WO2011051423A1

WO2011051423A1 - Treatment or prophylaxis of dementia, neurodegenerative disorders, schizophrenia, adhd, somnolence or epilepsy

Info

Publication number: WO2011051423A1
Application number: PCT/EP2010/066430
Authority: WO
Inventors: Robert Yiu Ki Lai; Marc Laruelle; Naga Venkatesha Murthy Pathi Jagannatham; Tharani Sivananthan; Neil Upton
Original assignee: Glaxo Group Limited
Priority date: 2009-11-02
Filing date: 2010-10-29
Publication date: 2011-05-05

Abstract

The present invention relates to the use of 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro- 1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone (Formula (I)) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of dementia and/or a neurodegenerative disease (e.g. Alzheimer's disease, in particular cognitive impairment therein), schizophrenia (e.g. cognitive impairment associated therewith), attention deficit hyperactivity disorder, somnolence, or epilepsy, in a human, by oral administration to the human using an escalating dosage regimen comprising: - an initial dosage regimen of from 2 to 15 micrograms (preferably from 5 to 10 micrograms) of the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day, and subsequently - a maintenance dosage regimen of from 30 to 150 micrograms (preferably from from 40 to 80 micrograms) of the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day.

Description

Treatment or prophylaxis of dementia, neurodegenerative disorders, schizophrenia, ADHD, somnolence or epilepsy

This invention relates to the use of 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or a pharmaceutically acceptable salt thereof in (e.g. in the manufacture of a medicament for) the treatment or prophylaxis of dementia and/or neurodegenerative disorders (in particular Alzheimer's disease, and/or cognitive impairments therein),

schizophrenia (e.g. cognitive impairments associated with schizophrenia), attention deficit hyperactivity disorder, somnolence, or epilepsy, in a human, using a novel dosage regimen.

Background of the Invention WO2004/056369 A1 (Glaxo Group Limited) discloses certain benzazepine derivatives, and pharmaceutically acceptable salts thereof, having affinity for and being antagonists and/or inverse agonists of the histamine H3 receptor, and their potential use in the treatment of: neurological diseases including Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficit, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke and sleep disorders including narcolepsy; psychiatric disorders including schizophrenia (particularly cognitive deficit of schizophrenia), attention deficit hyperactivity disorder, depression and addiction; and certain other diseases. WO2004/056369 A1 also discloses that the dose of the compound used in the treatment of the aforementioned disorders will vary, but that, as a general guide, suitable unit doses may be 0.05 to 1000 mg, more suitably 1 .0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three times a day; and that such therapy may extend for a number of weeks or months.

Page 9 lines 23-32 of WO2004/056369 A1 discloses that more preferred or especially preferred benzazepine compounds of the invention include:

5- (3-cyclobutyl-2,3,4,5-tetrahydro-1 H-benzo[c ]azepin-7-yloxy)-pyrazine-2- carboxylic acid methyl amide,

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone, or

6- (3-cyclobutyl-2,3,4,5-tetrahydro-1 H-benzo[c ]azepin-7-yloxy)-/V-methyl- nicotinamide;

or a pharmaceutically acceptable salt thereof (see also claims 20 and 21 ).

Example 217 (E217) of WO2004/056369 A1 discloses 1 -{6-[(3-cyclobutyl-2,3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

and a specific method for preparing it. A.D. Medhurst et al., "GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models", J. Pharmacol. Exp. Therap. , 2007, vol.321 (3), pp.1032-1045 discloses that the compound GSK189254: has a high affinity for the human and rat histamine H3 receptors; is a potent functional antagonist (and inverse agonist) of the human recombinant histamine H3 receptor; inhibited

[3H]R-a-methylhistamine ex vivo binding in the rat cortex following oral administration to the rat; and at certain oral doses improved performance of rats in the following cognition paradigms: passive avoidance, water maze, object recognition, and attentional set shift. GSK189254 is 6-(3-cyclobutyl-2, 3,4,5- tetrahydro-1 H-benzo[c ]azepin-7-yloxy)-/V-methyl-nicotinamide, or alternatively is named 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-/V-methyl-3- pyridinecarboxamide. In the Medhurst 2007 paper, the hydrochloride salt of GSK189254 is disclosed as being used, i.e. 6-[(3-cyclobutyl-2,3,4,5-tetrahydro- 1 H-3-benzazepin-7-yl)oxy]-/V-methyl-3-pyridinecarboxamide hydrochloride.

A.D. Medhurst et al., "Characterization of histamine H3 receptors in Alzheimer's disease brain and amyloid over-expressing TASTPM mice", British Journal of Pharmacology, 2009, vol.157, pp.130-138 (published online on 16 February 2009), investigated H3 receptor binding by [³H]GSK189254 inter alia in post- mortem brain slices from human Alzheimer's disease (AD) subjects, and in human age-matched non-neurological control brains. The data suggest that H3 receptor densities were generally similar in the AD brains and in the age-matched control brains, in the frontal cortex and temporal cortex. WO 2008/104590 A2 (Glaxo Group Limited) discloses, inter alia, a dosage form for oral administration comprising a carrier tablet, which carrier tablet is at least partially covered by a film comprising:

a) 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3- pyridinyl}-2-pyrrolidinone or a pharmaceutically acceptable salt thereof, and b) a stabiliser that reduces degradation of 1-{6-[(3-cyclobutyl-2, 3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone in the dosage form, when compared to a dosage form lacking said stabiliser. WO 2008/104590A2 discloses that, in one embodiment, the dosage form and/or the film contains between 1 μg and 1 mg 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro- 1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone when measured as the amount of base present (that is, excluding any amount of acid added to form salts); and that, in a more particular embodiment, the dosage form and/or the film contains between 1 μg and 200 μg, more particularly between 1 μg and 100 μg and even more particularly between 2 μg and 100 μg 1-{6-[(3-cyclobutyl-2, 3,4,5- tetrahydro-1 /-/-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone, when measured as the amount of free base present.

WO 2008/104590A2 discloses that 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone and its pharmaceutically acceptable salts thereof are H3 antagonists which are believed to be of potential use in the treatment of neurological diseases including Alzheimer's disease, dementia (including Lewy body dementia and vascular dementia), age-related memory dysfunction, mild cognitive impairment, cognitive deficit, epilepsy, migraine, Parkinson's disease, multiple sclerosis (including fatigue therein), stroke, pain of neuropathic origin (including neuralgias, neuritis and back pain), inflammatory pain (including osteoarthritis, rheumatoid arthritis, acute

inflammatory pain and back pain), and sleep disorders (including

hypersomnolence, excessive daytime sleepiness, narcolepsy, sleep deficits associated with Parkinson's disease and fatigue, especially in multiple sclerosis); psychiatric disorders including psychotic disorders (such as schizophrenia (particularly cognitive deficit of schizophrenia) and bipolar disorder), attention deficit hyperactivity disorder, depression (including major depressive disorder), anxiety and addiction; and other diseases including obesity and gastro-intestinal disorders.

Summary of the Invention

A novel dosage regimen has now been found for the use of 1 -{6-[(3-cyclobutyl- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or a pharmaceutically acceptable salt thereof in the treatment or prophylaxis of dementia and/or neurodegenerative disorders (in particular Alzheimer's disease, and/or cognitive impairments therein), schizophrenia (e.g. cognitive impairments associated with schizophrenia), attention deficit hyperactivity disorder, somnolence, or epilepsy, in a human. A small human clinical trial in mild-to-moderate Alzheimer's disease patients has found that two escalating (up-titrated) oral dosage regimens of 1-{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 /-/-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone (administered as the free base), one of which started at 5 micrograms administered once per day and generally finished at 40 micrograms administered once per day (Dose Titration A), and the other of which started at 10 micrograms administered once per day and generally finished at 80 micrograms administered once per day (Dose Titration B), appeared to cause fewer side effects (assessed as being drug-related) than a third escalating oral dosage regimen which started at 20 micrograms administered once per day and finished at 150 or 80 micrograms administered once per day of 1-{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone (administered as the free base) (Dose Titration C).

It is thought from these results that, at least in the treatment of mild-to-moderate Alzheimer's disease patients, to minimise side-effects thought to be caused by the drug, the initial dosage regimen of 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H- 3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof should be 5-10 micrograms administered orally once per day (measured as the free base), and should not be 20 or more micrograms administered orally once per day (measured as the free base), and that the dosage regimen should be escalated to a maintenance dose of 30-150 micrograms (in particular 40-100 or 40-80 micrograms) (measured as the free base) administered orally once per day.

This escalating (up-titration) oral dosage regimen, using 1 -{6-[(3-cyclobutyl- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or a pharmaceutically acceptable salt thereof, may also be suitable for the treatment or prophylaxis (e.g. treatment) of a number of diseases which are capable of being treated (or subject to prophylaxis) by histamine H3 antagonists and/or inverse agonists; in particular dementia and/or a neurodegenerative disease (e.g. Alzheimer's disease), schizophrenia, or attention deficit hyperactivity disorder, especially in the treatment of cognitive impairment therein.

Therefore, in a first aspect, the present invention provides the use of 1-{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone

or a pharmaceutically acceptable salt thereof in the manufacture of a

medicament for the treatment or prophylaxis (preferably treatment) of dementia and/or a neurodegenerative disease (e.g. Alzheimer's disease, mild cognitive impairment or cognitive ageing, in particular cognitive impairment therein; and/or e.g. cognitive impairment in dementia and/or a neurodegenerative disease), schizophrenia (e.g. cognitive impairment associated with schizophrenia), attention deficit hyperactivity disorder (e.g. cognitive impairment therein), somnolence, or epilepsy, in a human, by oral administration to the human using an escalating dosage regimen comprising:

- an initial dosage regimen of from 2 to 15 micrograms (preferably from 2 to 10 micrograms, or more preferably from 5 to 10 micrograms, or most preferably 10 micrograms) of the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day, and subsequently

- a maintenance dosage regimen of from 30 to 150 micrograms (preferably from 40 to 100 micrograms, or more preferably from 40 to 80 micrograms, or most preferably 80 micrograms) of the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day.

In a second aspect, the present invention provides 1 -{6-[(3-cyclobutyl-2, 3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis (preferably treatment) of dementia and/or a neurodegenerative disease (e.g. Alzheimer's disease, mild cognitive impairment or cognitive ageing, in particular cognitive impairment therein; and/or e.g. cognitive impairment in dementia and/or a neurodegenerative disease), schizophrenia (e.g. cognitive impairment associated with schizophrenia), attention deficit hyperactivity disorder (e.g. cognitive impairment therein), somnolence, or epilepsy, in a human, by oral administration to the human using an escalating dosage regimen comprising:

In a third aspect, the present invention provides a method of treatment or prophylaxis (preferably treatment) of dementia and/or a neurodegenerative disease (e.g. Alzheimer's disease, mild cognitive impairment or cognitive ageing, in particular cognitive impairment therein; and/or e.g. cognitive impairment in dementia and/or a neurodegenerative disease), schizophrenia (e.g. cognitive impairment associated with schizophrenia), attention deficit hyperactivity disorder (e.g. cognitive impairment therein), somnolence, or epilepsy, in a human,

the method comprising orally administering to the human 1 -{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone

or a pharmaceutically acceptable salt thereof using an escalating dosage regimen comprising:

- an initial dosage regimen of from 2 to 15 micrograms (preferably from 2 to 10 micrograms, or more preferably from 5 to 10 micrograms, or most preferably 10 micrograms) of the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day, and subsequently - a maintenance dosage regimen of from 30 to 150 micrograms (preferably from 40 to 100 micrograms, or more preferably from 40 to 80 micrograms, or most preferably 80 micrograms) of the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day.

In a fourth aspect, the present invention provides a pharmaceutical composition (e.g. tablet or capsule) for oral administration to a human, comprising 1-{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone

or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients;

wherein the pharmaceutical composition is for use in the treatment or prophylaxis (preferably treatment) of dementia and/or a neurodegenerative disease (e.g. Alzheimer's disease, mild cognitive impairment or cognitive ageing, in particular cognitive impairment therein; and/or e.g. cognitive impairment in dementia and/or a neurodegenerative disease), schizophrenia (e.g. cognitive impairment associated with schizophrenia), attention deficit hyperactivity disorder (e.g. cognitive impairment therein), somnolence, or epilepsy, in a human, by oral administration to the human using an escalating dosage regimen comprising: - an initial dosage regimen of from 2 to 15 micrograms (preferably from 2 to 10 micrograms, or more preferably from 5 to 10 micrograms, or most preferably 10 micrograms) of the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day, and subsequently

- a maintenance dosage regimen of from 30 to 150 micrograms (preferably from 40 to 100 micrograms, or more preferably from 40 to 80 micrograms, or most preferably 80 micrograms) of the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day. Brief Description of the Drawings

Figure 1 is a schematic illustration of the study design for Part B of the clinical trial described in Example 1 . Figure 2 is a schematic diagram showing the weekly dose review procedure used in Part B of the clinical trial described in Example 1. Figure 3 is a graph showing some of the efficacy results from the clinical trial described in Example 1 . Specifically, Figure 3 shows Day 29 CogState Effect Sizes and 95% Confidence Intervals for subjects titrating to 40 μg, or 80 μg, or 150 μg, or (40 μg, 80 μg, or 150 μg, combined data), of 1-{6-[(3-cyclobutyl- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone, administered orally once per day. The data shown in Figure 3 for subjects on 150 μg/day are the data for those subjects on Dose Titration C who successfully titrated from 20 to 40 to 80 to 150 μg/day. The data shown in Figure 3 for subjects on 80 μg/day are the combined data for: all subjects who titrated to a final dosage regimen of 80 μg/day, and so comprises five subjects on Dose Titration B (who successfully titrated from 10 to 20 to 40 to 80 μg/day), plus three subjects on Dose Titration C who started at 20 μg/day and ended at 80 μg/day. The data shown in Figure 3 for subjects on 40 μg/day are the combined data for: four subjects on Dose Titration A (who successfully titrated from 5 to 10 to 20 to 40 μg/day), plus one subject on Dose Titration B who started at 10 μg/day and ended at 40 μg/day, minus one subject removed from analysis.

Figure 4 is a graph showing some of the efficacy results from the clinical trial described in Example 1 . Specifically Figure 4 shows Day 29 CogState Effect Sizes and 95% Confidence Intervals for subjects titrating to 40 μg, or 80 μg, or (either 40 μg or 80 μg, combined data), of 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro- 1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone, administered orally once per day. The data shown in Figure 4 for subjects on 80 μg/day comprises only the five subjects on Dose Titration B who successfully titrated from 10 to 20 to 40 to 80 μg/day. The data shown in Figure 4 for subjects on 40 μg/day are the combined data for: four subjects on Dose Titration A (who successfully titrated from 5 to 10 to 20 to 40 μg/day), plus one subject on Dose Titration B who started at 10 μg/day and ended at 40 μg/day, minus one subject removed from analysis. Figure 5 is a schematic diagram illustrating the study design of the clinical study of Example 2.

Figure 6 is a schematic diagram showing the weekly dose review procedure, during the up-titration (escalation) phase, for the clinical study of Example 2.

Figure 7 is a schematic diagram showing the weekly dose review procedure to be used in the clinical study described in Example 2, showing specific possibilities for escalation (up-titration), maintenance, or decrease of the dosage regimen, depending on the tolerability of the preceding dosage regimen as assessed at the weekly dose review.

Detailed Description of the Invention

As mentioned herein, "cognitive ageing" is defined as meaning age-related cognitive decline and/or age-related memory dysfunction.

As mentioned herein, "somnolence" means sleepiness. In all aspects of the invention, in one particular embodiment of the treatment or prophylaxis (in particular treatment), the somnolence (sleepiness) in a human is

hypersomnolence or daytime somnolence (daytime sleepiness) in a human. More particularly, in the treatment or prophylaxis, the daytime somnolence in a human is excessive daytime sleepiness, or daytime somnolence associated with the treatment of Parkinson's disease or restless legs syndrome, in a human.

In all aspects of the invention, in one particular embodiment of the treatment or prophylaxis (preferably treatment), the neurodegenerative disease in a human is: Alzheimer's disease, mild cognitive impairment, cognitive ageing, Lewy body dementia, Parkinson's disease (in particular Parkinson's disease dementia), or vascular dementia, in a human. In all aspects of the invention, in one particular embodiment of the treatment or prophylaxis (preferably treatment), the dementia in a human is: Alzheimer's disease, Lewy body dementia, Parkinson's disease dementia, or vascular dementia, in a human. In all aspects of the invention, preferably, the treatment or prophylaxis (in particular treatment) is of dementia and/or a neurodegenerative disease (in particular Alzheimer's disease, mild cognitive impairment or cognitive ageing, in particular cognitive impairment therein; and/or in particular cognitive impairment in dementia and/or a neurodegenerative disease), schizophrenia (in particular cognitive impairment associated with schizophrenia), or attention deficit hyperactivity disorder (in particular cognitive impairment therein), in a human.

In all aspects of the invention, more preferably, the treatment or prophylaxis (in particular treatment) is of dementia and/or a neurodegenerative disease (in particular Alzheimer's disease, mild cognitive impairment or cognitive ageing, in particular cognitive impairment therein; and/or in particular cognitive impairment in dementia and/or a neurodegenerative disease), or schizophrenia (in particular cognitive impairment associated with schizophrenia), in a human.

In all aspects of the invention, still more preferably, the treatment or prophylaxis (in particular treatment) is of dementia and/or a neurodegenerative disease (in particular Alzheimer's disease, mild cognitive impairment or cognitive ageing, in particular cognitive impairment therein; and/or in particular cognitive impairment in dementia and/or a neurodegenerative disease), in a human. Preferably, the treatment or prophylaxis (in particular treatment) is of cognitive impairment in dementia and/or in a neurodegenerative disease, cognitive impairment associated with schizophrenia, or cognitive impairment in attention deficit hyperactivity disorder, in a human. More preferably, the treatment or prophylaxis (in particular treatment) is of cognitive impairment in: Alzheimer's disease, mild cognitive impairment, cognitive ageing, Lewy body dementia,

Parkinson's disease (such as Parkinson's disease dementia), vascular dementia, schizophrenia, or attention deficit hyperactivity disorder, in a human.

