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

Alzheimer Disease Clinical Trial

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Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03435861
• Other study ID #: RC31/16/8371
• Status: Completed
• Phase: Phase 2
• Start date: October 8, 2018
• Est. completion date: June 30, 2021

Study information

• Verified date: June 2023
• Source: University Hospital, Toulouse
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: June 30, 2021
• Est. primary completion date: April 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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

Related Conditions & MeSH terms

• Alzheimer Disease
• Encephalitis
• Infectious Encephalitis
• Inflammation

Intervention

Drug:
• VX-745
active drug capsules
• placebo
placebo capsules

Locations

Country	Name	City	State
France	CHU Toulouse	Toulouse

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Toulouse	Fondation Plan Alzheimer

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	brain inflammation assessed by [18F]-DPA714, Standard Uptake Value (SUV) 2	SUVs in the five lobes will be calculated.	3 month
Primary	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	Neuropsychological assessment to assess the following cognitive functions 1:	Memory: Rey Figure	3 month
Secondary	Neuropsychological assessment to assess the following cognitive functions 2:	Memory: DMS 48,	3 month
Secondary	Neuropsychological assessment to assess the following cognitive functions 1.1:	Language: confrontation naming (Gremots),	3 month
Secondary	Neuropsychological assessment to assess the following cognitive functions 2.2:	Language: FAS fluencies,	3 month
Secondary	Neuropsychological assessment to assess the following cognitive functions 3:	o Attention and executive functions: D2	3 month
Secondary	Neuropsychological assessment to assess the following cognitive functions 4:	o Attention and executive functions: TEA	3 month
Secondary	Neuropsychological assessment to assess the following cognitive functions 5:	o Attention and executive functions: SDMT WAIS	3 month
Secondary	Blood and CSF biomarkers of inflammation1	ApoE phenotype	3 month
Secondary	Blood and CSF biomarkers of inflammation 2	TSPO phenotype,	3 month
Secondary	Blood and CSF biomarkers of inflammation 3	TNFa,	3 month
Secondary	Blood and CSF biomarkers of inflammation 4	IL-1b,	3 month
Secondary	Blood and CSF biomarkers of inflammation 5	IFNg	3 month
Secondary	Blood and CSF biomarkers of inflammation 6	IL-12	3 month
Secondary	Blood and CSF biomarkers of inflammation 7	IFNa/b	3 month
Secondary	Blood and CSF biomarkers of inflammation 8	IL-10	3 month
Secondary	Blood and CSF biomarkers of inflammation 9	IL-6	3 month
Secondary	Blood and CSF biomarkers of inflammation 10	IL-8,	3 month
Secondary	Blood and CSF biomarkers of inflammation 11	MCP-1,	3 month
Secondary	Blood and CSF biomarkers of inflammation 12	GM-CSF	3 month
Secondary	Blood and CSF biomarkers of inflammation 13	IL-27	3 month
Secondary	Blood and CSF biomarkers of inflammation 14	chimiokines receptors,	3 month
Secondary	Blood and CSF biomarkers of inflammation 15	PD-1,	3 month
Secondary	Blood and CSF biomarkers of inflammation 16	CD14/16	3 month
Secondary	Blood and CSF biomarkers of inflammation 17	p-tau,	3 month
Secondary	Blood and CSF biomarkers of inflammation 18	abéta42,	3 month
Secondary	Blood and CSF biomarkers of inflammation 19	Abeta40,	3 month
Secondary	Blood and CSF biomarkers of inflammation 20	cells count	3 month
Secondary	Blood and CSF biomarkers of inflammation 21	TNFa	3 month
Secondary	Blood and CSF biomarkers of inflammation 22	IL-1b	3 month
Secondary	Blood and CSF biomarkers of inflammation 23	IL-12	3 month
Secondary	Blood and CSF biomarkers of inflammation 24	MCP-1	3 month
Secondary	Blood and CSF biomarkers of inflammation 25	GM-CSF	3 month
Secondary	Blood and CSF biomarkers of inflammation 26	IL-27,	3 month
Secondary	Blood and CSF biomarkers of inflammation 27	PD-1	3 month
Secondary	Blood and CSF biomarkers of inflammation 28	CD14/16	3 month