Multiple IV Dose Study Of PF-04360365 In Patients With Mild To Moderate Alzheimer's Disease

Study Overview
=================
Brief Summary
-----------------
Purpose of the study is to determine whether multiple dose administration of PF-04360365 is safe and well tolerated in patient with mild to moderate Alzheimer's disease.

Official Title
-----------------
A PHASE 2 MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED STUDY OF THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF MULTIPLE DOSES OF PF 04360365 IN PATIENTS WITH MILD TO MODERATE ALZHEIMER'S DISEASE.

Conditions
-----------------
Alzheimer's Disease

Intervention / Treatment
-----------------
* Biological: PF-04360365 0.1 mg/kg
* Biological: PF-04360365 0.5 mg/kg
* Biological: PF-04360365 1 mg/kg
* Drug: Placebo
* Biological: PF-04360365 3 mg/kg
* Biological: PF-04360365 8.5 mg/kg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males or females of non childbearing potential, age > or = 50 Diagnosis of probable Alzheimer's disease, consistent with criterial 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

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-04360365 0.1 mg/kg<br> | Biological: PF-04360365 0.1 mg/kg<br>* 0.1 mg/kg every 60 days (10 doses total)<br>|
| Experimental: PF-04360365 0.5 mg/kg<br> | Biological: PF-04360365 0.5 mg/kg<br>* 0.5 mg/kg every 60 days (10 doses total)<br>|
| Experimental: PF-04360365 1 mg/kg<br> | Biological: PF-04360365 1 mg/kg<br>* 1 mg/kg every 60 days (10 doses total)<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo every 60 days (10 doses total)<br>|
| Experimental: PF-04360365 3 mg/kg<br> | Biological: PF-04360365 3 mg/kg<br>* 3 mg/kg every 60 days (10 doses total)<br>|
| Experimental: PF-04360365 8.5 mg/kg<br> | Biological: PF-04360365 8.5 mg/kg<br>* 8.5 mg/kg every 60 days (10 doses total)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 AEs are events between first dose of study medication and up to 6 months after last dose that were absent before treatment or worsened relative to pre-treatment state. | Day 1 up to 6 months after last dose of study medication, assessed up to Month 24 | 
| 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/meningeal enhancement, parenchymal hematoma, subarachnoid hemorrhage, subdural hematoma, cortical infarcts, subcortical grey matter infarcts, white matter infarcts and white matter hyperintensities) were assessed from structural MRI. Participants with brain abnormality other than those listed above, assessed using MRI scan, were reported under other abnormality. Baseline was defined as the last assessment prior to the first study drug infusion. | Baseline up to Month 24 | 
| 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 was defined as the last assessment prior to the first study drug infusion. | Baseline up to Month 24 | 
| Mean Cerebrospinal Fluid (CSF) Concentration of PF-04360365 at 0 Hour on Day 0 | Only participants received PF-04360365 were analyzed for this outcome measure. | 0 Hour on Day 0 | 
| Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 1 | Only participants received PF-04360365 were analyzed for this outcome measure. | 0 Hour (pre-dose) on Day 1 | 
| Mean Plasma Concentration of PF-04360365 at 2 Hours on Day 1 | Only participants received PF-04360365 were analyzed for this outcome measure. | 2 Hours on Day 1 | 
| Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 60 | Only participants received PF-04360365 were analyzed for this outcome measure. | 0 Hour (pre-dose) on Day 60 | 
| Mean Plasma Concentration of PF-04360365 at 2 Hours on Day 60 | Only participants received PF-04360365 were analyzed for this outcome measure. | 2 Hours on Day 60 | 
| Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 on Day 90 | Only participants received PF-04360365 were analyzed for this outcome measure. | Day 90 | 
| Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 120 | Only participants received PF-04360365 were analyzed for this outcome measure. | 0 Hour (pre-dose) on Day 120 | 
