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

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ClinicalTrials.gov Identifier: NCT03435861
Recruitment Status : Recruiting
First Posted : February 16, 2018
Last Update Posted : November 21, 2018
Sponsor:
Collaborator:
Fondation Plan Alzheimer
Information provided by (Responsible Party):
University Hospital, Toulouse

Tracking Information
First Submitted Date  ICMJE December 22, 2017
First Posted Date  ICMJE February 16, 2018
Last Update Posted Date November 21, 2018
Actual Study Start Date  ICMJE October 8, 2018
Estimated Primary Completion Date January 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 9, 2018)
  • brain inflammation assessed by [18F]-DPA714, Standard Uptake Value (SUV) [ Time Frame: 3 month ]
    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
  • brain inflammation assessed by [18F]-DPA714, Standard Uptake Value (SUV) 2 [ Time Frame: 3 month ]
    SUVs in the five lobes will be calculated.
  • brain inflammation assessed by [18F]-DPA714, Standard Uptake Value (SUV)3 [ Time Frame: 3 month ]
    SUVs in specific regions of interest (ROIs: orbitofrontal, anterior cingulate, posterior cingulate and precuneus) will be calculated.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03435861 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 9, 2018)
  • Neuropsychological assessment to assess the following cognitive functions 1: [ Time Frame: 3 month ]
    Memory: Rey Figure
  • Neuropsychological assessment to assess the following cognitive functions 2: [ Time Frame: 3 month ]
    Memory: DMS 48,
  • Neuropsychological assessment to assess the following cognitive functions 1.1: [ Time Frame: 3 month ]
    Language: confrontation naming (Gremots),
  • Neuropsychological assessment to assess the following cognitive functions 2.2: [ Time Frame: 3 month ]
    Language: FAS fluencies,
  • Neuropsychological assessment to assess the following cognitive functions 3: [ Time Frame: 3 month ]
    o Attention and executive functions: D2
  • Neuropsychological assessment to assess the following cognitive functions 4: [ Time Frame: 3 month ]
    o Attention and executive functions: TEA
  • Neuropsychological assessment to assess the following cognitive functions 5: [ Time Frame: 3 month ]
    o Attention and executive functions: SDMT WAIS
  • Blood and CSF biomarkers of inflammation1 [ Time Frame: 3 month ]
    ApoE phenotype
  • Blood and CSF biomarkers of inflammation 2 [ Time Frame: 3 month ]
    TSPO phenotype,
  • Blood and CSF biomarkers of inflammation 3 [ Time Frame: 3 month ]
    TNFa,
  • Blood and CSF biomarkers of inflammation 4 [ Time Frame: 3 month ]
    IL-1b,
  • Blood and CSF biomarkers of inflammation 5 [ Time Frame: 3 month ]
    IFNg
  • Blood and CSF biomarkers of inflammation 6 [ Time Frame: 3 month ]
    IL-12
  • Blood and CSF biomarkers of inflammation 7 [ Time Frame: 3 month ]
    IFNa/b
  • Blood and CSF biomarkers of inflammation 8 [ Time Frame: 3 month ]
    IL-10
  • Blood and CSF biomarkers of inflammation 9 [ Time Frame: 3 month ]
    IL-6
  • Blood and CSF biomarkers of inflammation 10 [ Time Frame: 3 month ]
    IL-8,
  • Blood and CSF biomarkers of inflammation 11 [ Time Frame: 3 month ]
    MCP-1,
  • Blood and CSF biomarkers of inflammation 12 [ Time Frame: 3 month ]
    GM-CSF
  • Blood and CSF biomarkers of inflammation 13 [ Time Frame: 3 month ]
    IL-27
  • Blood and CSF biomarkers of inflammation 14 [ Time Frame: 3 month ]
    chimiokines receptors,
  • Blood and CSF biomarkers of inflammation 15 [ Time Frame: 3 month ]
    PD-1,
  • Blood and CSF biomarkers of inflammation 16 [ Time Frame: 3 month ]
    CD14/16
  • Blood and CSF biomarkers of inflammation 17 [ Time Frame: 3 month ]
    p-tau,
  • Blood and CSF biomarkers of inflammation 18 [ Time Frame: 3 month ]
    abéta42,
  • Blood and CSF biomarkers of inflammation 19 [ Time Frame: 3 month ]
    Abeta40,
  • Blood and CSF biomarkers of inflammation 20 [ Time Frame: 3 month ]
    cells count
  • Blood and CSF biomarkers of inflammation 21 [ Time Frame: 3 month ]
    TNFa
  • Blood and CSF biomarkers of inflammation 22 [ Time Frame: 3 month ]
    IL-1b
  • Blood and CSF biomarkers of inflammation 23 [ Time Frame: 3 month ]
    IL-12
  • Blood and CSF biomarkers of inflammation 24 [ Time Frame: 3 month ]
    MCP-1
  • Blood and CSF biomarkers of inflammation 25 [ Time Frame: 3 month ]
    GM-CSF
  • Blood and CSF biomarkers of inflammation 26 [ Time Frame: 3 month ]
    IL-27,
  • Blood and CSF biomarkers of inflammation 27 [ Time Frame: 3 month ]
    PD-1
  • Blood and CSF biomarkers of inflammation 28 [ Time Frame: 3 month ]
    CD14/16
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Neflamapimod on Brain Inflammation in Alzheimer's Disease Patients
Official Title  ICMJE Effect of Neflamapimod (VX-745) on Brain Inflammation Using Positron Emission Tomography (PET) Scan in Alzheimer's Disease (AD) Patients
Brief Summary

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.

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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Our mono-centric project will consist in a double-blinded randomized placebo-controlled study, assessing the effect of neflamapimod on brain inflammation in patients suffering of AD by using [18F]-DPA714
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Alzheimer Disease
Intervention  ICMJE
  • Drug: VX-745
    active drug capsules
    Other Name: neflamapimod
  • Drug: placebo
    placebo capsules
Study Arms  ICMJE
  • 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
    Intervention: Drug: VX-745
  • Placebo Comparator: placebo
    In the present study, placebo will be given twice a day (1 tab. , twice), orally for 12 weeks
    Intervention: Drug: placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 9, 2018)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 30, 2021
Estimated Primary Completion Date January 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Delphine VERNET 0561777216 vernet.d@chu-toulouse.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03435861
Other Study ID Numbers  ICMJE RC31/16/8371
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University Hospital, Toulouse
Study Sponsor  ICMJE University Hospital, Toulouse
Collaborators  ICMJE Fondation Plan Alzheimer
Investigators  ICMJE
Principal Investigator: Jeremie PARIENTE, MD University Hospital, Toulouse
PRS Account University Hospital, Toulouse
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP