Effect of Neflamapimod on Brain Inflammation in Alzheimer's Disease Patients (VIP)

Effect of Neflamapimod (VX-745) on Brain Inflammation Using Positron Emission Tomography (PET) Scan in Alzheimer's Disease (AD) Patients

For this project, neflamapimod and placebo will be provided free of charge by the EIP company (www.eippharma.com). Neflamapimod is currently tested in 2 clinical trials in AD, one in Europe (The Netherlands) and one in the USA (clinical trials.gov/VX-745). The company commenced in May 2015 dosing in two phase 2a clinical studies in patients with Early AD: one in the Netherlands that is focused on PET amyloid imaging as the primary biomarker of drug effect, and one in the US (California) that is focused on Cerebrospinal fluid (CSF) evaluation to determine CSF drug concentrations and effects on inflammatory markers and disease biomarkers. Pharmacokinetic evaluation in these patients has demonstrated blood drug concentration levels in the predicted therapeutic range; and importantly, the data from the US study demonstrate that the drug achieves target drug concentrations in CSF, thus confirming the drug robustly enters the brain in humans.

The present project offers us a unique chance to test this promising drug in AD patients. The aim of the study is to focus on PET neuroinflammation imaging as the primary biomarker of this drug effect. The chosen biomarker for imaging neuroinflammation in patients is [1 8F]-DPA714.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: VX-745; Drug: placebo

Detailed Description

The present project is an intervention proof of concept study to test the efficacy of neflamapimod in a population of AD patients at an early stage.

To track the impact of this drug in patients, the investigators will use an innovative radiotracer, [18F]DPA-714, as a promising ligand of microglial activation targeting the translocator protein (TSPO), specific of microglial activation. The use of [18F]DPA-714 will allow to monitor the evolution of neuroinflammation in patients as a function of treatment. The main objective will be to compare the level of inflammation using the [18F]DPA-714 in neflamapimod and placebo groups after 12 weeks of treatment. Blood and cerebrospinal fluid (CSF) samples and magnetic resonance imaging (MRI) will also be collected to assess inflammation markers and brain structure respectively in these patients.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Delphine VERNET; Phone Number: 0561777216; Email: vernet.d@chu-toulouse.fr

Study Locations

• France
  • Toulouse, France, 31000
    • CHU Toulouse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• A group of 40 AD patients at an early stage (prodromal) will be recruited. Patient's recruitment will follow the most recent research criteria for AD in its "typical form" (Dubois, Feldman et al. 2014):

  • Age 50 - 90 (inclusive)
  • Willing and able to provide informed consent
  • Objective memory impairment corroborated by level of performance on a standardized memory test (Free and Cued Selective Reminding test, (Grober, Hall et al. 2008)) < -1.5 DS according to established norms and
  • Documented cerebral amyloidopathy using CSF analysis or PET amyloid imaging and
  • Early stage of the disease (Mini Mental State Examination > 20) (Folstein, Robins et al. 1983).

Exclusion Criteria:

• • Evidence of neurodegenerative disease other than AD

  • Inability for any reason to undergo MRI scans (e.g. pacemaker). 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 (<60 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
  • 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VX-745; In the present study, VX-745 will be given at the dosage of 40 mg twice a day (1 tab. of 40 mg, twice), orally for 12 weeks	Drug: VX-745; active drug capsules; Other Names: neflamapimod
Placebo Comparator: placebo; In the present study, placebo will be given twice a day (1 tab. , twice), orally for 12 weeks	Drug: placebo; placebo capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
brain inflammation assessed by [18F]-DPA714, Standard Uptake Value (SUV)	To track the impact of this drug in patients, investigators will use an innovative radiotracer, [18F]DPA-714, as a promising ligand of microglial activation targeting the translocator protein (TSPO), specific of microglial activation. The use of [18F]DPA-714 will allow us to monitor the evolution of neuroinflammation in patients as a function of treatment. the main objective will be to compare the level of inflammation using the [18F]DPA-714 in neflamapimod and placebo. Regional cortical DPA-714 mean SUV will be measured in each subject using a Matlab (The MathWorks®) script. Mean global SUVs will be calculated	3 month
brain inflammation assessed by [18F]-DPA714, Standard Uptake Value (SUV) 2	SUVs in the five lobes will be calculated.	3 month
brain inflammation assessed by [18F]-DPA714, Standard Uptake Value (SUV)3	SUVs in specific regions of interest (ROIs: orbitofrontal, anterior cingulate, posterior cingulate and precuneus) will be calculated.	3 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuropsychological assessment to assess the following cognitive functions 1:	Memory: Rey Figure	3 month
Neuropsychological assessment to assess the following cognitive functions 2:	Memory: DMS 48,	3 month
Neuropsychological assessment to assess the following cognitive functions 1.1:	Language: confrontation naming (Gremots),	3 month
Neuropsychological assessment to assess the following cognitive functions 2.2:	Language: FAS fluencies,	3 month
Neuropsychological assessment to assess the following cognitive functions 3:	o Attention and executive functions: D2	3 month
Neuropsychological assessment to assess the following cognitive functions 4:	o Attention and executive functions: TEA	3 month
Neuropsychological assessment to assess the following cognitive functions 5:	o Attention and executive functions: SDMT WAIS	3 month
Blood and CSF biomarkers of inflammation1	ApoE phenotype	3 month
Blood and CSF biomarkers of inflammation 2	TSPO phenotype,	3 month
Blood and CSF biomarkers of inflammation 3	TNFa,	3 month
Blood and CSF biomarkers of inflammation 4	IL-1b,	3 month
Blood and CSF biomarkers of inflammation 5	IFNg	3 month
Blood and CSF biomarkers of inflammation 6	IL-12	3 month
Blood and CSF biomarkers of inflammation 7	IFNa/b	3 month
Blood and CSF biomarkers of inflammation 8	IL-10	3 month
Blood and CSF biomarkers of inflammation 9	IL-6	3 month
Blood and CSF biomarkers of inflammation 10	IL-8,	3 month
Blood and CSF biomarkers of inflammation 11	MCP-1,	3 month
Blood and CSF biomarkers of inflammation 12	GM-CSF	3 month
Blood and CSF biomarkers of inflammation 13	IL-27	3 month
Blood and CSF biomarkers of inflammation 14	chimiokines receptors,	3 month
Blood and CSF biomarkers of inflammation 15	PD-1,	3 month
Blood and CSF biomarkers of inflammation 16	CD14/16	3 month
Blood and CSF biomarkers of inflammation 17	p-tau,	3 month
Blood and CSF biomarkers of inflammation 18	abéta42,	3 month
Blood and CSF biomarkers of inflammation 19	Abeta40,	3 month
Blood and CSF biomarkers of inflammation 20	cells count	3 month
Blood and CSF biomarkers of inflammation 21	TNFa	3 month
Blood and CSF biomarkers of inflammation 22	IL-1b	3 month
Blood and CSF biomarkers of inflammation 23	IL-12	3 month
Blood and CSF biomarkers of inflammation 24	MCP-1	3 month
Blood and CSF biomarkers of inflammation 25	GM-CSF	3 month
Blood and CSF biomarkers of inflammation 26	IL-27,	3 month
Blood and CSF biomarkers of inflammation 27	PD-1	3 month
Blood and CSF biomarkers of inflammation 28	CD14/16	3 month

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Collaborators: Fondation Plan Alzheimer
• Investigators: Principal Investigator: Jeremie PARIENTE, MD, University Hospital, Toulouse

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 (Actual): October 8, 2018
• Primary Completion (Actual): April 30, 2021
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: December 22, 2017
• First Submitted That Met QC Criteria: February 9, 2018
• First Posted (Actual): February 19, 2018

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 19, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Infections; Neurocognitive Disorders; Central Nervous System Infections; Neurodegenerative Diseases; Dementia; Tauopathies; Neuroinflammatory Diseases; Encephalitis; Inflammation; Alzheimer Disease; Infectious Encephalitis
• Other Study ID Numbers: RC31/16/8371

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No