Study Evaluating The Safety Of AAB-003 (PF-05236812) In Subjects With Alzheimer's Disease

Study Overview
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Brief Summary
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This is a study to evaluate the safety of multiple doses of AAB-003 (PF-05236812) in patients with mild to moderate Alzheimer's Disease. Patients will receive either AAB-003 (PF-05236812) or placebo. Each patient's participation will last approximately 41 weeks.

Official Title
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A Phase 1, Multicenter, Randomized, Double-blind, Placebo-controlled, Adaptive, Multiple Ascending Dose Study Of The Safety, Tolerability And Pharmacokinetics Of Aab-003 (Pf-05236812) In Subjects With Mild To Moderate Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: AAB-003 (PF-05236812)
* Drug: AAB-003 (PF-05236812)
* Drug: AAB-003 (PF-05236812)
* Drug: AAB-003 (PF-05236812)
* Drug: AAB-003 (PF-05236812)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of probable Alzheimer's Disease with MMSE score of 16-26, and brain MRI consistent with the diagnosis of Alzheimer's Disease Concurrent use of cholinesterase inhibitor or memantine allowed, if stable. Caregiver will participate and be able to attend clinic visits with patient Exclusion Criteria: Significant neurological disease other than Alzheimer's Disease Major psychiatric disorder Contraindication to undergo brain MRI (e.g., pacemaker, CSF shunt, or foreign metal objects in the body) Women of childbearing potential

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 89 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.5 mg/kg AAB-003<br> | Drug: AAB-003 (PF-05236812)<br>* 0.5 mg/kg AAB-003, IV<br>|
| Experimental: 1 mg/kg AAB-003<br> | Drug: AAB-003 (PF-05236812)<br>* 1 mg/kg AAB-003, IV<br>|
| Experimental: 2 mg/kg AAB-003<br> | Drug: AAB-003 (PF-05236812)<br>* 2 mg/kg AAB-003, IV<br>|
| Experimental: 4 mg/kg AAB-003<br> | Drug: AAB-003 (PF-05236812)<br>* 4 mg/kg AAB-003, IV<br>|
| Experimental: 8 mg/kg AAB-003<br> | Drug: AAB-003 (PF-05236812)<br>* 8 mg/kg AAB-003, IV<br>|
| Placebo Comparator: Placebo<br> | Other: Placebo<br>* Placebo, IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) |  | Baseline up to 39 Weeks and at Early Withdrawal | 
| Number of Participants With Laboratory Abnormalities |  | Baseline up to 39 Weeks and at Early Withdrawal | 
| Number of Participants With Vital Signs of Potential Clinical Concern | Criteria for potential clinical concern in vital signs included: supine/sitting pulse rate of less than (<) 40 or more than (>) 120 beats per minute (bpm), and standing pulse rate of <40 or >140 bpm; systolic blood pressure (SBP) of more than or equal to (>=)30 millimeters of mercury (mm Hg) change from baseline in same posture and <90 mm Hg; diastolic blood pressure (DBP) >=20 mm Hg change from baseline in same posture and <50 mm Hg. Only supine vital signs were planned for this study. Unplanned sitting vital signs were collected only in the 8/mg and placebo groups and also reported. | Baseline up to 39 Weeks and at Early Withdrawal | 
| Number of Participants With Abnormal Physical Examination Findings |  | Baseline up to 39 Weeks and at Early Withdrawal | 
| Number of Participants With Abnormal Neurological Examination Findings | The neurological examination was done to the extent needed to assess the participant for any potential changes in neurological status, as determined by the investigator. The minimum items assessed were level of consciousness, speech, cranial nerves, motor, sensory, coordination, gait, and tendon reflexes. | Screening, Day 1 (Baseline) and Weeks 1,6,13,19,26,32, and 39, and at Early Withdrawal | 
| Maximum Observed Serum Concentration (Cmax) for AAB-003 at Day 1 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. | 
| Maximum Observed Serum Concentration (Cmax) for AAB-003 at at Week 26 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4, 6, and 24 hours post start of infusion. | 
| Average Concentration (Cavg) for AAB-003 in Serum at Day 1 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. | 
| Average Concentration (Cavg) for AAB-003 in Serum at Week 26 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4, 6, and 24 hours post start of infusion. | 
| Time to Reach Maximum Observed Serum Concentration (Tmax) for AAB-003 at Day 1 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. | 
| Time to Reach Maximum Observed Serum Concentration (Tmax) for AAB-003 at Week 26 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4, 6, and 24 hours post start of infusion. | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for AAB-003 in Serum at Day 1 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for AAB-003 in Serum at Day 1 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for AAB-003 in Serum at Day 1 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for AAB-003 in Serum at Week 26 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4, 6, and 24 hours post start of infusion. | 
| Systemic Clearance (CL) for AAB-003 in Serum at Day 1 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. | 
| Systemic Clearance (CL) for AAB-003 in Serum at Week 26 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4, 6, and 24 hours post start of infusion. | 
| Volume of Distribution at Steady State (Vss) for AAB-003 in Serum at Day 1 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. | 
| Volume of Distribution at Steady State (Vss) for AAB-003 in Serum at Week 26 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4, 6, and 24 hours post start of infusion. | 
| Serum Decay Half-Life (t1/2) for AAB-003 at Day 1 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. | 
| Serum Decay Half-Life (t1/2) for AAB-003 at Week 26 |  | Pre-dose, 1 hour (end of infusion), 1.5, 2, 4, 6, and 24 hours post start of infusion. | 
| Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) | The C-SSRS assessed whether the participant experienced the following: completed suicide (1), suicide attempt (2) (response of Yes on actual attempt), preparatory acts toward imminent suicidal behavior (3)(Yes on preparatory acts or behavior), suicidal ideation (4) (Yes on wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent), any suicidal behavior or ideation, self-injurious behavior (7)(Yes on Has participant engaged in non-suicidal self-injurious behavior). | Baseline up to Week 39 or Early Withdrawal | 
| Number of Participants With New Occurrence of Brain Magnetic Resonance Imaging (MRI) Finding | Brain MRIs were collected during the course of study to assess for any potential drug-related changes that might have constituted a safety concern for study participants. Findings suggestive of either vasogenic edema (VE) or intracranial hemorrhage represented adverse events of special circumstance and were to be reported immediately. | Baseline up to Week 32. | 
| Number of Participants With Vasogenic Edema of All Severity After Each Infusion Visit | VE of the brain, identified via MRI, was identified as an adverse event of special circumstance. | Day 1, Week 13, and Week 26 | 
| Number of Participants With Change From Baseline and Absolute Values in Electrocardiogram (ECG) Meeting Categorical Summarization Criteria | Criteria for ECG values of potential clinical concern are: interval between the start of the ECG P wave and the start of the QRS complex corresponding to the time between onset of atrial depolarization and onset of ventricular depolarization (PR): >= 300 milliseconds (msec), and >=25% increase when baseline >=200 msec/ >=50% increase when baseline less than or equal to (<=) 200 msec; time from ECG Q wave to the end of S wave corresponding to ventricular depolarization (QRS): >=200 msec, and >=25% increase when baseline >100 msec/ >=50% increase when baseline <=100 msec; QTc using Fridericia's formula (QTcF) interval: 450 to <480 msec, >=480 msec; QTcF change from baseline: 30 to <60 msec, and >=60 msec. | Baseline, Weeks 1,13,16,26,39 or Early Withdrawal | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized, Safety Study, Adaptive, Double Blind