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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Alzheimer Disease	Drug: neflamapimod; Other: placebo	Phase 2

Detailed Description:

Details provided elsewhere.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	152 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Intervention Model Description:	Double-blind, placebo-controlled
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	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
Actual Study Start Date :	December 29, 2017
Estimated Primary Completion Date :	June 30, 2019
Estimated Study Completion Date :	July 31, 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: neflamapimod; 40 mg hard gelatin capsules, taken twice daily with food.	Drug: neflamapimod; 40 mg neflamapimod capsule; Other Name: 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

Outcome Measures

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Primary Outcome Measures :

1. Improvement in total and delayed recall on the Hopkins Verval Learning Test - Revised (HVLT-R) [ Time Frame: 24 weeks ]
   Combined change in z-scores of total recall and delayed recall on the HVLT-R in neflamapimod-treated subjects compared to placebo-recipients

Secondary Outcome Measures :

1. Wechsler Memory Scale (WMS) Immediate and delayed Recall [ Time Frame: 24 weeks ]
   Change in WMS immediate and delayed recall composites in neflamapimod-treated subjects compared to placebo-recipients.
2. Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) [ Time Frame: 24 weeks ]
   Change in total score of Clinical Dementia Rating Scale - Sum of Boxes (range 0-18) in neflamapimod-treated subjects compared to placebo-recipients.
3. Mini-Mental State Examination (MMSE) [ Time Frame: 24 weeks ]
   Change in MMSE in neflamapimod-treated subjects compared to placebo-recipients
4. Cerebrospinal fluid phospho-tau [ Time Frame: 24 weeks ]
   Change in CSF levels of p-tau181 protein in neflamapimod-treated subjects compared to placebo-recipients.
5. Cereberspinal fluid amyloid beta 1-40 [ Time Frame: 24 weeks ]
   Change in CSF levels of amyloid beta 1-40 peptide in neflamapimod-treated subjects compared to placebo-recipients.

Eligibility Criteria

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Ages Eligible for Study:	55 Years to 85 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Contacts

Contact: Clinical Project Manager	617-945-0794	reverse-sd@eippharma.com

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Sponsors and Collaborators

EIP Pharma, LLC

Worldwide Clinical Trials

VU University Medical Center

Investigators

Study Director:	John Alam, MD	EIP Pharma

More Information

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Responsible Party:	EIP Pharma, LLC
ClinicalTrials.gov Identifier:	NCT03402659 History of Changes
Other Study ID Numbers:	EIP-VX17-745-304
First Posted:	January 18, 2018
Last Update Posted:	August 3, 2018
Last Verified:	August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases	Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders