 22.5 mg pridopidin, and 1 capsule containing 22.5 mg placebo bid (67.5 mg bid, total daily dose of 135 mg pridopidin).

Week 4: Patients receive 1 capsule containing 45 mg of pridopidine and 2 capsules containing 22.5 mg of pridopidine (90 mg bid means a total daily dose of pridopidine is 180 mg).

Weeks 5-12: Full dose period.

Patients randomly assigned to the treatment group receiving 45 mg of pridopidin bid receive 1 capsule containing 45 mg of pridopidin, 1 capsule containing 22.5 mg of placebo, and 1

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Patients randomly assigned to the treatment group receiving 67.5 mg of pridopidine bid receive 1 capsule containing 45 mg of pridopidine, 1 capsule containing 22.5 mg of pridopidine, and 1 capsule containing 45 mg of placebo bid (total daily dose is 135 mg).

Patients randomly assigned to the treatment group receiving pridopidine 90 mg bid receive 2 capsules containing pridopidine 45 mg and 1 capsule containing 22.5 mg placebo bid (total daily dose of 180 mg).

Patients randomly assigned to the pridopidine 112.5 mg bid treatment group receive 2 capsules containing pridopidine 45 mg and 1 capsule containing pridopidine 22.5 mg bid (total daily dose of 225 mg).

Other investigational medicinal products and dosages.

The placebo is administered in white hard gelatin capsules, which correspond to capsules containing 22.5 or 45 mg of pridopidin, but do not contain the active ingredient, but contain only excipients (silicified microcrystalline cellulose and magnesium stearate).

Patients randomly assigned to the placebo group receive 3 bid capsules throughout the study period, i.e. 3 capsules in the morning and 3 capsules in the afternoon (7-10 hours after the morning dose). On the day of the last visit, the daily dose is not taken (day 84/early termination).

Weeks 1 to 4: titration period.

Patients randomly assigned to the placebo group receive 2 capsules containing 22.5 mg placebo and 1 capsule containing 45 mg placebo bid.

Weeks 5 to 12: Full dose period.

Patients randomly assigned to the placebo group receive 2 capsules containing 45 mg placebo and 1 capsule containing 22.5 mg placebo bid.

In table. 2 shows the procedures and analyzes used in the study, as well as the timing of their implementation.

Table 2. Procedures and assays used in the study

Titration period Full dose period Visit V0 VI TS V2 TS V3 TS V4 V5 V6 V7 Day -14 to -1 0 6 14±3 20 2 8±4 35±3 42±5 5 6±5 84±7 98±7 Procedures and tests Screening BL W1 W3 W3 W5 W6 W7 W9 W12/early termination Follow-up Unscheduled visit Visit to the research center X X X X X X X X X Phone call X X X Informed agreement X Demography X Medical and psychiatric history X History of previous medications X Inclusion and exclusion criteria ³ X X Randomization X

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Clinical laboratory tests (hematology and biochemistry) Urinalysis Pregnancy test (for women of childbearing age) ^c Complete physical and neurological examination, including weighing (height is measured only during the screening period) ECG Measurement of vital signs C-SSRS (original version ) C-SSRS (last visit version) Visit Day Procedures and tests Blood sampling for genetic analysis ¹¹ UHDRS-TMS UHDRS-FA UHDRS-TFC UHDRS-IS PBA-s CIBIS CIBIC-Plus PDS PPT CGI-S CGI-C HD -QoL MSWS-12 Q-Motor Scores ^j TUG Test Cognitive Battery Analysis ¹¹ xd V0 -14 to -1 Screening X X X X ^e Pe VI 0 BL X ¹ X X X ¹ X X X X EIOD TI ts 6 W1 X ^e 1trovav V2 14±3 W3 [AND I ts 20 W3 n V3 2 8±4 W5 X ¹ X X X X X X [TC period 35±3 W6 X ^e entered: V4 42±5 W7 IA POL! V5 5 6±5 W9 X ¹ X X X X X X X X X ZOY doses V6 84±7 W12/ early completion V7 98±7 Follow-up X Unscheduled visit Collection of blood samples to determine drug concentration ¹ X X X X X X X Collection of information on adverse events X X X X X X X X X X X Collection of information about concomitant medicines X X X X X X X X X X X

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Titration period Full dose period Visit V0 VI TS V2 TS V3 TS V4 V5 V6 V7 Day From -14 TO -1 0 6 14±3 20 2 8±4 35±3 42±5 5 6±5 Θ4±7 9Θ±7 Procedures and tests Screening G BL W1 W3 W3 W5 W6 W7 W9 W12/early termination Follow-up unscheduled visit Investigational drug tolerance analysis before dose escalation (if any) X X X Distribution/collection of investigational drug X X X X X Checking Patient Compliance with Study Requirements X X X X X X Investigational drug administration” ¹

Legend:

^a - inclusion/exclusion criteria should be determined at screening and reviewed on day 0, before randomization of the patient, ^b - electrolytes only, ^c - serum pregnancy test is performed during the screening examination; at subsequent time points, a urine test for pregnancy is performed, ^d - one ECG is recorded. If results are obtained during screening that indicate a prolonged QTcF interval (defined as a QTcF interval >450 ms for men or >470 ms for women), then the ECG is repeated twice and the average of the 3 measurements taken at the time of screening is used to determination of the patient's suitability for participation in the study, ^e -ECG is recorded with three repetitions before the dose and 1-2 hours after the dose. If the ECG is recorded on the same day as the PK sample collection, the ECG is recorded before the PK sample collection. Additional 12-lead ECG analyzes are performed at the study site, at the discretion of the investigator, 1-2 hours after the daily daily dose for patients who experience an increase in QTcF > 50 ms from baseline after the morning dose.

^f - Day 56 ECG is optional and is at the discretion of the investigator if there are clinical circumstances that warrant an additional ECG, such as a patient with a pre-existing episode of hypokalemia in the absence of QT prolongation ^g - An ECG is not required at the follow-up visit, however it is measured for all patients with an existing cardiac problem and / or with a change in QTc compared to baseline, ^h - including CAG analysis, cytochrome P450 2D6 status, genetic long QT syndrome (determined only for patients who, after study drug, there is an increase in QT duration, leading to withdrawal from the study), or any other genetic tests associated with response to pridopidine, or Huntington's disease ⁱ - analyze first, ^j - including digitomotography assessments (rapid tapping of the index finger), dysdiadochomotography (brush pronation/supination), manumotography and choreomotography (grasping force and analysis of chorea) and pedomotography (accelerated tapping of the foot), ^k - includes a test for matching symbols and numbers, a Stroop test for reading words, a short Montreal scale assessments of cognitive functions and route building test B, l - at the first visit and on days 14 and 28, samples for determining the levels of pridopidine and TV-45065 metabolite are collected before the first dose and 1-2 hours after the dose at the study center. On days 42 and 84, samples are collected before the first dose, 1-2 hours after dosing at the study center, and before the patient leaves the center. If these samples are collected and the ECG is recorded on the same day, the PK samples are collected after the ECG is recorded. At the follow-up visit, 1 sample for PK is collected. When SAE appears in the near future, additional sampling for PK, ^m - each patient receives 3 capsules twice a day (bid), i.e. 3 capsules in the morning and 3 capsules in the afternoon (7-10 hours after the morning dose), throughout the study period. Study drug is not taken during the early termination visit. For study site visits, the morning dose is taken at the designated center.

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Screening and enrollment procedures (Visit 0).

The screening visit (Visit 0) takes place no more than 2 weeks prior to the baseline visit. During the screening visit, the following procedures are carried out:

obtaining written informed consent prior to any other study-related procedures, analysis of inclusion/exclusion criteria, analysis of medical and psychiatric history, analysis of medication history, collection of demographic information, clinical laboratory tests (hematology, biochemistry, urinalysis), serum analysis for pregnancy, for women of childbearing age only, vital signs measurements,

ECG in 12 leads (one); if results obtained during screening indicate a prolonged QTcF interval (defined as a QTcF interval >450 ms), then the ECG is repeated twice and the average of the 3 measurements taken during screening is used to determine the patient's eligibility for participation in the study. neurological examination (including determination of height and weight),

C-SSRS (original version),

UHDRS-TMC and UHDRS-IS, Q-Motor scores, short CAB tests (SDMT, Stroop Word Reading Test, Abbreviated MoCA and Path B Test), collection of blood samples for potential genetic analyses, informing patients about study related restrictions and compliance requirements.

Procedures carried out during the initial visit (Visit 1).

Patients who meet the inclusion/exclusion criteria determined during the screening process (Visit 0) go to Visit 1, during which baseline values are determined. During the baseline visit, the following procedures are performed at the study site prior to dosing:

analysis of inclusion/exclusion criteria, measurement of vital signs, collection of information on AE, collection of information on concomitant drugs, clinical laboratory tests (hematology, biochemistry, including electrolyte analysis, urinalysis); electrolyte test results should be available prior to dosing,

ECG in 12 leads with three repetitions,

C-SSRS (version from last visit),

UHDRS-TMC, UHDRS-FA, UHDRS-TFC, UHDRS-IS,

cgi-s,

CIBIS conducted by an independent appraiser,

pds,

TUG test,

ppt,

HD QoL,

MSWS-12, Q-Motor Scores, CAB Short Tests (SDMT, Stroop Word Reading Test, Abbreviated MoCA Scale, and Route Building Test B),

PBA-s, obtaining a 4 ml blood sample for plasma drug analysis, distribution of investigational drug (first dose received at the study site adjusted for potassium levels corresponding to the normal range), checking compliance with study rules.

During the initial visit, after the first dose is administered at the study site, the following procedures are performed:

1) ECG in 12 leads with three repetitions (1-2 hours after the dose);

2) obtaining a blood sample with a volume of 4 ml for the analysis of the drug in plasma (1-2 hours after the dose); samples are collected after ECG recording, but at the closest possible time to it.

Procedures during study drug treatment.

Titration period (weeks 0 to 4).

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Telephone contact on weeks 1 and 3 (days 6 and 20).

Patients are contacted by telephone on days 6 and 20 to determine study drug tolerability by assessing AE and concomitant medication, and to allow weekly dose increases during the titration period (see above), which is done the next day (if approved) .

Week - 14 day (visit 2).

During the visit on Day 14 (±3 days), Week 3 (Visit 2), perform the following procedures/assessments.

Before drug administration:

AE survey, concomitant drug use analysis, clinical laboratory tests (only for electrolytes); electrolyte results should be obtained prior to drug administration, a complete physical and neurological examination (including weight determination),

Triple 12-lead ECG, Vital Signs Measurement, Obtaining a 4-mL Blood Sample for Plasma Drug Analysis (After the ECG Recording, but As Soon as ECG Recorded), Collection/Distribution of Investigational Drug, Checking Compliance study rules, administration of the morning dose of study drug (adjusted for potassium levels corresponding to the normal range).

After drug administration:

ECG in 12 leads with triple repeats (1-2 hours after the dose), obtaining a blood sample with a volume of 4 ml of plasma for analysis of the drug in plasma 1-2 hours after the dose; samples for PK are collected after ECG recording, but at the closest time point to it.

Full dose period (weeks 5 to 12).

Weeks 5, 7 and 9-28, 42 and 56 days (visits 3, 4, and 5).

On days 28 (±4), 42 (±5 days), and 56 (±5 days), weeks 5, 7, and 9 (Visits 3, 4, and 5), the following procedures/assessments are performed.

Before dosing:

AE survey, concomitant drug use review, clinical laboratory tests (hematology, biochemistry including electrolytes, urinalysis), urinalysis for pregnancy only for women of childbearing age (28 and 56 days only), complete physical and neurological examination (including weight determination),

Triple 12-lead ECG (Note: Day 56 ECG is optional and at the discretion of the investigator if there are clinical circumstances that justify an additional ECG, such as a patient's pre-existing episode of hypokalemia in the absence of QT prolongation), measurement of vital signs functions,

C-SSRS (last visit version), days 28 and 42 only: Obtaining a 4 ml blood sample for plasma drug analysis (after ECG recording, but as soon as possible), collection/distribution of investigational drug (only on days 28 and 56), check compliance with study rules, administration of the morning dose of study drug (adjusted for potassium levels corresponding to the normal range).

After drug administration:

Triple 12-lead ECG (1-2 hours post-dose) (Note: ECG at day 56 is optional and is at the discretion of the investigator if there are clinical circumstances that justify an additional ECG, such as a pre-existing episode of hypokalemia in the patient in the absence of QT prolongation), on days 28 and 42 only: obtaining a 4 ml blood sample for analysis of the drug in plasma 1-2 hours after dosing; samples for PK are collected after the ECG recording, but at the closest possible time point to it, only on day 42: obtaining a 4 ml blood sample for plasma drug analysis before the patient leaves the research center.

In addition, only on days 28 and 56 (visits 3 and 5) the following procedures/evaluations are performed to determine the effectiveness, among which UHDRS-TMS, CIBIC-Plus,

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UHDRS-TFC and PDS: CIBIC-Plus, PDS, PPT, UHDRS-TMS, UHDRS-FA, UHDRS-TFC, UHDRS-IS, CGI-C,

TUG test, HD-QoL, MSWS-12, Q-Motor scores, short CAB tests (SDMT, Stroop Word Reading Test, Abbreviated MoCA Scale, and Route Building Test B), and PBA-s.

Telephone contact at week 6 (day 35).

Patients are contacted by telephone at day 35 (±3 days) to determine study drug tolerance by assessing AE and using concomitant medication.

Week 12 - Day 84 (visit 6) or early termination visit.

At Day 84 (±7 days), Week 12 (Visit 6), or at the time of the early termination visit, perform the following procedures/assessments.

Before drug administration:

AE interview, concomitant drug use review, clinical laboratory tests (hematology, biochemistry including electrolytes, urinalysis), urinalysis for pregnancy only for women of childbearing age, complete physical and neurological examination (including determination of weight ),

ECG in 12 leads with triple repeats, measurement of vital signs,

C-SSRS (last visit version), obtaining a 4 ml blood sample for analysis, plasma drug (after ECG recording, but as soon as possible), checking compliance with study rules, administration of the morning dose of study drug ( adjusted for potassium levels corresponding to the normal range) (Note: study drug is not administered during the early termination visit).

After drug administration:

Triple 12-lead ECG (1-2 hours post-dose), obtaining a 4-mL blood sample for plasma drug analysis (1-2 hours after drug administration at the study site and before the patient leaves the center [ after the ECG recording, but at the closest time to it]), collection of the study drug.

On Day 84 (Visit 6), the following procedures/assessments are performed to determine efficacy, among which UHDRS-TMS, CIBIC-Plus, UHDRS-TFC and PDS are primarily evaluated: CIBICPlus, PDS, PPT, UHDRS-TMS, UHDRS-FA, UHDRS-TFC, UHDRS-IS, CGI-C, TUG Test, HD-QoL, MSWS12, Q-Motor Scores, CAB Short Tests (SDMT, Stroop Word Reading Test, Abbreviated MoCA Scale, and Route Building Test B) and PBA -s. On day 84/early termination, the daily dose is not administered.

Follow-up visit.

There is a follow-up visit 2 weeks after the last dose of study drug (day 98, ±7 days). The following procedures/assessments are performed during this visit: AE questioning, concomitant drug use review, clinical laboratory tests (hematology, biochemistry, urinalysis), urinalysis for pregnancy only for women of childbearing potential, complete physical and neurological examination (including weight determination), optional 12-lead triple ECG to be recorded for all patients with existing cardiac problem and/or QTc change from baseline, vital signs measurement, UHDRS-TMS, Q-motor evaluations and collection of 4 ml blood samples for plasma drug analysis after ECG recording.

Procedures performed after study drug treatment/withdrawal.

If patients participate in the study, following its protocol, for at least 12 weeks of double-blind treatment, they are considered to have completed participation in the study.

For patients who have completed or terminated study participation prematurely, conduct final analyzes at week 12/early termination visit (Visit 6). Patients who did not complete their last visit within 7 days of their last dose of study drug were not evaluated for efficacy.

