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

Alzheimer's Disease Clinical Trial

Official title:

A PHASE 2 DOUBLE-BLINDED, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY EVALUATING THE SAFETY, TOLERABILITY AND PHARMACOKINETICS/ PHARMACODYNAMICS OF PF-04360365 IN MILD TO MODERATE ALZHEIMER'S DISEASE PATIENTS

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00945672
• Other study ID #: A9951007
• Secondary ID: 2009-011172-30PI
• Status: Completed
• Phase: Phase 2
• Start date: August 6, 2009
• Est. completion date: June 1, 2011

Study information

• Verified date: November 2023
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: June 1, 2011
• Est. primary completion date: June 1, 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease

Intervention

Biological:
• PF-04360365 10 mg/kg
10 mg/kg every 90 days (5 total doses)
• PF-04360365 7.5 mg/kg
10 mg/kg loading dose followed by 7.5 mg/kg monthly maintenance dosing (total of 13 doses)

Drug:
• placebo
placebo administered every 90 days or monthly to match experimental treatment arms.

Locations

Country	Name	City	State
Sweden	Sahlgrenska Sjukhuset, CTC	Göteborg
Sweden	Malmo Sjukhus, Neuropsykiatriska Kliniken	Malmo
Sweden	Sahlgrenska Universitetssjukhuset, Minnesmottagningen	Molndal
Sweden	Karolinska Universitetssjukhuset Huddinge	Stockholm

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Country where clinical trial is conducted

Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Mean Cerebrospinal Fluid (CSF) Concentration of Total Tau and Phospho-tau (P-tau) Proteins		Cohort M&Q: Pre dose (0 hr) on Day 0, 0 hr post dose on Day 180, 360; Cohort Q: 936, 1176 hrs post dose on Day 1(Day 40,50), 0 hr post dose on Day 60, 90; Cohort M: 216, 456 hrs post dose on Day 1(Day 10, 20), 0 hr post dose on Day 30
Other	Change From Baseline in Cerebrospinal Fluid (CSF) Protein Concentration at Day 10, 20, 30, 40, 50, 60, 90, 180 and 360		Cohort M&Q: Baseline, 0 hr post dose on Day 180, 360; Cohort Q: 936, 1176 hrs post dose on Day 1(Day 40,50), 0 hr post dose on Day 60, 90; Cohort M: 216, 456 hrs post dose on Day 1(Day 10, 20), 0 hr post dose on Day 30
Other	Change From Baseline in Red Blood Cells (RBCs) and White Blood Cells (WBCs) Concentration in Cerebrospinal Fluid (CSF) at Day 10, 20, 30, 40, 50, 60, 90, 180, 360		Cohort M&Q: Baseline, 0 hr post dose on Day 180, 360; Cohort Q: 936, 1176 hrs post dose on Day 1(Day 40,50), 0 hr post dose on Day 60, 90; Cohort M: 216, 456 hrs post dose on Day 1(Day 10, 20), 0 hr post dose on Day 30
Other	Change From Baseline in Glucose Concentration in Cerebrospinal Fluid (CSF) at Day 10, 20, 30, 40, 50, 60, 90, 180, 360		Cohort M&Q: Baseline, 0 hr post dose on Day 180, 360; Cohort Q: 936, 1176 hrs post dose on Day 1(Day 40,50), 0 hr post dose on Day 60, 90; Cohort M: 216, 456 hrs post dose on Day 1(Day 10, 20), 0 hr post dose on Day 30
Other	Number of Participants With Measurable Serum Anti-Drug Antibody (ADA) Concentration	A measurable ADA is defined as a serum anti-drug anti body response (total binding assay) greater than the lower limit of quantification (4.32).	Day 1 up to Month 18
Primary	Number of Participants With Treatment-emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)	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.	Day 1 up to 6 months after last dose of study medication (up to 18 months)
Primary	Number of Participants With Change From Baseline in Brain Magnetic Resonance Imaging (MRI) Abnormalities	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.	Baseline up to Month 18
Primary	Number of Participants With Gadolinium Use in Brain Magnetic Resonance Imaging (MRI)	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.	Baseline up to Month 18
Primary	Change From Baseline in Amyloid Load at Month 13 Using Positron Emission Tomography (PET) Technique: Cohort M	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.	Baseline, Month 13
Primary	Mean Cerebrospinal Fluid (CSF) Concentration of PF-04360365 at 0 Hour on Day 0	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour on Day 0 (Day prior to dosing)
Primary	Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 1	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 1
Primary	Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 1	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0.25 hours post-infusion start on Day 1
Primary	Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 on Day 10: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	216 hours post dose on Day 1 (samples taken on Day 10)
Primary	Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 on Day 20: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	456 hours post dose on Day 1 (samples taken on Day 20)
Primary	Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 at 0 Hour on Day 30: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 30
Primary	Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 30: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0.25 hours post-infusion start on Day 30
Primary	Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 on Day 40: Cohort Q	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	936 hours post dose on Day 1 (samples taken on Day 40)
Primary	Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 on Day 50: Cohort Q	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	1176 hours post dose on Day 1 (samples taken on Day 50)
Primary	Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 on Day 60: Cohort Q	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	1416 hours post-dose on Day 1 (samples taken on Day 60)
Primary	Mean Plasma Concentration of PF-04360365 at 0 Hours on Day 60: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 60
Primary	Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 60: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0.25 hours post-infusion start on Day 60
Primary	Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 at 0 Hour on Day 90	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 90
Primary	Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 90	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0.25 hours post-infusion start on Day 90
Primary	Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 120: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 120
Primary	Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 120: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0.25 hours post-infusion start on Day 120
Primary	Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 150: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 150
Primary	Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 150: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0.25 hours post-infusion start on Day 150
Primary	Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 at 0 Hour on Day 180	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 180
Primary	Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 180	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0.25 hours post-infusion start on Day 180
Primary	Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 210: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 210
Primary	Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 210: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0.25 hours post-infusion start on Day 210
Primary	Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 240: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 240
Primary	Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 240: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0.25 hours post-infusion start on Day 240
Primary	Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 270	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 270
Primary	Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 270	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0.25 hours post-infusion start on Day 270
Primary	Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 300: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 300
Primary	Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 300: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0.25 hours post-infusion start on Day 300
Primary	Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 330: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 330
Primary	Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 330: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0.25 hours post-infusion start on Day 330
Primary	Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 at 0 Hour on Day 360	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 360
Primary	Mean Plasma Concentration of PF-04360365 at 0.25 Hours on Day 360	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0.25 hours post-infusion start on Day 360
Primary	Mean Plasma Concentration of PF-04360365 at 720 Hours Post-dose on Day 360: Cohort Q	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	720 hours post-dose on Day 360 (samples taken on Day 390)
Primary	Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 390: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 390
Primary	Mean Plasma Concentration of PF-04360365 at 0 Hours on Day 540: Cohort Q	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hours (pre-dose) on Day 540
Primary	Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 540: Cohort M	Samples for PF-04360365 concentration were assayed using a validated, sensitive and specific enzyme-linked immunosorbent assay method.	0 hour (pre-dose) on Day 540
Primary	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	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).	0 hour on Day 0 (Day prior to dosing)
Primary	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
Primary	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
Primary	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
Primary	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)
Primary	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)
Primary	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)
Primary	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
Primary	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
Primary	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	Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) Total Score at Months 3, 6, 9, 13 and 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.	Baseline, Month 3, 6, 9, 13, 18
Secondary	Change From Baseline in Disability Assessment for Dementia (DAD) Total Score at Month 6, 13 and 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.	Baseline, Month 6, 13, 18
Secondary	Change From Baseline in Mini-Mental State Examination (MMSE) Total Score at 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.	Baseline, Month 13
Secondary	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
Secondary	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
Secondary	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

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