A Multiple Dose Study of PF-04360365 In Patients With Mild to Moderate Alzheimer's Disease

Phase 2

Completed

Conditions: Alzheimer's Disease

Interventions: Biological: PF-04360365 10 mg/kg
Biological: PF-04360365 7.5 mg/kg
Drug: placebo

Registration Number: NCT00945672

Lead Sponsor: Pfizer

Brief Summary: The purpose of this study is to determine whether multiple dose administration is safe and well tolerated in patients with mild to moderate Alzheimer's Disease.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 36

Inclusion Criteria

Males or females of non childbearing potential, age > or = 50.
Diagnosis of probable Alzheimer's disease, consistent with criteria from both:
- National Institute of Neurological and Communicable Disease and Stroke and Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA).
- Diagnostic and Statistical Manual of Mental Disorders (DSM IV).
Mini-mental status exam score of 16-26 inclusive.
Rosen-Modified Hachinski Ischemia Score of < or = 4.

Exclusion Criteria

Diagnosis or history of other demential or neurodegenerative disorders.
Diagnosis or history of clinically significant cerebrovascular disease.
Specific findings on magnetic resonance imaging (MRI); cortical infarct, micro hemorrhage, multiple white matter lacunes, extensive white matter abnormalities.
History of autoimmune disorders.
History of allergic or anaphylactic reactions.

Study & Design

Study Type: INTERVENTIONAL

Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
PF-04360365 10 mg/kg	PF-04360365 10 mg/kg	-
PF-04360365 7.5 mg/kg	PF-04360365 7.5 mg/kg	-
placebo	placebo	-

