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

Study Overview
=================
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.

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

Conditions
-----------------
Alzheimer Disease

Intervention / Treatment
-----------------
* Drug: neflamapimod
* Other: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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: CDR-Global Score of 0.5 or 1.0, with CDR memory subscore of at least 0.5. MMSE score ranging from 20 to 28, inclusive. 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.

Ages Eligible for Study
-----------------
Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind, placebo-controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: neflamapimod<br>40 mg hard gelatin capsules, taken twice daily with food. | Drug: neflamapimod<br>* 40 mg neflamapimod capsule<br>* Other names: VX-745;|
| Placebo Comparator: placebo<br>hard gelatin capsules containing excipients only, weight- and size-matched; taken twice daily with food. | Other: placebo<br>* matching placebo capsule<br>|

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 |