RewinD-LB - Clinical Study of Neflamapimod in Patients With Dementia With Lewy Bodies

A Phase 2b Clinical Study of the P38 Alpha Kinase Inhibitor Neflamapimod in Patients With Dementia With Lewy Bodies

The purpose of this study is to determine whether neflamapimod can improve learning skills, problem solving skills, and memory loss in people diagnosed with DLB. More specifically, improvement in verbal learning, memory, and attention, as well as cognitive and functional performance will be measured.

Study Overview

• Status: Completed
• Conditions: Dementia With Lewy Bodies
• Intervention / Treatment: Drug: Neflamapimod; Drug: Placebo

Detailed Description

This study includes a 16-week blinded treatment period (randomized 1:1 neflamapimod:placebo) and a 32 week open-label extension during which all participants receive neflamapimod.

• Study Type: Interventional
• Enrollment (Actual): 159
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • 's-Hertogenbosch, Netherlands, 5223
    • Brain Research Center - Den Bosch
  • Amsterdam, Netherlands, 1081
    • Brain Research Center - Amsterdam
  • Zwolle, Netherlands, 8025
    • Brain Research Center - Zwolle
• United Kingdom
  • Belfast, United Kingdom, BT12 6BA
    • Belfast Health & Social care Trust
  • Cambridge, United Kingdom, CB215EF
    • Cambridgeshire and Peterborough NHS Foundation Trust, Fulbourn Hospital - Windsor Research Unit
  • London, United Kingdom, SE5 8AF
    • South London and Maudsley NHS Foundation Trust
  • London, United Kingdom, W1G9JF
    • Re:Cognition Health
  • London, United Kingdom, WC1N 3BG
    • University College London (UCL) Clinical Research Facility, University College London Hospitals NHS Foundation Trust
  • Newcastle upon Tyne, United Kingdom, NE4 5PL
    • Campus Ageing Research Unit (CARU) - Newcastle upon Tyne, CNTW NHS Foundation Trust
  • Redruth, United Kingdom, TR15 3QE
    • Cornwall Partnership NHS Foundation Trust (University of Exeter)
  • Southampton, United Kingdom, SO30 3JB
    • Memory Assessment and Research Centre (MARC) - Moorgreen Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute
    • Sun City, Arizona, United States, 85351
      • Banner Sun Health Research Institute
    • Tucson, Arizona, United States, 85718
      • Banner Alzheimer's Institute - Edson Family Lewy Body Dementia Center
  • California
    • La Jolla, California, United States, 92037
      • UCSD Health Sciences - Movement Disorders Center
    • Newport Beach, California, United States, 92663
      • Hoag Memorial Hospital Presbyterian
    • Palo Alto, California, United States, 94304
      • Stanford Neuroscience Health Center
    • Pasadena, California, United States, 91105
      • SC3 Research Group
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado - Dept of Neurology
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Georgetown Univ Hospital - Dept of Neurology
  • Florida
    • Lake Worth, Florida, United States, 33462
      • JEM Research Institute
    • Melbourne, Florida, United States, 32940
      • ClinCloud
    • Orlando, Florida, United States, 32804
      • AdventHealth Neuroscience Research
    • Pensacola, Florida, United States, 32503
      • Panhandle Research and Medical Clinic
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Louisiana
    • Marrero, Louisiana, United States, 70072
      • Tandem Clinical Research
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins School of Medicine - Dept of Neurology
  • Massachusetts
    • Charlestown, Massachusetts, United States, 02129
      • Mass General Hospital/Harvard Medical School - Dept of Neurology
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Alzheimer's Disease Research Center
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center - Dept of Neurological Sciences
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Cleveland Clinic - Lou Ruvo Center for Brain Health
  • New York
    • New York, New York, United States, 10032
      • Columbia University - Taub Institute/Neurology Dept
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina - Dept of Neurology
  • Ohio
    • Canton, Ohio, United States, 44718
      • NeuroScience Research Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic - Center for Brain Health
    • Columbus, Ohio, United States, 43221
      • Ohio State University - Dept of Neurology
  • Oregon
    • Portland, Oregon, United States, 97225
      • Center for Cognitive Health
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital - Stanley Appel Neurology Dept
  • Virginia
    • Arlington, Virginia, United States, 22205
      • Sana Research
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University - Parkinson's and Movement Disorders Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Men and women aged ≥55 years.
2. Subject or subject's legally authorized representative is willing and able to provide written informed consent.