Primary Outcome Measures

Name	Time	Method
Number of Participants With Change From Baseline in Brain Magnetic Resonance Imaging (MRI) Abnormalities	Baseline up to Month 18	Number of participants with new clinical findings not evident on the baseline scans, such as brain edema, hemorrhage, encephalitis and other pathology (cerebral edema, cerebral/meningeal enhancement, micro hemorrhage, parenchymal hematoma, subarachnoid hemorrhage, subdural hematoma, cortical infarcts, subcortical grey matter infarcts, white matter infarcts and white matter hyper intensities) were assessed from structural magnetic resonance imaging (MRI). Participants with brain abnormality other than those listed above assessed using MRI scan were reported under 'other' category. Only those MRI findings in which at least 1 participant had event, were reported.
Number of Participants With Gadolinium Use in Brain Magnetic Resonance Imaging (MRI)	Baseline up to Month 18	Brain MRI included gadolinium contrast if investigator determined this was necessary for participant care either based on clinical signs or the non-contrast MRI. This decision was made by the investigator on the basis of change in the clinical examination or in response to a possible abnormality seen on the non-contrast brain MRI.
Change From Baseline in Amyloid Load at Month 13 Using Positron Emission Tomography (PET) Technique: Cohort M	Baseline, Month 13	Quantitative amyloid imaging was performed using PET technique using \[11C\] Pittsburgh Compound B (PIB) for following brain areas: frontal, temporal, parietal and occipital cortices, anterior and posterior cingular cortex, cerebellum, pons, and subcortical white matter. For target regions of interest, beta-amyloid plaque imaging radiotracer (PIB) retention data was expressed as standard uptake value ratio (SUVR) which was defined as a ratio of radioactivity uptake of the target region relative to the cerebellum reference region. This outcome measure was planned to be analyzed only for cohort M.
Mean Cerebrospinal Fluid (CSF) Concentration of PF-04360365 at 0 Hour on Day 0	0 hour on Day 0 (Day prior to dosing)	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Number of Participants With Treatment-emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)	Day 1 up to 6 months after last dose of study medication (up to 18 months)	An AE was any untoward medical occurrence in a participant who received study medication without regard to possibility of causal relationship. SAE: an AE resulting in any of 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 are events between first dose of study medication and up to 6 months after last dose (up to 18 months) that were absent before treatment or worsened relative to pre-treatment state. AEs included both serious and non-serious adverse events.
Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 on Day 10: Cohort M	216 hours post dose on Day 1 (samples taken on Day 10)	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 1	0 hour (pre-dose) on Day 1	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 1	0.25 hours post-infusion start on Day 1	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 on Day 20: Cohort M	456 hours post dose on Day 1 (samples taken on Day 20)	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 at 0 Hour on Day 30: Cohort M	0 hour (pre-dose) on Day 30	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 30: Cohort M	0.25 hours post-infusion start on Day 30	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 on Day 40: Cohort Q	936 hours post dose on Day 1 (samples taken on Day 40)	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 on Day 50: Cohort Q	1176 hours post dose on Day 1 (samples taken on Day 50)	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 on Day 60: Cohort Q	1416 hours post-dose on Day 1 (samples taken on Day 60)	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0 Hours on Day 60: Cohort M	0 hour (pre-dose) on Day 60	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 60: Cohort M	0.25 hours post-infusion start on Day 60	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 at 0 Hour on Day 90	0 hour (pre-dose) on Day 90	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 90	0.25 hours post-infusion start on Day 90	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 120: Cohort M	0 hour (pre-dose) on Day 120	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 120: Cohort M	0.25 hours post-infusion start on Day 120	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 150: Cohort M	0 hour (pre-dose) on Day 150	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 150: Cohort M	0.25 hours post-infusion start on Day 150	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 at 0 Hour on Day 180	0 hour (pre-dose) on Day 180	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 180	0.25 hours post-infusion start on Day 180	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 210: Cohort M	0 hour (pre-dose) on Day 210	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 210: Cohort M	0.25 hours post-infusion start on Day 210	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 240: Cohort M	0 hour (pre-dose) on Day 240	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 240: Cohort M	0.25 hours post-infusion start on Day 240	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 270	0 hour (pre-dose) on Day 270	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 270	0.25 hours post-infusion start on Day 270	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 300: Cohort M	0 hour (pre-dose) on Day 300	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 300: Cohort M	0.25 hours post-infusion start on Day 300	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 330: Cohort M	0 hour (pre-dose) on Day 330	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 330: Cohort M	0.25 hours post-infusion start on Day 330	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 at 0 Hour on Day 360	0 hour (pre-dose) on Day 360	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 360	0.25 hours post-infusion start on Day 360	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 720 Hours Post-dose on Day 360: Cohort Q	720 hours post-dose on Day 360 (samples taken on Day 390)	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 390: Cohort M	0 hour (pre-dose) on Day 390	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0 Hours on Day 540: Cohort Q	0 hours (pre-dose) on Day 540	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 540: Cohort M	0 hour (pre-dose) on Day 540	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.
Mean Cerebrospinal Fluid (CSF) Concentration of Amyloid Beta 1-x (A-beta 1-x), Amyloid Beta 1-40 (A-beta 1-40) and Amyloid Beta 1-42 (A-beta 1-42) at 0 Hour on Day 0	0 hour on Day 0 (Day prior to dosing)	A-beta is a peptide fragment of the amyloid precursor protein (found in the brain of participants suffering from of Alzheimer's disease (AD). In this outcome, CSF concentration of 3 variants of A-beta were reported: A-beta (1-X), A-beta (1-40) and A-beta (1-42).
Mean Cerebrospinal Fluid (CSF) Concentration of Amyloid Beta 1-x (A-beta 1-x), Amyloid Beta 1-40 (A-beta 1-40) and Amyloid Beta 1-42 (A-beta 1-42) at 216 Hours Post-dose on Day 1: Cohort M	216 hours post-dose on Day 1
Mean Cerebrospinal Fluid (CSF) Concentration of Amyloid Beta 1-x (A-beta 1-x), Amyloid Beta 1-40 (A-beta 1-40) and Amyloid Beta 1-42 (A-beta 1-42) at 456 Hours Post-dose on Day 1: Cohort M	456 hours post-dose on Day 1
Mean Cerebrospinal Fluid (CSF) Concentration of Amyloid Beta 1-x (A-beta 1-x), Amyloid Beta 1-40 (A-beta 1-40) and Amyloid Beta 1-42 (A-beta 1-42) at 0 Hour on Day 30: Cohort M	0 hour (pre-dose) on Day 30
Mean Cerebrospinal Fluid (CSF) Concentration of Amyloid Beta 1-x (A-beta 1-x), Amyloid Beta 1-40 (A-beta 1-40) and Amyloid Beta 1-42 (A-beta 1-42) at 936 Hours Post-dose on Day 1: Cohort Q	936 hours post-dose on Day 1 (Samples taken on Day 40)
Mean Cerebrospinal Fluid (CSF) Concentration of Amyloid Beta 1-x (A-beta 1-x), Amyloid Beta 1-40 (A-beta 1-40) and Amyloid Beta 1-42 (A-beta 1-42) at 1176 Hours Post-dose on Day 1: Cohort Q	1176 hours post-dose on Day 1 (Samples taken on Day 50)
Mean Cerebrospinal Fluid (CSF) Concentration of Amyloid Beta 1-x (A-beta 1-x), Amyloid Beta 1-40 (A-beta 1-40) and Amyloid Beta 1-42 (A-beta 1-42) at 1416 Hours Post-dose on Day 1: Cohort Q	1416 hours post-dose on Day 1 (Samples taken on Day 60)
Mean Cerebrospinal Fluid (CSF) Concentration of Amyloid Beta 1-x (A-beta 1-x), Amyloid Beta 1-40 (A-beta 1-40) and Amyloid Beta 1-42 (A-beta 1-42) at 0 Hour on Day 90: Cohort Q	0 hour (pre-dose) on Day 90
Mean Cerebrospinal Fluid (CSF) Concentration of Amyloid Beta 1-x (A-beta 1-x), Amyloid Beta 1-40 (A-beta 1-40) and Amyloid Beta 1-42 (A-beta 1-42) at 0 Hour on Day 180	0 hour (pre-dose) on Day 180
Mean Cerebrospinal Fluid (CSF) Concentration of Amyloid Beta 1-x (A-beta 1-x), Amyloid Beta 1-40 (A-beta 1-40) and Amyloid Beta 1-42 (A-beta 1-42) at 0 Hour on Day 360	0 hour (pre-dose) on Day 360

