Title

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

    Phase 2
  • Study Type

    Interventional
  • Intervention/Treatment

    vx-745 ...
  • Study Participants

    16
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.
Study Started
Apr 30
2015
Primary Completion
Sep 30
2016
Study Completion
Nov 30
2016
Results Posted
Apr 03
2018
Last Update
Apr 03
2018

Drug VX-745

Orally-active P38 MAP kinase alpha-selective inhibitor

VX-745 dose level 1 Experimental

Active Group 1: VX-745 dose level 1 twice daily

VX-745 dose level 2 Experimental

Active Group 1: VX-745 dose level 2 twice daily

Criteria

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

Summary

Overall Study Population

All Events

Event Type Organ System Event Term Overall Study Population

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.

Overall Study Population

137.0
percentage of baseline at Day 42 (Mean)
Standard Deviation: 115

Severe or Serious Adverse Events

Number of patients with severe or serious adverse events

Neflamapimod (VX-745) Dose Level 1

Neflamapimod (VX-745) Dose Level 2

Maximal CSF VX-745 Concentration

Ratio fo CSF to plasma drug concentration at time matched time points. Samples taken

Overall Study Population

0.062
ratio of plasma drug concentration (Mean)
Standard Deviation: 0.01

Episodic Memory Function

Total Recall in Hopkins Verbal Learning Test (HVLT). Range is 0-36, with increases in score indicating improvement in cognitive function.

Overall Study Population

3.5
points on HLVT Total Recall (range 0-36) (Mean)
Standard Deviation: 3.6

Total

9
Participants

Age, Continuous

71
years (Median)
Full Range: 66.0 to 74.0

Region of Enrollment

Sex: Female, Male

Overall Study

Neflamapimod (VX-745) Dose Level 1

Neflamapimod (VX-745) Dose Level 2