Still more preferably, the treatment or prophylaxis (in particular treatment) is of cognitive impairment in: Alzheimer's disease, mild cognitive impairment, cognitive ageing, schizophrenia, or attention deficit hyperactivity disorder, in a human.

Yet more preferably, the treatment or prophylaxis (in particular treatment) is of cognitive impairment in: Alzheimer's disease, mild cognitive impairment, cognitive ageing, schizophrenia, or attention deficit hyperactivity disorder, in a human.

Yet more preferably, the treatment or prophylaxis (in particular treatment) is of cognitive impairment in: Alzheimer's disease, schizophrenia, or attention deficit hyperactivity disorder, in a human.

Most preferably, the treatment or prophylaxis (in particular treatment) is of cognitive impairment in Alzheimer's disease in a human, in particular cognitive impairment in mild-to-moderate Alzheimer's disease in a human. In all aspects of the invention, preferably, the treatment or prophylaxis (in particular treatment) of Alzheimer's disease in a human is treatment or prophylaxis (in particular treatment) of mild-to-moderate Alzheimer's disease in a human. By "mild-to-moderate Alzheimer's disease" in a human is meant Alzheimer's disease in a human having, for example, a MMSE (Mini Mental State Examination) score of 12 to 26, or more particularly Alzheimer's disease in a human having, for example, a MMSE score of 16 to 26, such as 16 to 24. In all aspects of the invention, in one particular embodiment, the treatment or prophylaxis (in particular treatment) of Alzheimer's disease in a human is treatment or prophylaxis (in particular treatment) of mild Alzheimer's disease in a human. By "mild Alzheimer's disease" in a human is meant Alzheimer's disease in a human having, for example, a MMSE (Mini Mental State Examination) score of 20 to 26, in particular Alzheimer's disease in a human having, for example, a MMSE score of 20 to 24. In all aspects of the invention, in one particular embodiment, the treatment or prophylaxis (in particular treatment) of Alzheimer's disease in a human is treatment or prophylaxis (in particular treatment) of moderate Alzheimer's disease in a human. By "moderate Alzheimer's disease" in a human is meant Alzheimer's disease in a human having, for example, a MMSE (Mini Mental State Examination) score of 12 to 19, in particular Alzheimer's disease in a human having, for example, a MMSE score of 16 to 19.

In all aspects of the invention, in an alternative embodiment, the treatment or prophylaxis (in particular treatment) of Alzheimer's disease in a human is treatment or prophylaxis (in particular treatment) of severe Alzheimer's disease in a human. By "severe Alzheimer's disease" in a human is meant Alzheimer's disease in a human having, for example, a MMSE (Mini Mental State

Examination) score of 0 to 1 1 , in particular Alzheimer's disease in a human having, for example, a MMSE score of 4 to 1 1 , such as 5 to 1 1 or 5 to 10.

MMSE (Mini Mental State Examination) is a test containing questions which the patient (the human) is asked, and the MMSE score is the number of questions answered correctly.

Preferably, in all aspects of the invention, in the treatment or prophylaxis

(preferably treatment) of dementia and/or a neurodegenerative disease

(preferably Alzheimer's disease, mild cognitive impairment or cognitive ageing, in particular cognitive impairment therein; and/or e.g. cognitive impairment in dementia and/or a neurodegenerative disease), in a human;

the human has an age of 45 or more years, for example 50 to 105 years, such as 60 to 100 years e.g. 65 to 100 years.

The human can be male or female.

Typically, in all aspects of the invention, in the treatment or prophylaxis

(preferably treatment) of schizophrenia (e.g. cognitive impairment associated with schizophrenia) in a human; the human is an adult (i.e. a human having an age of 18 or more years, e.g. 18 to 90 years or 18 to 70 years, in particular 18 to 55 years). The human can be male or female.

In one particular embodiment, in all aspects of the invention, in the treatment or prophylaxis (preferably treatment) of schizophrenia (e.g. cognitive impairment associated with schizophrenia) in a human;

(i) the human has not had any acute exacerbation of schizophrenia in the six months before the start of the initial dosage regimen of the 1 -{6-[(3-cyclobutyl- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof, and/or

(ii) the human has been receiving an antipsychotic agent [such as: a typical antipsychotic agent (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone or loxapine) or an atypical antipsychotic agent (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, amisulpride or aripiprazole)] (e.g. a stabilised dosage regimen thereof) for a period before (preferably a period of three or more months before) the start of the initial dosage regimen of the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof.

In these circumstances, the human suffering from or susceptible to schizophrenia (e.g. cognitive impairment associated with schizophrenia) can in particular be an adult (i.e. a human having an age of 18 or more years, e.g. 18 to 70 years or 18 to 55 years).

In one particular embodiment, in all aspects of the invention, in the treatment or prophylaxis (preferably treatment) of attention deficit hyperactivity disorder (e.g. cognitive impairment therein), somnolence, or epilepsy, in a human;

the human can be adult (i.e. a human having an age of 18 or more years, e.g. 18 to 90 years or 18 to 70 years) or can be a child (i.e. paediatric population, e.g. a human child having an age of 2 to 17 years such as 4 to 17 years).

The human can be male or female.

Preferably, in all aspects of the invention, the initial dosage regimen is from 2 to 10 micrograms, more preferably from 5 to 10 micrograms, most preferably 10 micrograms, of the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day. Preferably, in all aspects of the invention, the maintenance dosage regimen is from 40 to 100 micrograms, more preferably from 40 to 80 micrograms, most preferably 80 micrograms, of the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day.

More preferably, in all aspects of the invention,

the initial dosage regimen is from 5 to 10 micrograms (in particular 10 micrograms) of the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof

(measured as the free base), administered orally once per day; and

the maintenance dosage regimen is from 40 to 80 micrograms (in particular 80 micrograms) of the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day.

Preferably, in all aspects of the invention, in the escalating dosage regimen, the total time taken to escalate the dosage regimen is 3 to 8 weeks (more preferably 3 to 6 weeks such as 4 to 6 weeks, preferably 4 weeks), measured from the start of the initial dosage regimen to the start of the maintenance dosage regimen.

Preferably, in all aspects of the invention, in the escalating dosage regimen, the once-daily oral dose of the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base) is increased by a factor of 1 .5 to 3 times (or more preferably is doubled) every 4 days to 3 weeks (or more preferably every 1 to 2 weeks, such as every week).

Therefore, more preferably, in all aspects of the invention, the escalating dosage regimen comprises:

- an initial dosage regimen of from 5 to 10 micrograms (preferably 10 micrograms) of the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and then

- a second dosage regimen of from 10 to 20 micrograms (preferably 20 micrograms) of the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and then - a third dosage regimen of from 20 to 40 micrograms (preferably 40 micrograms) of the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and then

- a maintenance dosage regimen of from 40 to 80 micrograms (preferably

80 micrograms) of the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day;

provided that the once-daily oral dose of the 1-{6-[(3-cyclobutyl-2, 3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base) is increased by a factor of 1 .5 to 3 times (or more preferably is doubled), when escalating from one dosage regimen to the next higher dosage regimen. Still more preferably, escalation from one dosage regimen to the next higher dosage regimen occurs every 4 days to 3 weeks (or more preferably every 1 to 2 weeks, such as every week), e.g. dependent on tolerability. Yet more preferably, the total time taken to escalate the dosage regimen is 3 to 8 weeks (more preferably 3 to 6 weeks such as 4 to 6 weeks, preferably 4 weeks), measured from the start of the initial dosage regimen to the start of the maintenance dosage regimen.

The active compound or salt and pharmaceutical compositions or medicaments containing it

In the context of the present invention, 1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1 H- 3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone (herein referred to as the "free base") or a pharmaceutically acceptable salt thereof encompasses solvates (e.g. hydrates) of the free base or of a pharmaceutically acceptable salt thereof.

1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone may be prepared according to known procedures, such as those disclosed in WO2004/056369. The disclosure of WO2004/056369 is

incorporated herein by reference.

Pharmaceutically acceptable acid addition salts of 1-{6-[(3-cyclobutyl-2, 3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone include hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2- naphthalenesulfonate) or hexanoate salts. Such salts can be formed by reaction with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated for example by crystallisation and filtration.

The 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}- 2-pyrrolidinone or the pharmaceutically acceptable salt thereof may contain the free base, a pharmaceutically acceptable salt (stoichiometric or non- stoichiometric), or any mixture of these.

Preferably, in all aspects of the invention, the 1-{6-[(3-cyclobutyl-2, 3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof is the "free base".

In one particular embodiment of the invention, a pharmaceutical composition or medicament is used containing the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The pharmaceutical composition or medicament is typically an orally- administrable pharmaceutical composition or orally-administrable medicament, such as a tablet or capsule. Preferably, the pharmaceutical composition or medicament used is an orally- administrable dosage form which comprises a carrier tablet, which carrier tablet is at least partially (e.g. partially) covered by a film, wherein the film comprises: a) 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3- pyridinyl}-2-pyrrolidinone or a pharmaceutically acceptable salt thereof, and b) a stabiliser (such as citric acid) that reduces degradation of 1-{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone in the dosage form, when compared to a dosage form lacking said stabiliser, and

c) optionally, a film former (e.g. hydroxypropylcellulose).

More preferably, the carrier tablet has at least one recess (e.g. two recesses on opposed major sides), and the film is present in at least one recess on the carrier tablet. In one particular embodiment, the carrier tablet contains a filler (e.g. present in 60-99% by weight of the carrier tablet); in which case more particularly the filler is microcrystalline cellulose or lactose (e.g. anhydrous lactose or lactose monohydrate). Examples of tablets which can be used with this invention, which are dosage forms being drug-film-coated carrier tablets as mentioned above, are disclosed in the Tablet Examples hereinafter. Typically, the pharmaceutical composition or medicament contains (e.g., for the dosage forms being drug-film-coated carrier tablets as mentioned above, the film at least partially covering the carrier tablet contains), from 2 μg to 150 μg (in particular 5

to 80 pg, e.g. 5, 10, 20, 40 or 80 pg) of the 1-{6-[(3-cyclobutyl- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base).

Preferably, the orally-administrable pharmaceutical composition or orally- administrable medicament (e.g. tablet or capsule), which contains the 1-{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone or the pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, is an orally-administrable immediate- release pharmaceutical composition or medicament.

By "immediate-release pharmaceutical composition or medicament" is meant one which has a disintegration time of 30 minutes or less (in particular 20 minutes or less or 15 minutes or less); and/or which has a dissolution time of 60 minutes or less (in particular 40 minutes or less or 30 minutes or less). In respect of a pharmaceutical composition or medicament, the disintegration time is typically measured as the time for the composition or medicament (e.g. tablet or capsule) to disintegrate (which does not require full dissolution) while immersed in a suitable aqueous immersion liquid, such as simulated gastric fluid or simulated intestinal fluid or water, typically at 37 ± 2 °C; this can e.g. be as measured using the method(s) disclosed in the US or European Pharmacopeia, such as the US Pharmacopeia 2002 edition (USP 25), section 701 "Disintegration", p.2010. In respect of a pharmaceutical composition or medicament, the dissolution time can be measured as the time for the composition or medicament (e.g. tablet or capsule) to dissolve while immersed in a suitable aqueous immersion liquid, such as water or simulated gastric fluid or simulated intestinal fluid, typically at 37 ± 0.5 °C; this can e.g. be as measured using the method(s) disclosed in the US or European Pharmacopeia, such as the US Pharmacopeia 2002 edition (USP 25), section 71 1 "Dissolution", p.201 1-2012. Combinations

1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone or its pharmaceutically acceptable salts may be used in

combination with other therapeutic agents.

When the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3- pyridinyl}-2-pyrrolidinone or a pharmaceutically acceptable salt thereof is intended for use in the treatment of Alzheimer's disease (in particular cognitive impairment in Alzheimer's disease), in one embodiment of the invention, it is used in combination with medicaments claimed to be useful as either disease modifying or symptomatic treatments of Alzheimer's disease. Suitable examples of such other therapeutic agents may be symptomatic agents, for example those known to modify cholinergic transmission such as M1 muscarinic receptor agonists or allosteric modulators, M2 muscarinic antagonists,

acetylcholinesterase inhibitors (such as tetrahydroaminoacridine, donepezil such as donepezil hydrochloride, rivastigmine, or galantamine), nicotinic receptor agonists or allosteric modulators (such as a7 agonists or allosteric modulators or α4β2 agonists or allosteric modulators), PPAR agonists (such as PPARy agonists), 5-HT₄ receptor partial agonists, 5-HT₆ receptor antagonists or 5HT1A receptor antagonists, or NMDA receptor antagonists or modulators (e.g.

memantine), or disease modifying agents such as β or γ-secretase inhibitors.

When the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3- pyridinyl}-2-pyrrolidinone or a pharmaceutically acceptable salt thereof is intended for use in the treatment or prophylaxis (e.g. treatment) of schizophrenia (in particular cognitive impairment associated with schizophrenia), in one embodiment of the invention, it is used in combination with one or more medicaments claimed to be useful as treatments of schizophrenia, such as: i) antipsychotic agents including typical antipsychotic agents (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone or loxapine), atypical antipsychotic agents (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, amisulpride or aripiprazole), glycine transporter 1 inhibitors or metabotropic receptor ligands; ii) drugs for

extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine, or trihexyphenidyl) and dopaminergics (such as amantadine); iii) antidepressants including serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine, dapoxetine or sertraline), dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine or milnacipran), noradrenaline reuptake inhibitors (such as reboxetine), tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline or trimipramine), monoamine oxidase inhibitors (such as

isocarboxazide, moclobemide, phenelzine or tranylcypromine), or others (such as buproprion, mianserin, mirtazepine, nefazodone or trazodone); iv) anxiolytics and/or sedatives including benzodiazepines such as alprazolam, lorazepam, diazepam or midazolam; or v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil such as donepezil hydrochloride, rivastigmine or galantamine). When the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3- pyridinyl}-2-pyrrolidinone or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent active against the same disease, the two active therapeutic agents can be present together in one dosage form, or more usually they are administered to the human in separate dosage forms (e.g. orally-administrable dosage forms) either at the same time of the day

(simulataneously) and/or at different times of the day (sequentially).

When the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3- pyridinyl}-2-pyrrolidinone or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent active against the same disease state the dose of 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 /-/-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone (or its pharmaceutically acceptable salt) may differ from that when the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin- 7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone (or its pharmaceutically acceptable salt) is formulated alone.

The following examples illustrate the invention but do not limit it in any way.

EXAMPLES

EXAMPLE 1 - CLINICAL TRIAL - A single blind, placebo-controlled, randomised study in mild-to-moderate Alzheimer's disease patients to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3- pyridinyl}-2-pyrrolidinone, a selective histamine H3 receptor antagonist.

Example 1 - Study Design

Part A of Example 1 clinical trial

Part A of the clinical trial was a single blind, placebo run-in, flexible dose titration in four patients with mild-to-moderate Alzheimer's disease. Subjects underwent nine days of treatment with study medication. For the first two days (Days -1 and -2) they received placebo orally, to allow acclimatization to the clinical study procedures. This was then followed by seven days oral dosing (Days 1 -7) with 1 - {6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone (as the "free base" form) (which in this Example is named the "drug", "study drug", "study medication", "active drug", "active agent", "active treatment" or similar terms) using a flexible dose titration regimen.

The first two subjects commenced dosing on Day 1 with a 2 μg once-daily oral dose of the study drug for three days, and, because this dose of the study drug was well-tolerated as judged by the investigator, they were escalated to 5 μg of the study drug orally once per day for the remaining four days. A further two subjects commenced dosing with the study drug at a dose of 5 μg of the study drug orally once daily for three days; and the subjects were escalated to 10 μg of the study drug orally once daily for the remaining four days (because the 5 μg dose was well tolerated as judged by the investigator).

The safety and tolerability data from the first two subjects (2 to 5 μg / day) were reviewed by the investigator and the GlaxoSmithKline study team prior to the decision being made on dose escalation for the next two subjects (5 to 10 μg / day).

Part B of Example 1 clinical trial

Part B of the clinical trial was a single blind, randomised, placebo controlled, parallel group, flexible dose titration study in three cohorts of eight subjects each. Each subject had mild-to-moderate Alzheimer's disease (see Example 1 - Study Population, Eligibility criteria subsection, hereinbelow, for details). In each cohort, six subjects were randomised to receive active treatment (the study drug, l-ie-tiS-cyclobutyl^^^^-tetrahydro-I H-S-benzazepin-y-y oxyl-S-pyridinyl}^- pyrrolidinone) and two subjects were randomised to receive placebo. The dosing period was 4 weeks and subjects followed the titration regimens as described below.

In Part B, the first dosing cohort, "Dose Titration A", started with an initial dosage regimen of a once-daily oral dose of 5 μg (5 micrograms) of the study drug, and the intention was to titrate these patients up to a final dosage regimen of a once- daily oral dose of 40 μg (40 micrograms) of the study drug (see description of Dose Titration A hereinafter for details). Because this 5 to 40 microgram/day dosing regimen was well tolerated (see Results section), subsequent cohorts, "Dose Titration B" and "Dose Titration C", received a dosing regimen with higher starting doses (10 and 20 micrograms of the study drug orally once daily, respectively), titrating up to higher final doses (see description of Dose Titrations B and C hereinafter for details). In Dose Titrations A, B and C, lower-than- intended final dosage regimens were generally used in cases where the initial dosage regimen was not well tolerated.

Subjects underwent a weekly review of safety and tolerability on Day 8 +/- 1 day, Day 15 +/- 1 day and Day 22 +/- 1 day, before taking their daily dose of medication (see Figure 1 for a schematic illustration of the study design for Part B of the Example 1 clinical trial).

Pharmacodynamic (PD) assessments took place at each weekly review prior to the daily dose of medication. A follow-up review took place within 2 weeks after the last dose of study drug. From seven days prior to Day 1 to the follow-up review, adverse events were recorded by carers and/or subjects in diary cards.