| Mean Plasma Concentration of PF-04360365 at 2 Hours on Day 120 | Only participants received PF-04360365 were analyzed for this outcome measure. | 2 Hours on Day 120 | 
| Mean Plasma Concentration of PF-04360365 on Day 150 | Only participants received PF-04360365 were analyzed for this outcome measure. | Day 150 | 
| Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 180 | Only participants received PF-04360365 were analyzed for this outcome measure. | 0 Hour (pre-dose) on Day 180 | 
| Mean Plasma Concentration of PF-04360365 at 2 Hours on Day 180 | Only participants received PF-04360365 were analyzed for this outcome measure. | 2 Hours on Day 180 | 
| Mean Plasma Concentration of PF-04360365 on Day 210 | Only participants received PF-04360365 were analyzed for this outcome measure. | Day 210 | 
| Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 240 | Only participants received PF-04360365 were analyzed for this outcome measure. | 0 Hour (pre-dose) on Day 240 | 
| Mean Plasma Concentration of PF-04360365 at 2 Hours on Day 240 | Only participants received PF-04360365 were analyzed for this outcome measure. | 2 Hours on Day 240 | 
| Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 300 | Only participants received PF-04360365 were analyzed for this outcome measure. | 0 Hour (pre-dose) on Day 300 | 
| Mean Plasma Concentration of PF-04360365 at 2 Hours on Day 300 | Only participants received PF-04360365 were analyzed for this outcome measure. | 2 Hours on Day 300 | 
| Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 360 | Only participants received PF-04360365 were analyzed for this outcome measure. | 0 Hour (pre-dose) on Day 360 | 
| Mean Plasma Concentration of PF-04360365 at 2 Hours on Day 360 | Only participants received PF-04360365 were analyzed for this outcome measure. | 2 Hours on Day 360 | 
| Mean Plasma Concentration of PF-04360365 on Day 390 | Only participants received PF-04360365 were analyzed for this outcome measure. | Day 390 | 
| Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 420 | Only participants received PF-04360365 were analyzed for this outcome measure. | 0 Hour (pre-dose) on Day 420 | 
| Mean Plasma Concentration of PF-04360365 at 2 Hours on Day 420 | Only participants received PF-04360365 were analyzed for this outcome measure. | 2 Hours on Day 420 | 
| Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 480 | Only participants received PF-04360365 were analyzed for this outcome measure. | 0 Hour (pre-dose) on Day 480 | 
| Mean Plasma Concentration of PF-04360365 at 2 Hours on Day 480 | Only participants received PF-04360365 were analyzed for this outcome measure. | 2 Hours on Day 480 | 
| Mean Plasma Concentration of PF-04360365 at 0 Hour on Day 540 | Only participants received PF-04360365 were analyzed for this outcome measure. | 0 Hour (pre-dose) on Day 540 | 
| Mean Plasma Concentration of PF-04360365 at 2 Hours on Day 540 | Only participants received PF-04360365 were analyzed for this outcome measure. | 2 Hours on Day 540 | 
| Mean Plasma and Cerebrospinal Fluid (CSF) Concentration of PF-04360365 on Day 570 | Only participants received PF-04360365 were analyzed for this outcome measure. | Day 570 | 
| Mean Plasma Concentration of PF-04360365 on Day 660 | Only participants received PF-04360365 were analyzed for this outcome measure. | Day 660 | 
| Mean Plasma Concentration of PF-04360365 on Day 720 | Only participants received PF-04360365 were analyzed for this outcome measure. | Day 720 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) Score at Baseline | ADAS-cog is a structured scale assessing the severity of cognitive impairment in Alzheimer's Disease. It comprised 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). ADAS-cog total score was calculated as the sum of scores for the 11 items and ranged from 0 to 70. Higher total and individual item scores indicate greater cognitive impairment. Baseline was defined as the last assessment prior to the first study drug infusion. | Baseline | 
