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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01821118

Enrollment

Registered

2013-03-29

Start date

2013-06-30

Completion date

2015-09-30

Last updated

2017-05-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cerebral Amyloid Angiopathy

Keywords

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

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.

Interventions

BIOLOGICALPonezumab

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.

OTHERplacebo

placebo (saline)- given via infusion total infusion time of 20 minutes

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

55 Years to 90 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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)	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.
Change From Baseline to Day 90 in Cerebrovascular Reactivity as Measured by the Slope (Amplitude Over Time to Peak) From Visual Task-evoked fMRI	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

Measure	Time frame	Description
Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Time to Peak From Visual Task-evoked fMRI	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.
Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Amplitude From Visual Task-evoked fMRI	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.
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	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.
Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	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.
Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	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.
Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	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.
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)	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.
Number of Participants With Laboratory Abnormalities	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).
Number of Participants With Vital Signs Values Meeting Categorical Summarization Criteria	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.
Overall Number of Participants With Positive Responses to Questions on the Columbia Suicide Severity Rating Scale (C-SSRS)	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.
Number of Participants With Significant Changes From Baseline in Physical Examination at Final Visit	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.
Number of Participants With Significant Changes in Neurological Examination Results	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.
Number of Participants With Anti-PF-04360365 Antibodies	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.

Countries

Canada, France, Netherlands, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
PF-04360365 Participants received a loading dose of PF-04360365 10 milligrams (mg)/kilograms (kg) on Day 1, followed by PF-04360365 7.5 mg/kg on Days 30 and 60. PF-04360365 was administered via intravenous (IV) infusion over a period of 10-15 minutes (min) and dosing was based on participant weight.	24
Placebo Participants received a loading dose of placebo matching PF-04360365 10 mg/kg on Day 1, followed by placebo matching PF-04360365 7.5 mg/kg on Days 30 and 60. Placebo was also administered via IV infusion over a period of 10-15 min.	12
Total	36

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	0	1

Baseline characteristics

Characteristic	PF-04360365	Placebo	Total
Age, Continuous	68.8 years STANDARD_DEVIATION 6.8	65.0 years STANDARD_DEVIATION 5.7	67.6 years STANDARD_DEVIATION 6.6
Sex: Female, Male Female	8 Participants	5 Participants	13 Participants
Sex: Female, Male Male	16 Participants	7 Participants	23 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	16 / 24	8 / 12
serious Total, serious adverse events	2 / 24	2 / 12

Outcome results

Primary

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.

Time frame: Baseline, Day 2

Population: The full analysis set (FAS) consisted of all participants who received at least 1 post-dose efficacy measurement. n=number of evaluable participants for the specified region of interest (ROI) at Day 2.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
PF-04360365	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)	Region of interest (ROI) 1 (n=20, 11)	0.954 percent/second	Standard Error 0.085
PF-04360365	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)	ROI2 (n=23, 11)	0.933 percent/second	Standard Error 0.05
Placebo	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)	Region of interest (ROI) 1 (n=20, 11)	0.969 percent/second	Standard Error 0.073
Placebo	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)	ROI2 (n=23, 11)	0.999 percent/second	Standard Error 0.055

Comparison: ROI1: Analysis of the change from baseline in log(slope) was carried out using a Bayesian linear model (ANCOVA). Treatment was a fixed effect within the model and the log(slope) at baseline was included as a covariate.90% CI: [0.82, 1.184]

Comparison: ROI2: Analysis of the change from baseline in log(slope) was carried out using a Bayesian linear model (ANCOVA). Treatment was a fixed effect within the model and the log(slope) at baseline was included as a covariate.90% CI: [0.825, 1.056]

Primary

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.

