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

Primary Purpose

Alzheimer's Disease

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
VX-745
Sponsored by
EIP Pharma Inc
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alzheimer's Disease

Eligibility Criteria

60 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Parexel International

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

VX-745 dose level 1

VX-745 dose level 2

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Severe or Serious Adverse Events
Number of patients with severe or serious adverse events
Maximal CSF VX-745 Concentration
Ratio fo CSF to plasma drug concentration at time matched time points. Samples taken
Episodic Memory Function
Total Recall in Hopkins Verbal Learning Test (HVLT). Range is 0-36, with increases in score indicating improvement in cognitive function.

Full Information

First Posted
April 3, 2015
Last Updated
April 2, 2018
Sponsor
EIP Pharma Inc
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1. Study Identification

Unique Protocol Identification Number
NCT02423200
Brief Title
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

2. Study Status

Record Verification Date
April 2018
Overall Recruitment Status
Completed
Study Start Date
April 2015 (undefined)
Primary Completion Date
September 2016 (Actual)
Study Completion Date
November 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
EIP Pharma Inc

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer's Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
VX-745 dose level 1
Arm Type
Experimental
Arm Description
Active Group 1: VX-745 dose level 1 twice daily
Arm Title
VX-745 dose level 2
Arm Type
Experimental
Arm Description
Active Group 1: VX-745 dose level 2 twice daily
Intervention Type
Drug
Intervention Name(s)
VX-745
Intervention Description
Orally-active P38 MAP kinase alpha-selective inhibitor
Primary Outcome Measure Information:
Title
Percent Change From Baseline to End of Treatment in Cerebrospinal Fluid Levels of Cytokines
Description
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.
Time Frame
Baseline and Day 42 of dosing with VX-745
Secondary Outcome Measure Information:
Title
Severe or Serious Adverse Events
Description
Number of patients with severe or serious adverse events
Time Frame
At baseline and at each study visit during (days 1, 7, 14, 21, 28, 35 and 42) and after (day 51) dosing
Title
Maximal CSF VX-745 Concentration
Description
Ratio fo CSF to plasma drug concentration at time matched time points. Samples taken
Time Frame
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.
Title
Episodic Memory Function
Description
Total Recall in Hopkins Verbal Learning Test (HVLT). Range is 0-36, with increases in score indicating improvement in cognitive function.
Time Frame
Change from baseline to Day 42

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hakop Gevorkyan, MD
Organizational Affiliation
Parexel
Official's Role
Principal Investigator
Facility Information:
Facility Name
Parexel International
City
Glendale
State/Province
California
ZIP/Postal Code
91206
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
33974419
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.
Results Reference
derived

Learn more about this trial

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

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