3. 3. Probable DLB by consensus criteria (McKeith et al, 2017), including a positive DaTscan™. Specifically, the subject must have the presence of dementia in association with:

   • At least two (2) core clinical features (fluctuating cognition, visual hallucinations, REM sleep disorder, and/or parkinsonism); or
   • One (1) core clinical feature plus an abnormal DaTscan™. Historical polysomnography (PSG)-verified REM sleep behavioral disorder (RBD), FDG-PET imaging, or MIBG myocardial scintigraphy can take the place of an abnormal DaTscan™ in a patient with only one core clinical feature.
4. CDR Global Score 0.5 (very mild dementia) or 1.0 (mild dementia) during Screening

5. Background dementia therapy:

   • Not currently receiving cholinesterase inhibitor therapy. If the patient received such therapy previously, that therapy must have been discontinued at least 3 months prior to randomization.
   • Receiving cholinesterase inhibitor therapy alone. If the patient is currently receiving cholinesterase inhibitor therapy, the patient must have 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.
   • Memantine therapy is allowed, if it had been started at least 3 months prior to randomization and the patient is also receiving cholinesterase inhibitor therapy. If the patient has never been on cholinesterase inhibitor therapy (naïve), then memantine monotherapy is allowed.
6. Normal or corrected eyesight and auditory abilities, sufficient to perform all aspects of the cognitive and functional assessments.
7. No history of learning difficulties that may interfere with their ability to complete the cognitive tests.
8. Received vaccination for SARS-CoV-19 unless medical contraindications prevent being vaccinated, or has a history of natural infection.
9. Must have reliable informant or caregiver.

Exclusion Criteria:

1. 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).
2. Plasma ptau181 result above the threshold that indicates evidence of pathology associated with Alzheimer's disease at Screening.
3. 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.
4. 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.
5. Diagnosis of alcohol or drug abuse within the previous 2 years.
6. 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.
7. 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. If patient is taking blood thinners (e.g., warfarin), and has no known liver issues, INR >3.
8. Known human immunodeficiency virus, hepatitis B, or active hepatitis C virus infection.
9. Participated in a study of an investigational drug less than six weeks or 5 half-lives of an investigational drug, whichever is longer, before enrollment in this study.
10. History of previous neurosurgery to the brain within the past five years.
11. If male with female partner(s) of child-bearing potential, unwilling or unable to adhere to contraception requirements specified in the protocol.
12. 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.
13. Weight less than 50kg.

All participants who complete the initial 16-week period of the study will be able to continue in the study and receive neflamapimod for an additional 32 weeks (8 months) regardless of whether they received neflamapimod of placebo during the the first 16 weeks.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Neflamapimod; Neflamapimod will be administered with food for 16 weeks in participants with DLB. Participants will receive 3 capsules per day (TID) with food (i.e., with the morning, mid-day and evening meals).	Drug: Neflamapimod; Neflamapimod is a highly specific inhibitor of the intra-cellular enzyme mitogen-activated protein kinase14 (p38α) provided in 40mg capsules; Other Names: VX-745
Placebo Comparator: Placebo; Placebo will be administered with food for 16 weeks in participants with DLB. Participants will receive 3 capsules per day (TID) with food (i.e., with the morning, mid-day and evening meals).	Drug: Placebo; Placebo is a capsule that looks just like neflamapimod but without the active ingredients
Experimental: Open-label extension; Neflamapimod will be administered with food for 32 weeks in participants with DLB who have completed the blinded treatment period. Participants will receive 3 capsules per day (TID) with food (i.e., with the morning, mid-day and evening meals).	Drug: Neflamapimod; Neflamapimod is a highly specific inhibitor of the intra-cellular enzyme mitogen-activated protein kinase14 (p38α) provided in 40mg capsules; Other Names: VX-745