Time frame: Baseline, Day 90

Population: The full analysis set (FAS) consisted of all participants who received at least 1 post-dose efficacy measurement. n=number of evaluable participants for the specified ROI at Day 90.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
PF-04360365	Change From Baseline to Day 90 in Cerebrovascular Reactivity as Measured by the Slope (Amplitude Over Time to Peak) From Visual Task-evoked fMRI	ROI1 (n=20, 10)	0.817 percent/second	Standard Error 0.064
PF-04360365	Change From Baseline to Day 90 in Cerebrovascular Reactivity as Measured by the Slope (Amplitude Over Time to Peak) From Visual Task-evoked fMRI	ROI2 (n=23, 10)	0.857 percent/second	Standard Error 0.055
Placebo	Change From Baseline to Day 90 in Cerebrovascular Reactivity as Measured by the Slope (Amplitude Over Time to Peak) From Visual Task-evoked fMRI	ROI1 (n=20, 10)	0.958 percent/second	Standard Error 0.063
Placebo	Change From Baseline to Day 90 in Cerebrovascular Reactivity as Measured by the Slope (Amplitude Over Time to Peak) From Visual Task-evoked fMRI	ROI2 (n=23, 10)	0.950 percent/second	Standard Error 0.06

Secondary

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.

Time frame: Baseline, 8 hours post dose on Day 1, Day 2, Day 30, 90 and 240

Population: All 36 participants who received study treatment were included in this pharmacodynamic analysis. n=number of participants with measurable AB at the specified time point.

Arm	Measure	Group	Value (MEAN)	Dispersion
PF-04360365	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-x, Day 1 (n=4, 3)	4374.0 picograms (pg)/milliliter (mL)	Standard Deviation 420.62
PF-04360365	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-x, Day 2 (n=4, 3)	13911.8 picograms (pg)/milliliter (mL)	Standard Deviation 3292.88
PF-04360365	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-x, Day 30 (n=4, 3)	94468.5 picograms (pg)/milliliter (mL)	Standard Deviation 11946.21
PF-04360365	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-x, Day 90 (n=4, 2)	111312.8 picograms (pg)/milliliter (mL)	Standard Deviation 24677.74
PF-04360365	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-x, Day 240 (n=4, 3)	30495.8 picograms (pg)/milliliter (mL)	Standard Deviation 10931.16
PF-04360365	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-40, Day 1 (n=23, 11)	4747.6 picograms (pg)/milliliter (mL)	Standard Deviation 1039.96
PF-04360365	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-40, Day 2 (n=23, 11)	12845.2 picograms (pg)/milliliter (mL)	Standard Deviation 2887.91
PF-04360365	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-40, Day 30 (n=23, 10)	68010.1 picograms (pg)/milliliter (mL)	Standard Deviation 17396.04
PF-04360365	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-40, Day 90 (n=23, 10)	87710.8 picograms (pg)/milliliter (mL)	Standard Deviation 18699.28
PF-04360365	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-40, Day 240 (n=23, 9)	20665.6 picograms (pg)/milliliter (mL)	Standard Deviation 7132.91
Placebo	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-40, Day 30 (n=23, 10)	-5.0 picograms (pg)/milliliter (mL)	Standard Deviation 46.81
Placebo	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-x, Day 1 (n=4, 3)	5.3 picograms (pg)/milliliter (mL)	Standard Deviation 26.01
Placebo	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-40, Day 1 (n=23, 11)	-8.4 picograms (pg)/milliliter (mL)	Standard Deviation 30.08
Placebo	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-x, Day 2 (n=4, 3)	-37.7 picograms (pg)/milliliter (mL)	Standard Deviation 29.02
Placebo	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-40, Day 240 (n=23, 9)	-6.2 picograms (pg)/milliliter (mL)	Standard Deviation 35.63
Placebo	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-x, Day 30 (n=4, 3)	-48.3 picograms (pg)/milliliter (mL)	Standard Deviation 103.32
Placebo	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-40, Day 2 (n=23, 11)	0.5 picograms (pg)/milliliter (mL)	Standard Deviation 30.9
Placebo	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-x, Day 90 (n=4, 2)	-62.0 picograms (pg)/milliliter (mL)	Standard Deviation 141.42
Placebo	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-40, Day 90 (n=23, 10)	0.7 picograms (pg)/milliliter (mL)	Standard Deviation 44.02
Placebo	Change From Baseline in Concentration of Total Plasma Amyloid Beta (AB)	AB1-x, Day 240 (n=4, 3)	13.0 picograms (pg)/milliliter (mL)	Standard Deviation 116.76

Secondary

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

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
PF-04360365	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Amplitude From Visual Task-evoked fMRI	ROI1, Day 2 (n=20, 11)	-0.0381 percent	90% Confidence Interval 0.028
PF-04360365	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Amplitude From Visual Task-evoked fMRI	ROI1, Day 90 (n=20, 10)	-0.1389 percent	90% Confidence Interval 0.02
PF-04360365	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Amplitude From Visual Task-evoked fMRI	ROI2, Day 2 (n=23, 11)	-0.0714 percent	90% Confidence Interval 0.018
PF-04360365	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Amplitude From Visual Task-evoked fMRI	ROI2, Day 90 (n=23, 10)	-0.1245 percent	90% Confidence Interval 0.018
Placebo	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Amplitude From Visual Task-evoked fMRI	ROI2, Day 90 (n=23, 10)	-0.0357 percent	90% Confidence Interval 0.026
Placebo	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Amplitude From Visual Task-evoked fMRI	ROI1, Day 2 (n=20, 11)	-0.0983 percent	90% Confidence Interval 0.037
Placebo	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Amplitude From Visual Task-evoked fMRI	ROI2, Day 2 (n=23, 11)	-0.0226 percent	90% Confidence Interval 0.026
Placebo	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Amplitude From Visual Task-evoked fMRI	ROI1, Day 90 (n=20, 10)	-0.053 percent	90% Confidence Interval 0.03

Comparison: ROI1, Day 2: Analysis of the change from baseline in log(amplitude) was carried out using a linear model (ANCOVA). Treatment was a fixed effect within the model and the log(amplitude) at baseline was included as a covariate.90% CI: [-0.1576, 0.2781]

Comparison: ROI1, Day 90: Analysis of the change from baseline in log(amplitude) was carried out using a linear model (ANCOVA). Treatment was a fixed effect within the model and the log(amplitude) at baseline was included as a covariate.90% CI: [-0.2843, 0.1124]

Comparison: ROI2, Day 2: Analysis of the change from baseline in log(amplitude) was carried out using a linear model (ANCOVA). Treatment was a fixed effect within the model and the log(amplitude) at baseline was included as a covariate.90% CI: [-0.2018, 0.1042]

Comparison: ROI2, Day 90: Analysis of the change from baseline in log(amplitude) was carried out using a linear model (ANCOVA). Treatment was a fixed effect within the model and the log(amplitude) at baseline was included as a covariate.90% CI: [-0.2689, 0.0914]

Secondary

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

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
PF-04360365	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Time to Peak From Visual Task-evoked fMRI	ROI1, Day 2 (n=20, 11)	1.012 seconds	Standard Error 0.028
PF-04360365	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Time to Peak From Visual Task-evoked fMRI	ROI1, Day 90 (n=20, 10)	1.065 seconds	Standard Error 0.02
PF-04360365	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Time to Peak From Visual Task-evoked fMRI	ROI2, Day 2 (n=23, 11)	1.008 seconds	Standard Error 0.018
PF-04360365	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Time to Peak From Visual Task-evoked fMRI	ROI2, Day 90 (n=23, 10)	1.039 seconds	Standard Error 0.018
Placebo	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Time to Peak From Visual Task-evoked fMRI	ROI2, Day 90 (n=23, 10)	1.028 seconds	Standard Error 0.026
Placebo	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Time to Peak From Visual Task-evoked fMRI	ROI1, Day 2 (n=20, 11)	1.007 seconds	Standard Error 0.037
Placebo	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Time to Peak From Visual Task-evoked fMRI	ROI2, Day 2 (n=23, 11)	1.010 seconds	Standard Error 0.026
Placebo	Change From Baseline to Day 2 and Day 90 in Cerebrovascular Reactivity as Measured by the Time to Peak From Visual Task-evoked fMRI	ROI1, Day 90 (n=20, 10)	1.015 seconds	Standard Error 0.03