Following medical review, the dose of the study drug or placebo may be increased, decreased or kept unchanged, as depicted in Figure 2, which is a schematic diagram showing the weekly dose review procedure for Part B of the Example 1 clinical trial. When, at the weekly review, the dose level was well tolerated, the dose was in general escalated to the next dose level. When the dose was increased, research staff asked the subject about any adverse events, for example on the evening of dosing with the increased dose, and on the following day.

Example 1 - Criteria For Moderate Tolerability Concerns The overall profile of adverse events which raise moderate tolerability concerns and requires dose reduction or withdrawal is characterised by: • Major criteria: any of criteria 1 to 4 apply; if these criteria do not apply then the adjunct criteria should be considered.

• Adjunct criteria: two or more of criteria [1 to 7] and 8 apply. Not withstanding these criteria, the investigator should exercise clinical judgement to reduce the dose or withdraw treatment even if the major and adjunct criteria are not met. On the other hand, if the investigator considers that despite meeting these criteria, it is not necessary to reduce the dose or withdraw the subject, then the GlaxoSmithKline Medical Monitor should be consulted.

Major criteria (for tolerability concerns):

1. Overall effect of adverse events leads to impairment of normal daily functions or curtailment of normal daily activities of the subject by >50% of normal.

2. CGIC (Clinician's Global Impression of Change) score is 6 or 7.

3. Emergence of hallucinations, mood disturbance, abnormal thoughts, aggression, agitation or other behavioural distances, or worsening of such preexisting symptoms in excess of expected normal fluctuations for the subject.

4. Worsening of cognitive function in excess of expected normal fluctuations for the subject, primarily based on subject or carer's reports and supported by evidence from the modified NOSGER questionnaire or Cogstate

neuropsychological tests. A NOSGER questionnaire ("Nurse Observed Scale in Geriatric patients") is a safety questionnaire about the patient as observed by the carer (e.g. nurse).

Adjunct criteria (for tolerability concerns)

1. Subject experiences >4 adverse events scored as moderate or severe intensity, during the previous week of treatment.

2. Subject experiences the effects of adverse events throughout >50% of the time daily on >4 days of the week. In other words, subject has only a relatively small proportion of time free from adverse events. This may occur even if each individual adverse event is mild and of short duration, but the subject experiences a combination or succession of adverse events.

3. Insomnia of moderate intensity which interferes with function/activities of daily living or insomnia which delays normal sleep by >2 h, for >4 nights of the week. 4. Sleep disturbance of moderate intensity, such that a subject feels sufficiently tired or exhausted the following day such as to interfere with function/activities of daily living, for >4 nights of the week.

5. Sleep disturbance which results in >3 waking episodes during a night's sleep for >4 nights of the week, or any waking episodes associated with behavioural disturbance such as wandering or risk of injury to subject or carer. 6. Vivid dreams or nightmares of moderate intensity such that the subject perceives that sleep is impaired, or sufficiently distressing to cause the subject to wake up, or perceived as distressing upon recollection the following day, for >4 nights of the week.

7. Gastrointestinal disturbances (e.g. nausea, vomiting, diarrhoea, and/or abdominal pain) of moderate intensity on >4 days of the week, characterised by one or more of the following: reduced oral intake, >2 episodes of vomiting per 24 h, >2 episodes of diarrhoea per 24 h, interference with function / daily activities. 8. No evidence that tolerability is improving or that adverse events are tolerating out, over the week of treatment.

Notwithstanding these criteria, the investigator should exercise clinical judgement to reduce the dose or withdraw treatment when it is appropriate to do so, even if by these criteria the dose may continue unchanged. On the other hand, if the investigator considers that despite meeting these criteria, it is reasonable to increase the dose, then the GlaxoSmithKline Medical Monitor should be consulted.

Example 1 - Criteria For Mild Tolerability Concerns

The overall profile of adverse events which raise mild tolerability concerns, and therefore such that the dose should continue unchanged, is characterised by:

• Not considered as of moderate tolerability concern, and

• Criteria [1 or 2] and all of criteria 3 to 5 below apply:

1. Overall the tolerability of adverse events is acceptable, with some impairment of normal daily functions but subjects are still able to continue with >50% of their normal activities.

2. CGIC (Clinician's Global Impression of Change) score is 5.

3. Not more than 1 of the adjunct criteria 1 to 7 for tolerability profile of moderate clinical concern.

4. No emergence of hallucinations, mood disturbance, abnormal thoughts, aggression, agitation or other behavioural distances, or worsening of such preexisting symptoms in excess of expected normal fluctuations for the subject.

5. No worsening of cognitive function in excess of expected normal fluctuations for the subject, primarily based on subject or carer's reports and supported by evidence from the modified NOSGER questionnaire (a safety questionnaire about the patient as observed by the carer (e.g. nurse)) or Cogstate

neuropsychological tests. Notwithstanding these criteria, the investigator should exercise clinical judgement to reduce the dose or withdraw treatment when it is appropriate to do so, even if by these criteria the dose may continue unchanged. On the other hand, if the investigator considers that despite meeting these criteria, it is reasonable to increase the dose, then the GlaxoSmithKline Medical Monitor should be consulted.

Example 1 - Criteria For No Dose Limiting Tolerability The overall profile of adverse events which has no tolerability concerns and permits dose escalation is characterised by:

• Not considered as moderate or mild tolerability concern, and

• Criteria [1 or 2] and all of criteria 3 to 5 below apply:

1. Overall effect of adverse events is well-tolerated, has minimal or no impairment of normal daily functions and the subject is able to continue with the most (>80%) of normal daily activities.

2. CGIC (Clinician's Global Impression of Change) score is 1 to 4.

3. No emergence of new hallucinations, mood disturbance, abnormal thoughts, aggression, agitation or other behavioural distances, and no worsening of such pre-existing symptoms in excess of expected normal fluctuations for the subject.

4. No worsening of cognitive function in excess of expected normal fluctuations for the subject, primarily based on subject or carer's reports and supported by evidence from the modified NOSGER questionnaire (a safety questionnaire about the patient as observed by the carer (e.g. nurse)) or Cogstate

neuropsychological tests.

5. None of the adjunct criteria in the tolerability profiles which are of moderate clinical concern apply.

Notwithstanding these criteria, the investigator should exercise clinical judgement and not increase the dose if it is considered that a higher dose will not be tolerated. Example 1 - General criteria regarding tolerability and dose variation

If a dose level is not well-tolerated at any point, the investigator may reduce the dose to the previously well-tolerated level, if appropriate. One further attempt at titrating up to the next higher dose level will be permitted, at the discretion of the investigator, after at least a further four days at the previously well-tolerated dose level. Subsequently, if the next higher dose level is well-tolerated for 7 days, subjects can resume the weekly dose-escalation regimen as before. If the higher dose level is still not tolerated despite a second attempt, the dose should be reduced to the previously well tolerated level and the subject will thereafter remain at the same dose for the rest of the treatment period. If this reduced dose level is still not tolerated, the subject should be withdrawn from treatment using the study drug. If a dose level leads to clinically significant sleep disturbance (e.g. risk of wandering and confusion at night, disruption of carer's sleep, or worsening of daytime function), as judged by the investigator, the dose should be reduced. Example 1 - Dose Titrations A, B and C, details of dosage regimens

Example 1, Dose Titration A (Cohort 1)

The first eight subjects will be allocated to Dose Titration A with an initial starting dosge regimen of 5 micrograms of the study drug 1 -{6-[(3-cyclobutyl-2, 3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone (or of matching placebo), administered orally once daily. Dose escalation in subsequent weeks (for those patients not on placebo) will follow the scheme in Table 1 below. Dose escalation must proceed through consecutive dose levels and it is not permissible to miss out (jump over) a dose level.

Table 1 - Dose Titration A (Cohort 1)

The Dose Titrations in Table 1 (and subsequent Tables 2 and 3) can be explained as follows, usually subject to the above-mentioned General criteria regarding tolerability and dose variation, and e.g. as illustrated in Figure 2:

- If, after any given week of dosing, there are moderate tolerability or safety concerns, then the dose is usually reduced to the next lower dose level or if the subject is already at 5 μg/day then the treatment is stopped (subject withdrawn). For example: dose level A3 (20 μg/day) would be reduced to dose level A2 (10 μg/day); and dose level A1 (5 μg/day) would change to a stop in treatment.

- If, after any given week of dosing, there are mild tolerability or safety concerns, then the dose is usually left unchanged at the same dose level. - If, after any given week of dosing, there are no tolerability or safety concerns, then the dose is usually increased to the next higher dose level. For example: dose level A1 (5 g/day) would be increased to dose level A2 (10 μg/day); and dose level A3 (20 g/day) would be increased to dose level A4 (40 μg/day).

Example 1, Dose Titration B (Cohort 2)

When at least 4 of the first 6 subjects randomised to the study drug, 1-{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 /-/-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone, in Dose Titration A have titrated up to and completed a week's treatment at dose level A4 (40 micrograms administered orally once daily), and assuming that the safety and tolerability data are supportive (including no more than two subjects withdrawing due to drug-related adverse events), the second cohort of subjects (those patients not on placebo) follow a titration regimen (Dose Titration B) [Table 2 below], which starts at 10 micrograms of the study drug administered orally once daily, and allows subjects to titrate flexibly to up to 80 micrograms administered orally once daily (e.g. depending on tolerability).

Table 2 - Dose Titration B (Cohort 2)

Example 1, Dose Titration C (Cohort 3) When at least 4 subjects randomised to the study drug, 1 -{6-[(3-cyclobutyl-

2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone, in Dose Titration B have been titrated up to and completed a week's treatment at dose level B4 (80 micrograms administered orally once daily), and assuming that the safety and tolerability data are supportive (including no more than two subjects withdrawing due to drug-related adverse events), the third cohort of subjects (those patients not on placebo) follow a titration regimen (Dose Titration C)

[Table 3 below] which starts at 20 micrograms of the study drug administered orally once daily, and allows subjects to titrate flexibly to up to 150 micrograms of the study drug administered orally once daily (e.g. depending on tolerability). Table 3 - Dose Titration C (Cohort 3)

Example 1 - Study Population

Number of Subjects

A sufficient number of subjects will be enrolled such that data from at least four evaluable subjects are available in Part A, prior to initiating Part B. Any subject who has received at least one dose of study medication and has undertaken at least one post-dose assessment will be evaluable. In Part B a sufficient number of subjects will be recruited such that at least 24 evaluable subjects are treated with the study drug. Subjects who have completed Part A cannot participate in Part B of the study.

Decisions regarding the replacement of subjects prematurely discontinued from study drug will be made by the investigator and GlaxoSmithKline Medical Monitor on a case by case basis. Example 1 - Eligibility Criteria

Inclusion Criteria

A subject is eligible for inclusion in this study only if all of the following criteria apply:

1. Male or female subjects with a clinical diagnosis of probable Alzheimer's disease in accordance with the NINCDS-ADRDA criteria and a Haschinski ischaemia score < 4 and an MRI (magnetic resonance imaging) or CT scan in the last 12 months.

2. The subject has an MMSE (Mini Mental State Examination) score at screening of 12 to 26 for Part A and 16 to 26 for Part B.

3. Age 50 years or above.

4. If female, the subject must be post-menopausal (i.e. 12 months without menstrual period) or surgically sterile. 5. Male subjects must be willing to abstain from sexual intercourse with pregnant or lactating women; or be willing to use a condom/spermicide in addition to having their female partner use another form of contraception, such as an intrauterine device (IUD), barrier methods (e.g. condom or occlusive cap (diaphragm or cervical vault/caps)), oral contraceptives, injectable progesterone, subdermal implants or a bilateral tubal ligation, if the woman could become pregnant, from the time of the first dose of the study drug until 84 days following completion of the study.

6. The subject has the ability to comply with the study procedures.

7. The subject has a permanent caregiver and is willing to attend all dose review and assessment sessions for Parts A and B.

8. The subject has provided full written informed consent prior to the

performance of any protocol specific procedure, or if unable to provide informed consent due to cognitive status, full written informed consent on behalf of the subject has been provided by a legally acceptable representative.

9. The caregiver has provided his / her written consent prior to the performance of any protocol specific procedure.

Exclusion Criteria

A subject is not eligible for inclusion in this study if any of the following criteria apply:

1. In the opinion of the investigator, following review of CT/MRI (magnetic resonance imaging) scans in the past 12 months and completion of neurological review there could be other probable causes of dementia which include, but are not limited to:

• History and/or evidence (CT or MRI scan performed since the onset of symptoms) of any other central nervous system (CNS) disorder that could be interpreted as the primary cause of dementia: e.g. cerebrovascular disease, structural or developmental abnormality, epilepsy, infections, or degenerative or inflammatory/demyelinating CNS conditions other than Alzheimer's Disease.

• Clinically significant focal findings on the neurological examination (excluding changes attributable to peripheral nervous system injury).

· Untreated abnormal result of any of the following tests: vitamin B12, syphilis serology, thyroid stimulating hormone (TSH), where this is thought to be the cause of, or to contribute to the severity of, the subject's dementia.

• Diagnosis of possible, probable or definite vascular dementia in accordance with National Institute of Neurological Disorders and Stroke- Association Internationale pour la Recherche I'Enseignement en Neurosciences (NINDS-AIREN) criteria. 2. History of significant psychiatric illness such as schizophrenia or bipolar affective disorder that in the opinion of the Investigator would interfere with participation in the study, or current depression (a score of≥8 on the Cornell Scale for Depression in Dementia), or subjects with other psychiatric features in their Alzheimer's Disease which would in the opinion of the investigator, would increase risk to safety.

3. History of significant sleep disturbance, for example, when it is associated with nocturnal wandering, or nocturnal confusion / disorientation / agitation, which in the opinion of the investigator, may increase safety risk.

4. History or presence of known or suspected seizures, or unexplained significant loss of consciousness within last 6 months. Subjects who had febrile seizures in childhood may be included if these ceased by age 10 and they have had no other type of seizure in their medical history and have not been on anti- epileptic medications.

5. History or presence of significant cardiovascular, gastro-intestinal, hepatic, or renal disease or other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs, or any other clinically relevant abnormality, medical or psychiatric condition, which, in the opinion of the

Investigator, makes the subject unsuitable for inclusion in the study.

6. History of alcohol or other substance abuse, according to the Diagnostic and Statistical Manual of Mental Disorders - Substance related disorders (DSM-IV) criteria.

7. Clinically significant abnormalities in laboratory tests, including subjects with active liver disease [to include subjects with ALT (alanine aminotransferase, i.e. alanine transaminase) or AST (aspartate aminotransferase) greater than 3 times the upper limit of normal and/or bilirubin greater than 1 .5 times the upper limit of normal] or uncontrolled thyroid disease.

8. Uncontrolled hypertension with systolic BP (blood pressure) >160 mmHg and/or diastolic BP >95 mmHg. Subjects with controlled hypertension with systolic BP < 160 mmHg and diastolic BP <95 mmHg for at least 4 weeks are acceptable.

9. Systolic BP <100 mmHg and/or diastolic BP <60 mmHg.

10. Subjects with a QTc (corrected QT) interval of >450ms or >480ms if they have bundle branch block or other ECG (electrocardiogram) abnormalities which, in the opinion of the investigator is clinically significant in that they may increase safety risk.

1 1 . History of hypersensivity to the study drug or its excipients.

12. Treatment with cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine or galantamine), memantine or selegiline within the previous month. No patients with Alzheimer's Disease who are already on these medications at the time of screening will be recruited, as it would be unethical to withdraw these medications for study participation. Only Alzheimer's Disease subjects who are not yet on these medications, or who have withdrawn from these medications for other reasons previously, may be enrolled into this study.

13. Subjects who are currently taking or who have taken in the last month any anti-psychotic drugs (e.g. typical or atypical dopaminergic antagonists or modulators) or any mood stabilization drugs [such as a SSRI (selective serotonin reuptake inhibitor), a DNRI (dopamine and norepinephrine reuptake inhibitor), a SNRI (serotonin-norepinephrine reuptake inhibitor), a monoamine oxidase (MAO) inhibitor, a tricyclic antidepressant, lithium, valproate, or cabamazepine].

14. Subjects who are currently taking Pgp inhibitors or any CYP3A4 inhibitors (CYP = Cytochrome).

15. Subjects on chronic sedative medications (> 4 days per week for the past 4 weeks).

16. Subject or caregiver is an immediate family member or employee of the participating Investigator, any of the participating site staff or GlaxoSmithKline staff.

17. Subject has received any other investigational treatment in the previous 3 months.

Example 1 - Results

1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone (as the free base, which in this Example is named the "drug", "study drug", "study medication", "active drug", "active agent", "active treatment" or similar) has been investigated in a safety and tolerability study in subjects (humans) with mild to moderate Alzheimer's Disease . All of the doses stated below refer to once daily oral administration. Example 1, Part A - Dosage regimens completed, tolerability and adverse events

Four subjects have completed Part A of the study, which involved dose titration from 2 μg to 5 μg, or from 5 μg to 10 μg over 7 days.

From preliminary data from Part A of the study, one subject experienced adverse events of pruritus and loose stools which were considered by the Investigator to be related to study drug. These adverse events were mild and resolved without the need for medical intervention.

Example 1, Part B - Dosage regimens intended and completed

Part B of the study had 18 subjects randomised to receive treatment with 1-{6- [(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone ("the study drug"). In Part B of the study, each subject followed (subject to tolerability) a dose titration regimen (escalating dosage regimen) comprising (intended) weekly dose escalations over a period of 4 weeks. For each titration regimen, six subjects were randomised to receive the study drug and two were randomised to receive placebo. The intended (subject-to- tolerability) titration (escalation) dosage regimens of the study drug investigated were as follows (see section "Example 1 - Dose Titrations A, B and C, details of dosage regimens" hereinabove for more details): Dose Titration A: escalation from 5 μg to 40 μg of the study drug (administered once daily orally).

Dose Titration B: escalation from 10 μg to 80 μg of the study drug (administered once daily orally).

Dose Titration C: escalation from 20 μg to 150 μg of the study drug (administered once daily orally).

