Clinical trial NCT02423200: Clinical Pharmacology of p38 MAP Kinase Inhibitor, VX-745, in Mild Cognitive Impairment Due to Alzheimer's Disease (AD) or Mild AD
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Lead sponsor: EIP Pharma Inc
Sponsor class: INDUSTRY
First posted: 2015-04-22
Enrollment: 16
Sex: ALL
Minimum age (years): 60
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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

Primary outcomes:
measure: Percent Change From Baseline to End of Treatment in Cerebrospinal Fluid Levels of Cytokines
timeFrame: Baseline and Day 42 of dosing with VX-745
Secondary outcomes:
measure: Severe or Serious Adverse Events
timeFrame: At baseline and at each study visit during (days 1, 7, 14, 21, 28, 35 and 42) and after (day 51) dosing
measure: Maximal CSF VX-745 Concentration
timeFrame: 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.
measure: Episodic Memory Function
timeFrame: Change from baseline to Day 42
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Parexel International
state: California
Study officials:
affiliation: Parexel
name: Hakop Gevorkyan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tormahlen NM, Martorelli M, Kuhn A, Maier F, Guezguez J, Burnet M, Albrecht W, Laufer SA, Koch P. Design and Synthesis of Highly Selective Brain Penetrant p38alpha Mitogen-Activated Protein Kinase Inhibitors. J Med Chem. 2022 Jan 27;65(2):1225-1242. doi: 10.1021/acs.jmedchem.0c01773. Epub 2021 May 11.