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

Phase 2

Completed

Conditions: Alzheimer Disease

Interventions: Other: placebo
Drug: neflamapimod

Registration Number: NCT03402659

Lead Sponsor: EIP Pharma Inc

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.

Detailed Description: Details provided elsewhere.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 161

Inclusion Criteria

Men and women age 55 to 85 years, inclusive.
Willing and able to provide informed consent.
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.
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.
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).
Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments.
Must have reliable informant or caregiver.

Exclusion Criteria

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.
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.
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.
Diagnosis of alcohol or drug abuse within the previous 2 years.
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.
Poorly controlled clinically significant medical illness.
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.
History of epilepsy or unexplained seizure within the past 5 years.
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
Known human immunodeficiency virus, hepatitis B, or active hepatitis C virus infection.
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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
placebo	placebo	hard gelatin capsules containing excipients only, weight- and size-matched; taken twice daily with food.
neflamapimod	neflamapimod	40 mg hard gelatin capsules, taken twice daily with food.

Primary Outcome Measures

Name	Time	Method
Total and Delayed Recall on the Hopkins Verbal Learning Test - Revised (HVLT-R)	Baseline and 24 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Cerebrospinal Fluid Neurofilament Light Chain	Baseline and 24 weeks	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.
Cerebrospinal Fluid Total Tau	Baseline and 24 weeks	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.
Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB)	Baseline and 24 weeks	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.
Cerebrospinal Fluid Amyloid Beta 1-42	Baseline and 24 weeks	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.
Cerebrospinal Fluid Neurogranin	Baseline and 24 weeks	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.
Wechsler Memory Scale (WMS) Immediate and Delayed Recall	Baseline and 24 weeks	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
Cerebrospinal Fluid Phospho-tau	Baseline and 24 weeks	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.
Cerebrospinal Fluid Amyloid Beta 1-40	Baseline and 24 weeks	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.
Mini-Mental State Examination (MMSE)	Baseline and 26 Weeks (Follow-up visit, 2 weeks from end of dosing)	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.
Cerebrospinal Fluid P-tau/AB1-42 Ratio	Baseline and 24 weeks	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.

Trial Locations

Locations (38): MassGeneral Institute for Neurodegenerative Disease
🇺🇸
Charlestown, Massachusetts, United States
Alzheimer's Memory Center and Research Institute
🇺🇸
Charlotte, North Carolina, United States
Cerebrovaskulární poradna s.r.o.
🇨🇿
Moravská Ostrava, Czechia
Clintrial S.R.O
🇨🇿
Prague, Czechia
Private Psychiatric Centre
🇨🇿
Prague, Czechia
MAC Clinical Research Tankersley
🇬🇧
Barnsley, United Kingdom
Amphia Ziekhuis
🇳🇱
Breda, Netherlands
Re:Cognition Health Birmingham
🇬🇧
Birmingham, United Kingdom
MAC Clinical Research Blackpool
🇬🇧
Blackpool, United Kingdom
Re:Cognition Health Plymouth
🇬🇧
Plymouth, United Kingdom
CITrials
🇺🇸
Santa Ana, California, United States
Northwest Clinical Trials
🇺🇸
Boise, Idaho, United States
Miami Dade Medical Research Institute
🇺🇸
Miami, Florida, United States
Pacific Research Network
🇺🇸
San Diego, California, United States
CCBR Clinical Research, Aalborg
🇩🇰
Aalborg, Denmark
Vestra Clinics S.R.O
🇨🇿
Rychnov Nad Kněžnou, Czechia
Alliance for Research
🇺🇸
Long Beach, California, United States
Viking Clinical Research
🇺🇸
Temecula, California, United States
Sensible Healthcare, LLC
🇺🇸
Ocoee, Florida, United States
Suncoast Neuroscience Associates, Inc.
🇺🇸
Saint Petersburg, Florida, United States
Florida Premier Research Institute
🇺🇸
Winter Park, Florida, United States
Manhattan Behavioral Medicine
🇺🇸
New York, New York, United States
Northwest Clinical Research Center
🇺🇸
Seattle, Washington, United States
Neuro HK, s.r.o. POLIKLINIKA CHOCEŇ, a.s.
🇨🇿
Choceň, Czechia
CCBR Clinical Research, Ballerup
🇩🇰
Ballerup, Denmark
CCBR Clinical Research, Vejle
🇩🇰
Vejle, Denmark
Alzheimer Research Center
🇳🇱
Amsterdam, Netherlands
Fulbourn Hospital
🇬🇧
Cambridge, United Kingdom
MAC Clinical Research Leeds
🇬🇧
Leeds, United Kingdom
MAC Clinical Research Liverpool
🇬🇧
Liverpool, United Kingdom
Re:Cognition Health London
🇬🇧
London, United Kingdom
St. Pancras Clinical Research
🇬🇧
London, United Kingdom
5 Boroughs/North West Boroughs Healthcare NHS Foundation Trust
🇬🇧
Warrington, United Kingdom
MAC Clinical Research Manchester
🇬🇧
Manchester, United Kingdom
Southern California Research, LLC
🇺🇸
Simi Valley, California, United States
Anchor Neuroscience
🇺🇸
Pensacola, Florida, United States
Progressive Medical Research
🇺🇸
Port Orange, Florida, United States
Jeroen Bosch Ziekenhuis
🇳🇱
's-Hertogenbosch, Netherlands