The actual dosage regimens achieved by the various subjects in Dose Titrations A, B and C were as shown in the following Tables 4, 5 and 6 (which exclude potential subjects who failed the initial screening tests):

Table 4 - Dosage regimens, administered orally once daily, of the study drug or placebo, which were achieved by subjects within Dose Titration A (Cohort 1)

^* In Subject number S-A1 , it is thought that the tolerability of the study drug at around Day 22 was sufficiently good to allow dose escalation from 20 to 40 micrograms administered orally once daily, but that the wrong dose selection was inadvertently selected and the dosage regimen of the subject was changed from 20 to 10 micrograms administered orally once daily starting from Day 22.

Table 5 - Dosage regimens, administered orally once daily, of the study drug or placebo, which were achieved by subjects within Dose Titration B (Cohort 2)

micrograms ed

S-C5 20 micrograms 20 micrograms 40 micrograms 80 micrograms completed

S-C6 20 micrograms 40 micrograms 80 micrograms 150 completmicrograms ed

S-C7 placebo placebo placebo placebo completed

S-C8 20 micrograms 40 micrograms 80 micrograms 80 micrograms completed

Example 1, Part B - Tolerability and adverse events Preliminary safety and tolerability information on subjects treated with the study drug at each dose titration regimen in Part B is described below. A clinical cut-off date of the 8 June 2009 was used for the preliminary safety and tolerability data from this study. In Dose Titration A, one subject (subject no. S-A8) experienced adverse events (AEs) of headache and retro-ocular pain, which were assessed to be drug- related, on the second day of dosing at 10 g/day of study drug. This subject also experienced nausea and abdominal pain, assessed as drug-related, during the second week at 10 g/day of study drug. These events were mild to moderate in intensity. The dose was reduced at the end of Week 2 to 5 g/day of study drug and the subject was maintained at this dose level for the remainder of the study. The subject experienced a single episode of abdominal pain and intermittent headache and retro-ocular pain lasting one day, at the reduced dose of 5 g/day of study drug.

In Dose Titration A, adverse events not considered to be related to study drug included chest pain, diarrhoea, dysuria, feeling irritable, vertigo and blurred vision in a total of 4 subjects receiving the study drug. Of the subjects receiving placebo within Dose Titration A, one subject experienced vomiting and one subject experienced increased urination.

In Dose Titration A, a serious adverse event (SAE), considered by the

Investigator to be unrelated to study drug, was reported in an 85-year old female subject. The subject experienced a compression fracture in the T12 and L2 vertebrae, 9 days after completing dosing at 40 g/day of study drug, and required hospitalisation. The SAE was of moderate severity. The fracture was treated surgically with kyroplasty. She completed Dose Titration A prior to this SAE and did not report any adverse events (AEs) during the 28-day treatment period with the study drug.

In Dose Titration B, one subject experienced a single episode of light- headedness on Day 6 of dosing at 80 g/day of study drug, considered to be mild in intensity and related to study drug.

In Dose Titration B, one subject receiving placebo experienced dizziness, cough and ache in stomach under the breast.

In Dose Titration C, one subject (either subject no. S-C2 or S-C5) experienced intermittent sleep disturbance which started on Day 3 of dosing at 20 g/day of study drug, which was considered to be moderate in intensity and related to study drug. The subject was maintained at 20μg/day for Week 2 and

experienced dry mouth in the second week which was considered to be mild and related to study drug. The dose was subsequently increased to 40 g/day of study drug in Week 3 and to 80 g/day of study drug in Week 4. In the morning following the first day of dosing at 80 μg/day, this subject experienced hypnopompic hallucinations (i.e. hallucinations when waking from sleep).

Approximately two more episodes of hypnopompic hallucinations were experienced over the 7 days of dosing at 80 g/day. These hypnopompic hallucinations lasted a few seconds and took the shape of a human form. They were considered to be mild in intensity and related to study drug by the

Investigator. The dose was not reduced and the subject continued to the end of the study at a dose of 80 g/day.

In Dose Titration C, a second subject (either subject no. S-C2 or S-C5) experienced sleep disturbance which started on Day 2 of dosing at 20 g/day of study drug and lasted for six days. This subject also experienced depressive mood on Day 2 of dosing at 20 g/day of study drug which had not yet recovered at the time of reporting. Both of these events were mild, intermittent and considered to be related to study drug by the Investigator. The subject was maintained at 20μg/day for Week 2 of dosing but was able to escalate to 40 μg/day of study drug in Week 3 and 80 g/day of study drug in Week 4. The subject continued to the end of the study at a dose of 80 g/day of study drug.

In Dose Titration C, a third subject (subject no. S-C8) reported feeling fatigued for approximately 1 hour a day from the start of dosing at 80 g/day of study drug (Day 15) for three days. The events were mild and considered to be related to the study drug by the Investigator. This subject was maintained at 80 g/day in Week 4 and experienced 3 episodes of headache. These episodes started approximately 2 hours after dosing on each occasion and lasted approximately 2 hours. The subject continued to the end of the study at a dose of 80 g/day of study drug.

In Dose Titration C, one subject experienced nausea on Day 1 of dosing at 150 g/day of study drug approximately 3 hours after dosing, with a single episode of vomiting in the evening of the same day. This subject also experienced a single episode of diarrhoea on Day 2 of dosing at 150 g/day. The subject continued to the end of the study at a dose of 150 g/day of study drug. In Dose Titration C, one subject experienced a single episode of indigestion on Day 1 of dosing at 80 g/day of study drug which lasted for approximately 3 hours. The subject also experienced tiredness on Day 6 of dosing at 80 g/day which lasted most of the day, and a single episode of disorientation on Day 1 of dosing at 150 g/day of study drug which lasted approximately 3 hours. All events were mild in intensity and considered to be related to the study drug by the Investigator. The subject continued to the end of the study at a dose of 150 μg/day of study drug.

In Dose Titration C, one subject has completed dosing at 150μg/day of study drug with no adverse events reported.

In Dose Titration C, one subject receiving placebo experienced elevated blood glucose, accidental fall and skin tears on the right arm following the fall. A second subject receiving placebo experienced tiredness, sleepiness and light- headedness.

There were no clinically significant changes in vital signs, ECG

(electrocardiogram) or laboratory safety parameters in any of the dose titration regimens as reported by the Investigators. No subjects have been withdrawn from this Example 1 study due to safety or tolerability issues.

It is concluded, from the above-mentioned tolerability data from this clinical trial in mild-to-moderate Alzheimer's disease patients (Example 1 ), that two escalating (up-titrated) oral dosage regimens of 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone (administered as the free base), one of which started at 5 micrograms administered once per day and generally finished at 40 micrograms administered once per day (Dose Titration A), and the other of which started at 10 micrograms administered once per day and generally finished at 80 micrograms administered once per day (Dose Titration B), appear to cause fewer side effects (assessed as being drug-related) than a third escalating oral dosage regimen which started at 20 micrograms administered once per day and finished at 150 or 80 micrograms administered once per day of l-ie-tiS-cyclobutyl^^^^-tetrahydro-I H-S-benzazepin-y-y oxyl-S-pyridinyl}^- pyrrolidinone (administered as the free base) (Dose Titration C).

Example 1, Part B - Efficacy (changes in cognitive function in mild-to- moderate Alzheimer's disease patients)

There appeared to be some preliminary signs and trends of positive changes in cognitive function (especially in function of episodic memory such as in delayed recall tasks for episodic memory), at some of the final (maintenance) dosage regimens of 40 g/day, 80 g/day or 150 g/day in subjects in Dose Titrations A, B and C, as is now described in more detail.

Changes in cognitive function were measured by the following CogState tasks (using the CogState neuropsychological test battery):

- Detection (which tests attention),

- Identification (which tests attention),

- One-Back/Card Learning ("One-Back") (which tests working memory),

- International Shopping List Task ("ISL") (which is an immediate recall task for episodic memory), and

- International Shopping List Recall ("ISL-R") (which is a delayed recall task for episodic memory).

Example 1, Part B CogState Effect Size data for all patients titrating to 40, 80 or 150 i g/day of study drug, regardless of initial dosage regimen

Figure 3 (a graph), and Table 7 below, describe the mean observed CogState Effect Sizes (Cohen's d) on Day 29 of 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H- 3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone [the "study drug"] compared to placebo (i.e. the mean Day 29 CogState effect at the relevant final daily dose of study drug, minus the mean CogState effect seen with patients on placebo) and 95% Confidence Intervals, for subjects titrating to a final dose of 40 μg, or 80 μg, or 150 μg, or (40 μg, 80 μg, or 150 μg, combined data) of the study drug administered orally once per day, regardless of the initial dosage regimen.

Twenty-one subjects contributed to the CogState Effect Size analysis shown in Figure 3 and Table 7, as follows:

- all six subjects who received placebo from Dose Titrations A, B and C;

- four subjects who received a final dosage regimen of 40 micrograms/day of study drug [note: of the five patients achieving a 40 g/day final dose (four patients and one patient from Dose Titrations A and B respectively), one was removed from the analysis];

- eight subjects who received a final dosage regimen of 80 micrograms/day of study drug, irrespective of the initial dosage regimen

[note: these are all eight subjects who titrated to a final dosage regimen of 80 μg/day, and so comprises five subjects from Dose Titration B who successfully titrated from 10 to 20 to 40 to 80 g/day, plus three subjects from Dose Titration C who started at 20 g/day and ended at 80 μg/day]; and

- three subjects who received a final dosage regimen of 150 micrograms/day of study drug

[note: these are the three subjects from Dose Titration C who successfully titrated from 20 to 40 to 80 to 150 pg/day].

Table 7 - Day 29 mean CogState Effect Sizes compared to placebo (i.e. study drug effect minus placebo effect); by daily dose received at Day 29 regardless of the initial dosage regimen; the 95% Confidence Interval (95% CI) for each mean Effect Size is shown in parentheses

Given the small number of subjects on each dose, an exploratory jack-knife analyses was conducted. The average jack-knife estimate from removing each subject in turn was generally consistent with the overall estimates, confirming the estimate was not being overly influenced by one or more subject. Comments on Table 7 CogState Effect Size data: In the Detection task (attention test), there appeared to be a trend to a small effect over placebo for all doses (40, 80 and 150 g/day study drug, combined data). There appeared to be trends to large effects over placebo in the Identification task (attention test) and ISL-R task (episodic memory test), for all doses (40, 80 and 150 g/day study drug, combined data), and for the 40 g/day, 80 g/day and 150 g/day doses. Additionally, there appeared to be trends to large effects over placebo in the ISL task (episodic memory test), for the 80 g/day and 150 g/day doses. In respect of these apparent positive cognitive effects, the small numbers of patients and the wide statistical variation in the results is noted. There appeared to be no statistical difference compared to placebo for the One-Back task (working memory test), based on the combined data for the 40, 80 and 150 g/day study drug.

Example 1, Part B CogState Effect Size data for patients with an initial dosage regimen of 5 or 10 [ig/day of study drug and titrating to a final dosage regimen of 40 or 80 [ig/day of study drug (i.e. only Dose Titrations A or B, Cohorts 1 or 2) Figure 4 (a graph), and Table 8 below, describe the mean observed CogState Effect Sizes (Cohen's d) on Day 29 of 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H- 3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone [the "study drug"] compared to placebo (i.e. the mean Day 29 CogState effect at the relevant final daily dose of study drug, minus the mean CogState effect seen with patients on placebo) and 95% Confidence Intervals; for subjects titrating to a final dosage regimen of 40 μg, or 80 μg, or (40 μg or 80 μg, combined data) of the study drug administered orally once per day, with the proviso that only those subjects receiving an initial dosage regimen of 5 or 10 μg/day of study drug are included (i.e. only subjects from Dose Titrations A or B, i.e. Cohorts 1 or 2, are included). Subjects from Dose Titration C (i.e. Cohort 3), receiving an initial dosage regimen of 20 μg/day of study drug, are excluded. Subjects receiving placebo in Dose Titration C (Cohort 3) are included, for consistency of analysis (allowing comparison to the Figure 3, Table 7 data). Fifteen subjects contributed to the CogState Effect Size analysis shown in Figure 4 and Table 8, as follows:

- all six subjects who received placebo from Dose Titrations A, B and C; - four subjects who received a final dosage regimen of 40 micrograms/day of study drug [note: of the five patients achieving a 40 g/day final dose (four patients and one patient from Dose Titrations A and B respectively), one was removed from the analysis]; and - five subjects from Dose Titration B who received a final dosage regimen of 80 micrograms/day, and who successfully titrated from 10 to 20 to 40 to 80 μg/day.

Table 8 - Day 29 mean CogState Effect Sizes compared to placebo (i.e. study drug effect minus placebo effect); by daily dose received at Day 29; for patients with an initial dosage regimen of 5 or 10 [ig/day of study drug and titrating to a final dosage regimen of 40 or 80 [ig/day of study drug (Dose Titrations A or B only); the 95% Confidence Interval (95% CI) for each mean Effect Size is shown in parentheses

Comments on Table 8 CogState Effect Size data: In the Detection task (attention test), there appeared to be a trend to a small effect over placebo for 40 g/day of study drug, but not for 80 μg/day. In the Identification task (attention test), there appeared to be a trend to a large effect over placebo for 40 g/day of study drug, but not for 80 μg/day. In the ISL task (immediate recall task for episodic memory), there appeared to be a trend to a large effect over placebo for the 80 μg/day final doses of the study drug, but not for 40 μg/day. In the ISL-R task (delayed recall task for episodic memory), there appeared to be trends to large effects over placebo for the 40 g/day and 80 g/day final doses of the study drug. In respect of these apparent positive cognitive effects, the small numbers of patients and the wide statistical variation in the results are noted. Summary of the Example 1 clinical study

From preliminary data in this Example 1 study, 1-{6-[(3-cyclobutyl-2, 3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone ("the study drug") has shown generally good tolerability in mild-to-moderate Alzheimer's Disease subjects, (a) when starting with an initial dosage regimen of 5 micrograms administered orally once daily and when escalating over 4 weeks to a final dosage regimen of 40 micrograms administered orally once daily, and (b) when starting with an initial dosage regimen of 10 micrograms administered orally once daily and when escalating over 4 weeks to a final dosage regimen of 40 or 80 micrograms administered orally once daily. The compound appeared previously to show effects on the neural processes during cognitive tasks in healthy subjects. From the Example 1 clinical study, the compound appears to show favourable cognitive changes in the performance of mild-to-moderate Alzheimer's Disease subjects on the CogState neuropsychological test battery (especially, favourable changes in the function of episodic memory such as in delayed recall tasks for episodic memory). As such, 1 -{6-[(3-cyclobutyl-2, 3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone (or a pharmaceutically acceptable salt thereof), especially in the above-mentioned and/or herein-defined tolerable dosage regimens, may bring about clinical improvement in cognitive function and/or in other symptoms in subjects with Alzheimer's Disease.

EXAMPLE 2 - CLINICAL TRIAL - A randomised, double-blind, placebo- controlled study to evaluate the efficacy and safety of the H3 receptor antagonist, 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]- 3-pyridinyl}-2-pyrrolidinone, in subjects with mild-to-moderate Alzheimer's disease.

This study, is a Phase I la proof of concept study to assess the efficacy of 1 -{6- [(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone (as the "free base" form) (which in this Example is named the "drug", "study drug", "study medication", "active drug", "active agent", "active treatment" or similar terms), in mild-to-moderate Alzheimer's disease (AD) patients.

Example 2 - Dosage Regimen Rationale Subjects will enter a two-week placebo run-in period before being randomised (1 :1 ) to receive the study drug or placebo for a period of 16 weeks (4 weeks titration and 12 weeks at maintenance). Subjects will start at a once-daily oral dosage regimen of 10 μg (10 micrograms) / day of the study drug or matching placebo and, subject to safety and tolerability, will undergo weekly titrations through successive dose levels to a target maintenance dosage regimen of 80 μg/day orally (once daily) of the study drug, according to the titration regimen in Table 9.

Subjects will undergo weekly review for assessment of safety and tolerability before each dose titration. The dose may be kept unchanged or decreased if in the Investigator's opinion there are safety or tolerability concerns. Guidance on dose adjustment is provided in the section on "Example 2 - Dose Adjustment / Stopping Criteria" below. Table 9 Intended Dose Titration Regimen for patients receiving the study drug (oral once-daily administration) in Example 2

All subjects are required to dose titrate through the successive levels. It is not permissible to skip a dose level.

The proposed titration regimen in this study is considered to be the optimal titration regimen, which balances tolerability with duration of time to attain potentially efficacious doses. Mild-to-moderate Alzheimer's disease subjects in the clinical study described in Example 1 herein, who titrated up from 1 C^g/day to 8C^g/day of the study drug orally once-daily, tolerated this dose regimen well. It is anticipated that most Alzheimer's disease subjects in the present study of Example 2 will be able to titrate from 10 g/day up to 80 g/day of the study drug, administered orally once daily.

From pre-clinical (non-human) cognition models, a brain H3 Receptor Occupancy (RO) of at least 70% was associated with improvement in performance in cognitive tasks.

Modulation of cognitive EEG (electroencephalogram) and ERP (event related potential) were observed at a fixed 20 ug/day oral dosage regimen of the study drug, in healthy elderly subjects (data not shown). In Alzheimer's disease subjects, there was preliminary evidence of cognitive improvement at doses of 40-80 g/day of the study drug (see Example 1 herein).

Based on data from a healthy human volunteer PET (Positron Emission

Tomography) study, to achieve and maintain a RO of approx. 70% or more over 24 hours in over 95% of subjects, it is predicted that an oral dosage regimen of approximately 40 - 80 g/day (preferably 80 g/day) of the study drug is required (see Table 10 below). At a dose of 20 g/day of the study drug, at least 95% of the subjects are predicted to reach 40% RO over 24 h and about half of the subjects are predicted to achieve a RO of at least 70% over 24 hours (see Table 10 below).

Predicted steady-state RO (brain H3 receptor occupancy) values for each dose titration regimen from human PET study (using the PK-RO model^* with correction for tracer mass dose) for once daily dosing

50% of the population have 95% of the population have these RO values RO at ss above these values

^* PK-RO (pharmacokinetic - receptor-occupancy) model was built using repeat dose data (not shown) from one human study, and RO values from a different (human PET) study, assuming a direct effect model.