Unscheduled visits.

An unscheduled visit may be made at any time during the course of the study at the request of the patient or at the discretion of the investigator. The date and reason for an unscheduled visit are recorded in the CRF, as are any other data received (for example, information on AEs, concomitant medications, and

- 18 039995 methods of treatment, as well as the results of procedures or tests). With the emergence of SAE, additional sampling for PK is carried out in the near future.

Study sample.

The study sample consists of male or female patients >21 years of age weighing >50 kg with a diagnosis of HD established by identifying the clinical features of HD and confirmed by the presence of >36 CAG repeats in the huntingtin gene. HD must be diagnosed in a patient >18 years of age. In addition, patients have: 1) UHDRS-TMS score >25 points at screening visit, and 2) an independent assessment (IS) of UHDRS<90% at screening visit. Patients are outpatients and able to make visits to the clinic.

Patient Inclusion Criteria.

Patients are included in the study only if they meet all of the following criteria:

a. The diagnosis of HD was based on clinical signs and the presence of >36 CAG repeats in the huntingtin gene.

b. The age of the man or woman is >21 years, and HD appears after 18 years of age.

c. Women of childbearing potential must consent to the use of appropriate contraceptive measures throughout the study, including during follow-up. Appropriate contraceptive measures are defined as appropriate implementation of an effective and acceptable method of contraception (use of hormonal agents, intrauterine devices, or double barrier contraceptives such as a condom and diaphragm, diaphragm and spermicidal gel, or spermicidal foam). Withdrawal is an acceptable method of contraception. Men must agree to use appropriate contraceptive measures with their partners (as above) throughout the duration of the study.

d. Body weight>50 kg.

e. Sum of UHDRS-TMS scores >25 points at screening visit.

f. UHDRS-IS score below 90% at the screening visit.

g. Able and willing to provide written informed consent prior to any study-related procedure performed at the screening visit.

h. Agree to provide a blood sample for genetic testing (including CAG testing, CYP2D6 status testing, genetic testing for long QT syndrome in patients who have experienced QT prolongation after administration of study drug, or any other genetic testing related to response to pridopidine, or with HD) at a visit during the screening period.

i. Willing and able to take medications orally and able to perform specific study procedures.

j. Are outpatients able to attend the study site and are assessed by the investigator as being able to continue visiting for the duration of the study.

k. Have a caregiver, informant, or family member available to accompany the patient to the clinic during study visits to obtain CIBIC-Plus and HD-QoL scores.

l. In patients taking approved antipsychotics, antidepressants, or other psychotropic medications, the medication dose should remain constant for at least 6 weeks before screening and throughout the study.

Criteria for exclusion of patients.

Patients are not eligible to participate in this study if they meet one of the following criteria:

a. Presence of a prolonged QTcF interval (defined as QTcF interval >450 ms for men and >470 ms for women) at the screening visit, or at the baseline visit. If data is obtained during the screening period indicating a prolongation of the QTcF interval compared to the initial (single) measurement, then the ECG is repeated twice, and the average of 3 measurements taken during the screening period is used to determine the patient's eligibility for participation in the study.

b. The presence of clinically significant heart disease at the visit during the screening period.

c. Having a history of long QT syndrome or a first degree of this condition.

d. Having a history of epilepsy or seizures within the last 5 years.

e. The presence of other serious medical conditions (including, without limitation, uncontrolled hypertension, respiratory diseases such as severe asthma, liver disease, kidney disease, AIDS, unstable psychiatric or other neurological disorders) that, in the opinion of the investigator, may put the patient at risk in the case of participation in the study, or may affect the results of the study, or the ability of the patient to participate in the study.

f. The presence at the visit during the screening period in the serum of patients with levels of potassium, magnesium and/or calcium that do not fall within the range of normal values established by the central laboratory.

- 19 039995

g. Taking drugs (within the last 6 weeks prior to screening) known to prolong the QT interval, or having a condition that may require taking such drugs during the study, where these drugs include, but are not limited to, unapproved antipsychotics, tricyclic antidepressants, and /or class I antiarrhythmics.

h. Medications (during the last 6 weeks before screening) that are metabolized by CYP2D6 and may decrease the seizure threshold.

i. Calculated according to the Cockcroft-Gault equation, creatinine clearance during the screening period is <60 ml/min.

j. The presence of any clinically significant abnormal laboratory screening result that, in the opinion of the Investigator, affects the patient's eligibility to participate in the study, or may put the patient at risk if he/she participates in the study.

k. Presence of alcohol and/or drug dependence (within 6 months prior to screening) established using the chemical dependence criteria described in the Diagnostic and Statistical Manual - Fourth Edition, Revised (DSM-IV TR).

l. The presence of active suicidal ideation, characterized by a score of the most severe suicidal thoughts of 4 (active suicidal thoughts with some intention to act, without a specific plan) or 5 (active suicidal thoughts with a specific plan and intent) on the C-SSRS scale.

m. Having a known risk of an intracranial event or a history of stroke or hemorrhage.

n. Pregnant or lactating women.

O. Known allergy to any ingredients of study drug or placebo (pridopidine, silicified microcrystalline cellulose, magnesium stearate).

R. Previous intake of pridopidine.

q. Treatment with tetrabenazine for 6 weeks of screening in this study.

r. Treatment with any investigational drug within 6 weeks of screening, or the patient planning to participate in another clinical trial to develop any investigational drug during that study.

Criteria and procedures for termination of participation.

Each patient has the right to refuse an investigational drug at any time. Each investigator has the right to discontinue a patient's investigational drug in the event of a comorbid condition, AE, pregnancy, or other reasons relating to the patient's health or well-being, or in the absence of an interaction.

If a patient decides to withdraw from the study following administration of the study drug(s), or if the investigator decides to withdraw the patient from the study, every effort will be made to complete and describe all observations up to the time of withdrawal. When a patient withdraws from the study, a full end-of-life assessment is performed and an explanation given as to why the patient is withdrawing from the study or being withdrawn from the study.

A patient who was included in the study but did not complete it is not replaced.

Treatment of patients.

Administration of investigational medicinal products.

After the baseline visit, patients are randomly assigned to 1-4 groups receiving pridopidine or placebo. Six capsules (with water) are orally administered every day; 3 capsules in the morning and 3 capsules in the afternoon (7-10 hours after the morning dose). The capsules are taken with or without food. After titration, patients continue the study in their dosing group.

Each package of medicinal product contains 3 differently labeled bottles containing the investigational drug and is provided to patients for use at home or at the study center if the drug intake coincides with a visit that is part of the study program.

Previous and concomitant treatment regimens or drugs.

Use of drugs not prohibited in the study is allowed at the discretion of the investigator. To the extent possible, patients continue to take medications already prescribed at the time they were enrolled in the study; dose changes and the introduction of new drugs are avoided unless deemed necessary by the investigator for optimal patient care.

Prohibited CYP2D6 substrates are administered only 1 week after discontinuation of pridopidine (i.e., allow 1 week for elimination) to allow recovery of the enzyme.

If a patient receives a prohibited treatment during the randomization phase of the study, he/she is encouraged to continue to participate in the study and make visits as scheduled; however, it may be necessary to withdraw the patient from the study drug regimen. If the patient refuses to make further visits, carry out assessments scheduled for week 12 (day 84)/early termination as possible (at least try to obtain information about the AE and the concomitant drug).

- 20 039995

At each clinic visit following a screening visit, the investigator asks patients if they have taken any medications (other than study drug) since the previous visit, including over-the-counter medications, vitamins, herbal or nutritional supplements.

approved medicines.

For patients taking approved antipsychotics, antidepressants, antiarrhythmics, or other medications, the medication dose should be kept constant for at least 6 weeks before screening and during the study.

Permitted antipsychotics include olanzapine, quetiapine, thiothixene, acetophenazine, triflupromazine, loxapine, tiapride, chlorprothixene, and bromperidol. Aripiprazole, risperidone, and perphenazine are allowed under the condition of dose reduction.

Permitted antidepressants include venlafaxine, paroxetine, sertraline, duloxetine, omipramol (opipramol), butriptyline, mianserin, moclobemide, tranylcypromine, buspirone, bupropion, reboxetine, and dibenzepine. Fluvoxamine, trimipramine, and mirtazapine are allowed with dose reduction.

Mexalatin and tocainide are antiarrhythmic drugs that are allowed subject to dose reduction.

Approved drugs that lower the seizure threshold include baclofen, bupropion, ciprofloxacin, cyclosporine, isoniazid, lindane, methylphenidate, metronidazole, penicillins, theophylline, amantadine, morphine, buprenorphine, diphenoxylate, alfentanil, fentanyl, remifentanil, meptazinol, and pethidine.

Prohibited drugs.

Antipsychotic drugs.

Ziprasidone, clozapine, haloperidol, mesoridazine, thioridazine, pimozide, zuclopenthixol, chlorpromazine, paliperidone, iloperidone, fluphenazine, prochlorperazine, trifluoperazine/trifluoperazine, flupentixol, benperidol, amisulpride, and sulpiride are not approved during Screening Week 6 (Visit 0) and during research time.

Antidepressants.

Lithium, the tricyclic/tetracyclic antidepressants trazodone, amitriptyline, nortriptyline, imipramine, desipramine, maprotiline, doxepin, clomipramine, protriptyline, and amoxapine, and the serotonin-norepinephrine reuptake inhibitors citalopram, escitalopram, and fluoxetine are not approved during the 6 weeks of Screening (visit 0) and during the study.

Antiarrhythmic drugs.

Disopyramide, procainamide, quinidine, flecainide, propafenone, amiodarone, dofetilide, ibutilide, and sotalol are not approved during the 6 weeks of Screening (Visit 0) and during the study.

Drugs that lower the seizure threshold.

Maprotiline, dipipanone, dihydrocodeine, methadone, oxycodone, papaveretum, pentazocine, and tramadol are not approved during the 6 weeks of Screening (Visit 0) and during the study.

Other prohibited drugs.

Due to their ability to influence QT prolongation or to be metabolized by CYP2D6 to form active metabolites, the following drugs are not approved during the 6 weeks of screening (visit 0) and during the study: astemizole, terfenadine, azithromycin, erythromycin, moxifloxacin, pentamidine, sparfloxacin, clarithromycin, chloroquine, halofantrine, bepridil, cisapride, domperidone, droperidol, levomethadil, methadone, codeine, tramadol, sevoflurane, and tamoxifen.

Determination of the total volume of blood.

Calculate the total volume of blood to be collected from each patient, and the results are given in table. 3.

Table 3. Total volume of blood obtained from each patient ______________

Analysis type Number of samples collected Volume of one sample Total volume of samples for analysis Pharmacokinetic 13 4 ml 52 ml Biochemical analysis of serum 8 10.5 ml 84 ml Hematology 7 3 ml 21 ml CAG Testing 1 4 ml 4 ml Genotyping CYP2D6 1 6 ml 6 ml Total 167 ml

CAG=cytosine-guanine-adenosine, CYP2D6=cytochrome P450 2D6.

- 21 039995

Performance analysis.

Unless otherwise indicated, the efficacy analyzes detailed in the sections below are performed on day 0 (Visit 0, Baseline), Day 28 (Visit 3), Day 56 (Visit 5), and Day 84 (Visit 6). Ratings

UHDRS-TMS and Q-Motor are also determined during the follow-up visit.

Primary variable and final criterion.

The primary variable and endpoint of efficacy in this study is the change in UHDRS-TMS score (defined as the sum of scores from all motor function sections of the UHDRS) at week 12 from baseline.

UHDRS includes a broad assessment of HD-related features. (Huntington Research Group 1996). It is a research tool designed to provide a uniform assessment of the clinical signs and course of HD.

The UHDRS TMS component score consists of 31 15-item UHDRS scores, where each score is scored on a 5-point scale from 0 (normal) to 4 (most abnormal).

Secondary variables and endpoints of performance.

Evaluation of the change in the patient's condition based on the impression of the doctor and caregivers.

The overall change in HD at week 12 was determined using the CIBIS score at baseline (day 0) and the CIBIC-Plus score at subsequent time points. CIBIC-Plus (ADCSCGIC version) is developed, validated and commonly used in dementia drug research for the treatment of Alzheimer's disease. (Joffres 2000).

An independent evaluator, whose only role is to make these overall assessments, determines the overall severity of the patient's illness before starting investigational drug administration. In a score known as CIBIS, the patient is categorized on a 7-point Likert scale from extremely severe HD to asymptomatic HD. At each subsequent assessment visit (weeks 5, 9, and 12), CIBIC-Plus is assessed by the same independent assessor who has no information on other assessments or on AEs experienced by the patient during the study (so as not to skew the CIBIC score). as a measure of effectiveness, or not to unmask the study). The independent evaluator is not allowed to discuss the patient's condition with the attending physician. Instead, the independent evaluator only takes into account the results of determining the cognitive, functional and behavioral characteristics of the patient, obtained as a result of interviewing the patient with the caregiver. The evaluator then compares the resulting data with the original estimate. The overall impression of change from baseline (CIBIC-Plus) is assessed on a 7-point scale: 1=clear improvement; 2=moderate improvement; 3=minimal improvement; 4=no change; 5=minimum impairment; 6=moderate deterioration; 7=clear deterioration; all estimates are compared with the original value. A higher score indicates worse overall function. In HD, the inclusion of caregiver-provided data is particularly important in determining the overall score, as previous studies have shown that patients tend to have limited understanding and acceptance of their deficits.

Scale for assessing physical disability.

PDS is used throughout the study as a measure of disability. Patients are scored on a scale from 10 (fixed body position requiring general care gastrotomy, catheterization) to 100 (normal, no signs of illness). (Myers 1991).

Performance evaluation of UHDRS.

The FA UHDRS measures functioning using 25 daily life tasks (eg, Can the patient be accepted into a paid position in his/her usual line of work?). Each question is answered yes or no.

Other functional variables and performance endpoints.

Other performance variables and outcome measures are described below.

Evaluation of the severity of the disease and its changes on a scale of general clinical impression.

CGI-S is evaluated at baseline (day 0) and CGI-C at all subsequent times (days 28, 56 and 84) to determine change from baseline.

The CGI-S scale was originally developed to assess the effectiveness of the treatment of patients with mental disorders (Guy 1976), but now it is widely used in various diseases. The severity of the disease is assessed by the researcher on a 7-point scale (from 1=normal condition, no disease, to 7=assigned to the majority of terminally ill patients). The score is based on the investigator's opinion, supported by a comprehensive, semi-structured patient/caregiver interview. The CGI-C scale is used to measure the change in a patient's clinical condition from a specific point in time, which is a 7-point scale ranging from 1 (great improvement) to 7 (great deterioration), with a score of 4 indicating no change.

Evaluation of the overall ability to function UHDRS.

The TFC UHDRS scale covers 5 areas of functioning related to disability (employment, finances, household chores, activities of daily living, and level of care required).

UHDRS independence scale.

In accordance with the UHDRS independence scale, the degree of patient independence is given as a percentage, from 10% (tube feeding, completely bedridden patient) to 100% (no need for special care). Grade values must end in 0 or 5 (for example, 10, 15, 20%, etc.). Patients with an UHDRS-IS score at the Screening visit of >90% are not eligible to participate in the study.

Explorator/other efficiency variables.

General/functional scales.

Quality of life in Huntington's disease.

HD-QoL is a standardized tool for measuring health-related quality of life. (Hocaoglu 2012) It is a validated, disease-specific measurement method developed for HD and can be used to provide an overall assessment of quality of life related to general health, as well as scores on several discrete scales. The HD-QoL scale is for people who live with HD; they include people at risk for HD, people who test positive for the huntingtin gene but do not have symptoms of the disease, and people who have the disease in the early and advanced stages. HD-QoL can be used for the entire HD spectrum.

Walking score for multiple sclerosis.

The MSWS-12 was originally developed to measure the impact of multiple sclerosis (MS) on walking ability. However, since other disabling neurological conditions also affect a person's ability to walk, this scale, after appropriate adaptation, is used as a general method for measuring walking and movement ability. This scale contains 12 items describing the impact of MS on the ability to walk, for the development of which 30 interviews of patients with MS, expert opinions and literature data were used. (Hobart 2003).

Physical performance test.

PPT quantifies a patient's performance through physical tasks. (Reuben 1990, Hocaoglu 2012) This is a standardized 9-item test that measures a patient's ability to perform functional tasks. Patients are given 2 chances to complete each of the 9 items, with assistive devices allowed for tasks that require standing (items 6 to 9). When determining the score, both the speed and accuracy of the items performed by patients are taken into account. The maximum test score is 36, with higher scores corresponding to higher performance.

Subscales of the general assessment of motor ability.

Assessment of motor ability of the hands according to UHDRS.

The hand motor ability score is defined as the sum of the UHDRS scores associated with finger tapping, pronation-supination of the hands, and the Luria technique (fist-hand test).

Gait and balance score according to UHDRS.

The gait and balance score is defined as the sum of the UHDRS scores associated with the gait, tandem walking, and retropulsion stability test.

Modified motor ability score according to UHDRS.

UHDRS-mMS is defined as the sum of the scores for the following sections of the UHDRS-TMS: dysarthria, tongue protrusion, finger tapping, hand pronation-supination, Luria technique, rigidity, bradykinesia, gait, tandem walking, and retropulsion stability test.

Other assessments of motor ability.

Quantitative assessments of motor ability.

Q-Motor scores are determined only at research centers that have the devices required to perform the scores and, if such devices are available, only for patients capable of performing the relevant tests.

Motor ability deficits can be objectively assessed using different Q-Motor scores. All Q-Motor scores are determined using calibrated temperature controlled force sensors and 3D position sensors with very high sensitivity and test-to-test stability across all sessions and centers of the multicenter clinical trial. Thus, Q-Motor measures aim to reduce the limited sensitivity of categorical clinical rating scales, the variability in single-rater and different-rater scores, and the placebo effects seen in rating scales such as the UHDRS-TMS. In addition, Q-Motor scores allow unintended motor adverse events to be objectively tracked in clinical trials.

The tasks described in the following sections were selected for use in this study. Data transmission is carried out using a secure web platform that allows for continuous centralized data monitoring and quality control. Data analysis is carried out using the blind automated method described in SAP.

Digitomotography (accelerated tapping with the index finger).

The patient places their hand on the stand so that the index finger is above the force sensor. Registration begins after a trial test. The patient is instructed to tap the finger at maximum speed during the period between 2 beeps. The start of tapping is defined as an increase in force of 0.05 N above the maximum initial level. The tapping is terminated if the force falls again to 0.05 N below the maximum initial level. Duration and variability in tapping duration (TD), onset intervals (IOI), peak intervals (IPI), and fingertip intervals (ITI) are criteria for the results of accelerated tapping experiments. In addition, peak tapping force variability (TF) is calculated as a coefficient of variation and the tapping frequency (Freq) is determined, i. the number of beats between the first and last beat divided by the time between them. For each hand, five tests of 10 s duration are carried out.

Disdiadochomotography (tapping with a brush in the position of pronation/supination).

This task allows you to evaluate the regularity of tapping with the palm and the back of the hand in turn, performed with a repeated movement of pronation/supination. The strength and duration of tapping with the hand is recorded as in the accelerated tapping task. Sound signals indicate the beginning and end of the test. For each hand, five tests of 10 s duration are carried out.

Manumotography and choreomotography (gripping force and chorea analysis).

This task allows you to evaluate the coordination of isometric gripping forces with precise clamping between the thumb and forefinger. The grip force is evaluated at the beginning of the grip, during the transport of objects and in the static phase of holding. Patients are instructed to grasp and lift the device equipped with a force sensor and a 3D position sensor by grasping it between thumb and forefinger and holding it stably next to a 10 cm marker. Grip force, 3D position and object orientation are recorded. Mean isometric grip forces and static phase grip force variability (expressed as coefficient of variation=standard deviation [SD]/mean x100) (GFV-C) are calculated over a 15 second period starting 8 s after the first beep. Five tests of 20 s duration are carried out for each hand. Chorea is evaluated by calculating a position score and an orientation score. The beginning and end of the test is marked with a sound signal.

Pedomotography (accelerated tapping of the foot) The patient places the foot on the device so that the ball of the foot is above the force sensor. Registration begins after a trial test. The patient is told to tap their foot at maximum speed during the period between 2 beeps. The start of tapping is defined as an increase in force of 0.05 N above the maximum initial level. The tapping is terminated if the force falls again to 0.05 N below the maximum initial level. The duration and variability of TD, IOI, IPI, and ITI are criteria for the results of accelerated tapping experiments. In addition, the peak TF variability is calculated as a coefficient of variation and the tapping Freq is determined, i.e. the number of beats between the first and last beat divided by the time between them. Five trials of 10 s duration are carried out for each leg.

Get up and go test.

TUG is a simple test for assessing the mobility of an individual, which requires both static and dynamic balance. This test determines the time it takes a person to get up from a chair, walk 3 meters, turn around, walk back to the chair and sit down. During the test, the person is expected to use their normal footwear and any necessary mobility aids. TUG is often used in the older population because it is easy to perform and most older people can perform it. The test takes little time, requires no special equipment or training, and is easily incorporated into the study as part of a routine medical examination. (Podsiadlo 1991) The use of the TUG test in combination with UHDRS is recommended for HD clinical trials. (Rao, 1991).

Test for the analysis of batteries of cognitive abilities.

The following sections describe the tests that are part of the short CAB.

Test for matching characters and numbers.

In the paper/pencil SDMT test, patients need to look at a key that contains pairs of specific characters and numbers from 1 to 9, and then look at a series of characters and complete them with the corresponding missing digits.

Stroop test for reading words.

The Stroop test with interference measures the patient's ability to concentrate and not be distracted. (Stroop 1935) The test consists of 3 items; you need to name the color of the rectangles (red,

- 24 039995 green or blue), read the names of the colors written in black and name the color of the ink used to print the words denoting the mismatched color. Each test consists of 100 stimuli presented on a map. The test is scored as the number of correct answers given within 45 seconds.

The Montreal Cognitive Assessment (Partial) MoCA is a publicly available paper and pencil test designed to detect mild cognitive impairment. (Bezdicek 2013) It includes assessments of visuo-spatial and operational function, memory, attention, speech, abstraction ability, delayed recall (optional) and orientation. In this study, an abbreviated version of MoCA is used, i.e. a partial MoCA scale (which includes an assessment of 3 sub-items - memory, speech and fluency).

Tests with the construction of the route A and B.

In part A of the route building test, the patient sees an image of scattered numbers enclosed in circles, and must connect the dots by drawing a line from one number to another in ascending order of numbers. Part B of the route building test is done in a similar way, except that the patient must alternate between letters and numbers (A-1-B-2-C-3, etc.). (Bowie 2006) Test A is only used as part of a workout.

Problem behavior analysis - short form.

Due to the presence of severe psychiatric symptoms in HD, it is recommended that the PBA-s form be used in all studies of HD that require behavioral assessment in order to comprehensively identify the most common psychiatric symptoms of HD. (Craufurd 2001, Kingma 2008) The PBA-s also includes questions regarding suicidal behavior, which is of particular importance in HD. The PBA-s questions address the same set of core behavioral symptoms as the UHDRS behavioral questions that have previously been used to define the overall mental criterion in most HD studies. The PBA-s contains more detailed questions and more specific guidance on conducting and defining assessments.

The PBA-s is a short, semi-structured interview covering the most common behavioral and mental manifestations of HD. The interview, which is not limited to one design but covers several broad symptom clusters relevant to HD, includes 11 items: low mood, suicidal thoughts, anxiety, irritability, anger/aggressive behavior, loss of motivation, perseverative thinking or behavior, obsessive-compulsive stereotypes of behavior, paranoid thinking, hallucinations, behavior suggesting disorientation. The severity of each symptom is rated on a 5-point scale according to well-defined scoring criteria, corresponding approximately to the following values: 0 = no symptom at all; 1=minor severity; 2=mild, 3=moderate (interfering with daily activities), and 4=severe or intolerable. The frequency of occurrence of each symptom is also assessed using the following 5-point scale: 0=no symptom; 1=less than once a week; 2=at least once a week; 3=most days (up to and including a certain part of each day); and 4=every day all day long. The severity and frequency scores are multiplied to obtain an overall RVA score for each symptom.

Safety assessment.

Adverse events.

Definition of an adverse event.

An adverse event (AE) includes any adverse medical event in a patient receiving a pharmaceutical product, whether or not it has a causal relationship to the treatment being performed.

In this study, any AE occurring after a clinical trial patient signed an informed consent form should be recorded and described as an AE.

Therefore, AE may include any undesirable and unintended physical sign, symptom, or laboratory parameter that increases or worsens in severity during the course of the study, or a significant worsening of disease during the course of the study, or any comorbid disease, whether or not considered to be associated with investigational drug. A new condition or deterioration of an existing condition is considered AE.

Stable chronic conditions (such as arthritis) that are present prior to enrollment in the study and do not worsen during the study are not considered AEs.

Worsening of the disease under study, as measured using the UHDRS and CAB scores, should be recorded as AE only if the description and/or result is indicative of a more serious condition than would be expected in the normal course of the disease in a particular patient.

Accordingly, AE may include any of the following: intercurrent illness, physical injury, events that may be related to concomitant medication,

- 25 039995 significant worsening (change in nature, severity or frequency) of the symptoms of the disease under study or other pre-existing conditions. (Note: a condition reported as pre-existing, symptoms of which appear intermittently (eg, headache) and observed during the study should be considered as an AE), drug interactions, events occurring during diagnostic procedures, or during any washout phase of this study, abnormal laboratory or diagnostic results that result in the removal of the patient from the study, are associated with clinical signs and symptoms, or SAE, or require treatment or additional diagnostic testing, or are considered clinically significant by the investigator. Note: Abnormal lab results at a screening visit that prevent a patient from enrolling in a study or receiving treatment in accordance with the study are not considered AEs, but are evaluated to monitor data from patients who do not meet screening criteria, all possible medical events. liver disease with hyperbilirubinemia (characterized by an aspartate aminotransferase (ACT) or alanine aminotransferase (ALT) level of at least 3 times the upper limit of the normal range (ULN), and a bilirubin level of at least 2 times the ULN, or an international coefficient value normalization >1.5), or events satisfying the Hy rule (Hy), requiring immediate discontinuation of study treatment and recorded as SAE. Events that satisfy the Hai (Well) rule are defined as follows:

drug-induced hepatocellular injury, in which an ALT or AST level of 3 times or more the ULN, tends to occur more frequently than a control (non-hepatotoxic) drug or placebo in some of the patients who have these elevated aminotransferase levels often exceeding 3xULN, there is also an increase in total serum bilirubin to a level >2xULN, in the absence of baseline evidence of cholestasis (serum alkaline phosphatase activity>2xULN), no other reasons explaining the combination of elevated aminotransferase and total bilirubin in serum, such as viral hepatitis A, B, or C, pre-existing or acute liver disease, or another drug likely to cause the observed injury.

Serious adverse events.

The definition of a serious adverse event SAE is an AE occurring at any dose that results in one of the following results or effects:

1) death,

2) life-threatening AE (i.e. an event that, if it occurs, poses an immediate threat to life); does not include an event which, if present in a more severe form, may cause death,

3) inpatient hospitalization, or extension of an existing hospitalization, means that admission of the patient to the hospital, and/or extension of hospital stay, is necessary for the treatment of AE, or that they are a consequence of this event. Hospitalization scheduled for a recommended procedure, or for the treatment of an existing condition that did not worsen while participating in the study, is not evidence of the onset of SAE,

4) permanent or severe disability or disability (refers to a significant impairment of the patient's ability to perform normal life functions)

5) congenital anomaly/congenital defect,

6) a major medical event that is not fatal, life threatening or does not require hospitalization, but may put the patient at risk and may require medical intervention to prevent 1 of the outcomes listed in this definition. Examples of such events include allergic bronchospasm requiring intensive care in the emergency department or at home; pathological changes in the blood or convulsions that do not require hospitalization; or the development of addiction or substance abuse. Note: Any suspected transmission of an infectious agent through a medicinal product is considered an important medical event.

An AE that does not meet any of the severity criteria listed above is considered a non-serious AE.

Removal due to an adverse event.

Any patient who experiences AE may be removed from the study at any time at the discretion of the investigator. If the patient is withdrawn in whole or in part due to AE, a blood sample is taken to measure the concentration of the study drug.

The patient is evaluated at the investigator's discretion (eg, before the event resolves or stabilizes, before the patient seeks professional medical attention, or until a cause unrelated to the investigational drug is determined or the investigation procedure is performed). The investigator should inform the medical observer as soon as possible of all patients he intends to remove due to AE. Additional reports should be provided upon request.

Portability.

Tolerability is measured as the number (%) of patients who failed to complete the study and as the number (%) of patients who failed to complete the study due to AE.

Pregnancy.

All pregnancies (pregnancies in women participating in the study and in partners of men participating in the study) occurring during the study, or within 14 days after the completion of the study, must be registered as SAE.

Any patient who becomes pregnant during the study is removed. All pregnant patients (or partners of patients) are monitored until the pregnancy is completed or terminated. If the pregnancy continues to term, its outcome (health of the baby before 8 weeks of age), including spontaneous or voluntary termination, details of delivery, and the presence or absence of any birth defects, congenital anomalies, or complications in the mother, and newborn, inform the customer. Any complication of pregnancy is considered AE or SAE, as the case may be.

If the pregnancy does not continue to the end of the term, take 1 of the following actions: in case of spontaneous abortion, it is considered as SAE; in case of artificial termination of pregnancy at the request of the patient due to malformations, the pregnancy is considered as SAE; and/or in the event of an artificial termination of pregnancy at the request of the patient, not associated with developmental anomalies, the pregnancy is not considered as SAE.

Clinical laboratory tests.

All clinical laboratory results that fall outside the range of normal values are interpreted by the investigator as belonging to 1 of the following categories:

1) abnormal, but not indicative of a clinically significant deterioration,

2) abnormal and indicative of a clinically significant deterioration.

The result of the laboratory analysis, indicating a significant deterioration (according to the medical opinion) in comparison with the initial result, is recorded and monitored. AE includes an abnormal result of a laboratory or diagnostic test (confirmed once on repeat testing) that results in removal of the patient from the study, temporary or permanent discontinuation of study drug treatment, or the need for medical attention or further diagnostic testing.

Clinical laboratory tests (serum chemistry, including electrolytes, haematology, and urinalysis) are performed at Screening (Visit 0), Baseline (Visit 1), Day 14 (Visit 2; electrolytes only), 28 Day (Visit 3), Day 42 (Visit 4), Day 56 (Visit 5), Day 84 or at early termination (Visit 6), and during the follow-up visit.

Specific laboratory analyzes are carried out according to the scheme below.

Biochemical analysis of serum.

Serum biochemical analysis is carried out for the content of the following substances:

calcium; phosphorus; sodium; magnesium; potassium; chloride; bicarbonate or carbon dioxide; glucose; urea nitrogen in the blood; creatinine; cholesterol; uric acid; ALT; ACT; lactate dehydrogenase; gamma-glutamyl transpeptidase (GGT); alkaline phosphatase; creatine phosphokinase (in case of elevated levels of creatine phosphokinase, the MB fraction should be measured); total protein, albumin; total bilirubin; direct bilirubin; indirect bilirubin; and prolactin.

Hematology.

With the help of hematological analysis determine:

hemoglobin; hematocrit; red blood cell count (RBC); the number of platelets; the number of white blood cells (WBC) and the number of certain types of leukocytes; absolute number of neutrophils; absolute number of lymphocytes; absolute number of eosinophils; absolute number of monocytes; absolute number of basophils; and the absolute number of atypical lymphocytes.

Analysis of urine.

Urine analysis is carried out to determine the following parameters:

protein; glucose; ketones; blood (hemoglobin); pH; specific gravity; leukocyte esterase; microscopic characteristics; bacteria; RBC; WBC; cylinders; and crystals.

Pregnancy tests.

Serum analysis for human chorionic gonadotropin (HCG) is performed for all women of childbearing age at the screening period. (Visit 0). Urinalysis for HCG is done for all women of childbearing age on Day 28 (Visit 3), Day 56 (Visit 5), Day 84, or early termination (Visit 6), at the follow-up visit, and if clinically indicated , at any other time. Any patient who becomes pregnant during the study is removed.

- 27 039995

Vital signs.

Vital signs are measured at the screening period (visit 0), baseline (visit 1), day 14 (visit 2), day 28 (visit 3), day 42 (visit 4), day 56 (visit 5), Day 84 or at early termination (Visit 6), and at the time of the follow-up visit. Vital signs include: pulse, blood pressure, body temperature.

Before measuring the pulse and blood pressure, the patient must be in the right place and rest for at least 5 minutes. Where possible, measurements should be taken before blood is drawn for clinical laboratory testing. Each time, vital signs are measured in a specific patient on the same arm. If an abnormal value is obtained for any vital sign, the measurement should be repeated as soon as possible. The value of any vital sign, assessed by the investigator as a clinically significant change (deterioration) from baseline, is considered AE and controlled.

Electrocardiography.

During screening (Visit 0), one resting 12-lead ECG is recorded. If this results in a prolonged QTcF interval (defined as a QTcF interval >450 ms for men, or >470 ms for women), then the ECG is repeated twice and the average of the 3 measurements taken during screening is used to determine fitness. patient to participate in the study.

ECGs are recorded in triplicate before dosing at the study center and 1-2 hours after dosing at the study center at the baseline visit (Visit 1), Day 14 (Visit 2), Day 28 (Visit 3), Day 42 day (Visit 4) and on Day 84, or at the time of the early termination visit (Visit 6). At the discretion of the investigator, a 12-lead ECG may be performed on Day 56 (Visit 5) if there are clinical circumstances that justify an additional ECG, such as a pre-existing episode of hypokalemia in the patient in the absence of QT prolongation.

Additional 12-lead ECG analyzes should be performed, at the discretion of the investigator, 1-2 hours after the daily daily dose for patients who experience an increase in QTcF > 50 ms from baseline after the morning dose. The QTcF value obtained on the device during morning ECG recording is compared with the baseline QTcF value described by the central ECG provider; if the change is >50 ms, conduct a daily ECG recording. This additional afternoon ECG measurement is performed for safety reasons, as the concentration of the study drug may be higher in the afternoon than in the morning.

Triple ECGs are also recorded during the follow-up visit, but only for patients with an existing cardiac problem and/or QTc change from baseline.

Whenever possible, ECG recordings should be performed prior to vital sign measurements and blood sampling for clinical laboratory or PK tests.

The interpretation of the ECG is the responsibility of a qualified physician at the central ECG provider. However, each ECG should be analyzed immediately at the research center to detect any QTcF prolongation indicative of a potential clinical problem and allow drug administration. Any ECG findings that are assessed by the investigator or the central ECG provider physician as a clinically significant change (worsening) from baseline are considered AEs, recorded in the primary records, transcribed into the CRF, and monitored as described.

Physical and neurological examinations.

Physical and neurological examinations, including weighing, are performed at Screening (Visit 0), Baseline Visit (Visit 1), Day 14 (Visit 2), Day 28 (Visit 3), Day 42 (Visit 4), Day 56 (Visit 5), day 84 or at the time of the early termination visit (Visit 6), and at the follow-up visit. Any physical or neurological examination findings that are judged by the investigator to be a clinically significant change (worsening) from baseline are considered AEs and monitored.

Height is measured only at the visit during the screening period.

Other criteria and safety variables.

Concomitant therapies or medications.

The use of concomitant therapy or concomitant medication is monitored throughout the study.

Columbia University scale for assessing the severity of suicidal manifestations.

The C-SSRS is used to assess the degree of a patient's suicidal ideation on a scale ranging from no suicidal thoughts to active suicidal thoughts with a specific plan and intent. (Posner 2011) C-SSRS is performed at Screening (Visit 0), Baseline Visit (Visit 1), Day 28 (Visit 3), Day 42 (Visit 4), Day 56 (Visit 5), and Day 84, or time of the early termination visit (Visit 6). Patients who have an active suicidal ideation at the screening visit, corresponding to a score of 4 or 5 on the C-SSRS scale, are not eligible for participation in the study.

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Analysis of pharmacokinetics and pharmacogenomics.

Pharmacokinetic variables.

As the main measurement of PK, the concentration of pridopidine in plasma is carried out.

The concentrations are also used for the PK model in the pridopidine group of patients and to calculate the individual exposure of patients participating in the study (Cmax and AUC).

Obtaining and processing blood samples.

Blood samples (4 ml each) are collected for plasma concentration determination by venipuncture or through an indwelling catheter in the morning prior to study drug administration at subsequent visits.

Titration period:

day 0 (baseline) - before the dose and 1-2 hours after the dose, day 14 - before the dose and 1-2 hours after the dose.

Full dose period:

day 28 before dosing and 1-2 hours after dosing, day 42 before dosing, 1-2 hours after dosing and before the patient leaves the study site, day 84 before dosing, after 1-2 h after administration and before the patient leaves the study site.

Follow-up visit.

A total of 13 samples are taken from each patient for PK analysis. In the case of SAE, an additional sample for PK is taken as soon as possible after its appearance. The date and time of receipt of each PK sample, as well as the date and time of the last drug administration prior to PK sample collection, are recorded in the original documentation and transcribed into the CRF. If the ECG is scheduled at the same time as the blood collection, the ECG is performed before the blood collection.

Samples are collected in tubes containing potassium ethylenediaminetetraacetate. Immediately after collection, samples are cooled and centrifuged for 45 minutes at approximately 4°C at 1500xg for 15 minutes. The plasma is then transferred into 2 polypropylene tubes (first aliquot [Set A] and backup aliquot [Set B]) and stored below -20°C until biological analysis.

Sample analysis.

Samples are analyzed using an appropriate approved method for the content of pridopidine and its main metabolite TV-45065 (formerly called ACR30). The lower limits of quantitative determination of pridopidine and TV-45065 in plasma are approximately 1.6 to 1.8 ng/ml and 1.5 to 1.9 ng/ml, respectively. Samples can be reanalyzed.

Pharmacogenetic variables.

At the screening visit, a blood sample (6 ml) is taken for potential genetic testing. Such tests include determination of CAG repeats, CYP2D6 status and genetic long QT syndrome (determined only for patients who, after administration of study drug, experience an increase in QT duration, leading to withdrawal from the study), or any other genetic tests associated with response to pridopidine, or with HD.

Pharmacogenetic samples are sent to the laboratory within 72 hours of collection under ambient conditions. If the laboratory does not perform DNA extraction within 24 hours, samples should be stored at -70°C until DNA extraction. After DNA extraction, the samples are stored at -20°C, or at -70°C.

Statistics.

Study design and randomization.

A double-blind, randomized, placebo-controlled, parallel-group study is being conducted to evaluate the efficacy and safety of pridopidine treatment in patients with HD. Patients are randomly assigned to receive treatment with pridopidine at doses of 45, 67.5, 90, or 112.5 mg bid, or matching placebo, in a ratio of 1:1:1:1:1.

Sample size and determination of the statistical power of the study.

Approximately 50 patients per group provide 80% power to detect a beneficial effect associated with a change in TMS of 4.5 points or more from baseline in patients in the active pridopidine group compared to placebo using the value SD 7.8 (calculated in the MermaiHD study [ACR16C008]) and a type I error of 5%.

Analyzed groups/samples.

A sample of patients who received treatment.

The Intent-to-Treat (ITT) sample includes all randomized patients. In this sample, treatment is prescribed based on the scheme in which patients were randomized, regardless of which treatment they actually receive.

Security study sample.

The safety population includes all randomized patients who receive at least 1 dose of study drug. In this population, treatment is given for

- 29 039995 on the basis of the regimen that patients actually receive, regardless of the treatment regimen in accordance with which they were randomized.

Sample for the study of pharmacokinetics.

The PK sample includes all randomized patients who have received at least 1 dose of study drug and have results indicating a plasma concentration sufficient to allow for the intended PK analysis. Patients are classified as actually receiving treatment, regardless of allocation to treatment groups.

Full Patient Analysis Sample (FAS).

The complete patient analysis sample (FAS) includes all patients in the ITT sample who are receiving at least 1 dose of study drug and have at least 1 efficacy evaluation after baseline.

Sample of patients who completed the study.

The study sample includes all patients in the ITT sample who completed the study.

Data processing rules.

When determining all variables in the statistical analysis, only experimental results obtained from patients are used. At the end of a double-blind study, repeated measures models are used to evaluate treatment effects.

Study sample.

Unless otherwise specified, the ITT sample is used to obtain all totals for the study sample. Summary information is provided by treatment group and for all patients. The safety study sample is used to generate safety variables. FAS is used to obtain performance variables. The primary efficacy variable is also analyzed in the sample of patients who completed the study.

Distribution of patients.

Results from screened patients, screened but not treated patients, safety and FAS patients, enrolled patients, and patients excluded from the study are summarized using descriptive statistics. Data from patients who withdraw from the study will also be summarized for reasons for withdrawal using descriptive statistics.

Demographic and background characteristics.

Demographic and baseline characteristics of patients are analyzed for comparison with treatment groups and summarized using descriptive statistics. Descriptive statistics (score, mean, SD, standard error, median, minimum and maximum) are used to define continuous variables. Data on the number and percentage of patients are used to define categorical variables. Categories for missing data are provided as needed.

Performance analysis.

Primary performance variables:

The primary efficacy variable in this study is the change in UHDRS-TMS value at week 12 from baseline.

Secondary functional performance variables:

overall CIBIC-Plus score at week 12 from baseline (as determined by an independent investigator), change in PDS score at week 12 from baseline, change in UHDRS-FA at week 12 from baseline.

Other functional performance indicators:

CGI-C at week 12 from baseline (determined by researcher and patient), change in UHDRS-TFC at week 12 from baseline, change in UHDRS-IS at week 12 from baseline.

Exploratory/other variables and performance endpoints.

General/functional scales:

change in HD-QoL at week 12 from baseline, change in MSWS-12 at week 12 from baseline, change in PPT at week 12 from baseline.

TMS subscales:

change in motor ability score at week 12 from baseline, change in gait and balance score at week 12 from baseline, change in UHDRS-mMS at week 12 from baseline, percentage of respondents defined as patients with change in TMS compared to baseline, <0 at week 12.

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Other assessments of motor functions:

change in Q-Motor scores at week 12 from baseline, change in TUG test score at week 12 from baseline.

Assessments of cognitive/psychiatric indicators:

change in short CAB at week 12 from baseline, change in PBA-s at week 12 from baseline.

Planned method of analysis.

FAS is used for all performance analyses. The pooled results are presented by treatment group.

Primary efficiency analysis.

The change in TMS from baseline is analyzed using a repeated measures model (SAS® MIXED procedure with REPEATED subcommand). The model includes the following fixed parameters: study week category by treatment, center, antipsychotic use or no use, and baseline TMS score. In repeated examinations of patients, an unstructured covariance matrix is used. In case the model does not converge, the maximum likelihood (ML) estimation method is used instead of the default restricted ML (REML). If the model still does not converge, use simpler covariance structures with fewer parameters, according to the following order: Heterogeneous autoregressive (1) (ARH(1)), Heterogeneous with compound symmetry (CSH), Autoregressive (1) (AR (1)) and System with compound symmetry (CS). Compare the amount of change in TMS at week 12 from baseline observed in the active drug and placebo groups.

Analysis of secondary functional variables of performance indicators.

The secondary endpoints of effectiveness are analyzed in the same manner as the primary endpoints of effectiveness, except that the design of the analysis includes the assessment of the endpoint of effectiveness at the baseline visit instead of determining the baseline TMS score. In the case of CIBIC-Plus, the analysis scheme includes the determination of the original CIBIS score instead of the original TMS score.

Analysis of other functional performance variables.

Other functional performance measures are analyzed in the same manner as the primary endpoints of performance, except that the design of the analysis includes the assessment of the endpoint of performance at the baseline visit instead of determining the baseline TMS score. In the case of CGI-C, the analysis scheme includes determining the original CGI-S score instead of the original TMS score.

Analyzes of exploratory/other performance indicators.

The exploratory/other endpoints of efficacy are analyzed in the same manner as the primary endpoints of efficacy, except that the design of the analysis includes the assessment of the endpoint of efficacy at the baseline visit instead of determining the baseline TMS score.

Pharmacokinetic/pharmacodynamic analyses.

The PK/PD model is being developed to describe the relationship between exposure and UHDRS-TMS. The model consists of the following elements: (i) structural function associated with UHDRS-TMS, pridopidine exposure (dose, AUC) and time; (ii) components of the variance characterizing the variability of model parameters among patients; (iii) components of the variance characterizing the residual variability. Model evaluation and selection is based on standard model diagnostics, matching of appropriate criteria, and simulation-based evaluations (eg, follow-up predictive checks). Attempts are being made to develop similar PK/PD models for secondary endpoints of efficacy.

Consolidation of small centers.

Centers with low patient numbers are grouped according to geographic region. The variables obtained in the pooled center are used in all statistical models that contain the center as a covariate.

Multiple comparisons and ambiguity.

Hochberg's step-up method for multiple comparisons among treatment groups and multiple secondary endpoints was used to maintain a Type I error of 5% in this experiment. Initially, the Hochberg method is used for 4 comparisons of 4 active doses with placebo. Then, any dose corresponding to a statistically significant result continues to be tested against 3 secondary endpoints using the Hochberg method.

Variable indicators and safety analysis.

Variable indicators of safety.

The overall safety and tolerability of pridopidine treatment is determined throughout the study by assessing the AE and the following additional safety variables:

- 31 039995 clinical laboratory results, vital signs,

ECG in 12 leads.

Security analysis.

All AEs are coded using the Medical Regulatory Dictionary (MedDRA). In the safety analysis, each patient is counted only once in each preferred SOC term or category. Final results are given for all AEs (overall and by severity), AEs determined by the Investigator to be related to study drug (i.e., according to perceived likelihood) (defined as related or not related) (overall and by severity). severity), serious AEs, and AEs leading to withdrawal from the study. The final results are given for experimental groups and for all patients. Lists of patients with SAE and AE requiring removal are presented.

Changes in laboratory results and vital signs are listed in descriptive order. All values are compared to predetermined ranges to identify potentially clinically significant changes or values, and such values are recorded.

The use of concomitant medicinal products is characterized by therapeutic class using descriptive statistics. Concomitant medicinal products include all drugs taken by a patient during treatment with an investigational medicinal product.

For continuous variables, for each time point, the descriptive statistics criteria (n, mean, SD, standard error, median, minimum and maximum) are given for the actual values and the change from baseline values. For categorical variables, the number and percentage of patients are reported. Descriptive information about SAE, removal of patients due to AE, and potentially clinically significant abnormal values (clinical laboratory test results or vital signs) based on previously defined criteria is also provided.

Pharmacokinetic analysis.

Plasma concentration data for pridopidine and the main metabolite TV-45065 are reported using descriptive statistics in terms of pridopidine dose and CYP2D6 metabolizer status.

The concentrations are also used for the PK-model in the group of patients receiving pridopidine, and to calculate the individual impact on the patients participating in the study (Cmax and AUC). A correlation is made between Cmax/AUC and efficacy and safety values. Other exploratory analyzes and additional covariate analyzes may also be performed.

Results.

