Clinical trial NCT03402659: Proof-of-Concept Study of a Selective p38 MAPK Alpha Inhibitor, Neflamapimod, in Subjects With Mild Alzheimer's Disease
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer Disease
Lead sponsor: EIP Pharma Inc
Sponsor class: INDUSTRY
Collaborators: name: Worldwide Clinical Trials
name: Amsterdam UMC, location VUmc
First posted: 2018-01-18
Enrollment: 161
Sex: ALL
Minimum age (years): 55
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blind, placebo-controlled
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Total and Delayed Recall on the Hopkins Verbal Learning Test - Revised (HVLT-R)
timeFrame: Baseline and 24 weeks
Secondary outcomes:
measure: Wechsler Memory Scale (WMS) Immediate and Delayed Recall
timeFrame: Baseline and 24 weeks
measure: Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB)
timeFrame: Baseline and 24 weeks
measure: Mini-Mental State Examination (MMSE)
timeFrame: Baseline and 26 Weeks (Follow-up visit, 2 weeks from end of dosing)
measure: Cerebrospinal Fluid Total Tau
timeFrame: Baseline and 24 weeks
measure: Cerebrospinal Fluid Phospho-tau
timeFrame: Baseline and 24 weeks
measure: Cerebrospinal Fluid Amyloid Beta 1-40
timeFrame: Baseline and 24 weeks
measure: Cerebrospinal Fluid Amyloid Beta 1-42
timeFrame: Baseline and 24 weeks
measure: Cerebrospinal Fluid Neurogranin
timeFrame: Baseline and 24 weeks
measure: Cerebrospinal Fluid Neurofilament Light Chain
timeFrame: Baseline and 24 weeks
measure: Cerebrospinal Fluid P-tau/AB1-42 Ratio
timeFrame: Baseline and 24 weeks
Other outcomes:
Locations:
city: Long Beach
country: United States
facility: Alliance for Research
state: California
city: San Diego
country: United States
facility: Pacific Research Network
state: California
city: Santa Ana
country: United States
facility: CITrials
state: California
city: Simi Valley
country: United States
facility: Southern California Research, LLC
state: California
city: Temecula
country: United States
facility: Viking Clinical Research
state: California
city: Miami
country: United States
facility: Miami Dade Medical Research Institute
state: Florida
city: Ocoee
country: United States
facility: Sensible Healthcare, LLC
state: Florida
city: Pensacola
country: United States
facility: Anchor Neuroscience
state: Florida
city: Port Orange
country: United States
facility: Progressive Medical Research
state: Florida
city: Saint Petersburg
country: United States
facility: Suncoast Neuroscience Associates, Inc.
state: Florida
city: Winter Park
country: United States
facility: Florida Premier Research Institute
state: Florida
city: Boise
country: United States
facility: Northwest Clinical Trials
state: Idaho
city: Charlestown
country: United States
facility: MassGeneral Institute for Neurodegenerative Disease
state: Massachusetts
city: New York
country: United States
facility: Manhattan Behavioral Medicine
state: New York
city: Charlotte
country: United States
facility: Alzheimer's Memory Center and Research Institute
state: North Carolina
city: Seattle
country: United States
facility: Northwest Clinical Research Center
state: Washington
city: Choceň
country: Czechia
facility: Neuro HK, s.r.o. POLIKLINIKA CHOCEŇ, a.s.
city: Moravská Ostrava
country: Czechia
facility: Cerebrovaskulární poradna s.r.o.
city: Prague
country: Czechia
facility: Clintrial S.R.O
city: Prague
country: Czechia
facility: Private Psychiatric Centre
city: Rychnov Nad Kněžnou
country: Czechia
facility: Vestra Clinics S.R.O
city: Aalborg
country: Denmark
facility: CCBR Clinical Research, Aalborg
city: Ballerup
country: Denmark
facility: CCBR Clinical Research, Ballerup
city: Vejle
country: Denmark
facility: CCBR Clinical Research, Vejle
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Amsterdam
country: Netherlands
facility: Alzheimer Research Center
city: Breda
country: Netherlands
facility: Amphia Ziekhuis
city: Barnsley
country: United Kingdom
facility: MAC Clinical Research Tankersley
city: Birmingham
country: United Kingdom
facility: Re:Cognition Health Birmingham
city: Blackpool
country: United Kingdom
facility: MAC Clinical Research Blackpool
city: Cambridge
country: United Kingdom
facility: Fulbourn Hospital
city: Leeds
country: United Kingdom
facility: MAC Clinical Research Leeds
city: Liverpool
country: United Kingdom
facility: MAC Clinical Research Liverpool
city: London
country: United Kingdom
facility: Re:Cognition Health London
city: London
country: United Kingdom
facility: St. Pancras Clinical Research
city: Manchester
country: United Kingdom
facility: MAC Clinical Research Manchester
city: Plymouth
country: United Kingdom
facility: Re:Cognition Health Plymouth
city: Warrington
country: United Kingdom
facility: 5 Boroughs/North West Boroughs Healthcare NHS Foundation Trust
Study officials:
affiliation: EIP Pharma
name: John Alam, MD
role: STUDY_DIRECTOR
References:
citation: Prins ND, Harrison JE, Chu HM, Blackburn K, Alam JJ, Scheltens P; REVERSE-SD Study Investigators. A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease. Alzheimers Res Ther. 2021 May 27;13(1):106. doi: 10.1186/s13195-021-00843-2.
citation: Tormahlen NM, Martorelli M, Kuhn A, Maier F, Guezguez J, Burnet M, Albrecht W, Laufer SA, Koch P. Design and Synthesis of Highly Selective Brain Penetrant p38alpha Mitogen-Activated Protein Kinase Inhibitors. J Med Chem. 2022 Jan 27;65(2):1225-1242. doi: 10.1021/acs.jmedchem.0c01773. Epub 2021 May 11.