^** Cmax = maximum observed concentration; Cmin = minimum observed concentration.

Data from neuropathological studies of brain slices from Alzheimer's disease subjects post-mortem suggest that the binding affinity of the H3 antagonist

GSK189254, which is also a benzazepine as is the study drug, is comparable between Alzheimer's disease subjects and healthy subjects [A.D. Medhurst, J.C. Roberts, J. Lee, C.P.L.-H. Chen, S.H. Brown, S. Roman, and M.K.P. Lai,

"Characterization of histamine H3 receptors in Alzheimer's disease brain and amyloid over-expressing TASTPM mice", British Journal of Pharmacology, 2009, vol.157, pp.130-138]. The overall data mentioned above suggests that to achieve >70% RO over 24 hours in over 95% of subjects, the oral dosage regimen required in Alzheimer's disease subjects is likely to be at least 40 g/day (preferably 80 g/day) of the study drug; and an oral dosage regimen of 20 g/day of the study drug will probably achieve >70% RO over 24 hours in about 50% of Alzheimer's disease subjects. Cognitive performance in the study described in Example 1 herein, in mild-to-moderate Alzheimer's disease subjects who titrated up to 40 g/day or higher (40, 80 or 150 g/day) of the study drug, appeared to show a numerical improvement over placebo in memory tasks (specifically, episodic memory tasks) and attention tasks (see Example 1 for details). In healthy subjects an oral once- daily dosage regimen of 20μg/day showed PD (pharmacodynamic) effects on cognitive ERP (event related potential) measures (data not shown). Overall, an oral once-daily dosage regimen of 20-40 g/day of the study drug may therefore be on the threshold of producing some clinically-evident cognitive benefit, at least for part of the dosing interval. Tolerability of the study drug: The highest repeat oral dose administered to healthy young subjects in a Phase 1 study was 150 g/day of the study drug, where tolerability was acceptable. However, repeat dosing was less well tolerated in healthy elderly subjects than in healthy young subjects, at a fixed dosage regimen of 20 g/day of the study drug administered orally for 12 days (the study drug was well tolerated in healthy young subjects at this fixed 20 μg/day oral dosage regimen).

From the clinical study of Example 1 , the tolerability of the study drug in mild-to- moderate Alzheimer's disease subjects, with titration of from 10 g/day to 80 g/day orally once daily of the study drug (see Example 1 ), appears to be better than in healthy elderly subjects with a fixed repeat oral dosage regimen of 10μg or 20μg/day (data not shown). A titration approach was not used in these healthy elderly subjects. The difference in tolerability of the study drug between healthy elderly and Alzheimer's disease subjects is thought likely to be due in part to the titration regimen employed in Alzheimer's disease subjects compared to the fixed repeat dosage regimen employed in healthy elderly subjects. It could also suggest that in Alzheimer's disease subjects with deficient neurotransmitter systems, the effects of the study drug on neurotransmitter release or the downstream postsynaptic response may be less than in healthy subjects despite comparable levels of RO. This might imply that, although in pre-clinical models and in cognitive ERP (event related potential) studies in healthy subjects a RO (brain H3 receptor occupancy) of about 70% or more is sufficient for modulation of cognitive processes, a higher RO may be required for a similar effect in subjects with Alzheimer's disease. Therefore, titrating subjects up to 80 g/day of the study drug orally once daily is intended to achieve near-saturation of RO throughout the dosing interval to "compensate" for possible reduced downstream pharmacodynamic sensitivity to H3 receptor blockade in Alzheimer's disease. A dosage regimen of 80μg/day of the study drug orally once daily is predicted to give at least 80% RO over 24 hours in over 95% of subjects (see Table 10 above). Data from the study described in Example 1 herein appears to show that subjects who titrated up to 80 g/day of the study drug showed numerically superior performance over placebo in memory (specifically, episodic memory) and attention tasks (see Example 1 herein). Therefore, in the present study of Example 2, an oral once-daily dosage regimen of 80 g/day of the study drug will be the highest dosage regimen which Alzheimer's disease subjects will be allowed to titrate to, in order to maximise the chance of producing cognitive benefits whilst being well-tolerated by the subjects.

Based on the good tolerability profile of previous titration regimens from the Example 1 study covering the 10 to 80 g/day dosage regimen range, and based on the dose levels thought to be required to achieve RO levels with cognitive benefits, it is proposed that, within the present Example 2 clinical study,

Alzheimer's disease subjects should start with an initial oral once-daily dosage regimen of 10 g/day of the study drug, and should aim to titrate up a target oral once-daily maintenance dosage regimen of 80 g/day of the study drug. If tolerability issues arise in an Alzheimer's disease subject within the present Example 2 clinical study, oral once-daily maintenance dosage regimens of 40 μg/day or 20 g/day of the study drug will be permitted. Example 2 - Summary of Risk Management

Adverse events (AEs) anticipated due to the study drug in Alzheimer's disease subjects may include sleep disturbance, hypnopompic hallucinations, nausea, vomiting, diarrhoea and light headedness (based e.g. on the Example 1 study). These AEs are more likely to be experienced by Alzheimer's disease subjects at the 80 g/day dose level. They may develop within the first few days of dosing at 80 g/day of the study drug. It is expected that most of these AEs will resolve spontaneously without the need for medical treatment. The Alzheimer's disease subjects' eligibility criteria are selected such as to minimise or eliminate risk factors likely to increase the risk of AEs.

The dose levels (daily oral dose of study drug) and the titration regimen have been selected such that they are likely to be well-tolerated in this Example 2 study, based on tolerability data from similar dose regimens in the study described in Example 1 herein. During the titration phase if a dose level is not well-tolerated, subjects may step down to their previously tolerated dose level for at least one more week, and are then permitted to have one more attempt at escalating to the next higher dose level. If this second attempt at the next higher dose level is still not tolerated, no further attempts will be permitted, and subjects will be discontinued from the study if their tolerated dose level is less than 20 g/day of study drug. Guidelines for dose adjustment are provided herein.

Example 2 - Objectives Primary Objective

• To assess the efficacy of the study drug on cognitive function in subjects with mild to moderate Alzheimer's disease after 16 weeks of treatment. Secondary Objectives

• To assess the efficacy of the study drug on global clinical status after 16 weeks of treatment.

• To assess the effects of the study drug on patients' and carers'

perception of clinical status after 16 weeks of treatment.

• To assess the effects of the study drug on neuropsychiatric or

behavioural symptoms after 16 weeks of treatment.

• To assess the effects of the study drug on activities of daily living after 16 weeks of treatment.

· To assess the safety and tolerability of the study drug after 16 weeks of treatment.

• To estimate the systemic exposure to the study drug during the 16 weeks of treatment.

• To investigate any relationship between systemic exposure of the study drug with changes in cognitive function or other efficacy outcome measures.

Example 2 - Endpoints

Primary Endpoints

• Change from baseline in the executive function/working memory

composite score in the CogState battery at Week 16

• Change from baseline in the episodic memory composite score in the CogState battery at Week 16.

Secondary Endpoints

• Change from baseline in the attention composite score in the CogState battery at Week 16.

• Change from baseline in ADAS-Cog (Alzheimer's Disease Assessment Scale - cognitive subscale) total score at Weeks 8 and 16

• Clinician's Interview-Based Impression of Change-plus (CIBIC+) score at Weeks 8 and 16.

· Change from baseline to Weeks 8 and 16 of the Disability Assessment for Dementia scale (DAD) total score • Patient's Global Impression of Change (PGIC) and Carer's Global

Impression of Change (CrGIC) at Weeks 8 and 16, Clinician Global Impression of Change (CGIC) at Week 16.

• Change from baseline in the Neuropsychiatric Inventory (NPI) at Weeks 8 and 16.

• Change from baseline in Mini Mental State Examination (MMSE) total score at Week 16

• Change from baseline during the titration phase, and to Weeks 8 and 16 of the Pittsburgh Sleep Quality Inventory (PSQI) and Epworth Sleepiness Scale (ESS).

• Olfaction tests will be included as an exploratory endpoint.

• Plasma concentrations of the study drug

Safety Endpoints

• Adverse events.

· CGIC, PGIC, CrGIC (during titration phase).

• NPI (during titration phase).

• 12-lead ECG (electrocardiogram), vital signs (systolic and diastolic blood pressure, heart rate).

• Clinical laboratory evaluations.

Example 2 - Investigational Plan Study Design / Schematic

This is a Phase lla multi-centre, randomised, double-blind, placebo-controlled, parallel group design in subjects with mild to moderate Alzheimer's disease (having a MMSE score of 16 to 24) (MMSE means Mini Mental State

Examination) to assess the efficacy, safety and tolerability of the study drug over 16 weeks of treatment.

It is planned that at least 152 subjects will be randomised to ensure 138 evaluable subjects. Subjects will be randomised 1 : 1 to the study drug or placebo. Following a screening period of up to two weeks, subjects will enter a two-week placebo run-in period before being randomised (1 :1 ) to receive the study drug or placebo for a period of 16 weeks which includes 4 weeks of titration to a target oral once-daily maintenance dosage regimen of 80 g/day of the study drug (subject to tolerability) followed by 12 weeks at the maintenance dosage regimen.

The maximum titration period is 4 weeks, during which the subjects will attend the unit for a weekly review for safety and tolerability. Subjects will titrate on a weekly basis from an initial oral once-daily dosage regimen of 10 g/day of the study drug up to a target oral once-daily maintenance dosage regimen of 80 μg/day of the study drug (subject to tolerability). Details of the titration regimen are described herein. Subjects will undergo weekly review for assessment of safety and tolerability before each dose titration. The dose may be kept unchanged or decreased if in the Investigator's opinion there are safety or tolerability concerns.

If tolerability issues arise in a subject, maintenance dosage regimens of 40 g/day or 20 g/day of the study drug (orally once-daily) will be permitted.

Subjects who cannot be maintained on at least 20 g/day (orally once-daily) will be withdrawn. The total treatment duration post-randomisation is 16 weeks inclusive of the titration period of 4 weeks. Scheduled visits will take place at screening, at the start of the placebo run-in period (Week -2, Day -14), at randomisation (Day 1 ) and post-randomisation at Weeks 1 , 2, 3, 4, 8, 12 and 16 weeks, with a follow up visit approximately two weeks after the last dose of study medication (see Figure 5 for a schematic illustration of the study design of the Example 2 clinical study). For visits during the dose titration (dose escalation) phase (Days 7, 14, 21 and 28) (see Figure 5), assessments and dose review may be made within +1 day of the target days. Once in the maintenance phase, assessments and dose review may be made within +/- 2 days of the target days (visits in Weeks 8 and 12).

Example 2 - Discussion of Design

As this is a monotherapy trial, only patients who have not been taking treatments for cognitive impairment in Alzheimer's disease for a period of at least 3 months prior to screening will be enrolled. They will not be permitted to commence treatments for cognitive impairment during the study. The study drug was found to improve cognition as monotherapy in preclinical models and showed modulation of activity in cognitive neural networks in healthy subjects receiving fixed (non-escalated) dosage regimens. Favourable cognitive changes in the performance of Alzheimer's disease subjects on monotherapy with the study drug have been seen on the CogState neuropsychological test battery (NTB) in the study described in Example 1 herein. A monotherapy design allows a pure evaluation of the efficacy and safety of the study drug and minimises the risk of confounding from potential pharmacodynamic interactions with other cognition- enhancing drugs.

The co-primary endpoints are the composite scores of executive function/working memory and episodic memory of the CogState NTB. The composite score of attention of the CogState NTB will be a secondary endpoint. Historically, clinical trials in mild to moderate Alzheimer's disease used ADAS-Cog (Alzheimer's Disease Assessment Scale - cognitive subscale) as the primary endpoint for efficacy in cognition but in recent years this is no longer considered to be a sufficiently sensitive endpoint to demonstrate treatment benefits on cognition in all circumstances [see for example: B. Vellas et al., "Endpoints for trials in Alzheimer's disease: a European task force consensus", Lancet Neurology, 2008, vol.7, pp.436- 450; and M. Irizzary, D. Webb D, C. Bains, S. Barrett, R. Lai, J. Laroche, D. Hosford, G. Maher-Edwards, and J. Weil, "Predictors of placebo group decline in the Alzheimer's Disease Scale-cognitive subscale (ADAS-Cog) in 24 week clinical trials of Alzheimer's disease", Journal of Alzheimer's Disease, 2008, vol.14, pp.301-31 1]. Novel cognitive tests have been proposed, particularly in subjects with mild Alzheimer's disease [B. Vellas et al., "Endpoints for trials in Alzheimer's disease: a European task force consensus", Lancet Neurology, 2008, vol.7, pp.436- 450], as potentially being more sensitive as a cognitive endpoint in Alzheimer's disease trials. The CogState neuropsychological test battery (NTB) is a battery of cognitive tests of executive function/working memory, episodic memory and attention which have been investigated in subjects with mild to moderate Alzheimer's disease with donepezil and memantine, which are approved treatments for Alzheimer's disease. Donepezil and memantine have shown improvement in performance in Alzheimer's disease subjects in the CogState battery of tests, including episodic memory and attentional tasks. In the present study of Example 2, the MMSE (Mini Mental State Examination) range of the Alzheimer's disease subjects (MMSE of 16 to 24) is selected such that they are likely to be able to understand the instructions and perform the CogState tests. The ADAS- Cog test will serve as a secondary endpoint in cognition in order to relate the effects observed with the novel CogState endpoints with an accepted regulatory endpoint, in accordance with the EMEA guidelines on clinical trials in Alzheimer's disease [European Medicines Agency Document Number CPMP/EWP/553/95 Rev.1.]. Efficacy on ADAS-Cog will also allow benchmarking of the study drug against the efficacy of other cognition-enhancing drugs in Alzheimer's disease which have been studied in recent clinical trials. Apart from cognitive endpoints, other clinical endpoints of neuropsychiatric symptoms, function in daily activities, global clinical status and sleep parameters will also be evaluated.

The ADAS-Cog showed some within-subject variability on repeated

administration over a short period of 4 - 6 weeks during recent clinical trials in subjects with mild to moderate Alzheimer's disease, even prior to the

administration of any study medication (whether placebo or active treatment). This may contribute to its apparent reduction in sensitivity in showing drug efficacy [M. Irizzary, D. Webb D, C. Bains, S. Barrett, R. Lai, J. Laroche, D. Hosford, G. Maher-Edwards, and J. Weil, "Predictors of placebo group decline in the Alzheimer's Disease Scale-cognitive subscale (ADAS-Cog) in 24 week clinical trials of Alzheimer's disease", Journal of Alzheimer's Disease, 2008, vol.14, pp.301-31 1].

In comparison, the CogState tests of cognition have shown good test-retest stability in Alzheimer's disease subjects with minimal learning effects on repeated administration in subjects treated with placebo during a small clinical trial [D. Darby et al., "Mild cognitive impairment can be detected by multiple assessments in a single day", Neurology, 2002, vol.59, pp.1042-1046].

In the present study of Example 2, to allow for within-subject variability seen with the initial CogState tests, a placebo run-in period is included to provide a more precise estimate of baseline performance over 2 weeks. It should similarly also provide a more precise estimate of baseline values in other clinical efficacy endpoints. Subjects will up-titrate on a weekly basis to a target oral once-daily maintenance dosage regimen of 8C^g/day, subject to tolerability and safety of the study drug in the subject. The CogState endpoints will be administered weekly during the first four weeks of titration and then monthly during the maintenance phase. The main time-points for other efficacy assessments will be Weeks 4 (Day 28), 8 and 16. At Day 28 subjects are required to attain at least 2C^g/day which might provide adequate receptor occupancy (RO) for producing cognitive improvement. Subjects who cannot achieve 2C^g/day by Day 28 will be withdrawn from the present study of Example 2. The final efficacy assessment is performed at Week 16.

Preclinical and Phase 1 clinical studies suggest cognitive effects may occur after a single dose of, or within two weeks of repeat dosing of, the study drug.

Previous clinical trials with donepezil and more recently with other cognition- enhancing drugs (such as phenserine) suggest that differentiation from placebo in terms of cognitive improvement appears after approximately 12 weeks of treatment and this benefit may become greater after 24 weeks of treatment.

In the present study of Example 2, after subjects have titrated over 4 weeks up to a oral once-daily dosage regimen of 80μg/day (or 40μg/day or 20μg/day if tolerability issues arise) they will continue to be dosed at this dose level for a further 12 weeks (until Week 16). It is hoped that this treatment duration will allow for demonstration of cognitive efficacy comparable to the typical time taken for onset of efficacy of other drugs such as donepezil [S. Rogers et al. and the Donepezil Study Group, "A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease", Neurology, 1998, vol.50, pp.136- 145]. Given the existing pre-clinical and clinical data on the study drug and other histamine H3 antagonists showing rapid onset of pharmacodynamic effects, it is thought reasonably likely that efficacy of the study drug in Alzheimer's Disease will be seen within 12 weeks of treatment at the final (maintenance) dosage regimen of the study drug.

Example 2 - Treatment Assignment

Subjects will first complete a 2 week placebo run-in period and will then be assigned to the study drug or matching placebo in a 1 :1 ratio in accordance with the randomisation schedule generated by Discovery Biometrics, prior to the start of the study, using validated internal software. The randomisation will be stratified by MMSE (Mini Mental State Examination) to ensure approximately 50% of mild Alzheimer's disease patients (having a MMSE score of 20 to 24) and 50% of moderate Alzheimer's disease patients (having a MMSE score of 16 to 19) are randomized equally to each treatment regimen. A description of each dosage regimen is provided in 1 1. For further details of the titration, see elsewhere within Example 2. Table 11 Treatment Dosage Regimens (administered orally once daily) to be used in the Example 2 study

^** Dosage regimen may be maintained at 2C^g/day or 4C^g/day if tolerability issues arise

Table 12 - Investigational Product Dosage /Administration, for Example 2 study

Example 2 - Dose Adjustment / Stopping Criteria

This protocol allows some alteration from the currently outlined dosing schedule, but the maximum daily dosage regimen will not exceed 8C^g/day of the study drug. Under the titration (escalation) scheme disclosed herein and the dose adjustment guidelines for the investigator disclosed herein, subjects will titrate to their individually best-tolerated dose level during the first 4 weeks, with which they will then continue for the rest of the study. The aim is to titrate up to a highest dose level of 8C^g/day of the study drug which is considered to optimize the chance of showing cognitive improvement. This dose is likely to be well tolerated based on evidence from a Phase 1 clinical study in healthy young subjects and from the safety and tolerability study in Alzheimer's disease subjects (the clinical study disclosed in Example 1 ).

