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

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

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.

Study Overview

• Status: Completed
• Conditions: Mild Cognitive Impairment; Alzheimer's Disease
• Intervention / Treatment: Drug: VX-745

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Alzheimer Research Center, VU Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: VX-745 dose 1; Active Group 1: VX-745 40 mg twice daily	Drug: VX-745; Orally-Active Selective P45 MAP Kinase inhibitor
EXPERIMENTAL: VX-745 dose 2; Active Group 2: VX-745 125 mg twice daily	Drug: VX-745; Orally-Active Selective P45 MAP Kinase inhibitor

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: EIP Pharma Inc
• Investigators: Principal Investigator: Philip Scheltens, MD, Alheimer Research Center, VU medisch centrum

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (ACTUAL): July 1, 2016
• Study Completion (ACTUAL): September 1, 2016

Study Registration Dates

• First Submitted: April 14, 2015
• First Submitted That Met QC Criteria: April 17, 2015
• First Posted (ESTIMATE): April 22, 2015

Study Record Updates

• Last Update Posted (ACTUAL): June 14, 2019
• Last Update Submitted That Met QC Criteria: March 13, 2019
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Pathological Conditions, Anatomical; Dementia; Tauopathies; Cognition Disorders; Alzheimer Disease; Cognitive Dysfunction; Plaque, Amyloid
• Other Study ID Numbers: EIP-VX00-745-302