Clinical Pharmacology of p38 MAP Kinase Inhibitor, VX-745, in Mild Cognitive Impairment Due to Alzheimer's Disease (AD) or Mild AD

Study Overview
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Brief Summary
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This study will assess the effects of VX-745 on markers of disease in the central nervous system of patients with MCI due to AD or with mild AD. The study will also evaluate the safety and tolerability of VX-745 in these patients during 6 weeks of dosing, as well as the plasma and cerebrospinal fluid concentrations of VX-745 during dosing.

Official Title
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A Randomized, Open-Label, Multiple Dose Clinical Pharmacology Study of Two Doses of a Selective p38 MAP Kinase Inhibitor, VX-745 in Patients With Mild Cognitive Impairment (MCI) Due to Alzheimer's Disease (AD) or With Mild AD

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: VX-745


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 60 - 85 (inclusive) Willing and able to provide informed consent Clinical presentation consistent with MCI due to AD or of mild AD Gradual progressive decline in memory function over >6 months Amnestic presentation on neuropsychological testing with rapid forgetting (% reduction 1.5 standard deviations below the mean) Clinical Dementia Rating (CDR) Sum of Box (SOB) score ≥0.5 Mini-Mental State Examination (MMSE) range: 20 to 30 Brain hypometabolism by 18F-2-fluoro-2-deoxyglucose (FDG)-PET Participants may be taking medications for AD, provided that the dose of these medications has been stable for >3 months. Exclusion Criteria: Evidence of neurodegenerative disease other than AD Inability for any reason to undergo MRI scans (e.g. pacemaker, vascular stent or stent graft). Patients who require sedation for screening procedures such as MRI may receive a short-acting sedative. Psychiatric disorder that would compromise ability to comply with study requirements History of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years 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 Psychotropic drugs taken within 1 month. Anticoagulant drugs taken within 1 week. 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 Donation of >500 mL of blood or blood products within 2 months History of alcohol and/or illicit drug abuse within 6 months. Infection with hepatitis A, B or C or HIV. 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 level 1<br>Active Group 1: VX-745 dose level 1 twice daily | Drug: VX-745<br>* Orally-active P38 MAP kinase alpha-selective inhibitor<br>|
| Experimental: VX-745 dose level 2<br>Active Group 1: VX-745 dose level 2 twice daily | Drug: VX-745<br>* Orally-active P38 MAP kinase alpha-selective inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to End of Treatment in Cerebrospinal Fluid Levels of Cytokines | Cytokines: Of nine cytokines assessed, only CSF IL-8 quantifiable at all time points. And so, only IL-8 levels are being reported herein. The analysis was exploratory and no statistical analysis was performed. | Baseline and Day 42 of dosing with VX-745 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severe or Serious Adverse Events | Number of patients with severe or serious adverse events | At baseline and at each study visit during (days 1, 7, 14, 21, 28, 35 and 42) and after (day 51) dosing | 
| Maximal CSF VX-745 Concentration | Ratio fo CSF to plasma drug concentration at time matched time points. Samples taken | All samples with quantifiable CSF drug levels were included (n=12). Eight were obtained 3-hours post-dose, either on Day 1 (n=4) or Day 42 (n=4). 3 samples were at 6-hours post-dose on Day 42; and one was at 6-hours post-dose on Day 1. | 
| Episodic Memory Function | Total Recall in Hopkins Verbal Learning Test (HVLT). Range is 0-36, with increases in score indicating improvement in cognitive function. | Change from baseline to Day 42 |