Comparison: ROI1, Day 2: Analysis of the change from baseline in log(time to peak) was carried out using a Bayesian linear model (ANCOVA). Treatment was a fixed effect within the model and the log(time to peak) at baseline was included as a covariate.90% CI: [0.933, 1.086]

Comparison: ROI1, Day 90: Analysis of the change from baseline in log(time to peak) was carried out using a Bayesian linear model (ANCOVA). Treatment was a fixed effect within the model and the log(time to peak) at baseline was included as a covariate.90% CI: [0.99, 1.114]

Comparison: ROI2, Day 2: Analysis of the change from baseline in log(time to peak) was carried out using a Bayesian linear model (ANCOVA). Treatment was a fixed effect within the model and the log(time to peak) at baseline was included as a covariate.90% CI: [0.947, 1.052]

Comparison: ROI2, Day 90: Analysis of the change from baseline in log(time to peak) was carried out using a Bayesian linear model (ANCOVA). Treatment was a fixed effect within the model and the log(time to peak) at baseline was included as a covariate.90% CI: [0.96, 1.063]

Secondary

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

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
PF-04360365	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	ROI1, Day 2 (n=20, 11)	0.0245 seconds	90% Confidence Interval 0.028
PF-04360365	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	ROI1, Day 90 (n=20, 10)	0.0558 seconds	90% Confidence Interval 0.02
PF-04360365	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	ROI2, Day 2 (n=23, 11)	0.0045 seconds	90% Confidence Interval 0.018
PF-04360365	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	ROI2, Day 90 (n=23, 10)	0.0275 seconds	90% Confidence Interval 0.018
Placebo	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	ROI2, Day 90 (n=23, 10)	0.0158 seconds	90% Confidence Interval 0.026
Placebo	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	ROI1, Day 2 (n=20, 11)	-0.022 seconds	90% Confidence Interval 0.037
Placebo	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	ROI2, Day 2 (n=23, 11)	-0.0174 seconds	90% Confidence Interval 0.026
Placebo	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	ROI1, Day 90 (n=20, 10)	-0.0179 seconds	90% Confidence Interval 0.03

Comparison: ROI1, Day 2: Analysis of the change from baseline in log(time to return to baseline) was carried out using a linear model (ANCOVA). Treatment was a fixed effect within the model and the log(time to return to baseline) at baseline was included as a covariate.90% CI: [-0.0207, 0.1136]

Comparison: ROI1, Day 90: Analysis of the change from baseline in log(time to return to baseline) was carried out using a linear model (ANCOVA). Treatment was a fixed effect within the model and the log(time to return to baseline) at baseline was included as a covariate.90% CI: [0.0084, 0.139]

Comparison: ROI2, Day 2: Analysis of the change from baseline in log(time to return to baseline) was carried out using a linear model (ANCOVA). Treatment was a fixed effect within the model and the log(time to return to baseline) at baseline was included as a covariate.90% CI: [-0.0352, 0.079]

Comparison: ROI2, Day 90: Analysis of the change from baseline in log(time to return to baseline) was carried out using a linear model (ANCOVA). Treatment was a fixed effect within the model and the log(time to return to baseline) at baseline was included as a covariate.90% CI: [-0.046, 0.0694]

Secondary

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.

Time frame: Screening; Days 0, 1, 30, 60, 90, and 240

Population: All 36 participants who received study treatment were included in the analysis. On Day 240, the number of evaluable participants in the placebo group was 11 instead of 12.

Arm	Measure	Group	Value (MEAN)	Dispersion
PF-04360365	Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	Day 1	25.1 units on a scale	Standard Deviation 3.1
PF-04360365	Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	Day 60	26.6 units on a scale	Standard Deviation 3.12
PF-04360365	Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	Day 0	25.5 units on a scale	Standard Deviation 3.41
PF-04360365	Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	Day 90	26.0 units on a scale	Standard Deviation 3.46
PF-04360365	Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	Day 30	27.0 units on a scale	Standard Deviation 2.46
PF-04360365	Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	Day 240	26.1 units on a scale	Standard Deviation 3.43
PF-04360365	Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	Screening	25.4 units on a scale	Standard Deviation 4.24
Placebo	Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	Day 240	26.5 units on a scale	Standard Deviation 2.73
Placebo	Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	Screening	25.9 units on a scale	Standard Deviation 1.73
Placebo	Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	Day 0	25.9 units on a scale	Standard Deviation 3.34
Placebo	Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	Day 1	25.8 units on a scale	Standard Deviation 2.73
Placebo	Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	Day 30	26.8 units on a scale	Standard Deviation 2.53
Placebo	Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	Day 60	26.8 units on a scale	Standard Deviation 3.33
Placebo	Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time	Day 90	26.7 units on a scale	Standard Deviation 3.14

Secondary

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.

Time frame: Baseline up to Day 240

Population: All 36 participants who received study drug were included in the AE summarization/analysis.

Arm	Measure	Group	Value (NUMBER)
PF-04360365	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)	Discontinued due to all causality TEAEs	0 participants
PF-04360365	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)	All causality TEAEs	16 participants
PF-04360365	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)	Treatment-related TEAEs	2 participants
PF-04360365	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)	All causality SAEs	2 participants
PF-04360365	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)	Treatment-related SAEs	0 participants
PF-04360365	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)	All causality severe TEAEs	2 participants
PF-04360365	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)	Treatment-related severe TEAEs	0 participants
Placebo	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)	Discontinued due to all causality TEAEs	0 participants
Placebo	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)	Treatment-related SAEs	1 participants
Placebo	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)	All causality TEAEs	8 participants
Placebo	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)	Treatment-related severe TEAEs	1 participants
Placebo	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)	Treatment-related TEAEs	2 participants
Placebo	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)	All causality severe TEAEs	2 participants
Placebo	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)	All causality SAEs	2 participants

Secondary

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.

Time frame: Day 1 up to Day 240

Population: All 24 participants who received PF-04360365 were included in this analysis.

Arm	Measure	Value (NUMBER)
PF-04360365	Number of Participants With Anti-PF-04360365 Antibodies	0 participants

Secondary

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.

Time frame: Baseline/Screening, Day 15, Day 45, Day 90,

Population: All 36 participants who received study treatment were analyzed for this endpoint.

Arm	Measure	Group	Value (NUMBER)
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cerebral edema, Screening	0 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cortical infarcts, Day 45	0 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cerebral edema, Day 90	1 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cortical infarcts, Day 90	0 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cortical infarcts, Day 15	0 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	White matter infarcts, Screening	3 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Total infarcts, Day 15	5 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cerebral edema, Day 15	0 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	White matter infarcts, Day 45	3 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Total infarcts, Day 45	5 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	White matter infarcts, Day 90	3 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	White matter infarcts, Day 15	3 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Subcortical gray matter infarcts, Screening	3 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Total infarcts, Day 90	5 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Subcortical gray matter infarcts, Day 15	3 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cerebral edema, Day 45	0 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Subcortical gray matter infarcts, Day 45	3 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cortical infarcts, Screening	0 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Subcortical gray matter infarcts, Day 90	3 participants
PF-04360365	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Total infarcts, Screening	5 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Subcortical gray matter infarcts, Day 90	1 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Total infarcts, Screening	3 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cortical infarcts, Screening	0 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cerebral edema, Screening	1 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cerebral edema, Day 15	1 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cerebral edema, Day 45	1 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cerebral edema, Day 90	1 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Total infarcts, Day 15	3 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Total infarcts, Day 45	3 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Total infarcts, Day 90	3 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cortical infarcts, Day 15	0 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cortical infarcts, Day 45	0 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Cortical infarcts, Day 90	0 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	White matter infarcts, Screening	2 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	White matter infarcts, Day 15	2 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	White matter infarcts, Day 45	2 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	White matter infarcts, Day 90	2 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Subcortical gray matter infarcts, Screening	1 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Subcortical gray matter infarcts, Day 15	1 participants
Placebo	Number of Participants With Brain Structural Magnetic Resonance Imaging (sMRI) Abnormalities	Subcortical gray matter infarcts, Day 45	1 participants

Secondary

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).

Time frame: Baseline up to Day 240