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

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

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: 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

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Incheon, Korea, Republic of
    • Inha University Hospital, Department of Neurology
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center
  • Seoul, Korea, Republic of, 136-705
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center, Department of Neurology
  • Seoul, Korea, Republic of, 143-914
    • Konkuk University Medical Center, Department of Neurology
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, Korea, Republic of, 463-707
      • Seoul National University Bundang Hospital, Department of Neurology
• United States
  • California
    • Escondido, California, United States, 92025
      • Early Phase Investigational Center
    • Escondido, California, United States, 92025
      • Synergy Clinical Research Center Of Escondido
  • Florida
    • Hallandale Beach, Florida, United States, 33009
      • MD Clinical
    • Ocala, Florida, United States, 34471
      • Renstar Medical Research
    • Ocala, Florida, United States, 34471
      • Franck's Pharmacy
    • Ocala, Florida, United States, 34471
      • Munroe Regional Medical Center
    • Ocala, Florida, United States, 34481
      • Advanced Imaging of Ocala
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Atlanta Center for Medical Research
  • Maryland
    • Bethesda, Maryland, United States, 20814
      • Foers Medical Arts Pharmacy
    • Rockville, Maryland, United States, 20850
      • CBH Health, LLC
  • Michigan
    • Kalamazoo, Michigan, United States, 49048
      • Borgess Medical Center
    • Kalamazoo, Michigan, United States, 49048
      • Borgess Research Institute
    • Kalamazoo, Michigan, United States, 49048
      • KNI/Southwest Michigan Imaging Center, LLC
  • Mississippi
    • Flowood, Mississippi, United States, 39232
      • Precise Research Centers
    • Flowood, Mississippi, United States, 39232
      • Brentwood Behavioral Healthcare
    • Flowood, Mississippi, United States, 39232
      • Marty's Pharmacy
  • Missouri
    • Creve Coeur, Missouri, United States, 63141
      • Millennium Psychiatric Associates, LLC
    • St. Louis, Missouri, United States, 63044
      • DePaul Health Center
  • New Jersey
    • Eatontown, New Jersey, United States, 07724
      • Memory Enhancement Center of America, Inc.
    • Edison, New Jersey, United States, 08837
      • Pharmacare USA
    • Oakhurst, New Jersey, United States, 07755
      • Central Jersey Radiology
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Medical Center
    • Philadelphia, Pennsylvania, United States, 19131-1689
      • Belmont Center For Comprehensive Treatment

