Cognitive Effects of Oral p38 Alpha Kinase Inhibitor Neflamapimod in Dementia With Lewy Bodies

NCT04001517 | Completed Phase 2 Results FDA Drug

• 1 other identifier: EIP19-NFD-501
• Study Type: interventional
• Target: 91
• Locations: 2 countries
• Sites: 24

Brief Summary

This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, proof-of-principle study of neflamapimod versus matching placebo (randomized 1:1) administered with food for 16 weeks in subjects with DLB. The primary objective is to evaluate the effect of neflamapimod on cognitive function as assessed in a study-specific Cogstate Neuropsychological Test Battery (NTB). Secondary endpoints include the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI-10), Timed Up and Go Test, and electroencephalogram (EEG) as a potential biomarker for DLB.

Conditions

Dementia With Lewy Bodies (DLB)

Outcome Measures

Primary Outcomes (1)

• Composite Z-score of a Study-specific Neuropsychological Test Battery (NTB) Including Tests From Cogstate Battery, Letter Fluency Test and Category Fluency Test

  Change from Baseline to Week 4, Week 8, and Week 16 in the composite z-score of a study-specific Neuropsychological Test Battery (NTB) that included the following six tests: Cogstate Detection test (DET), Cogstate Identification test (IDN), Cogstate One Card Learning test (OCL), Cogstate One Back test (ONB), Letter Fluency Test, and Category Fluency Test (CFT). Each score on the individual tests was converted to a z-score, and then a total z-score for the composite was calculated, in which each test is weighted equally. As the analysis is based on z-scores, there is no minimum or maximum value. A z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. A positive change in z-score indicate an improvement in cognition, i.e., a better outcome; and a negative change in z-score indicates a worsening in cognition, i.e., a worse outcome.

  As the analysis was by Mixed Model for Repeated Measures, all time points at which NTB was assessed utilized in the analysis. The difference reported is the mean difference over the entire course of the study.

Secondary Outcomes (6)

• Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB)

  As the analysis was by Mixed Model for Repeated Measures, both time points at which CDR-SB was assessed (week 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.

• Mini-Mental State Examination (MMSE)

  As the analysis was by Mixed Model for Repeated Measures, both time points at which MMSE was assessed (week 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.

• Neuropsychiatric Inventory (NPI-10) - Mean Change in Hallucinations Domain Score

  As the analysis was by Mixed Model for Repeated Measures, all time points at which NPI-10 was assessed (weeks 4, 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.

• International Shopping List Test (ISLT) - Immediate Recall

  As the analysis was by Mixed Model for Repeated Measures, both time points at which ISLT was assessed (Weeks 4, 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.

• Timed Up and Go Test (TUG)

  As the analysis was by Mixed Model for Repeated Measures, both time points at which the TUG was assessed (week 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.

Study Arms (2)

Neflamapimod

EXPERIMENTAL

40 mg capsules administered orally, BID or TID with food for 16 weeks; subjects will follow the BID regimen if weighing \<80 kg or the TID regimen if weighing ≥80 kg

Drug: Neflamapimod

Placebo

PLACEBO COMPARATOR

40 mg matching placebo capsules administered orally, BID or TID with food for 16 weeks; subjects will follow the BID regimen if weighing \<80 kg or the TID regimen if weighing ≥80 kg

Drug: Neflamapimod

Interventions

Neflamapimod DRUG

Double-Blind, Placebo-Controlled

Neflamapimod; Placebo

Eligibility Criteria

• Age: 55 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women aged ≥55 years.
• Subject or subject's legally authorized representative is willing and able to provide written informed consent.
• Probable DLB and identified cognitive deficits, according to current consensus criteria (McKeith et al, 2017), specifically one core clinical feature and a positive DaTscan. If a negative DaTscan, but the subject has historical PSG-verified RBD, the subject would also qualify.
• MMSE score of 15-28, inclusive, during Screening.
• Currently receiving cholinesterase inhibitor therapy, having received such therapy for greater than 3 months and on a stable dose for at least 6 weeks at the time of randomization. Except for reducing the dose for tolerability reasons, the dose of cholinesterase inhibitor may not be modified during the study.
• Normal or corrected eye sight and auditory abilities, sufficient to perform all aspects of the cognitive and functional assessments.
• No history of learning difficulties that may interfere with their ability to complete the cognitive tests.
• Must have reliable informant or caregiver.

