Study Evaluating the Safety,Tolerability and Efficacy of PF-04360365 in Adults With Probable Cerebral Amyloid Angiopathy

• ClinicalTrials.gov Identifier: NCT01821118
• Recruitment Status: Completed
• First Posted: March 29, 2013
• Results First Posted: November 3, 2016
• Last Update Posted: May 10, 2017
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

Cerebral Amyloid Angiopathy (CAA) is a condition caused by the build-up of a protein called amyloid, predominantly Aβ40, within the walls of brain blood vessels, especially those blood vessels in the occipital lobe of the brain. Probable CAA may be defined as two or more hemorrhages in the brain cortex in individuals 55 years of age or older. This study will examine the study drug (PF-04360365) vs. placebo (saline) at 10 mg/kg - Day 1 and the maintenance dose of the study drug (PF-04360365) vs. placebo (saline) at 7.5mg/kg on Days 30 and 60. Subjects will be followed for 6 months after receiving the last dose of study medication.

Condition or disease	Intervention/treatment	Phase
Cerebral Amyloid Angiopathy	Biological: Ponezumab; Other: placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double Blind Placebo Controlled Trial To Evaluate The Safety, Tolerability, Pharmacokinetics And Efficacy Of Pf-04360365 (Ponezumab) In Adult Subjects With Probable Cerebral Amyloid Angiopathy
• Study Start Date: June 2013
• Actual Primary Completion Date: September 2015
• Actual Study Completion Date: September 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1	Biological: Ponezumab; Infusion of Ponezumab (Day 1=10mg/kg; Day 30 and Day 60 dose = 7.5mg/kg) or placebo (saline); administered via infusion for a total infusion time of 20 minutes.
Placebo Comparator: 2	Other: placebo; placebo (saline)- given via infusion total infusion time of 20 minutes

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline to Day 2 in Cerebrovascular Reactivity as Measured by the Slope (Amplitude Over Time to Peak) From Visual Task-evoked Functional Magnetic Resonance Imaging (fMRI) [ Time Frame: Baseline, Day 2 ]
   Blood Oxygen Level Dependant (BOLD) fMRI was performed at Screening (Baseline) and on Days 2 and 90. During each of these sessions, BOLD fMRI images were acquired in rapid succession as a flashing radial black and white checkerboard was presented alternately with a gray screen. This well established visual stimulus is known to produce a reliable increase in BOLD fMRI signal within the visual cortex region of the occipital lobe. The time course of the BOLD fMRI signal was used to assess the vascular reactivity. Imaging sites also acquired cerebral blood flow data using Arterial Spin Labeled (ASL) scans at Screening and on Days 2 and 90. A standard T1-weighted image was also acquired to aid image analysis. All efficacy scans were analyzed centrally. Geometric means are presented in the original scale and standard errors (SE) are presented in logarithmic (log e) scale.
2. Change From Baseline to Day 90 in Cerebrovascular Reactivity as Measured by the Slope (Amplitude Over Time to Peak) From Visual Task-evoked fMRI [ Time Frame: Baseline, Day 90 ]
   BOLD fMRI was performed at Screening (Baseline) and on Days 2 and 90. During each of these sessions, BOLD fMRI images were acquired in rapid succession as a flashing radial black and white checkerboard was presented alternately with a gray screen. This well established visual stimulus is known to produce a reliable increase in BOLD fMRI signal within the visual cortex region of the occipital lobe. The time course of the BOLD fMRI signal was used to assess the vascular reactivity. Imaging sites also acquired cerebral blood flow data using ASL scans at Screening and on Days 2 and 90. A standard T1-weighted image was also acquired to aid image analysis. All efficacy scans were analyzed centrally. Geometric means are presented in the original scale and SEs are presented in log e scale.

