| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To assess the efficacy of GSK239512 on cognitive function in subjects with mild to moderate Alzheimer’s disease after 16 weeks of treatment |
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| E.2.2 | Secondary objectives of the trial |
• To assess the efficacy of GSK239512 on global clinical status after 16 weeks of treatment.
• To assess the effects of GSK239512 on patients’ and carers’ perception of clinical status after 16 weeks of treatment.
• To assess the effects of GSK239512 on neuropsychiatric or behavioural symptoms after 16 weeks of treatment.
• To assess the effects of GSK239512 on activities of daily living after 16 weeks of treatment.
• To assess the safety and tolerability of GSK239512 after 16 weeks of treatment.
• To estimate the systemic exposure to GSK239512 during the 16 weeks of treatment.
• To investigate any relationship between systemic exposure of GSK239512 with changes in cognitive function or other efficacy outcome measures.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects with a clinical diagnosis of probable Alzheimer’s disease in accordance with the NINCDS-ADRDA criteria.
2. A Haschinski ischaemia score </= 4.
3. Has undergone MRI 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 score at Screening of 16 to 24 inclusive.
5. Male or female aged ≥ 50 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 one of the contraception methods in Section 8.1 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 one of the contraception methods listed in Section 8.1. 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 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 GSK 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.
11. The caregiver has provided his / her written consent prior to the performance of any protocol specific procedure
12. AST and ALT < 2xULN; alkaline phosphatase and bilirubin </= 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
13. If the subject is on any prior medications, they should satisfy the requirements in Section 9 of the protocol.
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| E.4 | Principal exclusion criteria |
1. In the opinion of the investigator, following review of CT/MRI scans in the past 12 months and completion of neurological review there could be other probable causes of dementia
2. Prior diagnosis of significant psychiatric illness (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, or subjects with other psychiatric features in their AD which in the opinion of the investigator, increase risk to safety.
3.Subject has made a suicide attempt within the 6 months preceeding the screening visit or presents with suicidal ideation of type 4 or type 5 on the C-SSRS at the Screen or Baseline visits.
4. History of significant sleep disturbance which in the opinion of the investigator, may increase safety risk.
5. History or presence of known or suspected seizures, 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 CV, GI, 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 DSM-IV criteria.
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 ≥160 and/or diastolic ≥95 mmHg. Subjects with controlled hypertension with systolic BP < 160 mmHg and diastolic <95 mmHg for at least 4 weeks are acceptable.
11. Systolic BP <100 mmHg and/or diastolic <60 mmHg.
12. Subjects with a QTc of >450ms or >480ms if they have bundle branch block or other ECG abnormalities which, in the opinion of the investigator is 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. Use of 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
16. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that contraindicates their participation.
17. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
18. Pregnant females as determined by positive urine human chorionic gonadotropin (hCG) test at screening or prior to dosing.
19. Treatment with cholinesterase inhibitors (including Tacrine), memantine or selegiline within the last 3 months prior to screening.
20. Use of the following medications within the last 30 days or 5 half-lives of these medications from Screening:
• Any other treatments approved in the countries for treatment of cognitive symptoms of AD.
• Anti-psychotic drugs (typical or atypical dopaminergic antagonists or modulators).
• Mood stabilization drugs (e.g. lithium, valproate, cabamazepine).
• Barbiturates, MAO inhibitors, Gingko biloba and other herbal treatments for cognitive impairment.
• Potent P-glycoprotein inhibitors (e.g. itraconazole, ketoconazole, cyclosporin, loperamide, diltiazem, verapamil, spironolactone, quinidine, bepridil, quinine, carvedilol).
21. Subjects that are currently taking known inhibitors or inducers of the CYP3A4 enzyme.
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 on chronic sedative medications (> or equal to 4 days per week for the past 4 weeks prior to screening).
24. 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Change from baseline in the executive function/working memory composite score in the CogState battery at week 16.
-Change in baseline in the episodic memory composite score in the CogState battery at week 16 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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