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) in Neflamapimod-treated Participants Compared to Placebo Recipients (Blinded Treatment Period)	The primary objective is to demonstrate the efficacy of neflamapimod, compared to placebo, as a treatment for DLB, as assessed by the CDR-SB scale. CDR-SB scores range from 0 to 18 with a higher score indicating worsening of cognitive impairment.	16 weeks
Change in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) in Neflamapimod-treated Participants, Drug Batch A Compared to Drug Batch B (Open-label Extension)	The primary objective is to demonstrate the efficacy of neflamapimod, in recipients of Drug Batch A compared to Drug Batch B, as a treatment for DLB, as assessed by the CDR-SB scale. CDR-SB scores range from 0 to 18 with a higher score indicating worsening of cognitive impairment.	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Timed Up and Go Test (TUG) in Neflamapimod-treated Participants Compared to Placebo Recipients (Blinded Treatment Period)	Demonstrate that neflamapimod improves motor function in participants with DLB, compared to placebo, as assessed by the TUG test. TUG scores typically range from 6 to 20 seconds with a higher score indicating worse mobility. A score of >15 indicates an increased risk of falls.	16 weeks
Change in Timed Up and Go Test (TUG) in Neflamapimod-treated Participants, Drug Batch A Compared to Drug Batch B (Open-label Extension)	Demonstrate that neflamapimod improves motor function in participants with DLB, in recipients of Drug Batch A compared to Drug Batch B, as assessed by the TUG test. TUG scores typically range from 6 to 20 seconds with a higher score indicating worse mobility. A score of >15 indicates an increased risk of falls.	16 weeks
Change in the Composite Score of the Neuropsychological Test Battery (NTB), Including Tests of Attention, Executive Function, and Visual Learning in Neflamapimod-treated Participants Compared to Placebo Recipients (Blinded Treatment Period)	Demonstrate that neflamapimod improves cognition, compared to placebo, as assessed by a DLB-specific NTB in participants with DLB. NTB includes Cogstate Detection test (DET), Cogstate Identification test (IDN), Cogstate One Card Learning test (OCL), Cogstate One Back test (ONB). Each score on the individual tests is converted to a z-score, and then a total z-score for the composite is 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 indicates an improvement in cognition and a negative change in z-score indicates a worsening in cognition.	16 weeks
Change in the Composite Score of the Neuropsychological Test Battery (NTB), Including Tests of Attention, Executive Function, and Visual Learning in Neflamapimod-treated Participants, Drug Batch A Compared to Drug Batch B (Open-label Extension)	Demonstrate that neflamapimod improves cognition, in recipients of Drug Batch A compared to Drug Batch B as assessed by a DLB-specific NTB in participants with DLB. NTB includes Cogstate Detection test (DET), Cogstate Identification test (IDN), Cogstate One Card Learning test (OCL), Cogstate One Back test (ONB). Each score on the individual tests is converted to a z-score, and then a total z-score for the composite is 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 indicates an improvement in cognition and a negative change in z-score indicates a worsening in cognition.	16 weeks
Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-GCIC) Score at Week 16 in Neflamapimod-treated Participants Compared to Placebo Recipients (Blinded Treatment Period)	Demonstrate that neflamapimod improves global (cognition, function and behavior) disease status evaluated by a clinician with caregiver input, compared to placebo, in participants with DLB, as assessed ADCS-CGIC score. ADCS-CGIC scores range from 1 to 7, where 1 = marked improvement, 2= moderate improvement, 3 = minimal improvement, 4 = no change, 5 = minimal worsening, 6 = moderate worsening, and 7 = marked worsening.	16 weeks
Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-GCIC) Score at Week 16 in Neflamapimod-treated Participants, Drug Batch A Compared to Drug Batch B (Open-label Extension)	Demonstrate that neflamapimod improves global (cognition, function and behavior) disease status evaluated by a clinician with caregiver input, in recipients of Drug Batch A compared to Drug Batch B, in patients with DLB, as assessed ADCS-CGIC score. ADCS-CGIC scores range from 1 to 7, where 1 = marked improvement, 2= moderate improvement, 3 = minimal improvement, 4 = no change, 5 = minimal worsening, 6 = moderate worsening, and 7 = marked worsening.	16 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Outcome - Plasma Biomarker, Glial Fibrillary Acidic Protein (GFAP), Measurement at Week 32 (Open-label Extension)	Change from Baseline in GFAP levels in neflamapimod-treated participants, Drug Batch A compared to Drug Batch B, over 32 weeks. GFAP in plasma is measured in pg/mL (picograms per milliliter) and a reduction in levels is associated with clinical improvement	32 weeks

Collaborators and Investigators

• Sponsor: EIP Pharma Inc
• Collaborators: National Institute on Aging (NIA); Worldwide Clinical Trials; CervoMed, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2023
• Primary Completion (Actual): May 29, 2025
• Study Completion (Actual): June 16, 2025

Study Registration Dates

• First Submitted: April 12, 2023
• First Submitted That Met QC Criteria: May 17, 2023
• First Posted (Actual): May 22, 2023

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: May 1, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: DLB
• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Neurodegenerative Diseases; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Lewy Body Disease; VX-745
• Other Study ID Numbers: EIP21-NFD-504; R01AG080536 (U.S. NIH Grant/Contract); 2023-504373-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No