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) Total Score at Months 3, 6, 9, 13 and 18	Baseline, Month 3, 6, 9, 13, 18	ADAS-cog is a structured scale assessing the severity of cognitive impairment in Alzheimer's Disease. It comprises of following 11 items (range): word recall (0-10), naming objects and fingers (0-5), following commands (0-5), constructional praxis (0-5), ideational praxis (0-5), orientation (0-8), word recognition (0-12), recall of test instructions (0-5), spoken language ability (0-5), word-finding difficulty (0-5), comprehension of spoken language (0-5). The total score was calculated as the sum of the scores for the 11 items. ADAS-cog total score ranges from 0 (no impairment) to 70 (maximum impairment). Higher total and individual item scores indicate greater cognitive impairment.
Change From Baseline in Disability Assessment for Dementia (DAD) Total Score at Month 6, 13 and 18	Baseline, Month 6, 13, 18	DAD is a functional assessment based on interview with the caregiver of participants. It consists of 40 items, 17 related to self-care and 23 items involving instrumental activities of daily living. Each item scored as yes = 1, no = 0 and not applicable= N/A. A total score is obtained by adding the rating for each question and converting this to a total score out of 100. The items rated N/A are not considered for the total score. DAD total score range from 0 (more dysfunction) to 100 (better function), with higher scores indicating better functioning.
Change From Baseline in Mini-Mental State Examination (MMSE) Total Score at Month 13	Baseline, Month 13	Mini-Mental State Examination (MMSE) measured general cognitive functioning: orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two intersecting polygons. Total MMSE score ranged from 0 (worst cognitive state) to 30 (best cognitive state), where higher score indicates better cognitive state.
Mean Plasma Concentration of Amyloid Beta 1-x (A-beta 1-x)	Cohort M&Q: 0 hour(hr) & 0.25 hrs post dose (pd) on Day (D) 1,90,180,270,360, 0 hr pd on D 60,390; Cohort Q: 936,1176 hrs pd on D1(D 40,50); Cohort M: 216, 456 hrs pd on D1(D 10,20), 0.25 hrs pd on D 60, 0 hr & 0.25 hrs pd on D 30,120,150,210,240,300,330
Mean Plasma Concentration of Amyloid Beta 1-40 (A-beta 1-40)	Cohort M&Q: 0 hr & 0.25 hrs post dose(pd) on Day(D) 1,90,180,270,360, 0 hr pd on D 60,390,540; Cohort Q: 936, 1176 hrs pd on D1(D 40,50); Cohort M: 216, 456 hrs pd on D1(D 10,20), 0.25 hrs pd on D60, 0 hr & 0.25 hrs pd on D 30,120,150,210, 240,300,330
Mean Plasma Concentration of Amyloid Beta 1-42 (A-beta 1-42)	Cohort M&Q: 0 hr & 0.25 hrs post dose(pd) on Day(D) 1,90,180,270,360, 0 hr pd on D 60,390; Cohort Q: 936, 1176 hrs pd on D1(D 40,50); Cohort M: 216, 456 hrs pd on D1(D 10,20), 0.25 hrs pd on D60, 0 hr & 0.25 hrs pd on D 30,120,150,210, 240,300,330

Trial Locations

Locations (4): Sahlgrenska Sjukhuset, CTC
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Göteborg, Sweden
Malmo Sjukhus, Neuropsykiatriska Kliniken
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Malmo, Sweden
Sahlgrenska Universitetssjukhuset, Minnesmottagningen
🇸🇪
Molndal, Sweden
Karolinska Universitetssjukhuset Huddinge
🇸🇪
Stockholm, Sweden