Following administration of pridopidine for 12 weeks at 67.5, 90, and 112.5 mg bid, statistically significant changes in TMS were observed from baseline. In addition, statistically significant changes are present in the protocol containing sub-assessments of the previously described section of motor functions. These changes show that the administration of pridopidine at the indicated doses provides a successful treatment of movement disorders in patients suffering from HD. In addition, there is a change from baseline in the secondary variables and endpoints of efficacy described here, as well as in other functional variables and endpoints, from baseline, indicating that pridopidine administered at the indicated doses provides treatment for motor, mental, functional, or cognitive impairments. disorders in patients affected by HD.

Example 2: Phase 11 Randomized, double-blind, placebo-controlled, parallel-group titration study to determine the safety and efficacy of pridopidine administered at doses of 45, 67.5, 90, and 112.5 mg twice daily for the symptomatic treatment of patients with Huntington's disease, compared with placebo.

The present study evaluates the effect of pridopidine, administered at a dose of 67.5 to 112.5 mg twice daily (bid), on movement disorder in patients with HD after 26 weeks of treatment using a total motor performance score (TMS) in according to the Unified Huntington's Disease Rating Scale (UHDRS). The study also evaluates the effect of pridopidine administered for 26 weeks at a dose of 67.5 to 112.5 mg bid on physical performance (PPT). In addition, the study (i) determines the safety and tolerability of a range of pridopidine doses in patients with HD over 26 weeks of treatment, (ii) analyzes the pharmacokinetics (PK) of pridopidine in the study population, and (iii) investigates the relationship between pridopidine exposure and measured results ( for example, between clinical efficacy and toxicity parameters).

Study design.

General design and scheme of the study.

A multicenter, multinational, randomized, double-blind, placebo-controlled, parallel-group trial is being conducted to compare the efficacy and safety of 45, 67.5, 90, and 112.5 mg bid of pridopidine bid versus placebo in the treatment of movement disorders in patients with HD. The 45 mg dose level was not formally included in the efficacy analysis. In total, approximately 300 patients are enrolled in the study (60 patients in each treatment group).

Patients are randomized as in Example 1. Patients are screened as in Example 1.

During titration (days 0 to 27), patients make 2 visits to the study site: on day 0 (baseline) and on day 14. In addition, they participate in telephone conversations on days 6 and 20. At the baseline visit, the same procedure as in example 1 is followed, except that (i) the participating researcher evaluates the PPT, and (ii) UHDRS-TMC and PPT are assessed before obtaining scores on other scales.

Phone calls on days 6 and 20 are made to inquire about AEs and concomitant medications and to allow weekly dose increases the next day. During the site visit on Day 14, a blood sample is taken to monitor electrolytes prior to administration of the daily dose of study drug; if hypokalemia is observed, the administration of the drug is stopped until a normal electrolyte level is reached, maintained for 7 days. In addition to obtaining information about AE and concomitant drugs, vital signs are determined. 1-2 hours after the daily dose, a 12-lead triple ECG is recorded and then samples are collected for PK analysis.

During the full dose period (days 28 to 182), patients make a total of 7 study site visits on days 28, 42, 56, 84, 112, 140, and 182 (or at the time of early termination) and a phone call on 35 th day. Visits and procedures throughout the full dose period are scheduled around the time of the daily dose, with the exception of day 182, when only the morning dose is administered. During a telephone conversation on day 35, they ask about AE and concomitant treatment. At each visit to the study site, safety variables are determined, including ECG analysis in triplicate before dosing and 1-2 hours after dosing (ECG is optional at day 56) and clinical laboratory tests. Samples for PK, which determine the levels of pridopidine and TV-45065, are taken on days 28, 42 and 112 (before the daily dose and 1-2 hours after the daily dose), on days 84 and 140 (after 1-2 hours after the daily dose) and on day 182 (before the morning dose). If PK specimen collection and ECG recording are performed on the same day, PK specimens are collected after the ECG recording.

At days 28, 56, 84,112, 140 and 182, in addition to the safety analysis, an independent evaluator determines CIBIC-Plus, while the participating specialist evaluates UHDRS-TMS, PPT, PDS, change in the global clinical impression scale (CGI- C), TUG, PPT, UHDRS-FA, UHDRS-TFC, UHDRS-IS, short CAB and PBA-s. The patient puts scores on the MSWS-12 and HD-QoL scales, and also determines the Q-Motor. UHDRS-TMS and PPT are assessed before ratings are determined on other scales.

Patients who have completed all planned visits undergo final procedures and analyzes during the last visit (day 182). Patients who wish to withdraw from the study prior to its completion undergo procedures and tests scheduled for Day 112 at their last visit.

To assess safety, a follow-up visit is performed 2 weeks after the last dose of study drug, during which a triplicate ECG analysis (optional) and collection of samples for PK are performed. UHDRS-TMS and Q-Motor are also evaluated during this visit. Patients who complete this study may participate in an open-label extension study.

The scheme of the study of example 2 is shown in Fig. 2.

Primary and secondary variables and endpoints.

The primary variable and endpoint of efficacy in this study is the change from baseline in the UHDRS-TMS score (defined as the sum of the scores of all motor function sections of the UHDRS) at week 26. PPT, as a secondary variable and endpoint of efficacy, changes from baseline at week 26.

Other variables and end points of performance.

The following other variables and endpoints of efficacy are used in this study.

General functional scales:

overall CIBIC-Plus score at week 26 from baseline (as determined by an independent investigator), change in PDS score at week 26 from baseline, change in UHDRS FA at week 26 from baseline, CGI-C score at week 26 compared to baseline (as determined by the participant in the study and the patient), the change in UHDRS-TFC at week 26 compared to baseline,

- 33 039995 UHDRS-IS change at week 26 from baseline.

General/functional scales:

change in HD-QoL at week 26 from baseline, change in MSWS-12 at week 26 from baseline.

TMS subscales:

change in hand motor ability score (defined as the sum of UHDRS subsection scores related to finger tapping, hand pronation-supination, and the Luria technique [fist-hand-palm test]) at week 26 from baseline, change in gait and balance score ( defined as the sum of the scores of the UHDRS sections associated with gait, tandem walking, and the retropulsion stability test) at week 26 from baseline, the change in the UHDRS-mMS score (defined as the sum of the scores of the UHDRS sections associated with dysarthria, protrusion of the tongue, tapping fingers, pronation-supination of the hands, Luria technique, rigidity, bradykinesia, gait, tandem walking and retropulsion stability test) at 26 weeks from baseline, change in chorea score according to UHDRS at 26 weeks from baseline, change in UHDRS dystonia score at week 26 from baseline, % response patients defined as patients with a change from baseline in UHDRS TMS <0 at week 26.

Other assessments of motor functions:

change from baseline at week 26 in Q-Motor scores, including digitomotography (rapid index finger tapping), dysdiadochomotography (pronation/supination tapping), manumotography, and choreomotography (grip force and chorea analysis), and pedomotography (accelerated foot tapping), change in TUG test result at week 26 compared to baseline.

Assessments of cognitive/psychiatric indicators:

change in short CAB at week 26 from baseline: SDMT, emotion recognition, route building test, HVLT-R, 3 Hz paced tapping, OTS, change in PBA-s at week 26 from baseline.

Variable indicators and final safety criteria.

Safety variables and endpoints include:

AE throughout the study, changes from baseline in QTcF and other ECG parameters throughout the study, laboratory clinical safety measures (clinical chemistry, hematology, and urinalysis) throughout the study, changes in C-SSRS from baseline per throughout the study, vital signs throughout the study.

Variable indicators and final criteria of tolerance.

Variables and end points for tolerability include: number (%) of patients who failed to complete the study, number (%) of patients who failed to complete the study due to adverse events. Pharmacokinetic variables and end points.

As the main measurement of PK, the concentration of pridopidine in plasma is carried out. The concentrations are also used for the PK model in the pridopidine group of patients and to calculate the individual exposure of patients participating in the study (Cmax and AUC).

Randomization and blinding.

The allocation of patients is carried out through interactive randomization technology (IRT), using dynamic randomization to assign treatment groups to centers and take into account the use of antipsychotics. Patients are equally divided into 5 treatment groups participating in the study (4 groups receiving active drug and 1 group receiving placebo, with a distribution ratio of 1:1:1:1:1). The capsule sizes of the pridopidine 22.5 and 45 mg doses are different, so 2 different placebo capsule sizes are used, depending on the treatment group, to allow for a blind study. All drug packs have the same appearance to ensure blinding throughout each study period. Investigators, the customer, and any staff involved in examination, monitoring, patient analysis, and processing of patient results (with the exception of assigned clinical supply chain personnel) do not have information about the distribution of the patient until the database is blocked for analysis and no distribution of treatment regimens will be announced.

Investigational drugs and their dosage.

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The study drug (pridopidine and corresponding placebo) was administered as described below, the results are presented in Table 1. 4.

Study product and dosage.

The administration of pridopidine and the titration procedure are carried out as in example 1. The full dose period is carried out as in example 1, except that it lasts from 4 weeks (day 28 only) to 26 weeks, and not from 5 to 12 weeks. Example 2 uses the same other study drugs and the same doses as in Example 1.

Duration of patient participation.

Each patient's participation in the study lasts up to 30 weeks and includes a screening period of up to 2 weeks, a randomized double-blind study period of 26 weeks (comprising 4 weeks of titration and 22 weeks of the full dose period), and a follow-up period, which lasts 2 weeks after the last dose of study drug. The total duration of the study is approximately 15 months.

Procedures used in the study.

The procedures and analyzes used in the study, as well as the timing of their implementation, are described in Table. 5.

Table 4. Dose Administration (capsules are administered twice a day, _________ to reach the total daily dose)______

Treatment Titration period Full dose period 1 Week 2 weeks 3 week 4 week ^{a 4th} -26 weeks Pridopidin, 45 mg bid 1x22.5mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 1x22.5mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 1x22.5mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 1x22.5mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 1x45 mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=90mg) Pridopidin, 67.5 mg bid Pridopidin, 90 mg bid Pridopidin, 112.5 mg bid placebo 1x22.5mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 1x22.5mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 1x22.5mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 2x22.5mg placebo 1x45mg placebo 1x22.5mg pridopidine 1x22.5mg placebo 1x45mg placebo (TDD=45mg) 1x45mg pridopidine 2x22.5mg placebo (TDD=90mg) 1x45mg pridopidine 2x22.5mg placebo (TDD=90mg) 2x22.5mg placebo 1x45mg placebo 1x45mg pridopidine 2x22.5mg placebo (TDD=90mg) 1x45mg pridopidine 1x22.5mg pridopidine 1x22.5mg placebo (TDD=135mg) 1x45 mg pridopidine 1x22.5 mg pridopidine 1x22.5mg placebo (TDD=135mg) 2x22.5mg placebo 1x45mg placebo 1x45mg pridopidine 2x22.5mg placebo (TDD=90mg) 1x45mg pridopidine 1x22.5mg pridopidine 1x22.5mg placebo (TDD=135mg) 1x45 mg pridopidine 2x22.5 mg pridopidine (TDD=180 mg) 2x22.5mg placebo 1x45mg placebo 1x22.5 mg pridopidine 1x45 mg pridopidine 1x45 mg placebo (TDD=135 mg) 2x45 mg pridopidine 1x 22.5 mg placebo (TDD=180 mg) 1x22.5 mg pridopidine 2x45 mg pridopidine (TDD=225 mg) 1x22.5mg placebo 2x45mg placebo

TDD=total daily dose, ^a - except on day 28, ^b - only on day 28.

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Table 5. Procedures and assays used in the study

Titration period Full dose period Visit V0 VI ts V2 ts V3 ts V4 V5 V6 V7 V8 V9 VI0 Day From -14 up to -1 0 6 14±3 20 2 8±4 35±3 42±5 5 6±5 84±7 112±7 140±7 182±7 19 6±7 Procedures and analyzes Screening BL W1 W2 W3 W4 W5 W6 W8 W12 W16 W20 W26/E FU Out-of-pocket visit Visit to the research center X X X X X X X X X X X X Phone call X X X Informed agreement X Demography X Medical and psychiatric history X History of previous medications X Inclusion and exclusion criteria ³ X X Randomization X Clinical laboratory tests (hematology and biochemistry X X x ^b X X X X X X X X X Analysis of urine X X X X X X X X X X X Pregnancy test (for women of childbearing age) ^with X X X X X X X X X Complete physical and neurological examination, including weighing (height is measured only during the screening period) X X X X X X X X X X X ECG x ^d X ^e x ^f x ^f x ^f X9 x ^{f x1} x ^f x ^h x ^t X Measurement of vital signs X X X X X X X X X X X X C-SSRS (original version) X C-SSRS (version from last visit) X X X X X X X X

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Visit Day Procedures and tests Blood sampling for genetic analysis ¹¹ UHDRS-TMS UHDRS-FA UHDRS-TFC UHDRS-IS PBA-s CIBIS CIBIC-Plus PDS PPT CGI-S CGI-C HD-QoL MSWS-12 Q-Motor scores ¹ Titration period Full dose period VO VI TC V2 TC V3 TC V4 V5 V6 V7 V8 V9 VI0 From -14 0 6 14±3 20 28±4 35±3 42±5 56±5 84±7 112±7 140±7 182±7 196±7 to -1 Screen Ext. BL W1 W2 W3 W4 W5 W6 W8 W12 W16 W20 W26/ET FU ng visit X ¹¹ X ¹¹ X ¹¹ X ¹¹ X ¹¹ X ¹¹ X 11 XXXXXXX X ^{11 XXXXXXX} X XXXXXX XXXXXXX XXXXXXX XX X xxxxxxx TUG test X X X X X X X Analysis of batteries of cognitive abilities ¹¹ xx x xxxxx Collection of blood samples to determine drug concentration X ^e X ^p X° X° X ^p X° X ⁿ X ^h χρ X Collection of information on adverse events XXXXXXXXXXXXXXX X X X Collection of information about concomitant medicines Visit Day Procedures and analyzes Analysis of the tolerability of the investigational medicinal product before dose escalation (if any) Distribution/collection of investigational drug Verification of patient compliance with study requirements XXXXXXXXXXXXXXX X X X V0 From -14 up to -1 Screening Titration period Full dose period VI0 196+7 FU Out-of-pocket visit VI 0 BL X TS W1 V2 14+3 W2 X X TS 20 W3 V3 2 8+4 W4 TS 35+3 W5 V4 42+5 W6 V5 56+5 W8 X V6 84+7 W12 X V7 112+7 W16 X V8 140+7 W20 X V9 182+7 W26/ETX ^q Introduction investigational drug”

¥=Visit (at study site), TC=phone call, BL=baseline, W=week, ET=early termination, FU=follow-up,

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EKG=electrocardiogram,

C SSRS=Columbia University Suicidal Severity Scale,

UHDRS=Uniform Huntington's Disease Rating Scale,

CIBIS=clinician's impression of severity based on interview,

CIBIC Plus = a scale for assessing the patient's condition based on the impression of the doctor and caregivers,

CGIS=Clinical Global Impression Severity Score,

CGIC=Clinical Global Impression Scale Change Score,

TUG = test get up and go,

PDS=Physical Disability Rating Scale,

PPT = physical performance test,

HD QoL = HD quality of life rating scale,

MSWS=multiple sclerosis gait score,

CAG=cytosine-adenine-guanine,

TMS=total motor ability score,

IS=independence score,

PBA s=Problem Behavior Analysis - short form, TFC=Global Functioning Assessment, FA=Functioning Assessment,

Q Motor=measurement of motor function, SAE=serious adverse event.

Symbols (Table 5):

^a - Inclusion/exclusion criteria should be determined at screening and considered on day 0, before random allocation of the patient, b ________„„„„„

- electrolytes only

- during the screening examination, a serum test for pregnancy is performed (if necessary, a urinalysis is performed to confirm the results); at subsequent time points, a urine test for pregnancy is performed. Questionable results of the serum pregnancy test are checked twice and, if necessary, the patient is sent for a consultation with a gynecologist, ^d - one ECG is recorded during screening. If this results in a prolonged QTcF interval (defined as a QTcF interval >450 ms), then the ECG is repeated twice and the average of the 3 measurements taken during screening is used to determine the patient's eligibility for participation in the study, ^e . the time of the initial visit determine pre-dose QTcF as the average of 3 ECG (the intervals between which are from 10 to 20 minutes), and each ECG is recorded with three repetitions (total 9 records). ECG with three repetitions is also recorded 1-2 hours after the first administration of the drug. Samples for PK analysis are collected before the first dose and 1-2 hours after dosing at the study site. If sampling is performed on the same day as the ECG, samples for PK analysis are collected after ECG recording, f - ECG is recorded in triplicate before administration and 1-2 hours after the daily dose, ^g - ECG on day 56 is optional , it is recorded at the discretion of the investigator if there are clinical circumstances that justify an additional ECG, for example, a pre-existing episode of hypokalemia in a patient in the absence of QT prolongation, ^h - on day 182, before the last (morning) dose in the study, a triple ECG is performed and collect samples for PK analysis, ¹ - ECG is not required at the follow-up visit, but is measured for all patients with an existing cardiac problem and/or QTc change from baseline,

- ¹ - including CAG analysis, cytochrome P450 2D6 status, genetic long QT syndrome (determined only for patients who, after administration of study drug, experience an increase in QT duration leading to withdrawal from the study), or any other genetic analyzes associated with response to pridopidine, or with Huntington's disease, k

- analyzed first, ¹ - including assessments of digitomotography (rapid index finger tapping), dysdiadochomotography (pronation/supination hand strikes), manumotography and choreomotography (grip force and chorea analysis) and paedomotography (rapid foot tapping), ^m - includes character-number matching test, Stroop word reading test, brief Montreal Cognitive Rating Scale, and route building test B, ⁿ - Samples are collected for PK analysis at 14, 84, and 140 days 1-2 hours after administration of the morning dose. If sampling is performed on the same day as the ECG, samples for PK analysis are collected after the ECG is recorded,

- 38 039995 ^o - on days 28, 42 and 112, samples for PK analysis are collected before the administration of the morning dose and 1-2 hours after. If sampling is done on the same day as the ECG, PK samples are collected after the ECG recording, ^p - 1 PK sample is collected at the follow-up visit. With the emergence of SAE, additional sampling for PK is carried out in the near future. If these samples are collected and ECG recorded on the same day, PK samples are collected after ECG recording, ^q - collection only, ^r - each patient receives 3 capsules twice a day (bid), i.e. 3 capsules in the morning and 3 capsules in the afternoon (7-10 hours after the morning dose), throughout the study period. Study drug is not taken during the early termination visit. For study site visits, the morning dose is taken at the designated center.

The screening and enrollment procedures (Visit 0) were carried out as in Example 1, except that instead of a blood sample collection procedure for potential genetic tests, a blood sample collection procedure for CAG analysis, CYP2D6 metabolizer status, genetic analysis for the presence of long syndrome was carried out. interval (for patients who experience QT prolongation after administration of study drug), or any other potential genetic tests associated with pridopidine response or with HD.

At the baseline visit (Visit 1), the same procedures are performed as in Example 1, except that additional procedures are performed at the study center prior to dosing, and the UHDRS-TMS and PPT scores should be determined before scoring on other scales:

ECG in 12 leads with three repetitions (recorded after resting in supine position for at least 5 minutes); The pre-dose QTcF is determined as the average of 3 ECGs (recorded at intervals of 10 to 20 minutes), each of which is recorded in three repetitions (a total of 9 readings), and

CIBIS, UHDRS-TMS, UHDRS TFC and PDS are assessed before scoring other scales.

In addition, a patient who does not meet the inclusion criteria for the study based on the results of the initial test evaluations and is not eligible for participation in the study is not rescreened. Patients deemed eligible for study based on UHDRS TMS and UHDRS-IS results obtained during the screening period are not excluded from the study based on UHDRS TMS and UHDRS-IS results at baseline.

At the baseline visit (Visit 1), following the first dose, the study center performed the same procedures as in Example 1, except for a 12-lead triple ECG (1-2 hours post-dose) (recorded after lying down on the back for at least 5 minutes).

Procedures during study drug treatment.

Titration period (weeks 0 to 4).

Phone contact on weeks 1 and 3 (days 6 and 20).

Patients are contacted by phone on days 6 and 20 to assess study drug tolerability by assessing AE and concomitant medications, and to allow weekly dose increases during the titration period (see above) the following day (if possible).

Week -14 day (visit 2).

During the visit on day 14 (±3 days) 2 weeks (visit 2) the following procedures are carried out.

Before the daily dose:

AE survey, concomitant drug use analysis, clinical laboratory tests (only for electrolytes); electrolyte results should be obtained prior to drug administration, complete physical and neurological examination (including weight determination), vital signs measurements, investigational drug collection/distribution, compliance with study rules.

After the daily dose:

Triple 12-lead ECG (1-2 hours post-dose) (recorded after resting supine for at least 5 minutes), obtaining a 4 ml plasma sample for plasma drug analysis after 1-2 h after dosing; samples for PK are collected after ECG recording, but at the closest time point to it.

Full dose period (weeks 4 to 26).

Weeks 4, 6, 8, 12, 16 and 20-28, 42, 56, 84, 112 and 140 days (visits 3 to 8).

At 28 (±4 days), 42 (±5 days), 56 (±5 days), 84 (±7 days), 112 (+7 days) and 140 (+7 days) days, weeks 4,

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6, 8, 12, 16, and 20 (Visits 3 to 8) carry out the following procedures/assessments.

Before dosing:

AE survey, concomitant medication analysis, clinical laboratory tests (hematology, biochemistry, including electrolytes, urinalysis).

Only on days 28, 56, 84, 112 and 140:

urinalysis for pregnancy only for women of childbearing age complete physical and neurological examination (including determination of weight),

Triple 12-lead ECG (recorded after resting in supine position for at least 5 minutes) (Note: Day 56 ECG is optional and is at the discretion of the investigator if there are clinical circumstances that justify an additional ECG, such as an existing previous episode of hypokalemia in a patient in the absence of QT prolongation), measurement of vital signs,

C-SSRS (version from last visit).

Only for 28, 42 and 112 days:

obtaining a blood sample with a volume of 4 ml for the analysis of the drug in plasma (after ECG recording, but at the closest time to it).

Only on days 28, 56, 84, 112 and 140:

collection/distribution of the investigational medicinal product, verification of compliance with the rules of the study.

After the daily dose:

Triple 12-lead ECG (1-2 hours post-dose) (recorded after resting in supine position for at least 5 minutes) clinical circumstances that justify an additional ECG, such as a pre-existing episode of hypokalemia in the patient in the absence of QT prolongation).

Only on days 28, 42, 84, 112 and 140:

obtaining a 4 ml blood sample for drug analysis in plasma 1-2 hours after dosing; samples for PK are collected after ECG recording, but at the closest time point to it.

In addition, only on days 28, 56, 84, 112 and 140 do the following procedures/assessments to determine the effectiveness, which are carried out before or after the administration of the daily dose (the time of assessment is recorded in CRF), among which UHDRS-TMS and PPT: UHDRS-TMS, PPT, CIBIC-Plus, PDS,

UHDRS-FA, UHDRS-TFC, UHDRS-IS, CGI-C, TUG test, HD-QoL, MSWS-12, Q-Motor scores, CAB short tests (SDMT, Stroop word reading test, reduced MoCA scale, and test with route building B) and PBA-s.

Telephone contact at week 5 (day 35).

Patients are contacted by telephone at day 35 (±3 days) to determine study drug tolerance by assessing AE and using concomitant medication.

Week 26 - Day 182 (Visit 9) or early termination visit.

At Day 182 (±7 days), Week 26 (Visit 9), or at the time of the early termination visit, perform the following procedures/assessments.

Before drug administration:

AE interview, concomitant drug use review, clinical laboratory tests (hematology, biochemistry including electrolytes, urinalysis), urinalysis for pregnancy only for women of childbearing age, complete physical and neurological examination (including determination of weight ),

Triple 12-lead ECG (recorded after resting in supine position for at least 5 minutes), measuring vital signs,

C-SSRS (last visit version), obtaining a 4 ml blood sample for plasma drug analysis (after ECG recording, but as soon as possible), checking compliance with study rules, administration of the morning dose of study drug (adjusted potassium levels within the normal range) (note: study drug is not administered during the early termination visit).

After drug administration:

collection of the remaining study drug.

On Day 182 (Visit 9), the following procedures/assessments are performed to determine efficacy, before or after drug administration, among which UHDRS-TMS and PPT are primarily evaluated: UHDRS-TMS, PPT, CIBIC-Plus, PDS, UHDRS-FA , UHDRS-TFC, UHDRS-IS, CGI-C, TUG test, HD-QoL, MSWS-12, Q-Motor scores, CAB short tests (SDMT, Stroop Word Reading Test, MoCA Abbreviated Scale and Path Building Test B ) and PBA-s.

At Day 84/Early Stop Visit, no daily dose is administered.

Follow-up visit.

There is a follow-up visit 2 weeks after the last dose of study drug (day 196, ±7 days). During this visit, the following procedures/assessments are performed:

AE interview, concomitant drug use review, clinical laboratory tests (hematology, biochemistry, urinalysis), urinalysis for pregnancy only for women of childbearing age, complete physical and neurological examination (including weight determination), optional ECG at 12 triple leads (after resting in supine position for at least 5 minutes), which should be recorded for all patients with an existing cardiac problem and/or with a clinically significant change in QTc from baseline, measurement of vital signs,

UHDRS-TMS, Q-motor scores, 4ml blood sample acquisition for plasma drug analysis after ECG recording.

Procedures performed after study drug treatment/withdrawal.

If patients participate in the study, following its protocol, for at least 26 weeks of double-blind treatment, they are considered to have completed participation in the study.

For patients who have completed or terminated study participation prematurely, conduct final analyzes at week 26/early termination visit (Visit 9). Patients who did not complete their last visit within 7 days of their last dose of study drug were not evaluated for efficacy.

The sections of unscheduled visits and the study sample in example 2 are similar to the corresponding sections of example 1.

Selection and removal of patients.

The inclusion/exclusion criteria are documented throughout the selection process and, in addition, prior to randomization, the investigator documents the results of the analysis of the inclusion/exclusion criteria. Patients continue to be screened for inclusion/exclusion criteria at the baseline visit. If a patient no longer meets the inclusion/exclusion criteria at the initial visit, the patient may not participate in the study. Baseline laboratory values are not known until randomization is completed; when identifying the initial values of laboratory parameters, indicating that the patient cannot participate in the study, representatives of the center discuss them with a medical observer.

Example 2 uses the same Patient Inclusion Criteria, Patient Exclusion Criteria, Patient Removal Criteria and Procedure as in Example 1.

However, Example 2 uses the following additional criterion.

Patients with clinically significant cardiovascular disease at the screening visit are defined as follows: (i) the presence of a significant heart attack (eg, myocardial infarction), angina pectoris, or an episode of heart failure with New York Heart Association classification >2 symptoms within 12 weeks prior to randomization, or the presence of cardiac disease that, in the investigator's opinion, increases the risk of ventricular arrhythmia, (ii) a history of arrhythmia (multifocal ventricular premature beats, bigeminy, trigeminy, ventricular tachycardia) that is symptomatic or requiring treatment (general terminological criteria for grade 3 adverse events), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia, (iii) presence of left bundle branch block.

The Cockcroft-Gault equation is described as (140 age) x mass (kg) x [0.85 if the patient is female]/72 x serum creatinine (mg/dL).

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The Treatment of Patients/Administration of Study Drugs sections in Example 1 and Example 2 are identical.

Sections (i) Previously taken and concomitant regimens or drugs, (ii) Authorized drugs and (iii) Prohibited drugs, or procedures described therein, in example 1 and in example 2 are identical. However, in addition to these, if a change in the use or dosage of the antipsychotic agent is required in the opinion of the specialist during the study, this is recorded in the CRF and discussed with the medical supervisor. In addition, bupropion is an antidepressant that can be administered to study patients. Although PK interactions between bupropion and pridopidine are not expected to occur, bupropion is associated with seizures in about 0.4% (4/1000) of patients at doses up to 450 mg/day. This incidence of seizures may be up to 4 times higher than that associated with other commercially available antidepressants (wellbatrin label). A retrospective analysis of clinical experience with bupropion suggests that the risk of seizures can be minimized if the total daily dose of bupropion does not exceed 450 mg administered 3 times a day (with each single dose not exceeding 150 mg, and the rate of dose increase should be very gradual).

The total volume of blood.

The calculated values of the total blood volume to be obtained from each patient are shown in Table. 6.

Table 6. Total blood volume obtained from each patient

Analysis type Number of samples collected Volume of one sample Total volume for analysis Pharmacokinetics 13 4 ml 52 ml Serum biochemistry eleven 10.5 ml 115.5 ml Hematology 9 3 ml 27 ml Pharmacogenetic analyzes 1 10 ml 10 ml Total 204.5 ml

CAG=cytosine-guanine-adenosine, CYP2D6=cytochrome P450 2D6.

Efficiency mark.

Unless otherwise noted, the performance evaluations described in the following sections are performed on Day 0 (Visit 0, baseline), Day 28 (Visit 3), Day 56 (Visit 5), Day 84 (Visit 6), Day 112 (Visit 7), day 140 (visit 8) and day 182 (visit 9). With the exception of day 0, efficacy evaluations can be made before or after the daily dose, with the timing of the evaluation recorded in the CRF. UHDRS-TMS and Q-Motor assessments are also performed during the follow-up visit.

Example 2 uses the same primary variables and outcome measures as in Example 1.

Secondary variables and endpoints of performance.

Physical performance test.

The PPT test is described in Example 1. The secondary efficacy variable in this study is the change in PPT at week 26 from baseline.

Other variables and end points of performance.

Other performance variables and outcome measures are described in the sections below.

A scale for assessing the patient's condition based on the impression of the doctor and caregivers.

The overall change in HD at week 26 was measured as described in Example 1.

At each subsequent visit (Visits 3, 5, 6, 7, 8, and 9), a CIBIC-Plus assessment is performed as described in Example 1. However, for the purposes of this study, the caregiver is recommended to visit the patient at least 2-3 times a week, each visit must last at least 3 hours, and the suitability of the caregiver is determined by the researcher. If possible, the same person will be the caregiver throughout the study. If this is not possible, no more than 2 people will care for the patient throughout the study.

Scale for assessing physical disability.

PDS is used during the study as described in Example 1.

Functional ratings according to UHDRS.

Using the FA UHDRS scale, the functionality is evaluated as in example 1.

Evaluation of the severity of the disease and its changes on a scale of general clinical impression.

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CGI-S is assessed at baseline (Day 0) and CGI-C at all subsequent time points (Visits 3, 5, 6, 7, 8 and 9) to evaluate changes from baseline. Conducting CGI-S and CGI-C assessments is described in Example 1.

Assessment of overall ability to function according to UHDRS.

The TFC UHDRS scale covers 5 areas of functioning related to disability (employment, finances, household chores, activities of daily living and level of care required).

UHDRS independence scale.

The UHDRS independence scale is described in Example 1.

General/functional scales.

Quality of life in Huntington's disease.

The HD-QoL assessment is described in Example 1.

Walking score for multiple sclerosis.

The MSWS-12 evaluation is described in Example 1.

Subscales of the general assessment of motor ability:

assessment of motor ability of the hands according to UHDRS, the assessment of motor ability of the hands is described in example 1.

Gait and balance score according to UHDRS.

Gait and balance assessment is described in example 1.

Modified motor ability score according to UHDRS.

UHDRS-mMS is defined as the sum of the scores for the following sections of the UHDRS-TMS: dysarthria, tongue protrusion, finger tapping, hand pronation-supination, Luria technique, rigidity, bradykinesia, gait, tandem walking, and retropulsion stability test.