All subjects are required to dose titrate through the successive levels. It is not permissible to skip (miss out) a dose level. The total duration of the titration phase is 4 weeks and no further dose increases can be made at the end of Week 4. The dose level which was tolerated during Week 4 will be maintained for the rest of the study and must be at least 2C^g/day of the study drug. A dose level which was not tolerated during Week 4 will be reduced to the previously well-tolerated, lower dose level and maintained as such for the rest of the study, but again this must be at least 2C^g/day. Subjects who cannot titrate up to at least 2C^g/day of the study drug by Day 28 will be withdrawn from the study.

It is possible that some subjects will not be able to dose escalate every week, and may require more than one week at a particular dose level or may need to step down to the previous dose level before attempting to up-titrate again. Example 2 - Dosing Examples

Based on these general principles for titration, more specific examples of up- titration (escalation) dosage regimens are discussed for illustrative purposes and are detailed in Figure 7.

Subjects who cannot tolerate 10μg/day of the study drug during Week 1 will be withdrawn.

Subjects who tolerate 10μg/day of the study drug during Week 1 will be reviewed by the investigator and the dose may be increased or remain unchanged according to the guidelines for dose adjustment given herein. If a dose increase is judged to be appropriate, the subject will escalate (up-titrate) to 20μg/day of the study drug during Week 2. If, after Week 1 , the subject is considered by the investigator to be unsuitable for dose escalation to 20μg/day then s/he will continue with 10μg/day of the study drug for 1 more week (i.e. during Week 2) and will be reviewed again at the end of Week 2, when the dose may be increased to 20μg/day of the study drug. If, after Weeks 1 and 2 at ^g/day of the study drug, the subject is still considered by the investigator to be unsuitable for dose escalation to 20μg/day then the dose should be kept at ^g/day of the study drug for Week 3. This process is repeated at the end of Week 3. If, after Weeks 1 , 2 and 3 at ^g/day of the study drug, the subject is still considered by the Investigator to the unsuitable for dose escalation to 20μg/day of the study drug during Week 4 then s/he will be withdrawn. See Figure 7. Extending this example more generally, there may be subjects who will require more than 1 week at 2C^g/day or 4C^g/day of the study drug, before possibly stepping up to the next dose level. Such subjects will be able to attain at most 4C^g/day during Week 4 and beyond; this is an acceptable dose level to continue during the maintenance phase. Subjects who require 3 weeks at 10 or 2C^g/day of the study drug will at most be able to achieve 2C^g/day of the study drug during Week 4; and again this is acceptable dose level for the maintenance phase. A subject who cannot step up to at least 2C^g/day of the study drug at the start of Week 4 should be withdrawn from the study, and this may take place prior to the end of Week 4. See Figure 7.

In the scenario in which a subject does not tolerate a dose level well and has to step down, this is normally expected to take place at the weekly review after being on that dose level for 1 week. However, if a subject experiences significant tolerability problems prior to the next scheduled clinic visit, the investigator should review the subject at an unscheduled visit to decide on dose adjustment or withdrawal. The subject may step down to the previously tolerated dose level and continue for the rest of the week until the next scheduled clinic visit. If the subject has been on the lower dose level for≥ 4 days (4 or more days) by this next scheduled clinic visit, the investigator may attempt to step up again if tolerability is satisfactory. For example a subject may start 20μg/day of the study drug on Day 8 but needs to step down on Day 10 to 10μg/day of the study drug. At the visit on Day 14, if 10μg/day has been well-tolerated for 4 days (Day 10 - 13), the investigator may consider another attempt to step up to 20μg/day of the study drug on Day 15. On the other hand, if the subject has only been on the lower dose level for <3 days (3 days or less) by this next scheduled clinic visit, the investigator should not increase the dose for the following week. For example a subject may start 20μg/day of the study drug on Day 8 but needs to step down on Day 1 1 to 10μg/day of the study drug. At the visit on Day 14, even if 10μg/day has been well-tolerated for 3 days (Day 1 1 - 13), the dose should remain at 10μg/day of the study drug during Week 3. It is permissible to attempt to step up to 20μg/day on Day 22 (beginning of Week 4) for a second time (see Figure 7) but if this is not tolerated the subject should be withdrawn since s/he will not be able to achieve the minimum maintenance dose of 20μg/day required for therapeutic benefit.

In a similar manner, subjects who experience tolerability problems during Week 3 on 40μg/day of the study drug may have to step down to 20μg/day of the study drug during and before the end of Week 3 but, provided the subject has been on 20μg/day for 4 or more days during Week 3, they may have the opportunity to step up again to 40μg/day of the study drug for Week 4. If a subject steps down to 20μg/day of the study drug at Week 4 then they will not be able to have another attempt to step up to 4C^g/day at the end of Week 4 because this is the end of the titration phase, and they will have to continue with 2C^g/day of the study drug during the maintenance phase. Thus the titration regimen allows subjects who have to step down from a dose level to have at most only one more attempt at dose escalating again to that dose level. It is noted that no subjects in the Alzheimer's disease clinical study disclosed herein in Example 1 had to step down and try to dose escalate again.

It is anticipated that, by Day 28, a well-tolerated dosage regimen will have been identified which can be continued during the maintenance period. Given the restrictions above, this maintenance dosage regimen will be 20, 40 or 80μg/day of the study drug (administered orally once daily). If tolerability problems develop during Weeks 5 - 16, the subject's dose may be reduced (at the Investigator's discretion) to the next lower dose level, which must be at least 20μg/day of the study drug. This dose will be maintained until the end of the study. Subjects who cannot tolerate 20μg/day of the study drug during the maintenance phase will be withdrawn from the study. Unscheduled visits may be necessary if subjects experience tolerability issues. Example 2 - Dose Adjustment / Stopping Safety Criteria

Liver Chemistry Stopping Criteria

Liver chemistry threshold stopping criteria have been designed to assure subject safety and to evaluate liver event etiology during administration of investigational product and the follow-up period. Investigational product will be stopped if any of the following liver chemistry stopping criteria are met, in which ALT means alanine aminotransferase (i.e. alanine transaminase) and ULN means the upper limit of normal:

1. ALT > 3 x ULN and bilirubin > 2 x ULN

NOTE: serum bilirubin fractionation should be performed if testing is available. If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury).

2. ALT > 5 x ULN.

3. ALT > 3 x ULN if associated with the appearance or worsening of rash or hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia).

4. ALT > 3 x ULN persists for >4 weeks.

5. ALT > 3 x ULN and cannot be monitored weekly for 4 weeks.

Subjects with ALT > 3 x ULN and < 5 x ULN and bilirubin < 2 x ULN, who do not exhibit hepatitis symptoms or rash, can continue investigational product as long as they can be monitored weekly for 4 weeks. See herein for details on weekly follow-up procedures for these subjects.

QTc Withdrawal Criteria

A subject that meets the criteria below will be withdrawn from the study:

• QTcB or QTcF > 500 msec or uncorrected QT >600msec (machine or manual overread). QTcB and QTcF mean QT duration corrected for heart rate by Bazett's formula and Fridericia's formula respectively.

• If subject has bundle branch block then criteria is QTcB or QTcF > 530 msec

These criteria are based on an average QTc (corrected QT interval / duration) value of triplicate ECGs. If an ECG (electrocardiogram) demonstrates a prolonged QT interval, obtain 2 more ECGs over a brief period, and then use the averaged QTc values of the 3 ECGs to determine whether the subject should be discontinued from the study.

Example 2 - Clinical Dose Adjustment / Stopping Safety Criteria Guidelines for the investigator for dose (dosage regimen) adjustment, during the up-titration (escalation) phase of the Example 2 clinical study, based on safety and tolerability are provided in the schematic diagram shown in Figure 6. Figure 6 shows that, during the up-titration (escalation) phase, the dosage regimen of the study drug is adjusted, based on safety and tolerability, depending on whether the subject shows:

(a) Moderate tolerability or safety concerns (which leads to reduction in the daily dose / dosage regimen of the study drug or withdrawal of treatment), (b) Mild tolerability or safety concerns (which leads to no change in the daily dose / dosage regimen of the study drug), or

(c) No tolerability or safety concerns (which leads to an increase in the daily dose / dosage regimen of the study drug, unless the patient / subject has been on the existing daily dose / dosage regimen for 3 days or less).

The criteria to be applied to assess whether the patient / subject has (a) moderate, (b) mild, or (c) no tolerability or safety concerns are described below. Example 2 - Criteria for moderate tolerability concerns

The overall profile of adverse events which raise moderate tolerability concerns and requires dose reduction or withdrawal is characterised by:

• Major criteria: any of criteria 1 to 4 apply; if these criteria do not apply then the adjunct criteria should be considered.

• Adjunct criteria: two or more of criteria [1 to 7] and 8 apply.

Major criteria (for tolerability concerns)

1. Overall effect of adverse events leads to impairment of normal daily

functions or curtailment of normal daily activities of the subject by >50% of normal.

2. CGIC (Clinician's Global Impression of Change) score is 6 or 7.

3. Emergence of hallucinations, mood disturbance, abnormal thoughts,

aggression, agitation or other behavioural disturbances, or worsening of such pre-existing symptoms in excess of expected normal fluctuations for the subject. The investigator may, in his/her clinical judgement, consider that this criterion does not apply to hallucinations or mood changes which are mild (not distressing), transient and infrequent.

4. Worsening of cognitive function in excess of expected normal fluctuations for the subject, primarily based on subject or carer's reports (including PGIC and CrGIC), and supported by evidence from CogState neuropsychological tests.

Adjunct criteria (for tolerability concerns) 1. Subject experiences >4 adverse events scored as moderate or severe

intensity, during the previous week of treatment.

3. Insomnia of moderate intensity which interferes with function/activities of daily living or insomnia which delays normal sleep by >2 h, for >4 nights of the week.

4. Sleep disturbance of moderate intensity, such that a subject feels sufficiently tired or exhausted the following day such as to interfere with

function/activities of daily living, for >4 nights of the week.

5. Sleep disturbance which results in >3 waking episodes during a night's sleep for >4 nights of the week, or any waking episodes associated with behavioural disturbance such as wandering or risk of injury to subject or carer.

Vivid dreams or nightmares of moderate intensity such that the subject perceives that sleep is impaired, or sufficiently distressing to cause the subject to wake up, or perceived as distressing upon recollection the following day, for >4 nights of the week.

Gastrointestinal disturbances (e.g. nausea, vomiting, diarrhoea, and/or abdominal pain) of moderate intensity on >4 days of the week, characterised by one or more of the following: reduced oral intake, >2 episodes of vomiting per 24 h, >2 episodes of diarrhoea per 24 h, interference with function / daily activities.

No evidence that tolerability is improving or that adverse events are tolerating out, over the week of treatment. Notwithstanding these criteria, the investigator should exercise clinical judgement to reduce the dose or withdraw treatment when it is appropriate to do so, even if by these criteria the dose may continue unchanged. On the other hand, if the investigator considers that despite meeting these criteria, it is reasonable to increase the dose, then the GlaxoSmithKline Medical Monitor should be consulted.

Example 2 - Criteria for mild tolerability concerns

· Not considered as of moderate tolerability concern, and

• Criteria [1 or 2] and all of criteria 3 to 5 below apply:

1. Overall the tolerability of adverse events is acceptable, with some

impairment of normal daily functions but subjects are still able to continue with >50% of their normal activities.

2. CGIC (Clinician's Global Impression of Change) score is 5.

3. Not more than 1 of the adjunct criteria 1 to 7 for tolerability profile of

moderate clinical concern.

4. No emergence of hallucinations or mood disturbance, or if present, they are mild, transient, infrequent and not distressing. No emergence of abnormal thoughts, aggression, agitation or other behavioural disturbances. No worsening of such pre-existing symptoms in excess of expected normal fluctuations for the subject.

5. No worsening of cognitive function in excess of expected normal fluctuations for the subject, primarily based on subject or carer's reports and supported by evidence from CogState neuropsychological tests. Notwithstanding these criteria, the investigator should exercise clinical judgement to reduce the dose or withdraw treatment when it is appropriate to do so, even if by these criteria the dose may continue unchanged. On the other hand, if the investigator considers that despite meeting these criteria, it is reasonable to increase the dose, then the GlaxoSmithKline Medical Monitor should be consulted.

Example 2 - Criteria for no dose limiting tolerability

The overall profile of adverse events which has no tolerability concerns and permits dose escalation is characterised by:

• Not considered as moderate or mild tolerability concern, and

• Criteria [1 or 2] and all of criteria 3 to 5 below apply:

1. Overall effect of adverse events is well-tolerated, has minimal or no

impairment of normal daily functions and the subject is able to continue with the most (>80%) of normal daily activities.

2. CGIC (Clinician's Global Impression of Change) score is 1 - 4.

3. No emergence of new hallucinations, mood disturbance, abnormal thoughts, aggression, agitation or other behavioural disturbances, and no worsening of such pre-existing symptoms in excess of expected normal fluctuations for the subject.

4. No worsening of cognitive function in excess of expected normal fluctuations for the subject, primarily based on subject or carer's reports and supported by evidence from CogState neuropsychological tests.

Notwithstanding these criteria, the investigator should exercise clinical judgement and not increase the dose if it is considered that a higher dose will not be tolerated. Furthermore, if the subject has stepped down to a lower dose level prior to a scheduled visit and has been at this lower dose level for < 3 days only prior to the weekly scheduled clinic visit, then dose escalation should not take place even if there are no tolerability concerns at the lower dose.

Example 2 - General criteria regarding tolerability and dose variation

During the dose titration phase of the study, if a dose level is not well-tolerated at any point, the investigator may reduce the dose to the previously well-tolerated level which may take place at the scheduled visits, or at an unscheduled visit if judged necessary by the Investigator. For all subjects, no more than 4 weeks dose titration will be permitted. If this tolerated dose is less than 20 g/day of the study drug after 4 weeks of titration, the subject will be withdrawn. If a dose level leads to clinically significant sleep disturbance (e.g. risk of wandering and/or confusion at night, disruption of carer's sleep, and/or worsening of daytime function), as judged by the investigator, the dose should be reduced. Other safety considerations that may lead to dose adjustment/stopping include: specific adverse events of clinical concern, or changes in specific lab values, ECG (electrocardiogram) parameters and/or vital signs which the investigator considers clinically significant.

If the Investigator considers that dose escalation is appropriate at the visit at the end of any of the first 3 weeks during the titration phase (Day 7, 14 or 21 ), subjects will be dispensed with medication at the next, higher dose level to take home. The Investigator will contact the subject and/or caregiver in the morning of the day after the clinic visit (Day 8, 15 or 22) by telephone to check that the subject's clinical status is still suitable for dose escalation. If it is still clinically appropriate for the subject to increase the dose, the subject will take the study medication at the higher dose level as dispensed. Otherwise the Investigator should arrange an unscheduled visit to review the subject's clinical status and re- dispense study medication at a lower dose level than originally planned for dose escalation. If the subject has a non-cohabiting carer, the Investigator should make contact with the subject and/or caregiver again, later on the day of dose escalation (Day 8, 15 or 22), to check tolerability to the higher dose level. It is recommended that caregiver(s) who are not resident with the subject visit the subject at least once on the relevant day (Day 8, 15 or 22) if dose escalation is planned. The Investigator / Study nurse should then make telephone contact with the subject and/or caregiver during the rest of each week.

If the Investigator considers that dose escalation is not appropriate due to safety or tolerability reasons at the visit at the end of any of the first 3 weeks during the titration phase (Day 7, 14 or 21 ), the dose for the subsequent week will be decreased or remain unchanged, and medication dispensed accordingly at the same or lower dose level as on Day 7, 14 or 21.

Example 2 - Study Population Number of Subjects

A minimum of 152 subjects will be randomised, with the aim that there will be at least 138 evaluable subjects, of whom at least 60 subjects receive 40 g/day or 80 g/day of the study drug. An evaluable subject is one who has undertaken at least one cognitive assessment with the CogState NTB at Day 28 and enters the maintenance phase. With 152 randomised subjects it is expected that at least 100 subjects complete the study.

Ongoing dose level monitoring will be performed by an independent statistician or programmer within GlaxoSmithKline, to monitor the number of subjects starting the maintenance phase on 20 g/day, 40 g/day or 80 g/day of the study drug. Should, after 152 subjects are randomised, the number of evaluable subjects receiving 40 g/day or 80 g/day of the study drug be lower than the anticipated 60 evaluable subjects, then the randomisation may be allowed to continue until a minimum of 60 evaluable subjects enter the maintenance phase on 40 g/day or 80 g/day or a maximum of 200 subjects are randomised.

Example 2 - Eligibility Criteria

Example 2 - Inclusion Criteria A subject is eligible for inclusion in this study only if all of the following criteria apply:

1. Male or female subjects with a clinical diagnosis of probable Alzheimer's disease in accordance with the NINCDS-ADRDA criteria, with symptoms of Alzheimer's disease for at least 3 months.

2. A Haschinski ischaemia score < 4.

3. Has undergone MRI (magnetic resonance imaging) or CT scan in the last 12 months. (For subjects not meeting this criteria, as scan will be conducted as part of the screening procedures).

4. The subject has an MMSE (Mini Mental State Examination) score at Screening of 16 to 24 inclusive.

5. Male or female aged 50 years or above, at the time of signing the informed consent.

6. If female, the subject must be post-menopausal, i.e. 12 months of spontaneous amenorrhea [in questionable cases a blood sample with

simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory] or surgically sterile (documented tubal ligation or hysterectomy). [Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use sexual abstinence or a contraception method if they wish to continue their HRT during the study.

Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post- menopausal status, they can resume use of HRT during the study without use of a contraceptive method.] 7. Male subjects must agree to use sexual abstinence or a contraception method . This criterion must be followed from the time of the first dose of study medication until 14 days after the last dose of study medication.

