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

Alzheimer Disease Clinical Trial

— REVERSE-SD  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03402659
• Other study ID #: EIP-VX17-745-304
• Status: Completed
• Phase: Phase 2
• Start date: December 29, 2017
• Est. completion date: July 31, 2019

Study information

• Verified date: September 2021
• Source: EIP Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Details provided elsewhere.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 161
• Est. completion date: July 31, 2019
• Est. primary completion date: June 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 55 Years to 85 Years

Eligibility

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 Aß1-42R 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.

Related Conditions & MeSH terms

• Alzheimer Disease

Intervention

Drug:
• neflamapimod
40 mg neflamapimod capsule

Other:
• placebo
matching placebo capsule

Locations

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

Sponsors (3)

Lead Sponsor	Collaborator
EIP Pharma Inc	VU University Medical Center, Worldwide Clinical Trials

Countries where clinical trial is conducted

United States,  Czechia,  Denmark,  Netherlands,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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