Proof-of-Concept Study of a Selective p38 MAPK Alpha Inhibitor, Neflamapimod, in Subjects With Mild Alzheimer's Disease (REVERSE-SD)

A Double-Blind, Placebo-Controlled Proof-of-Concept Study of a Selective p38 MAP Kinase Alpha Inhibitor, Neflamapimod, Administered for 24 Weeks in Subjects With Mild Alzheimer's Disease

This is a phase 2b, double-blind, placebo controlled proof-of-concept study of a an oral small molecule selective inhibitor of p38 alpha kinase, neflamapimod, administered for 24 weeks in subjects with mild Alzheimer's disease. The primary objective is to demonstrate significant improvement relative to placebo-treatment in episodic memory function, as assessed by the Hopkins Verbal Learning Test. Secondary endpoints include Clinical Dementia Rating scale (CDR), Wechsler Memory Scale (WMS), Mini-Mental-Status-Examination (MMSE) and Cerebrospinal fluid (CSF) biomarkers of AD disease activity and progression.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: neflamapimod; Other: placebo

Detailed Description

Details provided elsewhere.

• Study Type: Interventional
• Enrollment (Actual): 161
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czechia
  • Choceň, Czechia, 565 01
    • Neuro HK, s.r.o. POLIKLINIKA CHOCEŇ, a.s.
  • Moravská Ostrava, Czechia, 702 00
    • Cerebrovaskularni poradna s.r.o.
  • Prague, Czechia, 100 00
    • Clintrial S.R.O
  • Prague, Czechia, 109 00
    • Private Psychiatric Centre
  • Rychnov Nad Kněžnou, Czechia, 516 01
    • Vestra clinics s.r.o
• Denmark
  • Aalborg, Denmark, DK-9000
    • CCBR Clinical Research, Aalborg
  • Ballerup, Denmark, DK-2750
    • CCBR Clinical Research, Ballerup
  • Vejle, Denmark, DK-7100
    • CCBR Clinical Research, Vejle
• Netherlands
  • 's-Hertogenbosch, Netherlands, 5223 GZ
    • Jeroen Bosch Ziekenhuis
  • Amsterdam, Netherlands, 1081 GM
    • Alzheimer Research Center
  • Breda, Netherlands, 4817 CK
    • Amphia Ziekhuis
• United Kingdom
  • Barnsley, United Kingdom, S75 3DL
    • MAC Clinical Research Tankersley
  • Birmingham, United Kingdom, B16 8LT
    • Re:Cognition Health Birmingham
  • Blackpool, United Kingdom, FY2 0JH
    • MAC Clinical Research Blackpool
  • Cambridge, United Kingdom, CB21 5EF
    • Fulbourn Hospital
  • Leeds, United Kingdom, LS10 1DU
    • MAC Clinical Research Leeds
  • Liverpool, United Kingdom, L34 1BH
    • MAC Clinical Research Liverpool
  • London, United Kingdom, W1G 9JF
    • Re:Cognition Health London
  • London, United Kingdom, WC1X 8QD
    • St. Pancras Clinical Research
  • Manchester, United Kingdom, M13 9NQ
    • MAC Clinical Research Manchester
  • Plymouth, United Kingdom, PL5 8BT
    • Re:Cognition Health Plymouth
  • Warrington, United Kingdom, WA22 8WA
    • 5 Boroughs/North West Boroughs Healthcare NHS Foundation Trust
• United States
  • California
    • Long Beach, California, United States, 90807
      • Alliance for Research
    • San Diego, California, United States, 92103
      • Pacific Research Network
    • Santa Ana, California, United States, 92705
      • CITrials
    • Simi Valley, California, United States, 93065
      • Southern California Research, LLC
    • Temecula, California, United States, 92591
      • Viking Clinical Research
  • Florida
    • Miami, Florida, United States, 33176
      • Miami Dade Medical Research Institute
    • Ocoee, Florida, United States, 34761
      • Sensible Healthcare, LLC
    • Pensacola, Florida, United States, 32502
      • Anchor Neuroscience
    • Port Orange, Florida, United States, 32127
      • Progressive Medical Research
    • Saint Petersburg, Florida, United States, 33713
      • Suncoast Neuroscience Associates, Inc.
    • Winter Park, Florida, United States, 32789
      • Florida Premier Research Institute
  • Idaho
    • Boise, Idaho, United States, 83704
      • Northwest Clinical Trials
  • Massachusetts
    • Charlestown, Massachusetts, United States, 02129
      • MassGeneral Institute for Neurodegenerative Disease
  • New York
    • New York, New York, United States, 10036
      • Manhattan Behavioral Medicine
  • North Carolina
    • Charlotte, North Carolina, United States, 28270
      • Alzheimer's Memory Center and Research Institute
  • Washington
    • Seattle, Washington, United States, 98007
      • Northwest Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 53 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Men and women age 55 to 85 years, inclusive.
2. Willing and able to provide informed consent.

3. Must have mild cognitive impairment (MCI) or mild AD with evidence of progression ("Mild-AD"), as defined by the following:

   1. CDR-Global Score of 0.5 or 1.0, with CDR memory subscore of at least 0.5.
   2. MMSE score ranging from 20 to 28, inclusive.
   3. Positive biomarker for AD, as defined by a CSF Aβ1-42R below the threshold and phospho-tau above the threshold for the assay utilized in the study and assessed by the central laboratory.
4. Computed tomography (CT) or magnetic resonance imaging (MRI) findings within 2 years of Screening that are compatible with AD and no other pathologic processes that might potentially account for the subject's cognitive impairment.
5. If the subject is taking a single drug for AD (e.g., donepezil or other cholinesterase inhibitors or memantine; dual therapy is excluded), he/she has been on a stable dose for at least 2 months prior to baseline, and the dose must remain unchanged during the study unless required for management of adverse events (AEs).
6. Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments.
7. Must have reliable informant or caregiver.

Exclusion Criteria:

1. Evidence that the primary basis for cognitive impairment is neurodegenerative disease other than AD, including, but not limited to, vascular dementia, dementia with Lewy bodies, and Parkinson's disease.
2. Suicidality, defined as active suicidal thoughts within 6 months before Screening or at Baseline, defined as answering yes to items 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS), or history of suicide attempt in previous 2 years, or, in the Investigator's opinion, at serious risk of suicide.
3. History of major and active psychiatric disorder, moderate to severe depressive symptoms, and or other concurrent medical condition that, EIP-VX17-745-304, Version 1.0, 17 November, 2017 Page 7 of 46 EIP Pharma, LLC Confidential in the opinion of the Investigator, might compromise safety and/or compliance with study requirements.
4. Diagnosis of alcohol or drug abuse within the previous 2 years.
5. History of cancer within the last 5 years, except basal cell carcinoma, squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years.
6. Poorly controlled clinically significant medical illness.
7. History of serum B12 abnormality, anemia with hemoglobin ≤10 g/dL, thyroid function abnormality, electrolyte abnormality, or positive syphilis serology that have not been corrected and/or otherwise addressed.
8. History of epilepsy or unexplained seizure within the past 5 years.
9. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × the upper limit of normal (ULN), total bilirubin >2 × ULN, and/or International Normalized Ratio (INR) >1.5
10. Known human immunodeficiency virus, hepatitis B, or active hepatitis C virus infection.
11. Subject participated in a study of an investigational drug less than 3 months or 5 half-lives of the investigation drug, whichever is longer, before enrollment in this study.

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: neflamapimod; 40 mg hard gelatin capsules, taken twice daily with food.	Drug: neflamapimod; 40 mg neflamapimod capsule; Other Names: VX-745
Placebo Comparator: placebo; hard gelatin capsules containing excipients only, weight- and size-matched; taken twice daily with food.	Other: placebo; matching placebo capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total and Delayed Recall on the Hopkins Verbal Learning Test - Revised (HVLT-R)	Combined change from baseline in z-scores of total and delayed recall on the Hopkins Verbal Learning Test - Revised (HVLT-R) in neflamapimod-treated subjects compared to placebo. The primary endpoint was analyzed using Mixed Model for Repeated Measures (MMRM) with fixed effects for treatment, background AD-specific therapy, CDR-Global Score of 0.5 versus 1.0, scheduled visit (nominal) and scheduled visit by treatment interaction, random effect for subject and baseline Z-score as a covariate. For baseline total and delayed recall, a z-score for each subject is defined by z=(x-m)/s where x is the subject's recall at baseline, and m and s are the overall mean and overall standard deviation of recall at baseline across all subjects. A composite baseline z-score for each subject is calculated using equal weighting in the following way: Z=0.5*z-score for total recall at baseline + 0.5*z-score for delayed recall at baseline. For HVLT-R, higher score indicates improvement.	Baseline and 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Wechsler Memory Scale (WMS) Immediate and Delayed Recall	Change from baseline in Wechsler Memory Scale(WMS) immediate and delayed recall composites in neflamapimod-treated subjects compared to placebo. WMS scores were analyzed using Mixed Model for Repeated Measures (MMRM) with fixed effects for treatment, background AD-specific therapy, CDR-Global Score of 0.5 versus 1.0, scheduled visit (nominal) and scheduled visit by treatment interaction, random effect for subject and baseline Z-score as a covariate. Composite scores for immediate and delayed recall are the combination of all immediate and delayed recall task raw scores and ranges from 0-228. A higher score indicates improvement. The following tests in WMS are done both for immediate and delayed recall: Logical Memory test, in which subject is read a story; Verbal-Paired Associates, in which subject is given pairs of words and asked remember which words go together; and Visual Reproduction, in which subject is given drawings of specific shapes	Baseline and 24 weeks
Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB)	Change from baseline in total score of Clinical Dementia Rating Scale - Sum of Boxes (range 0-18) in neflamapimod-treated subjects compared to placebo. CDR-SB scores were analyzed using Mixed Model for Repeated Measures (MMRM) with fixed effects for treatment, background AD-specific therapy, CDR-Global Score of 0.5 versus 1.0, scheduled visit (nominal) and scheduled visit by treatment interaction, random effect for subject and baseline Z-score as a covariate. CDR-SB score is calculated by adding the individual scores from 6 domains, Memory, Orientation, Judgement and Problem Solving, Community Affairs, Home and Hobbies, and Personal Care. CDR-SB scores range from 0-18, where a lower score indicates improvement. The scale is administered in a semi-structured interview format with both the patient and the caregiver/informant.	Baseline and 24 weeks
Mini-Mental State Examination (MMSE)	Changes from baseline in Mini-Mental State Examination (MMSE) scores were compared using an ANCOVA with treatment group, background AD-specific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value. The MMSE is scored from 0-30 with a higher score indicating improvement. The MMSE includes questions that test orientation, attention, memory, language and visual-spatial skills.	Baseline and 26 Weeks (Follow-up visit, 2 weeks from end of dosing)
Cerebrospinal Fluid Total Tau	Change from, baseline in Total Tau (t-tau) were compared using an ANCOVA with treatment group, background ADspecific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value.	Baseline and 24 weeks
Cerebrospinal Fluid Phospho-tau	Change from baseline in Phospho-Tau (p-tau181) were compared using an ANCOVA with treatment group, background AD-specific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value.	Baseline and 24 weeks
Cerebrospinal Fluid Amyloid Beta 1-40	Change from baseline in Amyloid beta (AB1-40) were compared using an ANCOVA with treatment group, background AD-specific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value.	Baseline and 24 weeks
Cerebrospinal Fluid Amyloid Beta 1-42	Change from baseline in Amyloid beta (AB1-42) were compared using an ANCOVA with treatment group, background AD-specific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value.	Baseline and 24 weeks
Cerebrospinal Fluid Neurogranin	Change from baseline in Neurogranin were compared using an ANCOVA with treatment group, background ADspecific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value.	Baseline and 24 weeks
Cerebrospinal Fluid Neurofilament Light Chain	Change from baseline in Neurofilament Light Chain (NFL) were compared using an ANCOVA with treatment group, background AD-specific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value.	Baseline and 24 weeks
Cerebrospinal Fluid P-tau/AB1-42 Ratio	Changes in the ratio of Phospho-Tau/Amyloid Beta (p-tau181/AB1-42) were compared using an ANCOVA with treatment group, background AD-specific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value.	Baseline and 24 weeks

Collaborators and Investigators

• Sponsor: EIP Pharma Inc
• Collaborators: Amsterdam UMC, location VUmc; Worldwide Clinical Trials
• Investigators: Study Director: John Alam, MD, EIP Pharma

Publications and helpful links

General Publications

• Prins ND, Harrison JE, Chu HM, Blackburn K, Alam JJ, Scheltens P; REVERSE-SD Study Investigators. A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease. Alzheimers Res Ther. 2021 May 27;13(1):106. doi: 10.1186/s13195-021-00843-2.
• 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): December 29, 2017
• Primary Completion (Actual): June 30, 2019
• Study Completion (Actual): July 31, 2019

Study Registration Dates

• First Submitted: January 11, 2018
• First Submitted That Met QC Criteria: January 11, 2018
• First Posted (Actual): January 18, 2018

Study Record Updates

• Last Update Posted (Actual): October 27, 2021
• Last Update Submitted That Met QC Criteria: September 28, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: EIP-VX17-745-304

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