8. The subject has the ability to comply with the study procedures as judged by the investigator.

9. Subject lives with, or has substantial periods (e.g. at least a few hours each day) of contact with, a permanent caregiver who is willing to attend all visits, oversee the subject's compliance with protocol-specified procedures and study medication, and report on subject's status. A permanent caregiver is one who is able to provide care to the subject for the duration of the study without interruption for more than 1 week at a time. If at times during the study the permanent caregiver is unable to look after the subject, this period of absence of the caregiver must be covered by another caregiver. A permanent caregiver need not be living in the same residence with the subject. For such a caregiver, the investigator has to be satisfied that the subject can contact the caregiver readily during the times when the caregiver is not with the subject. If in doubt about whether a subject's care arrangements are suitable for inclusion, the investigator should discuss this with the GlaxoSmithKline Medical Monitor.

10. The subject has provided full written informed consent prior to the performance of any protocol specific procedure, or if unable to provide informed consent due to cognitive status, full written informed consent on behalf of the subject has been provided by a legally acceptable representative.

1 1 . The caregiver has provided his or her written consent prior to the performance of any protocol specific procedure

12. AST (aspartate aminotransferase) and ALT (alanine aminotransferase, i.e. alanine transaminase) < 2 x ULN (upper limit of normal); alkaline

phosphatase and bilirubin < 1.5 x ULN (isolated bilirubin >1 .5 x ULN is

acceptable if bilirubin is fractionated and direct bilirubin <35%).

13. If the subject is on any prior medications, they should be a permitted medication. Permitted medications include: paracetamol (< 2 g/day); and/or any one or more of following medications provided it/they have been received at a stable dose for at least 1 month prior to screening and the dose remains unchanged during the study: vitamin E; dietary supplements which may have benefits on cognitive impairment (e.g. fish oils or beta-hydroxybutyrate); statins; thyroid hormones; anti-diabetic medications; anti-hypertensive medications;

tricyclic antidepressants (TCA) which do not have anti-cholinergic effects;

monoamine reuptake inhibitors [SSRI (selective serotonin reuptake inhibitor), SNRI (serotonin-norepinephrine reuptake inhibitor), DNRI (dopamine and norepinephrine reuptake inhibitor) and/or NERI); and/or sedatives on a PRN basis (the sedative(s) should be received not more than 3 nights a week and not within 5 half-lives prior to each study visit).

Example 2 - Exclusion Criteria

A subject is not eligible for inclusion in this study if any of the following criteria apply: 1. In the opinion of the investigator, following review of CT / MRI (magnetic resonance imaging) scans in the past 12 months and completion of neurological review there could be other probable causes of dementia which include, but are not limited to:

• History and/or evidence (CT or MRI scan performed since the onset of symptoms) of any other central nervous system (CNS) disorder that could be interpreted as the primary cause of dementia: e.g.

cerebrovascular disease, structural or developmental abnormality, epilepsy, infections, or degenerative or inflammatory/demyelinating CNS conditions other than Alzheimer's disease.

• Clinically significant focal findings on the neurological examination

(excluding changes attributable to peripheral nervous system injury).

• Untreated abnormal result of any of the following tests: vitamin B12, syphilis serology, thyroid stimulating hormone (TSH), where this is thought to be the cause of, or to contribute to the severity of, the subject's dementia.

• Diagnosis of possible, probable or definite vascular dementia in

accordance with National Institute of Neurological Disorders and Stroke- Association Internationale pour la Recherche I'Enseignement en Neurosciences (NINDS-AIREN) criteria.

2. Prior diagnosis of significant psychiatric illness such as schizophrenia or bipolar affective disorder with current symptoms related to the diagnoses such that in the opinion of the Investigator would interfere with participation in the study, or current depression (a score of≥8 on the Cornell Scale for Depression in Dementia), or subjects with other psychiatric features (including but not limited to having hallucinations) in their Alzheimer's disease which, in the opinion of the investigator, increase risk to safety.

3. Subjects, who in the investigator's judgement, pose a significant suicide risk. Evidence of serious suicide risk may include any history of suicidal behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS (Columbia Suicide Severity Rating Scale) in the last 2 months prior to screening.

4. History or presence of significant sleep disturbance, such as severe insomnia or sleep disturbance associated with nocturnal wandering, or nocturnal confusion / disorientation / agitation, which, in the opinion of the investigator, may increase safety risk.

5. History or presence of known or suspected seizures, or unexplained significant loss of consciousness within last 6 months. Subjects who had febrile seizures in childhood may be included if these ceased by age 10 and they have had no other type of seizure in their medical history and have not been on anti- epileptic medications. 6. History or presence of significant cardiovascular, gastro-intestinal, hepatic, or renal disease or other condition known to interfere with the

absorption, distribution, metabolism, or excretion of drugs, or any other clinically relevant abnormality, medical or psychiatric condition, which, in the opinion of the Investigator, makes the subject unsuitable for inclusion in the study.

7. History of alcohol or other substance abuse, according to the Diagnostic and Statistical Manual of Mental Disorders - Substance related disorders (DSM- IV) criteria, within 3 years prior to the onset of Alzheimer's disease symptoms, or since the onset of Alzheimer's disease symptoms.

8. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening

9. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

10. Uncontrolled hypertension with systolic BP (blood pressure) >160 mmHg and/or diastolic BP >95 mmHg. Subjects with controlled hypertension with systolic BP < 160 mmHg and diastolic BP <95 mmHg for at least 4 weeks are acceptable.

1 1 . Systolic BP <100 mmHg and/or diastolic BP <60 mmHg.

12. Subjects with a QTc (corrected QT) interval of >450ms or >480ms if they have bundle branch block or other ECG (electrocardiogram) abnormalities which, in the opinion of the investigator is/are clinically significant in that they may increase safety risk.

13. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

14. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

15. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline Medical Monitor, contraindicates their participation.

16. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.

17. Pregnant females as determined by positive urine human chorionic gonadotropin (hCG) test at screening or prior to dosing.

18. Treatment with cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine or galantamine), memantine or selegiline within the last 3 months prior to screening. No patients with Alzheimer's disease who are already on these medications at the time of screening will be recruited, as it would be unethical to withdraw these medications for study participation. Only Alzheimer's disease subjects who are not yet on these medications, or who have withdrawn from these medications for other reasons previously, may be enrolled into this study. 19. Use of any of the following prohibited medications, either currently, or within 30 days or 5 half-lives of these medications prior to screening(whichever is longer):

• any other treatments approved in the country(ies) for treatment of

cognitive symptoms of Alzheimer's disease.

• gingko biloba or any other herbal treatment for cognitive impairment

• anti-psychotic drugs (e.g. typical or atypical dopaminergic antagonists or modulators).

• any central nervous system (CNS) stimulants (e.g., modafinil).

· mood stabilization drugs (e.g. lithium, valproate, or cabamazepine).

• barbiturates.

• monoamine oxidase (MAO) inhibitors, in particular MAO A inhibitors or MAO B inhibitors.

• P-glycoprotein (p-gp) inhibitors which are potent (e.g. itraconazole,

ketoconazole, atorvastatin, dipyridamole, cyclosporin, loperamide, diltiazem, verapamil, spironolactone, quinidine, bepridil, quinine, or carvedilol).

• known potent inhibitors or inducers of the CYP3A4 enzyme. Examples of prohibited CYP3A4 inhibitors include: amiodarone, conivaptan, cimetidine, chloramphenicol, clarithromycin, diethyl-dithiocarbamate, dilitiazem, erythromycin, fluconazole, fluvoxamine, gestodene, grapefruit juice, itraconazole, ketoconazole, mifepristone, modafinil, nefazodone, norfloxacin, norfluoxetine, rifampin, star fruit, verapamil, and

voriconazole).

· anti-cholinergic drugs or drugs which have anti-cholinergic effects (e.g. amitriptyline or amantidine). [For cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine or galantamine), memantine or selegiline, see Exclusion Criterion 18 hereinabove for the circumstances under which they are excluded.]

· anti-histamines which are CNS penetrant.

• chronic sedative medications (≥ 4 days per week for the past 4 weeks prior to screening), such as a benzodiazepine sedative.

• any other investigational drug.

20. Use of other prescription or non-prescription drugs, including herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GlaxoSmithKline

Medical Monitor the medication will not interfere with the study procedures or compromise subject safety, or is a permitted medication as defined in Inclusion Criterion 13 hereinabove.

21 . Subjects who plan to commence treatment with one or more prohibited medications as defined in Exclusion Criterion 19 hereinabove.

22. Consumption of red wine, Seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication until the follow-up visit. 23. Subjects who have commenced or are already undertaking a cognitive rehabilition programme within 1 month of screening. Subjects who have stopped their cognitive rehabilitation programme at least 1 month prior to screening need not be excluded if they satisfy other eligibility criteria.

24. Unwillingness or inability to follow the procedures outlined in the protocol.

25. Subject or caregiver is an immediate family member or employee of the participating Investigator, any of the participating site staff, or of GlaxoSmithKline staff.

COGNITIVE AND OTHER TESTS

The following cognitive and other tests can be (and/or in some cases have been) performed, e.g. on the subjects (patients) taking part in the clinical studies of Example 1 and/or Example 2. Computerised Psychometric Testing

Computerised Psychometric Testing, e.g. for use on Alzheimer's disease patients in Example 1 and/or 2, can comprise (i) CogState test battery, or (ii) ADAS-Cog (Alzheimer's Disease Assessment Scale - cognitive subscale).

1. CogState neuropsychological test battery CogState, a set of computerised, non invasive, psychometric tests as described below, are designed to assess the following parameters: simple reaction time, choice reaction time, working memory and verbal learning. In Example 1 and/or

2, the CogState test battery is normally the first assessment on study

assessment days.

1.1 Episodic Memory

• International Shopping List Test Immediate Recall, and International Shopping List Delayed Recall The CogState International Shopping List test is a computer controlled verbal learning test. In this test subjects are read a list of 10 words. Each word is a concrete noun and describes an item of food that is found commonly in the culture/society in which testing is occurring. The examiner asks the subjects "I am going to read to you a list of items I want you to get from the

supermarket/store/market/shop etc". After the 10 words have been read, the subject tries to recall as many of the words as they can. When they can recall no more words the same list is read a second time with the words in the same order after the same instruction. The process of reading the list and waiting for responses occurs three times. At the completion of the computerized battery the subject is asked to recall as many of the items as they can from the shopping list. This provides a measure of delayed recall.

• Paired Associate Learning (PAL)

The CogState PAL task is a measure of associate learning. For this test, the subject must learn and remember the pictures hidden beneath different locations on the screen. The subject must tap the target (yellow ball) in the center of the screen to begin. As each picture to be learned is revealed, the subject must tap each peripheral location and remember where the picture was located. Following the learning trial, the same pictures will be presented in the centre of the screen, and the subject must tap on the peripheral location where that picture previously appeared. The software measures the number of errors made while

remembering where pictures are located.

1.2 Executive Function / Working Memory

• Controlled Oral Word Association This CogState task is a brief (<4 minutes) measure of language fluency, planning and working memory. Study participants are instructed to generate as many as words as they can think of beginning with a specific letter in one minute. They are then requested to do exactly the same for two furthers letters. Study participants are requested not to say proper nouns, words beginning with the same stem but with a different ending and not to repeat themselves. Stimulus letters for this test are selected on the basis that they have high frequency scores when tested in normal healthy volunteers. Each correct response scores one point. Performance for all three letters is summed to yield a total number of acceptable responses.

• Category Naming

This CogState test measures semantic fluency, planning and working memory. For this task study participants are required to generate as many exemplars of the category 'Animals' as they can in one minute. The animals mentioned must be real animals but can be living or extinct for the purposes of this test. The rules of the Category Naming test require that study participants do not receive credit for imaginary animals or for repetitions. Each correct response scores one point and the key metric for this test is the total number of acceptable responses. · One-back

One back working memory task: The CogState One back memory task is a measure of working memory. On this task the subject is shown a single stimulus in the centre of the computer screen (a card turns face up). They must decide "YES" or "NO" as to whether the current card matches the card that had been seen on the immediately previous trial. The software measures the speed and accuracy of each response.

1.3 Attention

• Detection Task The CogState detection task is a measure of simple reaction time and has been shown to provide an assessment of psychomotor function in healthy adults and in adults with Alzheimer's disease. For this test, the subject must press a "YES" response key as soon as they detect an event (i.e. a card turning face up presented in the centre of the computer screen). The software measures the response time to detect each event.

• Identification task

The CogState identification task is a measure of choice reaction time and has been shown to provide an assessment of visual attention. In this task an event (a card turning face up) occurs in the centre of the computer screen and the subject must decide "YES" or "NO" as to whether this event meets a predefined and unchanging criterion (is the colour of the card red?). The software measures the speed and accuracy of each response.

The test battery will take approximately 18 minutes.

2. ADAS-Cog cognitive test (Alzheimer's Disease Assessment Scale - cognitive subscale)

The 1 1-item ADAS-Cog [W.G. Rosen et al., "A new rating scale for Alzheimer's disease", American Journal of Psychiatry, 1984, vol.141 , pp.1356-1364] assesses a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items are evaluated by tests, but some are dependent on clinician ratings on a five point scale.

Scores range from 0 to 70 with higher scores indicating greater dysfunction. The scale is completed by a trained and experienced neurologist, psychiatrist, neuropsychologist or another trained and experienced person (e.g. as approved by GlaxoSmithKline). This person may also administer the secondary efficacy instruments, but he/she should be a separate individual from the person who completes the CIBIC+ global functioning assessment (described below). The scale is based on the performance of the subject, and takes approximately 30 to 40 minutes to administer.

Neuropsychiatric Inventory (NPI)

The NPI [J. L. Cummings et al., "The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia", Neurology, 1994, vol.44, pp.2308- 2314] is an assessment of the frequency and severity of behavioral disturbances in dementia. The inventory comprises 10 dimensions: delusions, hallucinations, dysphoria, apathy, euphoria, disinhibition, aggressiveness and agitation, irritability, anxiety, and aberrant motor activity. Each dimension has a screening question with between 7 and 9 follow-up questions relating to symptoms, asked if the answer to the screening question is 'yes'. The NPI takes approximately 10 minutes for the investigator to administer by talking to the caregiver.

Sleep Scales

1. Epworth Sleep Scale (ESS)

Subjective sleepiness is measured using the Epworth Sleepiness Scale (ESS), a patient rated measure of excessive daytime sleepiness. The scale involves subjective assessment of multiple "sleepiness" questions when considering the previous week. Patients estimate their likelihood of falling asleep during eight normal daily situations on a four point scale. Patients are asked to rate their level of sleepiness in normal daytime situations. They are asked to grade from 0 to 3 their likelihood of dozing or falling asleep, in contrast to just feeling tired.

Grades: 0 = would never doze, 1 = slight chance of dozing, 2 = moderate chance of dozing, 3 = high chance of dozing.

Situations: Sitting and reading; Watching television; Sitting inactive in a public place, such as a theatre or meeting; As a passenger in a car for an hour without a break; Lying down to rest in the afternoon; Sitting and talking to someone; Sitting quietly after lunch (without alcohol); In a car, while stopped in traffic.

2. Pittsburgh Sleep Quality Index (PSQI)

The Pittsburg Sleep Quality Index [D.J. Buysse et al., "Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research", Psychiatry Res. , 1989, vol.28, pp.193-213] measures sleep quality compared to the previous month. This scale covers a number of domains and includes Subjective Sleep Quality, Sleep Latency, Sleep Duration, Habitual Sleep Efficiency, Sleep

Disturbances, Use of Sleep Medications and Daytime Dysfunction. The scale is composed of 19 self-rates questions and 5 questions rated by a bed partner or roommate (only the self-rated items are used in scoring the scale).

Disability Assessment for Dementia scale (DAD)

The DAD [I. Gelinas et al., "Development of a functional measure for persons with Alzheimer's disease: the disability assessment for dementia", Am. J. Occup. Ther., 1999, vol.53, pp.471 -481 ] assesses the ability of a subject to execute basic and instrumental activities of daily living (ADL) and leisure activities. The scale includes 23 items relating to instrumental ADL and 17 items relating to basic self-care. The DAD is conducted as a questionnaire completed by the caregiver, and takes approximately 20 minutes to complete.

Clinicians Interview Based Impression of Change Plus (CIBIC+) The CIBIC+ global functioning assessment [L. Schneider et al., "Validity and reliability of the Alzheimer's Disease Cooperative Study - Clinical Global

Impression of Change", Alzheimer Disease & Associated Disorders, 1997, vol.1 1 (2), PP.S22-S32] comprises a 7-point rating of severity (assessed at baseline) and change (assessed at subsequent time points). The CIBIC+ assessments will be performed by an independent rater. The rater must be a trained and experienced neurologist, psychiatrist, neuropsychologist or another trained and experienced person (e.g. approved by GlaxoSmithKline) who is not the principal Investigator for the study and who is not involved in any other aspect of the subject's care or assessment, and who does not have access to other subject data for this study. The procedure requires separate structured 15-20 minute interviews with the subject and the caregiver.

Mini Mental State Examination (MMSE)

The MMSE [M.F. Folstein et al., ' "Mini-Mental State" A practical method for grading the cognitive state of patients for the clinician', J. Psych. Research,

1975, vol.12, pp.189-198] consists of 1 1 tests of orientation, memory (recent and immediate), concentration, language and praxis. Scores range from 0 to 30, with lower scores indicating greater cognitive impairment. The scale is completed by the investigator, based on the performance of the subject, and takes

approximately 5 to 10 minutes to administer. The MMSE may be administered by the same person who conducts the CogState battery and ADAS-Cog.

Clinician / Carer / Patient Global Impression of Change

Global disease severity can be scored by the clinician (CGIC), the carer (CrGIC) and/or the patient (PGIC) using a verbal rating scale. The scale is rated from 1 to 7 as follows:

1. Very much improved

2. Much improved

3. Minimally improved

4. No change

5. Minimally worse

6. Much worse

7. Very much worse. TABLET EXAMPLES

The following Tablet Examples are representative of examples of tablets which may be prepared, and most of which can be used in the invention.