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) Score at Month 19 | ADAS-cog is a structured scale assessing the severity of cognitive impairment in Alzheimer's Disease. It comprised 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). ADAS-cog total score was calculated as the sum of scores for the 11 items and ranged from 0 to 70. Higher total and individual item scores indicate greater cognitive impairment. Baseline was defined as the last assessment prior to the first study drug infusion. | Baseline and Month 19 | 
| Disability Assessment for Dementia (DAD) Score at Baseline | DAD is a functional assessment based on interview with the caregiver. It consisted of 40 items, 17 related to self-care and 23 items involving instrumental activities of daily living. Each item was scored as yes = 1, no = 0 and not applicable= N/A. A total score was obtained by adding the rating for each question and converting this to a total score out of 100. The items rated N/A were not considered for the total score. DAD total score ranged from 0 to 100, with higher scores indicating better functioning. Baseline was defined as the last assessment prior to the first study drug infusion. | Baseline | 
| Change From Baseline in Disability Assessment for Dementia (DAD) Score at Month 19 | DAD is a functional assessment based on interview with the caregiver. It consisted of 40 items, 17 related to self-care and 23 items involving instrumental activities of daily living. Each item was scored as yes = 1, no = 0 and not applicable= N/A. A total score was obtained by adding the rating for each question and converting this to a total score out of 100. The items rated N/A were not considered for the total score. DAD total score ranged from 0 to 100, with higher scores indicating better functioning. Baseline was defined as the last assessment prior to the first study drug infusion. | Baseline and Month 19 | 
| Mean Plasma Concentration of Amyloid Beta 1-x (Aβ1-x) |  | 0 Hour (pre-dose) and 2 hours on Day 1, 60, 120, 180, 240, 300, 360, 420, 480, 540; Day 90, 150, 210, 390, 570, 660, 720 | 
| Mean Plasma Concentration of Amyloid Beta 1-40 (Aβ1-40) |  | 0 Hour (pre-dose) and 2 hours on Day 1, 60, 120, 180, 240, 300, 360, 420, 480, 540; Day 90, 150, 210, 390, 570, 660, 720 | 
| Mean Plasma Concentration of Amyloid Beta 1-42 (Aβ1-42) | Results are not reported for PF-04360365 0.1, 0.5, 1.0 mg/kg, Placebo (Part A and B) arms because plasma Aβ1-42 concentrations were sporadic and below the lower limit of quantification (20 pg/mL). | 0 Hour (pre-dose) and 2 hours on Day 1, 60, 120, 180, 240, 300, 360, 420, 480, 540; Day 90, 150, 210, 390, 570, 660, 720 | 
| Mean Cerebrospinal Fluid (CSF) Concentration of Amyloid Beta 1-x (Aβ1-x) |  | Day 0 (Hour 0), 90, 570 | 
| Mean Cerebrospinal Fluid (CSF) Concentration of Amyloid Beta 1-40 (Aβ1-40) |  | Day 0 (Hour 0), 90, 570 | 
| Mean Cerebrospinal Fluid (CSF) Concentration of Amyloid Beta 1-42 (Aβ1-42) |  | Day 0 (Hour 0), 90, 570 | 
| Mean Cerebrospinal Fluid (CSF) Concentration of Total Tau and Phospho-tau (P-tau) |  | Day 0 (Hour 0), 90, 570 | 
| Number of Participants With Abnormal Cerebrospinal Fluid (CSF) Protein, Red Blood Cells (RBCs), White Blood Cells (WBCs), and Glucose Concentration | Abnormality was defined as concentration either less than lower limit of normal (LLN) or more than upper limit of normal (ULN). Baseline was defined as the last assessment prior to the first study drug infusion | Baseline up to Month 24 | 
| Number of Participants With Serum Anti-Drug Anti Body (ADA) | Serum samples were analyzed for the presence or absence of anti-PF-04360365 antibodies using validated semi-quantitative enzyme linked immunosorbent assay (ELISA). Only participants receiving PF-04360365 were analyzed for this outcome measure. | Day 1 up to Month 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
amyloid, Alzheimer's disease, antibody