Chorea UHDRS score.

For UHDRS, chorea scores are maximal on a scale of 0 (none) to 4 (significant/prolonged) for each of the following body parts: face, mouth, trunk, right upper limb, left upper limb, right lower limb, and left lower limb. The maximum chorea score is the sum of all scores.

UHDRS dystonia score.

In UHDRS, the maximum score for dystonia is determined on a scale from 0 (none) to 4 (significant/prolonged) for each of the following body parts: trunk, right upper limb, left upper limb, right lower limb, and left lower limb. The maximum score for dystonia is the sum of all scores.

Share of TMS respondents.

Percentage of responders defined as patients with UHDRS-TMS change from baseline <0 at week 26.

Other assessments of motor ability.

Quantitative assessments of motor ability,

Q-motor ratings are described in example 1.

Digitomotography (accelerated tapping with the index finger).

Digitomotography (accelerated tapping with the index finger) is carried out as in example 1.

Disdiadochomotography (tapping with a brush in the position of pronation/supination).

Disdiadochomotography (tapping with the brush in the position of pronation / supination) is carried out as in example 1.

Manumotography and choreomotography (gripping force and chorea analysis).

This test is described in example 1.

Pedomotography (accelerated foot tapping).

This test is described in example 1.

Test Get up and go.

The TUG test is carried out as described in Example 1.

Analysis of batteries of cognitive abilities.

The following sections describe the tests that are part of the CAB.

Test for matching characters and numbers.

The SDMT is a paper-and-pencil test that analyzes psychomotor speed and working memory. Participants need to look at the key at the top of the page, which contains pairs of characters and numbers. The rest of the page shows rows of symbols and the participant has 90 seconds to write the numbers corresponding to each symbol.

Emotion recognition.

Emotion recognition by facial expression is carried out using computer-generated photographs depicting the main emotions or a neutral facial expression. Participants are asked to indicate the emotion expressed in each photo by selecting one of the words: fear, disgust, happiness, sadness, surprise, anger, and a neutral facial expression (10 stimuli per emotion).

Tests with the compilation of routes A and B.

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Part A of the route design test is described in Example 1. Route A is only used as part of a workout.

Hopkins Verbal Learning Test, Modified.

The HVLT-R provides a brief analysis of verbal learning and memory (recognition and recall). This test is easy to perform and evaluate, and is well tolerated even by patients with significant impairment. Its use to measure verbal learning and memory has been validated in brain-impaired populations (eg, Alzheimer's disease, HD, amnesic disorder). Each form contains a list of 12 nouns (goals), 4 words taken from each of the 3 semantic categories. Semantic categories differ among the 6 forms, but the forms are very similar in terms of psychometric properties. Preliminary scores are obtained for the ability to recall everything, delayed recall, retention (percentage of information retained in memory) and recognition discrimination index. The HVLT-R is highly repeatable, and its constructive, ongoing, and discriminant validity are well established.

Tapping test with a given tempo.

Psychomotor function is assessed using the Pace Tap Test. Participants press the left and right mouse buttons, alternating thumbs, at 3.0 Hz. First, they listen to a beep corresponding to the desired tapping speed, and then start pressing the buttons in time with the beep. After 11 presses in time with the beep, the repetition of the beep is stopped and the participants attempt to continue pressing the buttons at the same rate until the end of the test (another 31 presses).

Cambridge Test One Touch Stockings (OTS).

OTS is a spatial planning task that measures the function of the anterior lobe of the brain. OTS is a variant of the Cambridge Stockings task that emphasizes working memory as the participant must visualize the solution. As in the Cambridge stockings test, the participant is shown 2 boards with the image of 3 different-colored balls. The scoreboards are arranged in such a way that they can be easily imagined as stockings or socks suspended from the crossbar, in which the balls are stacked. This arrangement makes 3D concepts obvious to the participant and follows verbal instructions.

At the bottom of the screen is a row of numbered squares. First, the tester demonstrates to the participant how to use the balls on the lower board to copy their location on the upper board, and solves 1 demonstration problem in which 1 action must be performed. Then the participant must solve 3 more problems, in 2, 3 and 4 actions. After that, the participant is shown several more problems, and he must determine in his mind how many actions are required to solve them, and then touch the square with the corresponding number at the bottom of the screen.

Problem behavior analysis - short form.

Visual attention and the ability to solve switching tasks are assessed using a route building test, which is carried out using a standard sheet of paper containing an image of 25 circles. In part A of the route building test, participants need to connect circles containing numbers as quickly as possible in ascending order. In part B of the route building test, participants need to connect circles containing numbers and letters as quickly as possible, in ascending order, alternating letters and numbers (for example, 1, A, 2, B, 3, C, etc.). Test A is only used as part of a workout.

Safety assessment.

In this example (Example 2), safety is assessed by qualified study personnel based on the following indications: registered AEs, clinical laboratory test results, vital signs measurements, ECG results, physical and neurological examination results (including body weight determination) and data on the use of concomitant medicinal products.

During the study, the independent Safety Committee analyzes the accumulated safety data in 2 cases:

the first analysis is carried out 6 weeks after the enrollment of 10 patients in each treatment group (ie, a total of 50 patients). The second analysis is performed 6 weeks after the enrollment of approximately 20 patients in each treatment group (ie, a total of 100 patients);

The Safety Committee is composed of independent physicians experienced in the relevant field of therapy (i.e. at least a cardiologist and neurologist) and other relevant experts such as statisticians and PKs. They have the right to recommend discontinuation of 1 or more treatment groups for safety reasons.

Adverse events and removal due to adverse events.

See section Adverse Events and Deletion Due to Adverse Events in Example 1.

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Clinical laboratory tests.

All clinical laboratory tests were performed as described in the Clinical Laboratory Tests section of Example 1, except for the time schedule below.

Clinical laboratory tests (serum chemistry, including electrolytes, hematology, and urinalysis) are performed at Screening (Visit 0), Baseline Visit (Visit 1), Day 14 (Visit 2; electrolytes only), Day 28 ( visit 3), day 42 (visit 4), day 56 (visit 5), day 84 (visit 6), day 112 (visit 7), day 140 (visit 8), day 182 (visit 9), or during the visit early termination, as well as during the follow-up visit.

Pregnancy tests.

Serum testing for human chorionic gonadotropin (HCG) is performed on all women of childbearing age at screening (Visit 0). Urinalysis for HCG is performed for all women of childbearing age on Day 28 (Visit 3), Day 56 (Visit 5), Day 84 (Visit 6), Day 112 (Visit 7), Day 140 (Visit 8), Day 182 (Visit 9), or during the early termination visit, during the follow-up visit and, if clinically indicated, at any other time. Doubtful results of a serum pregnancy test are checked twice and, if necessary, the patient is sent for a consultation with a gynecologist. Any patient who becomes pregnant during the study is removed.

Vital signs.

Vital signs are measured at Screening (Visit 0), Baseline Visit (Visit 1), Day 14 (Visit 2), Day 28 (Visit 3), Day 42 (Visit 4), Day 56 (Visit 5), 84 Day (Visit 6), Day 112 (Visit 7), Day 140 (Visit 8), Day 182 (Visit 9), or at the time of the early termination visit and also at the follow-up visit. Vital signs include: pulse, blood pressure, body temperature and the following procedures described in example 1.

Electrocardiography.

One resting 12-lead ECG is performed after resting in the supine position for at least 5 min, during the screening period (Visit 0). If data is obtained during the screening period indicating a long QTcF interval (defined as a QTcF interval >450 ms), then the ECG is repeated twice and the average of 3 measurements during the screening period is used to determine if the patient is eligible for participation in the study.

At the baseline visit, pre-dose QTcF is determined as the average of 3 ECGs (10 to 20 minutes apart) with each ECG recorded in triplicate (9 total). ECG with three repetitions is also recorded 1-2 hours after the first administration of the drug.

ECG is recorded in triplicate before drug administration at the study center and 1-2 hours after dosing at the study center on day 14 (Visit 2), day 28 (Visit 3), day 42 (Visit 4), day 84 (Visit 4). 6), day 112 (visit 7), day 140 (visit 8). On day 182 (Visit 9), or at the early termination visit, a triple ECG is recorded prior to the morning dose. At the discretion of the investigator, a 12-lead ECG is also recorded on day 56 (Visit 5) if there are clinical circumstances that justify an additional ECG, such as a pre-existing episode of hypokalemia in the patient in the absence of QT prolongation.

Triple ECGs are recorded at the follow-up visit only for patients with a pre-existing cardiac problem and/or a QTc change from baseline.

Before each ECG measurement, the patient rests in the supine position for at least 5 minutes. Whenever possible, ECG recordings are performed prior to vital sign measurements and blood collection for clinical laboratory or PK analyses.

The interpretation of the ECG is the responsibility of a qualified physician at the central ECG provider. However, each ECG should be analyzed immediately at the research center to detect any QTcF prolongation indicative of a potential clinical problem and allow drug administration. Analysis of the ECG obtained during the screening period in order to include the patient in the study can be carried out on the spot, i.e. no central ECG provider interpretation is required for inclusion. Any ECG findings that are assessed by the investigator or central ECG provider physician as a clinically significant change (worsening) from baseline are considered AEs, recorded in the primary records, transcribed into the CRF, and monitored.

Physical and neurological examinations.

Physical and neurological examinations, including weighing, are performed at Screening (Visit 0), Baseline Visit (Visit 1), Day 14 (Visit 2), Day 28 (Visit 3), Day 42 (Visit 4), Day 56 (Visit 5), Day 84, Day 112 (Visit 7), Day 140 (Visit 8), Day 182 (Visit 9), or at the early termination visit and at the follow-up visit. Any results of a physical or neurological examination that are assessed by the investigator as a clinically significant change (deterioration) from baseline are considered AEs, recorded in

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CRF and are monitored.

Height is measured only at the visit during the screening period.

Other criteria and safety variables.

The use of concomitant therapy or concomitant medication is monitored throughout the study.

Columbia University scale for assessing the severity of suicidal manifestations.

The C-SSRS is used to assess the degree of a patient's suicidal ideation on a scale ranging from no suicidal thoughts to active suicidal thoughts with a specific plan and intent (Posner 2011). C-SSRS is done at Screening (Visit 0), Baseline Visit (Visit 1), Day 28 (Visit 3), Day 42 (Visit 4), Day 56 (Visit 5), Day 84, Day 112 (Visit 7) , Day 140 (Visit 8), Day 182 (Visit 9), or at the time of the early termination visit. Patients who have an active suicidal ideation at the screening visit, corresponding to a C-SSRS score of 4 or 5, are not eligible to participate in the study.

Analysis of pharmacokinetics and pharmacogenomics.

Pharmacokinetic variables are described in Example 1.

Obtaining and processing blood samples.

Blood samples (4 ml each) are collected for plasma concentration determination by venipuncture or through an indwelling catheter in the morning prior to study drug administration at subsequent visits.

Titration period:

day 0 (baseline) - before the first dose and 1-2 hours after its administration,

Day 14 - 1-2 hours after the daily dose.

Full dose period:

day 28 - before the daily dose and 1-2 hours after the daily dose, day 42 - before the daily dose and 1-2 hours after the daily dose, day 84 - 1-2 hours after the daily dose, day 112 - before the daily dose and 1-2 hours after the daily dose, day 140 - 1-2 hours after the daily dose, day 182 - before the morning dose.

Follow-up visit.

A total of 13 samples are taken from each patient for PK analysis.

In the case of SAE, an additional sample for PK is taken as soon as possible after its appearance.

The date and time of receipt of each PK sample, as well as the date and time of the last drug administration prior to PK sample collection, are recorded in the original documentation and transcribed into the CRF. Only significant deviations (>5%) from the planned blood collection time are commented on the corresponding CRF page.

If the ECG is scheduled on the same day as the blood collection, the ECG is performed before the blood collection.

Samples are collected in tubes containing potassium ethylenediaminetetraacetate. Immediately after collection, samples are cooled and centrifuged for 45 minutes at approximately 4°C at 1500xg for 15 minutes. The plasma is then transferred into 2 polypropylene tubes (first aliquot [Set A] and backup aliquot [Set B]) and stored below -20°C until biological analysis.

Sample analysis.

Samples are analyzed as described in Example 1.

Pharmacogenetic variables.

At the screening visit, a blood sample (10 ml) is collected in 2 plastic tubes containing potassium ethylenediaminetetraacetate (K2EDTA) for genetic analysis. Such tests include determination of CAG repeats, CYP2D6 status and genetic long QT syndrome (determined only for patients who, after administration of study drug, experience an increase in QT duration, leading to withdrawal from the study), or any other genetic tests associated with response to pridopidine, or with HD. CAG repeat assays in a sample obtained during the screening period are not used to assess a patient's eligibility for study participation; it is estimated using historical data.

Pharmacogenetic samples are sent to the laboratory within 72 hours of collection under ambient conditions. If the laboratory does not perform DNA extraction within 24 hours, samples should be stored at -70°C until DNA extraction. After DNA extraction, the samples are stored at -20°C, or at -70°C.

Brief description of performance analysis.

Primary performance variable.

The primary efficacy variable in this study is the change in UHDRS-TMS value at week 26 from baseline.

Secondary performance variable.

The secondary efficacy variable in this study is the change in PPT at week 26 from baseline.

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Other performance variables.

General functional scales:

overall CIBIC-Plus score at week 26 from baseline (as determined by an independent investigator), change in PDS score at week 26 from baseline, change in UHDRS FA at week 26 from baseline, CGI-C score at week 26 from baseline (as determined by the participating practitioner and patient), change in UHDRS-TFC at week 26 from baseline, change in UHDRS-IS at week 26 from baseline.

General/functional scales:

change in HD-QoL at week 26 from baseline, change in MSWS-12 at week 26 from baseline.

TMS subscales:

change in motor ability score at week 26 from baseline, change in gait and balance score at week 26 from baseline, change in UHDRS-mMS score at week 26 from baseline, change in UHDRS-chorea score at week 26 from baseline, change in UHDRS dystonia score at week 26 from baseline, percentage of responders defined as patients with UHDRS TMS change from baseline <0 at week 26.

Other assessments of motor functions:

change in Q-Motor scores at week 26 from baseline, change in TUG test score at week 26 from baseline.

Assessments of cognitive/psychiatric indicators:

change in short CAB at week 26 from baseline, change in PBA-s at week 26 from baseline.

Primary efficiency analysis.

The pridopidine 45 mg bid versus placebo group is used for additional comparison with previous pridopidine trials (ACR16C008 [MermaiHD] and ACR16C009 [HART]) in which pridopidine 45 mg bid was used as the maximum dose.

In addition, any treatment group that is terminated for safety reasons is not formally tested for efficacy and therefore is not tested for Type I error.

The change in UHDRS-TMS from baseline is analyzed using a repeat measurements model (SAS® MIXED procedure with REPEATED subcommand). The model includes the following fixed parameters: study week category by treatment, center, antipsychotic use or no use, and baseline UHDRS-TMS score. In repeated examinations of patients, an unstructured covariance matrix is used. In case the model does not converge, the maximum likelihood (ML) estimation method is used instead of the default restricted ML (REML). If the model still does not converge, use simpler covariance structures with fewer parameters, according to the following order: Heterogeneous autoregressive (1) (ARH(1)), Heterogeneous with compound symmetry (CSH), Autoregressive (1) (AR (1)) and System with compound symmetry (CS). Compare the amount of change from baseline in UHDRS-TMS at week 26 observed in active drug groups (groups receiving 67.5, 90, or 112.5 mg bid who did not withdraw from the study for safety reasons) and in the placebo group.

Sensitivity analysis.

Sensitivity analyzes are performed as described below to assess whether the effect observed by UHDRS-TMS depends on the UHDRS-TMS chorea subscore, the UHDRS-TMS dystonia subscore, or the UHDRS-TMS involuntary movements (chorea+dystonia) subscore.

