Study Evaluating the Safety,Tolerability and Efficacy of PF-04360365 in Adults With Probable Cerebral Amyloid Angiopathy
Primary Purpose
Cerebral Amyloid Angiopathy
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Ponezumab
placebo
Sponsored by
About this trial
This is an interventional treatment trial for Cerebral Amyloid Angiopathy focused on measuring Cerebral amyloid angiopathy (CAA), cerebrovascular reactivity, functional MRI, randomized, double blind, safety, efficacy
Eligibility 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.
Sites / Locations
- UCLA Ronald Reagan Medical Center
- MGH Stroke Research Center
- Boston Medical Center - Menino Pavilion
- Boston Medical Center - Shapiro Center
- Anthinoula A. Martinos Center for Biomedical Imaging
- Barnes Jewish Hospital
- Columbia University
- University of Calgary/Foothills Medical Centre
- Sunnybrook Health Sciences Centre
- CHRU de Lille - Hôpital Roger Salengro
- CHRU de Lille
- University Medical Center Utrecht
- University College of London
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
1
2
Arm Description
Outcomes
Primary Outcome Measures
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)
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.
Change From Baseline to Day 90 in Cerebrovascular Reactivity as Measured by the Slope (Amplitude Over Time to Peak) From Visual Task-evoked fMRI
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
Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Time to Peak From Visual Task-evoked fMRI
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.
Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Amplitude From Visual Task-evoked fMRI
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.
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
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.
Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)
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.
Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities
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.
Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time
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.
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)
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.
Number of Participants With Laboratory Abnormalities
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).
Number of Participants With Vital Signs Values Meeting Categorical Summarization Criteria
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.
Overall Number of Participants With Positive Responses to Questions on the Columbia Suicide Severity Rating Scale (C-SSRS)
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.
Number of Participants With Significant Changes From Baseline in Physical Examination at Final Visit
A complete physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, skeletal, and neurological systems.
Number of Participants With Significant Changes in Neurological Examination Results
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.
Number of Participants With Anti-PF-04360365 Antibodies
Blood samples were collected from participants who received active treatment to assess for presence/absence of anti-PF-04360365 antibodies.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01821118
Brief Title
Study Evaluating the Safety,Tolerability and Efficacy of PF-04360365 in Adults With Probable Cerebral Amyloid Angiopathy
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 Type
Interventional
2. Study Status
Record Verification Date
April 2017
Overall Recruitment Status
Completed
Study Start Date
June 2013 (undefined)
Primary Completion Date
September 2015 (Actual)
Study Completion Date
September 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Pfizer
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cerebral Amyloid Angiopathy
Keywords
Cerebral amyloid angiopathy (CAA), cerebrovascular reactivity, functional MRI, randomized, double blind, safety, efficacy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
36 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1
Arm Type
Experimental
Arm Title
2
Arm Type
Placebo Comparator
Intervention Type
Biological
Intervention Name(s)
Ponezumab
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
placebo
Intervention Description
placebo (saline)- given via infusion total infusion time of 20 minutes
Primary Outcome Measure Information:
Title
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)
Description
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.
Time Frame
Baseline, Day 2
Title
Change From Baseline to Day 90 in Cerebrovascular Reactivity as Measured by the Slope (Amplitude Over Time to Peak) From Visual Task-evoked fMRI
Description
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.
Time Frame
Baseline, Day 90
Secondary Outcome Measure Information:
Title
Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Time to Peak From Visual Task-evoked fMRI
Description
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.
Time Frame
Baseline, Day 2, Day 90
Title
Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Amplitude From Visual Task-evoked fMRI
Description
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.
Time Frame
Baseline, Day 2, Day 90
Title
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
Description
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.
Time Frame
Baseline, Day 2, Day 90
Title
Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)
Description
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.
Time Frame
Baseline, 8 hours post dose on Day 1, Day 2, Day 30, 90 and 240
Title
Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities
Description
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.
Time Frame
Baseline/Screening, Day 15, Day 45, Day 90,
Title
Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time
Description
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.
Time Frame
Screening; Days 0, 1, 30, 60, 90, and 240
Title
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)
Description
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.
Time Frame
Baseline up to Day 240
Title
Number of Participants With Laboratory Abnormalities
Description
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).
Time Frame
Baseline up to Day 240
Title
Number of Participants With Vital Signs Values Meeting Categorical Summarization Criteria
Description
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.
Time Frame
Baseline up to Day 240
Title
Overall Number of Participants With Positive Responses to Questions on the Columbia Suicide Severity Rating Scale (C-SSRS)
Description
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.
Time Frame
Baseline up to Day 240
Title
Number of Participants With Significant Changes From Baseline in Physical Examination at Final Visit
Description
A complete physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, skeletal, and neurological systems.
Time Frame
Baseline up to Final Visit (Day 240)
Title
Number of Participants With Significant Changes in Neurological Examination Results
Description
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.
Time Frame
Baseline up till Day 240
Title
Number of Participants With Anti-PF-04360365 Antibodies
Description
Blood samples were collected from participants who received active treatment to assess for presence/absence of anti-PF-04360365 antibodies.
Time Frame
Day 1 up to Day 240
10. Eligibility
Sex
All
Minimum Age & Unit of Time
55 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pfizer CT.gov Call Center
Organizational Affiliation
Pfizer
Official's Role
Study Director
Facility Information:
Facility Name
UCLA Ronald Reagan Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
MGH Stroke Research Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Boston Medical Center - Menino Pavilion
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118
Country
United States
Facility Name
Boston Medical Center - Shapiro Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118
Country
United States
Facility Name
Anthinoula A. Martinos Center for Biomedical Imaging
City
Charlestown
State/Province
Massachusetts
ZIP/Postal Code
02129
Country
United States
Facility Name
Barnes Jewish Hospital
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Columbia University
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
University of Calgary/Foothills Medical Centre
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T2N 2T9
Country
Canada
Facility Name
Sunnybrook Health Sciences Centre
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M4N 3M5
Country
Canada
Facility Name
CHRU de Lille - Hôpital Roger Salengro
City
Lille Cedex
State/Province
NAP
ZIP/Postal Code
59037
Country
France
Facility Name
CHRU de Lille
City
Lille Cedex
State/Province
NAP
ZIP/Postal Code
59037
Country
France
Facility Name
University Medical Center Utrecht
City
Utrecht
ZIP/Postal Code
3584 CX
Country
Netherlands
Facility Name
University College of London
City
London
ZIP/Postal Code
WC1N 3BG
Country
United Kingdom
12. IPD Sharing Statement
Links:
URL
https://trialinfoemail.pfizer.com/pages/landing.aspx?StudyID=A9951024&StudyName=Study%20Evaluating%20the%20Safety%2CTolerability%20and%20Efficacy%20of%20PF-04360365%20in%20Adults%20with%20Probable%20Cerebral%20Amyloid%20Angiopathy%20
Description
To obtain contact information for a study center near you, click here.
Learn more about this trial
Study Evaluating the Safety,Tolerability and Efficacy of PF-04360365 in Adults With Probable Cerebral Amyloid Angiopathy
We'll reach out to this number within 24 hrs