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Positive Anti-product Antibody Response to AAB-003 in Serum	Human serum anti-drug antibodies (ADA) samples were analyzed for the presence or absence of anti-AAB-003 antibodies by enzyme-linked immunosorbent assay (ELISA) method	Day 1 (predose), Week 13 (predose), Week 26 (predose) and Week 39 or Early Withdrawal
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) Score at Weeks 13, 26 and 39	The ADAS-cog 70 Point is a structured scale (approximately 40 min to complete) that evaluates memory, orientation, attention, reasoning, language and constructional praxis. This study used the 11-item cognitive subscale of the ADAS-Cog with scores ranging from 0 to 70 points; higher scores indicated greater cognitive impairment.	Baseline, Weeks 13, 26 and 39
Change From Baseline in Disability Assessment in Dementia (DAD) Score at Weeks 13, 26 and 39	The DAD is a functional assessment based on an interview with the caregiver that takes approximately 20 min to administer and it is comprised of 40 items, 17 related to self-care and 23 items involving instrumental activities of daily living. The DAD is scored from 0 to 100 (higher scores indicate better functioning).	Baseline, Weeks 13, 26 and 39
Change From Baseline in Behavioral Symtoms as Measured by the Neuropsychiatric Inventory (NPI) at Weeks 13, 26 and 39	The NPI is an instrument used to assess changes of behavior that have appeared in a defined period of time in participants with Alzheimer's disease (AD) and other dementias. Twelve (12) behavioral areas are assessed in the NPI - delusions, apathy, hallucinations, disinhibition, agitation, irritability, depression, aberrant motor behavior, anxiety, nighttime behaviors, euphoria, appetite, and eating changes. The NPI score is based on frequency and severity of specific behaviors within these categories as reported by the caregiver. A separate caregiver distress score may also be included. The NPI ranges from 0 to 144 (higher scores indicate greater psychopathology).	Baseline, Weeks 13, 26 and 39
Change From Baseline on the Clinical Dementia Rating (CDR) Sum of Boxes (CDR-SB) and Global CDR Rating at Weeks 26 and 39	The CDR scale is a clinician-rated dementia staging instrument that tracks the progression of cognitive impairment in the following 6 categories - memory, orientation, judgment and problem solving, involvement in community affairs, home and hobbies, and personal care based on the CDR interview. The CDR is based on discussions between the clinician with the participant and caregiver using a structured format. A global CDR score is established by clinical scoring rules with values of 0 (no dementia), 0.5 (questionable dementia), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia). A more quantitative version of the CDR scale is obtained by summing up the ratings in each of the 6 categories to provide the (CDR-SB). The CDR-SB scale ranges from 0 to 18 where higher score indicates severe dementia.	Baseline, Weeks 26 and 39
Change From Baseline on the Mini Mental State Exam (MMSE) Score at Weeks 13, 26, and 39	The MMSE is a brief 30-point questionnaire test that is used to assess cognition. It is commonly used to screen for dementia. In the time span of about 10 min, it samples various functions, including arithmetic, memory and orientation. Scores range from 0 to 30 (higher scores indicate less impairment) and participants with scores of 16 to 26 were eligible.	Baseline, Weeks 13, 26 and 39
Cerebrospinal Fluid (CSF) Concentration of AAB-003 at Week 32	Participants enrolled in the 2, 4 and 8 mg/kg cohorts participated in an optional CSF collection. Participants enrolled in the maximum tolerated dose (MTD) cohort were mandatorily collected for CSF.	Week 32 or Early Withdrawal
Change From Baseline in CSF Amyloid-beta x-40 Concentration at Week 32 for AAB-003 8 mg/kg and Placebo Groups		Baseline and Week 32
CSF Amyloid-beta x-40 Concentration at Baseline and Week 32 for AAB-003 2 mg/kg and 4 mg/kg Groups		Baseline and Week 32
Change From Baseline in CSF Amyloid-beta x-42 Concentration at Week 32 for AAB-003 8 mg/kg and Placebo Groups		Baseline and Week 32
CSF Amyloid-beta x-42 Concentration at Baseline and Week 32 for AAB-003 2 mg/kg and 4 mg/kg Groups		Baseline and Week 32
Change From Baseline in CSF Tau Concentration at Week 32 for AAB-003 8 mg/kg and Placebo Groups		Baseline and Week 32
CSF Tau Concentration at Baseline and Week 32 for AAB-003 2 mg/kg and 4 mg/kg Groups		Baseline and Week 32
Change From Baseline in CSF P-tau Concentration at Week 32 for AAB-003 8 mg/kg and Placebo Groups		Baseline and Week 32
CSF P-tau Concentration at Baseline and Week 32 for AAB-003 2 mg/kg and 4 mg/kg Groups		Baseline and Week 32
Maximum Observed Plasma Concentration (Cmax) for Amyloid-Beta x-40		Weeks 1, 3, 6, 10, 13 (pre-dose, 1 hour [end of infusion]), Week 26 (pre-dose, 1 hour [end of infusion], 1.5, 2, 4, 6, and 24 hours post start of infusion), and Weeks 32 and 39.
Time to Reach Maximum Observed Plasma Concentration (Tmax) for Amyloid-Beta x-40		Weeks 1, 3, 6, 10, 13 (pre-dose, 1 hour [end of infusion]), Week 26 (pre-dose, 1 hour [end of infusion], 1.5, 2, 4, 6, and 24 hours post start of infusion), and Weeks 32 and 39.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Amyloid-Beta x-40		Baseline; Day 2 (24 hours post start of infusion); Weeks 1, 6, and 13 (pre-dose, 1 hour [end of infusion]), Week 26 (pre-dose, 1 hour [end of infusion], 1.5, 2, 4, 6, and 24 hours post start of infusion), and Weeks 32 and 39.
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for Amyloid-Beta x-40		Baseline; Day 2 (24 hours post start of infusion); Weeks 1, 6, and 13 (pre-dose, 1 hour [end of infusion]), Week 26 (pre-dose, 1 hour [end of infusion], 1.5, 2, 4, 6, and 24 hours post start of infusion), and Weeks 32 and 39.
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for Amyloid-Beta x-40		Weeks 1, 3, 6, 10, 13 (pre-dose, 1 hour [end of infusion]), Week 26 (pre-dose, 1 hour [end of infusion], 1.5, 2, 4, 6, and 24 hours post start of infusion), and Weeks 32 and 39.
Plasma Decay Half-Life (t1/2) for Amyloid-Beta x-40		Baseline; Day 2 (24 hours post start of infusion); Weeks 1, 6, and 13 (pre-dose, 1 hour [end of infusion]), Week 26 (pre-dose, 1 hour [end of infusion], 1.5, 2, 4, 6, and 24 hours post start of infusion), and Weeks 32 and 39.

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: JANSSEN Alzheimer Immunotherapy Research & Development, LLC

Publications and helpful links

General Publications

• Delnomdedieu M, Duvvuri S, Li DJ, Atassi N, Lu M, Brashear HR, Liu E, Ness S, Kupiec JW. First-In-Human safety and long-term exposure data for AAB-003 (PF-05236812) and biomarkers after intravenous infusions of escalating doses in patients with mild to moderate Alzheimer's disease. Alzheimers Res Ther. 2016 Mar 1;8(1):12. doi: 10.1186/s13195-016-0177-y.

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: August 19, 2010
• First Submitted That Met QC Criteria: August 30, 2010
• First Posted (Estimate): September 2, 2010

Study Record Updates

• Last Update Posted (Actual): February 23, 2017
• Last Update Submitted That Met QC Criteria: January 3, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Randomized; Double Blind; Adaptive; Safety Study
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: B2601001; 3245K1-1000 (Other Identifier: Alias Study Number)