Three variables are calculated:

change in sum of scores for UHDRS-TMS items excluding chorea items at week 26 from baseline, change in sum of scores for UHDRS-TMS items excluding dystonia items at week 26 from baseline, change in sum UHDRS-TMS item scores excluding chorea and dystonia items at week 26 from baseline.

These variables are analyzed in the same manner as the primary endpoints of efficacy, except that instead of the baseline UHDRS-TMS value, the model uses the variable score obtained at the baseline visit.

Analysis of secondary performance variables.

Any dose that produces a statistically significant effect observed in the primary analysis continues to be tested with secondary end points defined at the 5% alpha level.

The change in PPT from baseline is analyzed using a repeated measurement model (SAS® MIXED procedure with REPEATED subcommand). The model includes the following fixed parameters: study week category by treatment, center, use or non-use of antipsychotics, and baseline PRT score. In repeated examinations of patients, an unstructured covariance matrix is used. In case the model does not converge, use the ML estimation method instead of the default REML. If the model still does not converge, use simpler covariance structures with fewer parameters, according to the following order: ARH(1), CSH, AR(1), and CS. Compare the amount of change in the PPT value determined during the visit at week 26, compared with baseline, observed in the groups receiving the active drug, and in the group receiving placebo.

Analyzes of other performance variables.

Differences between respondents are compared between active and placebo groups using logistic regression analysis (SAS® LOGISTIC procedure) stratified by country using the STRATA subcommand, taking into account the following factors: treatment group, antipsychotic use or no use and baseline UHDRS-TMS score.

The other endpoints of effectiveness are analyzed in the same way as the primary endpoint of effectiveness, except that instead of the baseline UHDRS-TMS value, the model uses the estimate of the endpoint of effectiveness obtained at the baseline visit.

In the case of CIBIC-Plus, instead of the original UHDRS-TMS value, the model uses the CIBIS score obtained during the initial visit.

In the case of CGI-C, instead of the original UHDRS-TMS value, the model uses the CGI-S score obtained during the initial visit.

Impact response analyses.

Determine the correlation between Cmax/AUC, efficacy and safety.

Consolidation of small centers.

Centers with low numbers of patients are pooled. The variables obtained in the pooled center are used in all statistical models that contain the center as a covariate.

Multiple comparisons and ambiguity.

Hochberg's step-up method for multiple comparisons among treatment groups, combined with a hierarchical method among primary efficacy endpoints and secondary efficacy endpoints, was used to maintain a Type I error of 5% in this experiment.

The pridopidine 45 mg bid versus placebo group is used for additional comparison with previous pridopidine trials (ACR16C008 [MermaiHD] and ACR16C009 [HART]) in which pridopidine 45 mg bid was used as the maximum dose. Therefore, multiple placebo comparisons are made up to a maximum of 3 doses, with type I error checking in this study: 67.5, 90 and 112.5 mg bid. Initially, the Hochberg method is used to compare 3 (or less) active doses (67.5, 90 and 112.5 mg bid) with placebo. Then, using a hierarchical method, any dose that produces a statistically significant effect continues to be tested against a secondary endpoint at an alpha level of 5%.

In addition, any treatment group that is terminated for safety reasons is not formally tested for efficacy and therefore is not tested for Type I error.

Variable indicators and safety analysis.

Variable indicators of safety.

The overall safety and tolerability of pridopidine treatment is determined throughout the study by assessing the AE and the following additional safety variables:

results of clinical laboratory tests, vital signs,

ECG in 12 leads,

C-SSRS.

Security analysis.

All AEs are coded using the Medical Regulatory Dictionary (MedDRA). In the safety analysis, each patient is counted only once in each preferred SOC term or category. The final results are given for all AEs (in general and in terms of

- 48 039995 severity), AEs defined by the investigator as related to the study drug (defined as related or not related) (in general and by severity), serious AEs, and AEs leading to withdrawal from the study. The final results are given for experimental groups and for all patients. Lists of patients with SAE and AE requiring removal are presented.

Changes in laboratory results and vital signs are listed in descriptive order. All values are compared to predetermined ranges to identify potentially clinically significant changes or values, and such values are recorded.

The use of concomitant medicinal products is characterized by therapeutic class using descriptive statistics. Concomitant medicinal products include all drugs taken by a patient during treatment with an investigational medicinal product.

For continuous variables, for each time point, the descriptive statistics criteria (n, mean, SD, standard error, median, minimum and maximum) are given for the actual values and the change from baseline values. For categorical variables, the number and percentage of patients are reported. Descriptive information about SAE, removal of patients due to AE, and potentially clinically significant abnormal values (clinical laboratory test results or vital signs) based on previously defined criteria is also provided.

If any patient dies during the study, a list of deaths is provided and all relevant information is discussed in the patient's medical history included in the Clinical Study Report.

Pharmacokinetic analysis.

Plasma concentration data for pridopidine and the main metabolite TV-45065 are reported using descriptive statistics in terms of pridopidine dose and CYP2D6 metabolizer status. The concentrations are also used for the PK-model in the group of patients receiving pridopidine, and to calculate the individual impact on the patients participating in the study (Cmax and AUC).

Results.

Following administration of pridopidine for 26 weeks at 67.5, 90, and 112.5 mg bid, statistically significant changes in UHDRS-TMS from baseline were observed. In addition, statistically significant changes are present in the protocol containing sub-assessments of the previously described section of motor functions. These changes show that the administration of pridopidine at the indicated doses provides a successful treatment of movement disorders in patients suffering from HD. In addition, there is a change from baseline in the secondary variables and endpoints of efficacy described here, as well as in other functional variables and endpoints, from baseline, indicating that pridopidine administered at the indicated doses provides treatment for motor, mental, functional, or cognitive impairments. disorders in patients affected by HD.

Example 3: Phase II. Randomized, double-blind, placebo-controlled, parallel-group titration study to determine the safety and efficacy of 45, 67.5, 90, and 112.5 mg pridopidine administered twice daily for the symptomatic treatment of patients with disease Huntington compared to placebo.

Example 3 is identical to example 2, except for the following. If there are any differences between the procedures described in Example 2 and those described below, the procedures below are for use in Example 3.

The Modified Physical Performance Test (mPPT) is used instead of the Physical Performance Test (PPT). The Walk-12 scale is used in place of the Multiple Sclerosis Walking Scale (MSWS).

An EQ5D or EQ5D-5L score is performed at (at least): baseline visit and visit 9 (day 182).

UHDRS-TMC and mPPT are evaluated at days 28, 56, 84, 112, 140 and 182.

At days 28, 84 and 182, in addition to the safety assessment, UHDRS-TMS and MPPT, CIBIC-Plus, PDS, CGI-C, TUG test, UHDRS-FA, UHDRS-TFC, UHDRS-IS and PBA-s are evaluated. Preferably, UHDRS-TMS and mPPT are scored before other scales are scored. The patient completes the Walk-12 and conducts the Q-Motor assessment. UHDRS-FA, UHDRS-TFC and UHDRS-IS are also run on day 140. CAB is performed only on days 84 and 182. The HD-QoL and EQ5D scales are evaluated only on day 182.

The procedures described in Table. 5 and the corresponding sections of Example 2 and the procedures used in Example 3 differ as follows: PBA-s, CIBIC-Plus, PDS, CGI-C, MSWSWalk-12 and TUG test are performed during the following visits: baseline (V1); 4 weeks (V3), 12 weeks (V6) and 26 weeks/early termination (V9). The HD-QoL score is assessed at baseline visit (V1) and at 26 weeks/early termination (V9). The EQ5D-5L scale is assessed at the baseline visit (V1) and

- 49 039995 at 26 weeks/early termination (V9). Q-Motor evaluations are performed at screening (V0), baseline visit (V1), week 4 (V3), week 12 (V6), week 26/early termination (V9), and at follow-up visit. Analysis of the battery of cognitive abilities is carried out during the following visits: at the screening period (V0); original (V1); at 12 weeks (V6) and at 26 weeks/early termination (V9).

On days 28, 56, 84, 112 and 140, the following procedures/efficacy evaluations are performed in priority order before or after the daily dose (with registration of evaluation time): UHDRS-TMS and mPPT. On days 28 and 84, in addition to UHDRS-TMS and mPPT, which are evaluated first, the following procedures/efficacy evaluations are carried out before or after the administration of the daily dose (with registration of evaluation time): CIBIC-Plus, PDS, UHDRS-FA, UHDRS- TFC, UHDRS-IS (UHDRS-FA, UHDRS-TFC, UHDRS-IS also performed at day 140), CGI-C, TUG test, Walk-12, Q-Motor and PBA-s scores. In addition, CAB tests (SDMT, emotion recognition, route planning, HVLTR, tapping at a given pace at 3 Hz, OTS) are performed only on day 84.

Abstinence is an acceptable method of contraception only when it relates to the subject's preferred and usual lifestyle. Intermittent abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (withdrawal), and the lactational amenorrhea method (LAM) are not acceptable methods of contraception.

Primary and secondary efficacy evaluations (UHDRS-TMS and mPPT) are performed on Day 0 (Visit 0, Baseline), Day 28 (Visit 3), Day 56 (Visit 5), Day 84 (Visit 6), Day 112 (Visit 7) , 140 days (visit 8) and 182 days (visit 9). Exploratory performance evaluations are performed only on day 0 (visit 0, baseline), day 28 (visit 3), day 84 (visit 6), and day 182 (visit 9); except for CAB, which only take place on day 0 (visit 0, baseline), day 84 (visit 6), and day 182 (visit 9); and UHDRS FA, UHDRS TFC and UHDRS IS, which are also carried out at day 140. With the exception of day 0, efficacy evaluations are carried out before or after the daily dose, recording the time of evaluation. UHDRS-TMS and mPPT are evaluated before other exploratory endpoints of efficacy. UHDRS-TMS and Q-Motor assessments are also performed during the follow-up visit.

The secondary variable of the efficacy analysis in this study is the change in mPPT at week 26 from baseline. (Brown 2000) mPPT quantifies a patient's ability to perform physical tasks (Brown, 2000). This is a standardized 9-item test that measures a patient's ability to perform functional tasks. When performing tasks that require the patient to be in a standing position (points 6 to 9), the use of assistive devices is allowed. When determining the score, both the speed and accuracy with which patients complete the tasks of the corresponding items are taken into account. The maximum test score is 36, with higher scores corresponding to increased ability.

The Multiple Sclerosis Walking Scale (MSWS-12) is being adapted to be used as a general measure of walking ability and motor ability and is referred to as Walk-12.

A level 3 version of the EQ-5D (EQ-5D-3L) was introduced in 1990 (EuroQol Group 1990). It mainly consists of the EQ-5D Descriptive System and the EQ Visual Analog Scale (EQ VAS). The EQ-5d-3L descriptive system includes the following 5 dimensions: motor ability, self-care ability, activities of daily living, pain/discomfort, and anxiety/depression. In the development of 5L, the 5-parameter structure of the original EQ-5D-3L was retained, however, the levels for each parameter were increased to 5 levels based on qualitative and quantitative studies carried out by the EuroQol group. Each of the options can be labeled as: no problems, minor problems, moderate problems, severe problems, and intolerable/very severe problems. The EQ-VAS is still part of the EQ-5D-5L but has been modified to make it more user friendly. The respondent is asked to indicate his/her health status by ticking (or putting a cross) in the box next to the most appropriate definition in each of the 5 options. The EQ VAS records a respondent's self-assessment of health on a vertical, visual analog scale, with endpoints marked as best imagined health and worst imagined health. This information can be used as a quantitative measure of clinical outcome as assessed by individual respondents. It should be noted that the numbers 1-3 are not related to arithmetic properties and should not be used as a base score. Patients may have caregiver/informant help when performing EQ5D, if necessary.

CAB assessments are optional.

With respect to the HVLT-R, learning ability tests 1-3 (i.e., ability to remember everything) and test 4 (i.e., the delayed recall test) receive approximate scores.

New symptoms of HD or worsening of pre-existing symptoms should be recorded as AE only if the demonstration-description and/or result is indicative of a more serious condition than would be expected in the normal course of the disease in a particular patient.

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When there is a change in UHDRS-TMS from baseline in the FUAS population, an additional sensitivity analysis is performed using efficacy data obtained after discontinuation of the study drug.

The change from baseline in HD-QoL and EQ5D-5L scores at week 26/early termination was analyzed using an analysis of covariance (ANCOVA) model. This model uses the following fixed parameters: treatment, center, antipsychotic use or not, and baseline HD-QoL or EQ5D-5L score. For individuals who completed the study early, these endpoints are determined using the last documented value (LOCF).

Results.

Following doses of pridopidine 67.5 mg, 90 mg, and 112.5 mg bid for 26 weeks, there were statistically significant changes in UHDRS-TMS from baseline. In addition, statistically significant changes are observed in the sub-assessment protocol of the section related to motor functions described above. These changes suggest that the administration of pridopidine at these doses provides a successful treatment of movement disorders in patients suffering from HD. A change from baseline is also observed for the secondary variables and endpoints of efficacy, as well as for the other functional variables and endpoints described here, indicating that administration of pridopidine at the indicated doses provides treatment for motor, mental, functional, or cognitive disorders. in HD patients.

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Claims (15)

CLAIM 1. The use of a pharmaceutical composition containing pridopidine or a pharmaceutically acceptable salt thereof to reduce functional impairment in a human patient suffering from Huntington's disease, where the composition is administered in a daily dose of 90, 135, 180 or 225 mg of pridopidine or a pharmaceutically acceptable salt thereof, and where reduction in impairment of functional ability is measured by the assessment of the general ability to function (TFC) in accordance with the Unified Huntington's Disease Rating Scale (UHDRS). 2. Use according to claim 1, wherein the composition is administered once or twice a day. 3. Use according to claim 1 or 2, wherein the composition is administered for at least 26 weeks. 4. The use according to any one of claims 1 to 3, wherein the composition is administered to a patient whose overall motor ability score (TMS) according to the Unified Huntington's Disease Rating Scale (UHDRS) is >25 before starting treatment or to a patient who has a score of independence (IS) according to the Uniform Huntington's Disease Rating Scale (UHDRS) below 90% before starting treatment. 5. Use according to any one of claims 1-3, wherein the composition is administered to a patient who has >36 CAG repeats in the huntingtin gene. 6. Use according to any one of claims 1 to 5, wherein the composition is administered to the patient at a daily dose of 180 or 90 mg. 7. Use according to claim 6, wherein the composition is administered to the patient at a unit dose of 45, 67.5 or 90 mg and is administered twice a day. 8. Use according to claims 1 to 7, wherein the pharmaceutically acceptable salt of said pridopidine is selected from hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, - 55 039995 ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate and toluene-p-sulfonate. 9. A method for reducing functional impairment in a human patient suffering from Huntington's disease, wherein the method comprises administering a pharmaceutical composition containing pridopidine or a pharmaceutically acceptable salt thereof to said human patient, wherein the composition is administered at a daily dose of 90, 135, 180, or 225 mg of pridopidine or a pharmaceutically acceptable salt thereof, and wherein the reduction in impairment of functional ability is measured by the Overall Functioning Ability (TFC) assessment according to the Huntington's Disease Uniform Rating Scale (UHDRS). 10. The method of claim 9 wherein the composition is administered once or twice a day. 11. The method of claim 9 or 10 wherein the composition is administered for at least 26 weeks. 12. The method of any one of claims 9-11, wherein the composition is administered to a patient whose UHDRSTMS score is >25 before starting treatment or to a patient whose UHDRS-IS is below 90% before starting treatment. 13. The method of any one of claims 9-11, wherein the composition is administered to a patient who has >36 CAG repeats in the huntingtin gene. 14. The method according to any one of claims 9 to 13, wherein the composition is administered to the patient at a daily dose of 180 or 90 mg. 15. Method according to and. 14, where the composition is administered to the patient at a standard dose of 45 or 90 mg twice daily.