| 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 | 12.1 |
| 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 |
| The primary objective of this Protocol is to assess the efficacy of PF 04447943, relative to placebo, on a performance based measure of cognition in subjects with mild to moderate AD who are on stable donepezil therapy. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
1. To evaluate the effects of PF 04447943 on other clinically relevant measures including behavior, and clinician rated global change;
2. To evaluate the safety and tolerability of PF 04447943, relative to placebo, in subjects with mild to moderate AD who are on stable donepezil therapy;
3. To evaluate the pharmacokinetics of PF 04447943 in subjects with mild to moderate AD who are on stable donepezil therapy.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Age range: 55-90 years of age inclusive.
2. Men and women.
3. Women must be of non childbearing potential defined as either surgically sterile (both ovaries removed or hysterectomy) or post menopausal for at least 2 years
4. Male subjects must be surgically sterile or must agree to use effective contraception during the period of the trial and for at least 28 days after dosing. The definition of effective contraception is provided in Section 4.4.
5. Diagnostic evidence of probable AD consistent with DSM IV and NINCDS ADRDA criteria. The diagnosis of probable AD must be made by the site Physician at the time of the Screening visit. This evidence must be fully documented in the participant’s file (source documents) prior to the Baseline Visit.
6. MRI (preferred) or CT (if MRI not feasible in the opinion of the Investigator) within the last 12 months consistent with a diagnosis of probable Alzheimer’s disease without any other clinically significant co morbid pathologies found. If there has been a significant change in clinical status suggestive of stroke or other possible neurological disease with onset between the time of the last MRI or CT and the Screening evaluation, the scan should be repeated if considered appropriate by the Investigator. Subjects with MRI or CT indicating cortical infarct, strategically located subcortical gray matter infarct (eg, hippocampus, thalamus), multiple white matter lacunes or extensive white matter abnormalities should be excluded.
7. Subjects with mild to moderate probable Alzheimer’s disease with a Mini Mental State Exam (MMSE) score between 14 26 inclusive at Screening.
8. Subjects must be on donepezil 10 mg q day for at least 90 days prior to screening and be tolerating the medication well, without significant side effects, in the opinion of the investigator.
9. Modified Hachinski Ischemia score ≤4.
10. Subjects must live in the community and have a reliable caregiver or family member who agrees to accompany the patient to all clinic visits, provide information about the patient as required by the Protocol, and ensure compliance with the study medication. The caregiver must be a constant and reliable informant. Subjects with moderate Alzheimer’s disease (MMSE 14-20) must reside with their caregiver. It is preferred that subjects with mild Alzheimer’s disease (MMSE 21-26) also reside with their caregiver but at a minimum the caregiver should have at least 4 hours of direct contact with such subjects 5 days per week.
11. Subjects must be able to swallow oral medication in the form of tablets. Tablets are not to be crushed.
12. Subjects with controlled hypertension (sitting systolic BP ≤160 mmHg and diastolic BP ≤95 mmHg) may be included in the study.
13. Subjects’ screening 12 lead ECG must demonstrate predominantly normal sinus rhythm. QTcF must be ≤ 450 msec. Minor abnormalities (including sinus bradycardia
≤50 beats per minute) documented as clinically insignificant by the Investigator will be allowed. Subjects with right bundle branch block (complete or partial) or pacemakers may be included in the study, if considered clinically stable. Subjects with a history of atrial fibrillation are to be excluded.
14. Subjects must be in reasonably good health in the opinion of the Investigator based on medical history, physical examination, vital signs, and 12 lead ECG with no serious or unstable disease within the past 3 months. Subjects with mild, chronic, stable disease (eg, controlled hypertension, osteoarthritis) may be enrolled if deemed medically prudent by the Investigator.
15. Subjects and caregivers must provide written Informed Consent and be willing to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
16. Subjects with Type 2 diabetes stabilized by diet and/or oral hypoglycemic agents (3 months on a stable dose) are eligible provided they are medically managed by their treating Physician and monitored regularly to ensure adequacy of control. Subjects with known diabetes should have an HbA1C of ≤8% and a fasting serum glucose value of ≤170 mg/dl at Screening. Insulin use is not allowed.
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| E.4 | Principal exclusion criteria |
| Subjects presenting with any of following will not be included in study: 1.Presence of illness apart from AD that could contribute to cognitive dysfunction. Examples include other neurodegenerative disorders (eg, Lewy body dementia, fronto temporal dementia, vascular dementia); psychiatric disorders that meet DSM IV criteria for psychotic disorders, bipolar disorder, alcohol or substance abuse (occurring within the past 10 years);AIDS dementia; tertiary syphilis; or any form of dementia other than Alzheimer’s disease. 2. Current vitamin B12 level <271 pg/mL or 200 pmol/L, and elevated serum methylmalonic acid (MMA) level. 3.Active hyperthyroidism or hypothyroidism. Subjects with treated thyroid conditions who are clinically euthyroid and stable on treatment for at least 3 months prior to Screening may participate.. 4. Significant suicidal ideation with actual plan andintent or suicidal ideation and for whom it has been determined that it is unsafe to participate in this study. 5. Clinically significant cardiovascular disease in the 6 months prior to screening. Examples of clinically significant cardiovascular disease include myocardial infarction, coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (PTCA), severe or unstable angina; serious intermittent arrhythmia, clinically significant ECG conduction abnormalities, and moderate to severe heart failure (NYHA Stage III/IV). 6.Orthostatic blood pressure changes or orthostatic symptoms (such as dizziness, light headedness, etc.) which are considered clinically significant by the investigator. Orthostatic hypotension is defined as a decrease of ≥20 mmHg for systolic blood pressure or ≥10 mmHg for diastolic blood pressure within 3 minutes of standing from the supine position. Lesser degrees of BP reduction may still be considered clinically significant if the subject becomes symptomatic upon standing, especially in the presence of a significant increase in heart rate (≥30 BPM). 7. Transient Ischemic Attack (TIA) in the past 3 months. 8. Clinically significant history of cerebrovascular accident (CVA) or stroke, other than incidental lacunar infarction in a nonsignficant location on brain imaging. 9. History of a seizure disorder. 10. Clinically significant pulmonary disease that requires treatment or results in clinically significant pulmonary symptoms (eg, interstitial lung disease, moderate or severe or unstable asthma, COPD [emphysema or chronic bronchitis], chronic or acute pneumonitis). If the subject has a past history of asthma but has not required treatment for 1 year, participation is allowed. 11. History of cancer within the last 5 years, other than treated localized basal cell or squamous cell carcinoma of the skin, and stable localized prostate cancer (carcinoma in situ) not requiring treatment. 12. Evidence or history of diabetes mellitus Type 1. 13. Subjects who are taking or are expected to use prohibited concomitant drugs or restricted concomitant drugs outside the guidelines provided in Appendix 3 and Section 5.5 unless permitted by agreement of sponsor. 14. Treatment with an investigational drug within 3 months or 5 half lives (whichever is longer) preceding Screening. 15. Subjects intending to donate blood or blood components while receiving study medication or within 90 days after the last dose of study medication. Donation of approximately 1 pint [500 ml] of blood within 2 months prior to screening isalso excluded.16. Subjects with a total body weight <90 lb (40.9 kg). 17. Any clinically significant laboratory abnormalities at Screening. 18.Elevated transaminase levels and/or bilirubin of greater than 2 times the upper limit of normal (ULN). 19. Creatinine level >1.3. 20. History of regular alcohol consumption exceeding 14 drinks/week for females or 21 drinks/week for men (1 drink = 5 oz of wine or 12 oz [360 mL] of beer or 1.5 oz [45 mL] of hard liquor) within 6 months of Screening. 21. Evidence or history of clinically significant severe allergic reactions to drugs (eg, severe cutaneous and/or systemic allergic reactions). 22. Subjects unable to complete the ADAS cog at the Screening Visit. 23. Significant sensory (such as severely impaired hearing or vision) or motor difficulties that would prevent participation in all aspects of the study. (A cane [walking stick] or walker is permitted). 24. Participation in any other studies in which the ADAS cog is used, or studies in which involve cognitive rehabilitation, either during the current study or within 1 month of the Screening visit. 25. Any other medical condition, or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or that may interfere with the interpretation of study results and, that, in the judgment of the investigator, would make the subject inappropriate for entry into this study |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Alzheimer’s Disease Assessment Scale Cognitive Subscale 70 (ADAS cog) at Week 12 |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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