CompletedNCT03435861VIPUpdated Jun 22, 2023

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

A Phase 2 interventional study of VX-745 and placebo in Alzheimer Disease, sponsored by University Hospital, Toulouse. Completed at 1 site in France. Open to participants aged 18 Years to 90 Years. Per ClinicalTrials.gov, last updated 2023-06-22.

Sponsored by University Hospital, Toulouse · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 34
Allocation: Randomized
Ages: 18 Years to 90 Years
Sex: All

Study 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.

Read the 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.

Conditions studied

Alzheimer Disease

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Who can participate

Ages eligible: 18 Years to 90 Years
Sexes eligible: All
Accepts healthy volunteers: No

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

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 design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 34 participants (actual)

Study arms

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
Placebo comparator
placebo
In the present study, placebo will be given twice a day (1 tab. , twice), orally for 12 weeks
Drug: placebo

Interventions

DrugVX-745
active drug capsules
Also known as: neflamapimod
Drugplacebo
placebo capsules

What researchers measure

Primary outcomes

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

Secondary outcomes

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

Study locations

1 site

CHU Toulouse
Toulouse, 31000, France

References and documents

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. PubMed 33974419 ↗

Individual participant data

Plan to share: No

Registry details

Key details

Study ID: NCT03435861
Lead sponsor: University Hospital, Toulouse
Collaborators: Fondation Plan Alzheimer
Responsible party: Sponsor
First posted: Feb 19, 2018
Start date: Oct 8, 2018
Primary completion: Apr 30, 2021
Completion: Jun 30, 2021
Last update: Jun 22, 2023

Study contacts

Jeremie PARIENTE, MD

principal investigator · University Hospital, Toulouse

Oversight

Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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