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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

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.


Condition or disease Intervention/treatment Phase
Alzheimer Disease Drug: VX-745 Drug: placebo Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
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
Official Title: Effect of Neflamapimod (VX-745) on Brain Inflammation Using Positron Emission Tomography (PET) Scan in Alzheimer's Disease (AD) Patients
Actual Study Start Date : October 8, 2018
Estimated Primary Completion Date : January 30, 2020
Estimated Study Completion Date : January 30, 2021


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 Name: 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




Primary Outcome Measures :
  1. 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


  2. brain inflammation assessed by [18F]-DPA714, Standard Uptake Value (SUV) 2 [ Time Frame: 3 month ]
    SUVs in the five lobes will be calculated.

  3. 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.


Secondary Outcome Measures :
  1. Neuropsychological assessment to assess the following cognitive functions 1: [ Time Frame: 3 month ]
    Memory: Rey Figure

  2. Neuropsychological assessment to assess the following cognitive functions 2: [ Time Frame: 3 month ]
    Memory: DMS 48,

  3. Neuropsychological assessment to assess the following cognitive functions 1.1: [ Time Frame: 3 month ]
    Language: confrontation naming (Gremots),

  4. Neuropsychological assessment to assess the following cognitive functions 2.2: [ Time Frame: 3 month ]
    Language: FAS fluencies,

  5. Neuropsychological assessment to assess the following cognitive functions 3: [ Time Frame: 3 month ]
    o Attention and executive functions: D2

  6. Neuropsychological assessment to assess the following cognitive functions 4: [ Time Frame: 3 month ]
    o Attention and executive functions: TEA

  7. Neuropsychological assessment to assess the following cognitive functions 5: [ Time Frame: 3 month ]
    o Attention and executive functions: SDMT WAIS

  8. Blood and CSF biomarkers of inflammation1 [ Time Frame: 3 month ]
    ApoE phenotype

  9. Blood and CSF biomarkers of inflammation 2 [ Time Frame: 3 month ]
    TSPO phenotype,

  10. Blood and CSF biomarkers of inflammation 3 [ Time Frame: 3 month ]
    TNFa,

  11. Blood and CSF biomarkers of inflammation 4 [ Time Frame: 3 month ]
    IL-1b,

  12. Blood and CSF biomarkers of inflammation 5 [ Time Frame: 3 month ]
    IFNg

  13. Blood and CSF biomarkers of inflammation 6 [ Time Frame: 3 month ]
    IL-12

  14. Blood and CSF biomarkers of inflammation 7 [ Time Frame: 3 month ]
    IFNa/b

  15. Blood and CSF biomarkers of inflammation 8 [ Time Frame: 3 month ]
    IL-10

  16. Blood and CSF biomarkers of inflammation 9 [ Time Frame: 3 month ]
    IL-6

  17. Blood and CSF biomarkers of inflammation 10 [ Time Frame: 3 month ]
    IL-8,

  18. Blood and CSF biomarkers of inflammation 11 [ Time Frame: 3 month ]
    MCP-1,

  19. Blood and CSF biomarkers of inflammation 12 [ Time Frame: 3 month ]
    GM-CSF

  20. Blood and CSF biomarkers of inflammation 13 [ Time Frame: 3 month ]
    IL-27

  21. Blood and CSF biomarkers of inflammation 14 [ Time Frame: 3 month ]
    chimiokines receptors,

  22. Blood and CSF biomarkers of inflammation 15 [ Time Frame: 3 month ]
    PD-1,

  23. Blood and CSF biomarkers of inflammation 16 [ Time Frame: 3 month ]
    CD14/16

  24. Blood and CSF biomarkers of inflammation 17 [ Time Frame: 3 month ]
    p-tau,

  25. Blood and CSF biomarkers of inflammation 18 [ Time Frame: 3 month ]
    abéta42,

  26. Blood and CSF biomarkers of inflammation 19 [ Time Frame: 3 month ]
    Abeta40,

  27. Blood and CSF biomarkers of inflammation 20 [ Time Frame: 3 month ]
    cells count

  28. Blood and CSF biomarkers of inflammation 21 [ Time Frame: 3 month ]
    TNFa

  29. Blood and CSF biomarkers of inflammation 22 [ Time Frame: 3 month ]
    IL-1b

  30. Blood and CSF biomarkers of inflammation 23 [ Time Frame: 3 month ]
    IL-12

  31. Blood and CSF biomarkers of inflammation 24 [ Time Frame: 3 month ]
    MCP-1

  32. Blood and CSF biomarkers of inflammation 25 [ Time Frame: 3 month ]
    GM-CSF

  33. Blood and CSF biomarkers of inflammation 26 [ Time Frame: 3 month ]
    IL-27,

  34. Blood and CSF biomarkers of inflammation 27 [ Time Frame: 3 month ]
    PD-1

  35. Blood and CSF biomarkers of inflammation 28 [ Time Frame: 3 month ]
    CD14/16



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03435861


Contacts
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Contact: Delphine VERNET 0561777216 vernet.d@chu-toulouse.fr

Locations
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France
CHU Toulouse Recruiting
Toulouse, France, 31000
Contact: Jeremie Pariente, Pr         
Sponsors and Collaborators
University Hospital, Toulouse
Fondation Plan Alzheimer
Investigators
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Principal Investigator: Jeremie PARIENTE, MD University Hospital, Toulouse

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Responsible Party: University Hospital, Toulouse
ClinicalTrials.gov Identifier: NCT03435861     History of Changes
Other Study ID Numbers: RC31/16/8371
First Posted: February 16, 2018    Key Record Dates
Last Update Posted: November 21, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Alzheimer Disease
Encephalitis
Inflammation
Pathologic Processes
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders