Proof-of-Concept Study of a Selective p38 MAPK Alpha Inhibitor, Neflamapimod, in Subjects With Mild Alzheimer's Disease
Condition: Alzheimer Disease
MeSH terms: Alzheimer Disease
Intervention: neflamapimod; placebo
Intervention description: 40 mg neflamapimod capsule; matching placebo capsule
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Double-blind, placebo-controlled
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 161.0
Sex: All
Minimum age: 55 Years
Maximum age: 85 Years
Healthy volunteers: No

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.
    

Eligibility 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.