Secondary Outcome Measures :

1. Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Time to Peak From Visual Task-evoked fMRI [ Time Frame: Baseline, Day 2, Day 90 ]
   BOLD fMRI was performed at Screening (Baseline) and on Days 2 and 90. During each of these sessions, BOLD fMRI images were acquired in rapid succession as a flashing radial black and white checkerboard was presented alternately with a gray screen. This well established visual stimulus is known to produce a reliable increase in BOLD fMRI signal within the visual cortex region of the occipital lobe. The time course of the BOLD fMRI signal was used to assess the vascular reactivity. Imaging sites also acquired cerebral blood flow data using ASL scans at Screening and on Days 2 and 90. A standard T1-weighted image was also acquired to aid image analysis. All efficacy scans were analyzed centrally. Geometric means are presented in the original scale and SEs are presented in log e scale.
2. Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Amplitude From Visual Task-evoked fMRI [ Time Frame: Baseline, Day 2, Day 90 ]
   BOLD fMRI was performed at Screening (Baseline) and on Days 2 and 90. During each of these sessions, BOLD fMRI images were acquired in rapid succession as a flashing radial black and white checkerboard was presented alternately with a gray screen. This well established visual stimulus is known to produce a reliable increase in BOLD fMRI signal within the visual cortex region of the occipital lobe. The time course of the BOLD fMRI signal was used to assess the vascular reactivity. Imaging sites also acquired cerebral blood flow data using ASL scans at Screening and on Days 2 and 90. A standard T1-weighted image was also acquired to aid image analysis. All efficacy scans were analyzed centrally. All values are presented in log e scale.
3. Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Time to Return to Baseline From Visual Task-evoked fMRI [ Time Frame: Baseline, Day 2, Day 90 ]
   BOLD fMRI was performed at Screening (Baseline) and on Days 2 and 90. During each of these sessions, BOLD fMRI images were acquired in rapid succession as a flashing radial black and white checkerboard was presented alternately with a gray screen. This well established visual stimulus is known to produce a reliable increase in BOLD fMRI signal within the visual cortex region of the occipital lobe. The time course of the BOLD fMRI signal was used to assess the vascular reactivity. Imaging sites also acquired cerebral blood flow data using ASL scans at Screening and on Days 2 and 90. A standard T1-weighted image was also acquired to aid image analysis. All efficacy scans were analyzed centrally. All values are presented in log e scale.
4. Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB) [ Time Frame: Baseline, 8 hours post dose on Day 1, Day 2, Day 30, 90 and 240 ]
   Cerebral amyloid angiopathy (CAA) is caused by the progressive deposition of amyloid, predominantly AB40, within the walls of cerebral blood vessels with a predisposition for the vessels of the occipital lobe. As such, it is of interest to investigate the effect of PF-04360365 on AB concentrations. AB1-x and AB1-40 were investigated.
5. Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities [ Time Frame: Baseline/Screening, Day 15, Day 45, Day 90, ]
   Brain sMRI abnormalities included cerebral edema and total infarcts (including cortical infarcts, white matter infarcts, and subcortical gray matter infarcts). "Total infarcts" is the total number of participants with at least 1 type of infarct.
6. Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time [ Time Frame: Screening; Days 0, 1, 30, 60, 90, and 240 ]
   The Montreal Cognitive Assessment (MoCA) was used as a safety outcome measure to assess any changes in cognition. The MoCA is a 1-page 30-point test administered in approximately 10 minutes. The MoCA assessed short term memory, visuospatial abilities, multiple aspects of executive functions, attention, concentration, working memory, and language, as well as orientation to time and place. The total scale ranges from 0 to 30, with lower numbers indicating lower cognition performance.
7. Number of Participants With All Causality and Treatment-related Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) [ Time Frame: Baseline up to Day 240 ]
   An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. AEs comprised both SAEs and non-SAEs. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse events (TEAEs) were defined as newly occurring AEs or those worsening after first dose.
8. Number of Participants With Laboratory Abnormalities [ Time Frame: Baseline up to Day 240 ]
   Number of participants with laboratory test abnormalities without regard to baseline abnormality. Laboratory test parameters included hematology, liver function (including Hy's Law Criteria), renal function, electrolytes, clinical chemistry, and urinalysis (dipstick and microscopy).
9. Number of Participants With Vital Signs Values Meeting Categorical Summarization Criteria [ Time Frame: Baseline up to Day 240 ]
   Categorical summarization criteria in vital signs included: supine systolic blood pressure (SBP) of less than (<)90 millimeters of mercury (mm Hg) or more than (>) 160 mm Hg; supine diastolic blood pressure (DBP) <50 mm Hg or >100 mm Hg; supine pulse rate of <60 beats per minute (bpm) or >100 bpm; maximum changes (increase or decrease) from baseline in supine SBP of >=20 mm Hg; maximum increase from baseline in supine DBP of >=20 mm Hg; and maximum decrease from baseline in supine DBP of >=10 mm Hg.
10. Overall Number of Participants With Positive Responses to Questions on the Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline up to Day 240 ]
    C-SSRS assessed whether participant responded "yes" to the following: completed suicide, suicide attempt, preparatory acts toward imminent suicidal behavior, suicidal ideation, self-injurious behavior with no suicidal intent.
11. Number of Participants With Significant Changes From Baseline in Physical Examination at Final Visit [ Time Frame: Baseline up to Final Visit (Day 240) ]
    A complete physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, skeletal, and neurological systems.
12. Number of Participants With Significant Changes in Neurological Examination Results [ Time Frame: Baseline up till Day 240 ]
    A complete/full neurological examination included assessment of the cranial nerves; muscle strength, tone, cortical drift, abnormal movements; deep tendon reflexes; sensory exam, coordination, gait and station.
13. Number of Participants With Anti-PF-04360365 Antibodies [ Time Frame: Day 1 up to Day 240 ]
    Blood samples were collected from participants who received active treatment to assess for presence/absence of anti-PF-04360365 antibodies.