You may not qualify if:

• Diagnosis of any other ongoing central nervous system (CNS) condition other than DLB, including, but not limited to, post-stroke dementia, vascular dementia, Alzheimer's disease (AD), or Parkinson's disease (PD).
• 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 C-SSRS, or history of suicide attempt in previous 2 years, or, in the Investigator's opinion, at serious risk of suicide.
• Ongoing major and active psychiatric disorder and/or other concurrent medical condition that, 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.
• Poorly controlled clinically significant medical illness, such as hypertension (blood pressure \>180 mmHg systolic or 100 mmHg diastolic); myocardial infarction within 6 months; uncompensated congestive heart failure or other significant cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder, or metabolic/endocrine disorders or other disease that would interfere with assessment of drug safety.
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2 × the upper limit of normal (ULN), total bilirubin \>1.5 × ULN, and/or International Normalized Ratio (INR) \>1.5.
• Known human immunodeficiency virus, hepatitis B, or active hepatitis C virus infection.
• Participated in a study of an investigational drug less than 3 months or 5 half-lives of an investigational drug, whichever is longer, before enrollment in this study.
• History of previous neurosurgery to the brain.
• If male with female partner(s) of child-bearing potential, unwilling or unable to adhere to contraception requirements specified in the protocol.
• If female who has not has not reached menopause \>1 year previously or has not had a hysterectomy or bilateral oophorectomy/salpingo-oophorectomy, has a positive pregnancy test result during Screening and/or is unwilling or unable to adhere to the contraception requirements specified in the protocol.

Sponsors & Collaborators

• EIP Pharma Inc: lead
• Worldwide Clinical Trials: collaborator

Study Sites (24)

University of California San Diego (UCSD)

La Jolla, California, 92037, United States

Location

Pacific Neuroscience Institute

Santa Monica, California, 90404, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Elite Clinical Research

Miami, Florida, 33144, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66103, United States

Location

Massachusetts General Hospital

Charlestown, Massachusetts, 02129, United States

Location

University of Michigan

Ann Arbor, Michigan, 48105, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Cleveland Clinic - Lou Ruvo Center for Brain Health

Las Vegas, Nevada, 89106, United States

Location

New York Presbyterian Hospital - Columbia University Medical Center

New York, New York, 10032, United States

Location

University of Rochester

Rochester, New York, 14618, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

The Ohio State University

Columbus, Ohio, 43210, United States

Location

Summit Research Network

Portland, Oregon, 97210, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

University of Virginia

Charlottesville, Virginia, 22908, United States

Location

National Clinical Research, Inc.

Richmond, Virginia, 23294, United States

Location

Northwest Clinical Research Center

Bellevue, Washington, 98007, United States

Location

University of Washington

Seattle, Washington, 98104, United States

Location

Inland Northwest Research

Spokane, Washington, 99202, United States

Location

Brain Research Center

's-Hertogenbosch, Netherlands

Location

Brain Research Center

Amsterdam, Netherlands

Location

Related Publications (2)

• Alam JJ, Maruff P, Doctrow SR, Chu HM, Conway J, Gomperts SN, Teunissen C. Association of Plasma Phosphorylated Tau With the Response to Neflamapimod Treatment in Patients With Dementia With Lewy Bodies. Neurology. 2023 Oct 24;101(17):e1708-e1717. doi: 10.1212/WNL.0000000000207755. Epub 2023 Sep 1.

  PMID: 37657939 DERIVED

• Jiang Y, Alam JJ, Gomperts SN, Maruff P, Lemstra AW, Germann UA, Stavrides PH, Darji S, Malampati S, Peddy J, Bleiwas C, Pawlik M, Pensalfini A, Yang DS, Subbanna S, Basavarajappa BS, Smiley JF, Gardner A, Blackburn K, Chu HM, Prins ND, Teunissen CE, Harrison JE, Scheltens P, Nixon RA. Preclinical and randomized clinical evaluation of the p38alpha kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration. Nat Commun. 2022 Sep 21;13(1):5308. doi: 10.1038/s41467-022-32944-3.

  PMID: 36130946 DERIVED

MeSH Terms

Conditions

Lewy Body Disease

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Results Point of Contact

• Title: Dr. John Alam
• Organization: EIP Pharma

johnjalam@gmail.com

6176698426

Study Officials

• John Alam, MD

  EIP Pharma

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 7, 2019
• First Posted: June 28, 2019
• Study Start: September 30, 2019
• Primary Completion: June 30, 2020
• Study Completion: June 30, 2020
• Last Updated: June 29, 2023
• Results First Posted: November 2, 2021

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

NL (2); US (22)