A PET Study of the Effects of p38 MAP Kinase Inhibitor, VX-745, on Amyloid Plaque Load in Alzheimer's Disease (AD)

Study Overview
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Brief Summary
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This study will assess the effects of administration of VX-745 for 12 weeks on amyloid plaque burden in Alzheimer's disease (AD). Subjects who meet entry criteria will undergo 11C-PiB (Carbon-11-labeled Pittsburgh Compound B) positron emission tomography (PET) at baseline and after 45 days of dosing with VX-745. Cognitive testing will also be conducted at baseline and day 45.

Official Title
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A Clinical Study of Two Doses of a Selective p38 MAP Kinase Inhibitor, VX-745, to Evaluate the Effects of 12-Week Oral Twice-Daily Dosing on Amyloid Plaque Load as Assessed by Quantitative Dynamic 11C-PiB Positive Emission Tomography (PET) Amyloid Scanning

Conditions
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Alzheimer's Disease, Mild Cognitive Impairment

Intervention / Treatment
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* Drug: VX-745


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide informed consent Diagnosis of mild cognitive impairment (MCI) due to probable AD or of mild AD MMSE range: 20 to 28 Evidence of amyloid pathology by amyloid PET scan Participants may be taking medications for AD, provided that the dose of these medications has been stable for >3 months Proficiency in Dutch and adequate visual and auditory abilities to be able to perform all aspects of the cognitive and functional tests Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments. Exclusion Criteria: Evidence of neurodegenerative disease other than AD Inability for any reason to undergo PET and fMRI scans (including notably: history of allergic reaction of any severity to 11C-PiB injection; pacemaker, vascular stent or stent graft) Psychiatric disorder that would compromise ability to comply with study requirements Significant cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder or metabolic/endocrine disorders or other disease that would preclude treatment with p38 MAP kinase inhibitor and/or assessment of drug safety and efficacy Recent (<90 days) changes to AD medications prescribed for cognitive reasons or with the potential to impact cognition Participation in a study of an investigational drug less than 6 months or 5 half-lives of the investigational drug, whichever is longer, before enrollment in the study Male subjects with female partner of child-bearing potential who are unwilling or unable to adhere to contraception requirements Female subjects who have not reached menopause or have not had a hysterectomy or bilateral oophorectomy/salpingoophorectomy Positive urine or serum pregnancy test or plans desires to become pregnant during the course of the trial Any factor deemed by the investigator to be likely to interfere with study conduction

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VX-745 dose 1<br>Active Group 1: VX-745 40 mg twice daily | Drug: VX-745<br>* Orally-Active Selective P45 MAP Kinase inhibitor<br>|
| Experimental: VX-745 dose 2<br>Active Group 2: VX-745 125 mg twice daily | Drug: VX-745<br>* Orally-Active Selective P45 MAP Kinase inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Amyloid Plaque Burden by 11C-PiB PET | Percent change in global cortical amyloid specific PET signal (BPND) | Baseline compared to following 12 weeks' dosing with VX-745 | 
| Number of 11C-PiB Responders | Number of patients meeting protocol pre-specified definition of response: > 7% reduction in global cortical BPND | Day 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Wechsler Memory Scale (WMS) Immediate Recall Composite | WMS immediate-recall composite score consisted of the sum of the scores on Logical Memory I, Verbal Paired Associates I, and Visual Reproduction I. The composite score ranges from 0 to 136; with higher score indicating better performance. | Baseline to Day 84 | 
| Wechsler Memory Scale (WMS) Delayed Recall Composite | WMS delayed-recall composite score at each testing sessions consisted of the sum of the scores on Logical Memory II, Verbal Paired Associates II, and Visual Reproduction II. The composite score ranges from 0 to 136; with higher scores indicating better performance. | Change from baseline to Day 84 |