Eligibility Criteria

• Ages Eligible for Study: 55 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patients diagnosed with probable CAA using the Boston criteria; with no clinical cognitive impairment
• In general good health

Exclusion Criteria:

• Co-morbid diagnosis of clinically documented Alzheimer's disease or significant cognitive impairment
• Clinically significant syncope, epilepsy, head trauma or clinically significant unexplained loss of consciousness within the last 5 years
• Subject's body weight exceeding 100kg
• Women of childbearing potential.

Contacts and Locations

Locations

United States, California

UCLA Ronald Reagan Medical Center

Los Angeles, California, United States, 90095

United States, Massachusetts

MGH Stroke Research Center

Boston, Massachusetts, United States, 02114

Boston Medical Center - Menino Pavilion

Boston, Massachusetts, United States, 02118

Boston Medical Center - Shapiro Center

Boston, Massachusetts, United States, 02118

Anthinoula A. Martinos Center for Biomedical Imaging

Charlestown, Massachusetts, United States, 02129

United States, Missouri

Barnes Jewish Hospital

St. Louis, Missouri, United States, 63110

United States, New York

Columbia University

New York, New York, United States, 10032

Canada, Alberta

University of Calgary/Foothills Medical Centre

Calgary, Alberta, Canada, T2N 2T9

Canada, Ontario

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada, M4N 3M5

France

CHRU de Lille - Hôpital Roger Salengro

Lille Cedex, NAP, France, 59037

CHRU de Lille

Lille Cedex, NAP, France, 59037

Netherlands

University Medical Center Utrecht

Utrecht, Netherlands, 3584 CX

United Kingdom

University College of London

London, United Kingdom, WC1N 3BG

Sponsors and Collaborators

Pfizer

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. 

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01821118
• Other Study ID Numbers: A9951024; 2013-001557-27 ( EudraCT Number )
• First Posted: March 29, 2013
• Results First Posted: November 3, 2016
• Last Update Posted: May 10, 2017
• Last Verified: April 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pfizer:

Cerebral amyloid angiopathy (CAA); cerebrovascular reactivity; functional MRI; randomized; double blind; safety; efficacy

Additional relevant MeSH terms:

Cerebral Amyloid Angiopathy; Cerebral Amyloid Angiopathy, Familial; Amyloidosis; Proteostasis Deficiencies; Metabolic Diseases; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Cerebral Small Vessel Diseases; Amyloidosis, Familial; Metabolism, Inborn Errors; Genetic Diseases, Inborn