| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
|
| 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. |
|
| 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.
3. To evaluate the pharmacokinetics of PF-04447943 in subjects with mild to moderate AD. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age range: 55-85 years of age inclusive
2. Men and women. Women must be of non-childbearing potential defined as either surgically sterile (bilateral tubal ligation, both ovaries removed, or hysterectomy) or post-menopausal for at least 2 years
3. 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
4. Diagnostic evidence of probable AD consistent with DSM-IV and NINCDS-ADRDA criteria (made by the site Physician at the time of the Screening visit). This evidence must be fully documented in the participant’s file prior to the Baseline Visit
5. 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
6. Subjects with mild to moderate probable Alzheimer’s disease with a Mini Mental State Exam (MMSE) score between 14-26 inclusive at Screening
7. Modified Hachinski Ischemia score ≤4
8. 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
9. Subjects must be able to swallow oral medication in the form of tablets. Tablets are not to be crushed
10. Subjects with controlled hypertension (sitting systolic BP <160 mmHg or a sitting
diastolic BP <95 mmHg) may be included in the study
11. Subjects’ screening 12-lead ECG must demonstrate predominantly normal sinus
rhythm. 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) and pacemakers may be included
in the study, if considered clinically stable.
12. Subjects must be in reasonably good health in the opinion of the Investigator based on medical history, physical examination, vital signs, 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
13. Subjects and caregivers must provide written Informed Consent and be willing to
comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures
14. 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 random serum glucose value of <170 mg/dl at Screening |
|
| E.4 | Principal exclusion criteria |
1. Presence of illness apart from AD that could contribute to cognitive dysfunction. Examples include but are not limited to 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. Subjects with a current vitamin B12 level below either 271 pg/mL or 200 pmol/L, associated with an elevated serum methylmalonic acid (MMA) level.
3. Subjects with thyroid disease unless they are euthyroid and stable on treatment for at least 3 months prior to Screening. Stable treatment must be maintained throughout the study.
4. Subjects felt to have significant suicidal ideation with actual plan and intent or suicidal ideation and for whom it has been determined that it is unsafe to participate in this study. All subjects must be assessed for potential suicidality as described in Section 7.2.4. of the protocol.
5. Subjects with clinically significant cardiovascular disease in the past 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; A serious arrhythmia; Clinically significant ECG conduction abnormalities; Moderate to severe heart failure (NYHA Stage III/IV).
6. Subjects with a history of orthostatic blood pressure changes or orthostatic symptoms (such as dizziness, lightheadedness, etc.) which are considered clinically significant by the investigator. Orthostatic hypotension is 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. Subjects experiencing a Transient Ischemic Attack (TIA) in the past 6 months.
8. Subjects with any history of cerebrovascular accident (CVA) or stroke.
9. Subjects with any history of a seizure disorder.
10. Participants with pulmonary disease (eg, interstitial lung disease, moderate or severe or unstable asthma, COPD [emphysema or chronic bronchitis], chronic or acute pneumonitis) or evidence of clinically significant pulmonary symptoms. (Note: If asthma is mild and has not required treatment for 1 year, participant would be allowed).
11. History of cancer within the last 5 years. Treated basal cell or squamous cell carcinoma of the skin is allowed, and stable localized prostate cancer not requiring treatment is allowed.
12. Subjects with evidence or history of diabetes mellitus Type 1.
13. Subjects with a history of acetylcholinesterase inhibitor or memantine use within 84 days (12 weeks) of Baseline.
14. 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.
15. Treatment with an investigational drug within 3 months or 5 half lives (whichever is longer) preceding Screening.
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 clearance <30 ml/min. Creatinine clearance will be estimated using the method of Cockroft and Gault12 as shown on page 23 of the protocol.
20. History of regular alcohol consumption exceeding 7 drinks/week for females or 14 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. Subjects with evidence or history of clinically significant allergic reactions to drugs (eg, severe cutaneous and/or systemic allergic reactions).
22. Subjects unable to complete ADAS cog at the Screening Visit will be excluded from participation.
23. Subjects with any sensory (eg, impaired hearing or vision) or motor difficulties preventing their participation in all aspects of the study. (A cane [walking stick] or walker is permitted).
24. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Alzheimer’s Disease Assessment Scale-Cognitive Subscale 70 (ADAS-cog)3 at Week 12. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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