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

• ClinicalTrials.gov Identifier: NCT01193608
• Recruitment Status: Completed
• First Posted: September 2, 2010
• Results First Posted: February 23, 2017
• Last Update Posted: February 23, 2017
• Sponsor: Pfizer
• Collaborator: JANSSEN Alzheimer Immunotherapy Research & Development, LLC
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Alzheimer's Disease	Drug: AAB-003 (PF-05236812); Other: Placebo	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 88 participants
• Allocation: Randomized
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: September 2010
• Actual Primary Completion Date: October 2013
• Actual Study Completion Date: October 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Baseline up to 39 Weeks and at Early Withdrawal ]
2. Number of Participants With Laboratory Abnormalities [ Time Frame: Baseline up to 39 Weeks and at Early Withdrawal ]
3. Number of Participants With Vital Signs of Potential Clinical Concern [ Time Frame: Baseline up to 39 Weeks and at Early Withdrawal ]
   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.
4. Number of Participants With Abnormal Physical Examination Findings [ Time Frame: Baseline up to 39 Weeks and at Early Withdrawal ]
5. Number of Participants With Abnormal Neurological Examination Findings [ Time Frame: Screening, Day 1 (Baseline) and Weeks 1,6,13,19,26,32, and 39, and at Early Withdrawal ]
   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.
6. Maximum Observed Serum Concentration (Cmax) for AAB-003 at Day 1 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. ]
7. Maximum Observed Serum Concentration (Cmax) for AAB-003 at at Week 26 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4, 6, and 24 hours post start of infusion. ]
8. Average Concentration (Cavg) for AAB-003 in Serum at Day 1 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. ]
9. Average Concentration (Cavg) for AAB-003 in Serum at Week 26 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4, 6, and 24 hours post start of infusion. ]
10. Time to Reach Maximum Observed Serum Concentration (Tmax) for AAB-003 at Day 1 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. ]
11. Time to Reach Maximum Observed Serum Concentration (Tmax) for AAB-003 at Week 26 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4, 6, and 24 hours post start of infusion. ]
12. Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for AAB-003 in Serum at Day 1 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. ]
13. Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for AAB-003 in Serum at Day 1 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. ]
14. Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for AAB-003 in Serum at Day 1 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. ]
15. Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for AAB-003 in Serum at Week 26 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4, 6, and 24 hours post start of infusion. ]
16. Systemic Clearance (CL) for AAB-003 in Serum at Day 1 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. ]
17. Systemic Clearance (CL) for AAB-003 in Serum at Week 26 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4, 6, and 24 hours post start of infusion. ]
18. Volume of Distribution at Steady State (Vss) for AAB-003 in Serum at Day 1 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. ]
19. Volume of Distribution at Steady State (Vss) for AAB-003 in Serum at Week 26 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4, 6, and 24 hours post start of infusion. ]
20. Serum Decay Half-Life (t1/2) for AAB-003 at Day 1 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4 and 6 hours post start of infusion. ]
21. Serum Decay Half-Life (t1/2) for AAB-003 at Week 26 [ Time Frame: Pre-dose, 1 hour (end of infusion), 1.5, 2, 4, 6, and 24 hours post start of infusion. ]
22. Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline up to Week 39 or Early Withdrawal ]
    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").
23. Number of Participants With New Occurrence of Brain Magnetic Resonance Imaging (MRI) Finding [ Time Frame: Baseline up to Week 32. ]
    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.
24. Number of Participants With Vasogenic Edema of All Severity After Each Infusion Visit [ Time Frame: Day 1, Week 13, and Week 26 ]
    VE of the brain, identified via MRI, was identified as an adverse event of special circumstance.
25. Number of Participants With Change From Baseline and Absolute Values in Electrocardiogram (ECG) Meeting Categorical Summarization Criteria [ Time Frame: Baseline, Weeks 1,13,16,26,39 or Early Withdrawal ]
    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.

Other Outcome Measures:

1. Number of Participants With Positive Anti-product Antibody Response to AAB-003 in Serum [ Time Frame: Day 1 (predose), Week 13 (predose), Week 26 (predose) and Week 39 or Early Withdrawal ]
   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
2. Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) Score at Weeks 13, 26 and 39 [ Time Frame: Baseline, 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.
3. Change From Baseline in Disability Assessment in Dementia (DAD) Score at Weeks 13, 26 and 39 [ Time Frame: Baseline, 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).
4. Change From Baseline in Behavioral Symtoms as Measured by the Neuropsychiatric Inventory (NPI) at Weeks 13, 26 and 39 [ Time Frame: Baseline, 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).
5. Change From Baseline on the Clinical Dementia Rating (CDR) Sum of Boxes (CDR-SB) and Global CDR Rating at Weeks 26 and 39 [ Time Frame: Baseline, 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.
6. Change From Baseline on the Mini Mental State Exam (MMSE) Score at Weeks 13, 26, and 39 [ Time Frame: Baseline, 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.
7. Cerebrospinal Fluid (CSF) Concentration of AAB-003 at Week 32 [ Time Frame: Week 32 or Early Withdrawal ]
   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.
8. Change From Baseline in CSF Amyloid-beta x-40 Concentration at Week 32 for AAB-003 8 mg/kg and Placebo Groups [ Time Frame: Baseline and Week 32 ]
9. CSF Amyloid-beta x-40 Concentration at Baseline and Week 32 for AAB-003 2 mg/kg and 4 mg/kg Groups [ Time Frame: Baseline and Week 32 ]
10. Change From Baseline in CSF Amyloid-beta x-42 Concentration at Week 32 for AAB-003 8 mg/kg and Placebo Groups [ Time Frame: Baseline and Week 32 ]
11. CSF Amyloid-beta x-42 Concentration at Baseline and Week 32 for AAB-003 2 mg/kg and 4 mg/kg Groups [ Time Frame: Baseline and Week 32 ]
12. Change From Baseline in CSF Tau Concentration at Week 32 for AAB-003 8 mg/kg and Placebo Groups [ Time Frame: Baseline and Week 32 ]
13. CSF Tau Concentration at Baseline and Week 32 for AAB-003 2 mg/kg and 4 mg/kg Groups [ Time Frame: Baseline and Week 32 ]
14. Change From Baseline in CSF P-tau Concentration at Week 32 for AAB-003 8 mg/kg and Placebo Groups [ Time Frame: Baseline and Week 32 ]
15. CSF P-tau Concentration at Baseline and Week 32 for AAB-003 2 mg/kg and 4 mg/kg Groups [ Time Frame: Baseline and Week 32 ]
16. Maximum Observed Plasma Concentration (Cmax) for Amyloid-Beta x-40 [ Time Frame: 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. ]
17. Time to Reach Maximum Observed Plasma Concentration (Tmax) for Amyloid-Beta x-40 [ Time Frame: 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. ]
18. Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Amyloid-Beta x-40 [ Time Frame: 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. ]
19. Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for Amyloid-Beta x-40 [ Time Frame: 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. ]
20. Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for Amyloid-Beta x-40 [ Time Frame: 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. ]
21. Plasma Decay Half-Life (t1/2) for Amyloid-Beta x-40 [ Time Frame: 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. ]

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, California

Early Phase Investigational Center

Escondido, California, United States, 92025

Synergy Clinical Research Center of Escondido

Escondido, California, United States, 92025

United States, Florida

MD Clinical

Hallandale Beach, Florida, United States, 33009

Franck's Pharmacy

Ocala, Florida, United States, 34471

Munroe Regional Medical Center

Ocala, Florida, United States, 34471

Renstar Medical Research

Ocala, Florida, United States, 34471

Advanced Imaging of Ocala

Ocala, Florida, United States, 34481

United States, Georgia

Atlanta Center for Medical Research

Atlanta, Georgia, United States, 30308

United States, Maryland

Foers Medical Arts Pharmacy

Bethesda, Maryland, United States, 20814

CBH Health, LLC

Rockville, Maryland, United States, 20850

United States, Michigan

Borgess Medical Center

Kalamazoo, Michigan, United States, 49048

Borgess Research Institute

Kalamazoo, Michigan, United States, 49048

KNI/Southwest Michigan Imaging Center, LLC

Kalamazoo, Michigan, United States, 49048

United States, Mississippi

Brentwood Behavioral Healthcare

Flowood, Mississippi, United States, 39232

Marty's Pharmacy

Flowood, Mississippi, United States, 39232

Precise Research Centers

Flowood, Mississippi, United States, 39232

United States, Missouri

Millennium Psychiatric Associates, LLC

Creve Coeur, Missouri, United States, 63141

DePaul Health Center

St. Louis, Missouri, United States, 63044

United States, New Jersey

Memory Enhancement Center of America, Inc.

Eatontown, New Jersey, United States, 07724

Pharmacare USA

Edison, New Jersey, United States, 08837

Central Jersey Radiology

Oakhurst, New Jersey, United States, 07755

United States, Pennsylvania

Belmont Center for Comprehensive Treatment

Philadelphia, Pennsylvania, United States, 19131-1689

Albert Einstein Medical Center

Philadelphia, Pennsylvania, United States, 19141

Korea, Republic of

Seoul National University Bundang Hospital, Department of Neurology

Seongnam-si, Gyeonggi-do, Korea, Republic of, 463-707

Inha University Hospital, Department of Neurology

Incheon, Korea, Republic of

Samsung Medical Center, Department of Neurology

Seoul, Korea, Republic of, 135-710

Korea University Anam Hospital

Seoul, Korea, Republic of, 136-705

ASAN Medical Center

Seoul, Korea, Republic of, 138-736

Konkuk University Medical Center, Department of Neurology

Seoul, Korea, Republic of, 143-914

Sponsors and Collaborators

Pfizer

JANSSEN Alzheimer Immunotherapy Research & Development, LLC

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01193608
• Other Study ID Numbers: B2601001; 3245K1-1000 ( Other Identifier: Alias Study Number )
• First Posted: September 2, 2010
• Results First Posted: February 23, 2017
• Last Update Posted: February 23, 2017
• Last Verified: January 2017

Keywords provided by Pfizer:

Randomized; Safety Study; Adaptive; Double Blind

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders