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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01821118
First received: March 4, 2013
Last updated: September 14, 2016
Last verified: September 2016
  Purpose
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 Intervention Phase
Cerebral Amyloid Angiopathy
Biological: Ponezumab
Other: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, 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

Resource links provided by NLM:


Further study details as provided by Pfizer:

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) [ Time Frame: Baseline, Day 2 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Day 90 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Day 2, Day 90 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Day 2, Day 90 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Day 2, Day 90 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Day 1 (pre dose and 8 hours post dose), Day 2, Day 30, Day 90, Day 240 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline/Screening, Day 15, Day 45, Day 90, ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Screening; Days 0, 1, 30, 60, 90, and 240 ] [ Designated as safety issue: Yes ]
    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. A score of more than or equal to (>=) 26 to 30 (maximum possible point) is considered as normal. An average of 22 points is considered as mild cognitive impairment. Lower scores indicate decreasing cognitive function.

  • 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 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline up to Day 240 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline up to Day 240 ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: Baseline up to Day 240 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline up to Final Visit (Day 240) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline up till Day 240 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Day 1 up to Day 240 ] [ Designated as safety issue: Yes ]
    Blood samples were collected from participants who received active treatment to assess for presence/absence of anti-PF-04360365 antibodies.


Enrollment: 36
Study Start Date: June 2013
Study Completion Date: September 2015
Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   55 Years to 90 Years   (Adult, Senior)
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01821118

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:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01821118     History of Changes
Other Study ID Numbers: A9951024  2013-001557-27 
Study First Received: March 4, 2013
Results First Received: September 14, 2016
Last Updated: September 14, 2016
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on December 08, 2016