Tablet Example 1 : Preparation of round tablets containing 0.05mg 1 -{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone The core components were passed through a nominal 30 mesh screen and then blended together in a suitable blender and compressed on a rotary tablet press to produce round biconcave tablets with a diameter of 9.525 mm and an approximately 0.8 mm deep trough on both sides of the tablet. Compression was followed by de-dusting and metal checking. The tablets were the transferred to a coating pan and coated to a target 4% (w/w) gain.

The composition of the carrier tablets is given below:

Core

A carrier solution was prepared by dissolving 4 g hydroxypropyl cellulose (HPC) (Klucel™ Grade EF, available from Aqualon), 2 g anhydrous citric acid and 0.02 g butylated hydroxyanisole (BHA) in methanol, filtering through a 10 micron filter and then bringing the final volume to 100 ml with methanol.

1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone was dissolved in the carrier solution with a sonicator until a uniform solution was obtained with a final concentration of 5 mg/g (w/w). 10 mg dosing solution was dispensed onto each tablet in an array of carrier tablets. The tablets were dried in a forced air oven at about 40°C for 10-20 minutes.

The composition of the finished tablets is as follows

^* the methanol is removed during manufacturing process

Tablet Examples 2-4: Preparation of round tablets containing 0.002 mg, 0.01 mg or 0.2 mg 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone

Tablets containing 0.002 mg, 0.01 mg or 0.2 mg 1 -{6-[(3-cyclobutyl-2,3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone were prepared in the manner described in Tablet Example 1 except that the concentration of 1 - {6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 /-/-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone in the dosing solution was varied.

Tablet Example 5: Preparation of round tablets containing 0.01 mg 1 -{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone

The core components were passed through a nominal 30 mesh screen and then blended together in a suitable blender and compressed on a rotary tablet press to produce round biconcave tablets with a diameter of 7.9 mm and an

approximately 0.8 mm deep trough on both sides of the tablet. Compression was followed by de-dusting and metal checking. The tablets were the transferred to a coating pan and coated to a target 4% (w/w) gain.

The composition of the carrier tablets is given below:

Core

Pregelatinized Starch (Starch 1500) 16.2 mg 9% w/w Magnesium Stearate 1.8 mg 1 % w/w

Total carrier tablet (uncoated) 180 mg

Film Coat

^*Removed during processing A carrier solution was prepared by dissolving 5 g hydroxypropyl cellulose (HPC) (Klucel™ Grade EF, available from Aqualon), and 3 g anhydrous citric acid in methanol, filtering through a 10 micron filter and then bringing the final volume to 100 ml with methanol. 1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone was dissolved in the carrier solution with a sonicator (and by also using a magnetic stirrer) until a uniform solution was obtained with a final concentration of 2.5 mg/g (w/w). 4 mg of carrier solution was dispensed onto each tablet in an array of carrier tablets. The tablets were dried in a forced air oven at about 50°C for 10-20 minutes.

The composition of the finished tablets is as follows

^* the methanol is removed during manufacturing process

Tablet Examples 6-10: Preparation of round tablets containing 0.002 mg, 0.005 mg, 0.02 mg, 0.05 mg or 0.1 mg 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro- 1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2 -pyrrolidinone

Tablets containing 0.002 mg, 0.005 mg, 0.02 mg, 0.05 mg or 0.1 mg 1-{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone were prepared in the manner described in Tablet Example 5 except that the concentration of 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin- 7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone in the carrier solution was varied.

Tablet Examples 11 -13: Preparation of round tablets containing 0.04 mg, 0.08 mg, or 0.15 mg 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin- 7-yl)oxy]-3-pyridinyl}-2 -pyrrolidinone

Tablets containing 0.04 mg, 0.08 mg or 0.15 mg 1 -{6-[(3-cyclobutyl-2, 3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone are prepared in the manner described in Tablet Example 5 except that the concentration of 1-{6- [(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone in the carrier solution was varied.

Tablet Example 14 - Further coating, with a pad printed overcoat, of the tablets prepared in any of Tablet Examples 1 to 13

The tablets prepared in any of Tablet Examples 1 to 13 can optionally be further coated so that they comprise a further coating over (covering) all of the film which contains the active compound or salt. This optional further coating is a pad printed overcoat, i.e. is an overcoat which is prepared by a pad printing process.

The pad printed overcoat comprises titanium dioxide and Nisso™HPC

(hydroxypropylcellulose) Grade SSL. The pad printing overcoat process uses one of the following coating mixtures comprising HPC and titanium dioxide in ethanol, all of which have the following generalised composition: 20 to 25% Nisso ™ HPC SSL; 31 to 38% titanium dioxide; and 41 to 49% ethanol:

Tablet Example 14A. 22% Nisso™ HPC SSL; 34% titanium dioxide; 44% ethanol. Tablet Example 14B. 21 % Nisso ^{I M} HPC SSL; 38% titanium dioxide; 41 % ethanol.

Tablet Example 14C. 25% Nisso™ HPC SSL; 34% titanium dioxide; 41 % ethanol.

Tablet Example 14D. 20% Nisso™ HPC SSL; 31 % titanium dioxide; 49% ethanol.

After production, the pad printed overcoat on the tablets can then optionally be further printed with any desired design.

The following examples (Tablet Example 15 and Tablet Example 16) are representative of examples of tablets which may be prepared which and may be used in the invention:

Tablet Example 15: Preparation of a Orally Disintegrating Tablet (ODT) Carrier Substrate

a) Preparation of ODT Carrier Substrate StarLac and Neotame are passed through a nominal 20 mesh screen. The mixture and unsieved mint flavoring are transferred to a suitable blender and blended for approximately 10 minutes. Magnesium stearate is passed through a nominal 30 mesh screen, transferred to the blender and the entire mixture blended for approximately 2 minutes. The weights of material used are calculated from the percentage weights given in Table A. The blend is compressed to meet the desired specifications (for example round, biconcave tablets, range in diameter from -8 mm to -9.5 mm) on a suitable rotary press utilizing appropriate tablet tooling. The tablets are passed through a de-duster and metal checker.

Table A

^* StarLac: mixture of 85% alpha-lactose monohydrate (Ph. Eur./USP-NF) and 15% maize starch (Ph. Eur./USP-NF) b) Preparation of ethylcellulose coat for application to tablet by Pad- Printing

Ethylcellulose is dissolved in methanol with stirring, and triethyl citrate added. The weights of material used are calculated from the percentage weights given in Table B. Sufficient methanol is added to bring to target on w/w basis. The solution is transferred to the ink cup of a pad printing machine equipped with a suitable image cliche with a round image, slightly smaller diameter then the actual tablet diameter. A suitable polymer pad is installed to match the cliche image plate. Tablets are presented to the pad printer in a defined array, matching the cliche. The pad printer may apply 2-4 tamps to the carrier tablet to apply a coat that will provide a protective layer to mitigate solvent infiltration into the uncoated carrier substrate during the liquid dispensing process.

Table B

^*** Methanol eliminated by evaporation.

Tablet Example 16: Alternative preparation of an Orally Disintegrating Tablet (ODT) carrier substrate

Mannitol, crospovidone XL, xylitol and Neotame are passed through a nominal 20 mesh screen, the mixture and the unsieved Mint Flavoring transferred to a suitable blender and blended for approximately 10 minutes. Magnesium stearate and colloidal silicon dioxide are passed through a nominal 30 mesh screen, transferred to the blender and the entire mixture blended for approximately 2 minutes. The weights of material used are calculated from the percentage weights given in Table C. The blend is compressed to meet the desired specifications (for example round, biconcave tablets, range in diameter from -8 mm to -9.5 mm) on a suitable rotary press utilizing an appropriate tablet tooling. The tablets are passed through a de-duster and metal checker.

An ethylcellulose coat may be prepared and applied as described for Tablet Example 15.

Table C COMPOSITION SPECI FICATION % (w/w) FUNCTION

Mannitol (Grade 300 Ph. Eur/USP-NF/JP 73.15% Diluent/sweetener

Direct Compression)

Crospovidone XL Ph. Eur/USP-NF 20.00% Disintegrant

Xylitol (Grade 300 Ph. Eur/USP-NF/JP 5.00% Diluent/sweetener for Direct

Compression)

Mint Flavoring Non Compendial 0.90% Flavoring

Neotame NF 0.10% Sweetener

Magnesium Stearate Ph. Eur/USP-NF/JP 0.75% Lubricant

Colloidal silicon Ph. Eur/USP-NF/JP 0.10% Lubricant dioxide

PROPERTIES: The stability of the drug substance in the tablets may be tested as set out below: Dissolve 5 tablets in diluent (1 :9 acetonitrile: 50 mM potassium dihydrogen orthophosphate, adjusted to pH 3 with orthophosphoric acid) to produce a final concentration of active agent of between 1-10 μg/ml and sonicate for 10 minutes. Check for complete disintegration and sonicate further if required. Allow to cool to ambient temperature and then centrifuge an aliquot of the sample at 14,000 rpm. Prepare samples using placebo tablets to act as control samples.

Using the following instrument conditions, equilibrate the chromatographic system with 95% A, 5%B. Record the chromatograms for the sample and placebo preparations.

Column: XBridge C18 3 μΜ 15 cm x 4.6 mm i.d.

Column Temperature: 40°C

Mobile Phase A: 10 mM ammonium bicarbonate, pH 10 with ammonia

Mobile Phase B: Acetonitrile

Flow Rate: 1 ml/min

Detector wavelength: 250 nm

Injection volume: 100 μΙ

Gradient Profile:

Following comparison of the chromatograms to identify impurities/degradation products, the percentage content of each impurity/degradation product in the control and sample injections can be calculated by dividing the area of the impurity/degradation product peak by the summed total of the peak for 1-{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone and all impurities/degradation products, and multiplying by 100.

The total impurity/degradation product content can be calculated by summing the percentage content of each impurity/degradation product present. Typically, only impurities/degradation products present in an amount of greater than or equal to 0.05 or 0.03% are included in the calculation of total impurity/degradation product content.

Claims

CLAIMS:

1. The use of 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone

or a pharmaceutically acceptable salt thereof in the manufacture of a

- an initial dosage regimen of from 2 to 15 micrograms of the 1-{6-[(3-cyclobutyl- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day, and subsequently

- a maintenance dosage regimen of from 30 to 150 micrograms of the 1 -{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day.

2. The use as claimed in claim 1 , wherein the initial dosage regimen is from 2 to 10 micrograms of the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day. 3. The use as claimed in claim 2, wherein the initial dosage regimen is from 5 to 10 micrograms of the 1-{6-[(3-cyclobutyl-2,

3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day.

4. The use as claimed in claim 3, wherein the initial dosage regimen is 10 micrograms of the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day.

5. The use as claimed in claim 1 , 2, 3 or 4, wherein the maintenance dosage regimen is from 40 to 100 micrograms of the 1 -{6-[(3-cyclobutyl-2, 3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day.

6. The use as claimed in claim 1 , 2, 3 or 4, wherein the maintenance dosage regimen is from 40 to 80 micrograms of the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro- 1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day.

7. The use as claimed in claim 1 , 2, 3 or 4, wherein the maintenance dosage regimen 80 micrograms of the 1 -{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day.

8. The use as claimed in any one of the preceding claims, wherein the initial dosage regimen is from 5 to 10 micrograms of the 1 -{6-[(3-cyclobutyl-2, 3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and

the maintenance dosage regimen is from 40 to 80 micrograms of the 1- {6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day.

9. The use as claimed in claim 8, wherein the initial dosage regimen is 10 micrograms of the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and the maintenance dosage regimen is 80 micrograms of the 1 -{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day.

10. The use as claimed in any one of the preceding claims, wherein, in the escalating dosage regimen, the total time taken to escalate the dosage regimen is 3 to 6 weeks, measured from the start of the initial dosage regimen to the start of the maintenance dosage regimen.

1 1 . The use as claimed in any one of the preceding claims, wherein, in the escalating dosage regimen, the once-daily oral dose of the 1-{6-[(3-cyclobutyl- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base) is doubled every 1 to 2 weeks.

12. The use as claimed in any one of the preceding claims, wherein the escalating dosage regimen comprises:

- an initial dosage regimen of from 5 to 10 micrograms of the 1-{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and then

- a second dosage regimen of from 10 to 20 micrograms of the 1-{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and then

- a third dosage regimen of from 20 to 40 micrograms of the 1 -{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and then

- a maintenance dosage regimen of from 40 to 80 micrograms of the 1-{6- [(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day;

provided that the once-daily oral dose of the 1-{6-[(3-cyclobutyl-2, 3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base) is increased by a factor of 1 .5 to 3 times (e.g. is doubled), when escalating from one dosage regimen to the next higher dosage regimen.

13. The use as claimed in claim 12, wherein the escalating dosage regimen comprises:

- an initial dosage regimen of 10 micrograms of the 1-{6-[(3-cyclobutyl- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and then

- a second dosage regimen of 20 micrograms of the 1 -{6-[(3-cyclobutyl- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and then

- a third dosage regimen of 40 micrograms of the 1-{6-[(3-cyclobutyl- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and then

- a maintenance dosage regimen of 80 micrograms of the 1 -{6-[(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2- pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day.

14. The use as claimed in any one of the preceding claims, wherein the medicament is for the treatment of Alzheimer's disease (e.g. cognitive impairment therein) in a human.

15. The use as claimed in any one of claims 1 to 13, wherein the medicament is for the treatment or prophylaxis of schizophrenia (e.g. cognitive impairment associated with schizophrenia) in a human.

16. 1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3- pyridinyl}-2-pyrrolidinone

17. 1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3- pyridinyl}-2-pyrrolidinone or a pharmaceutically acceptable salt thereof as claimed in claim 16, wherein the initial dosage regimen is from 5 to 10

micrograms of the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7- yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and

18. 1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3- pyridinyl}-2-pyrrolidinone or a pharmaceutically acceptable salt thereof as claimed in claim 16 or 17, wherein, in the escalating dosage regimen, the total time taken to escalate the dosage regimen is 3 to 6 weeks, measured from the start of the initial dosage regimen to the start of the maintenance dosage regimen.

19. 1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3- pyridinyl}-2-pyrrolidinone or a pharmaceutically acceptable salt thereof as claimed in claim 16, 17 or 18, wherein the escalating dosage regimen comprises:

- an initial dosage regimen of 10 micrograms of the 1-{6-[(3-cyclobutyl- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and then - a second dosage regimen of 20 micrograms of the 1 -{6-[(3-cyclobutyl- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and then

- a third dosage regimen of 40 micrograms of the 1-{6-[(3-cyclobutyl-

2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and then

20. 1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3- pyridinyl}-2-pyrrolidinone or a pharmaceutically acceptable salt thereof as claimed in claim 16, 17, 18 or 19, for use in the treatment of Alzheimer's disease (e.g. cognitive impairment therein) in a human, or for use in the treatment or prophylaxis of schizophrenia (e.g. cognitive impairment associated with schizophrenia) in a human.

21 . A method of treatment or prophylaxis (preferably treatment) of dementia and/or a neurodegenerative disease (e.g. Alzheimer's disease, mild cognitive impairment or cognitive ageing, in particular cognitive impairment therein; and/or e.g. cognitive impairment in dementia and/or a neurodegenerative disease), schizophrenia (e.g. cognitive impairment associated with schizophrenia), attention deficit hyperactivity disorder (e.g. cognitive impairment therein), somnolence, or epilepsy, in a human,

22. A method as claimed in claim 21 , wherein the initial dosage regimen is from 5 to 10 micrograms of the 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3- benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and

23. A method as claimed in claim 21 or 22, wherein, in the escalating dosage regimen, the total time taken to escalate the dosage regimen is 3 to 6 weeks, measured from the start of the initial dosage regimen to the start of the maintenance dosage regimen.

24. A method as claimed in claim 21 , 22 or 23, wherein the escalating dosage regimen comprises:

25. A method as claimed in claim 21 , 22, 23 or 24, which is a method of treatment of Alzheimer's disease (e.g. cognitive impairment therein) in a human, or a method of treatment or prophylaxis of schizophrenia (e.g. cognitive impairment associated with schizophrenia) in a human.

26. A pharmaceutical composition (e.g. tablet or capsule) for oral

administration to a human, comprising 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahyd 3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

wherein the pharmaceutical composition is for use in the treatment or prophylaxis (preferably treatment) of dementia and/or a neurodegenerative disease (e.g. Alzheimer's disease, mild cognitive impairment or cognitive ageing, in particular cognitive impairment therein; and/or e.g. cognitive impairment in dementia and/or a neurodegenerative disease), schizophrenia (e.g. cognitive impairment associated with schizophrenia), attention deficit hyperactivity disorder (e.g. cognitive impairment therein), somnolence, or epilepsy, in a human, by oral administration to the human using an escalating dosage regimen comprising: - an initial dosage regimen of from 2 to 15 micrograms of the 1-{6-[(3-cyclobutyl- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day, and subsequently

27. A pharmaceutical composition as claimed in claim 26, wherein the initial dosage regimen is from 5 to 10 micrograms of the 1 -{6-[(3-cyclobutyl-2, 3,4,5- tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and

28. A pharmaceutical composition as claimed in claim 26 or 27, wherein, in the escalating dosage regimen, the total time taken to escalate the dosage regimen is 3 to 6 weeks, measured from the start of the initial dosage regimen to the start of the maintenance dosage regimen.

29. A pharmaceutical composition as claimed in claim 26, 27 or 28, wherein the escalating dosage regimen comprises:

- an initial dosage regimen of 10 micrograms of the 1 -{6-[(3-cyclobutyl- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or the pharmaceutically acceptable salt thereof (measured as the free base), administered orally once per day; and then

- a second dosage regimen of 20 micrograms of the 1 -{6-[(3-cyclobutyl-

30. A pharmaceutical composition as claimed in claim 26, 27, 28 or 29, for use in the treatment of Alzheimer's disease (e.g. cognitive impairment therein) in a human, or for use in the treatment or prophylaxis of schizophrenia (e.g.

cognitive impairment associated with schizophrenia) in a human.