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

Study Overview
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Brief Summary
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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.

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

Conditions
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Dementia With Lewy Bodies

Intervention / Treatment
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* Drug: Neflamapimod
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged ≥55 years. Subject or subject's legally authorized representative is willing and able to provide written informed consent. Probable DLB by consensus criteria (McKeith et al, 2017), including a positive DaTscan™, who are currently receiving cholinesterase inhibitor therapy. If the DaTscan is negative, but the subject has historical polysomnography (PSG)-verified REM sleep behavioral disorder (RBD), this will also qualify as probable DLB. CDR Global Score 0.5 or 1.0 during Screening 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. If the patient is not currently receiving cholinesterase inhibitor therapy, but received such therapy previously, that therapy must have been discontinued at least 3 months prior to randomization. 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 (memantine monotherapy, i.e., without concomitant cholinesterase inhibitor therapy, is excluded). Normal or corrected eyesight 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. Received vaccination for SARS-CoV-19 unless medical contraindications prevent being vaccinated. Must have reliable informant or caregiver. Exclusion Criteria: 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). Plasma ptau181 > 2.4 pg/mL (i.e., above cut-off for pathology associated with Alzheimer's disease) at Screening. 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 six weeks or 5 half-lives of an investigational drug, whichever is longer, before enrollment in this study. History of previous neurosurgery to the brain within the past five years. 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. Weight less than 60kg. 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.

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 2b (hypothesis-testing), multi-center, randomized, double-blind, placebo-controlled study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Neflamapimod<br>Neflamapimod will be administered with food for 16 weeks in subjects with DLB. Subjects will receive 3 capsules per day (TID) with food (i.e., with the morning, mid-day and evening meals). | Drug: Neflamapimod<br>* Neflamapimod is a highly specific inhibitor of the intra-cellular enzyme mitogen-activated protein kinase14 (p38α) provided in 40mg capsules<br>* Other names: VX-745;|
| Placebo Comparator: Placebo<br>Placebo will be administered with food for 16 weeks in subjects with DLB. Subjects will receive 3 capsules per day (TID) with food (i.e., with the morning, mid-day and evening meals). | Drug: Placebo<br>* Placebo is a capsule that looks just like neflamapimod but without the active ingredients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) in neflamapimod-treated subjects compared to placebo recipients. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Timed Up and Go Test (TUG) in neflamapimod-treated subjects compared to placebo recipients. | Demonstrate that neflamapimod improves motor function in patients 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 the composite score of the Neuropsychological Test Battery (NTB), including tests of attention, executive function, and visual learning in neflamapimod-treated subjects compared to placebo recipients. | Demonstrate that neflamapimod improves cognition, compared to placebo, as assessed by a DLB-specific NTB in patients with DLB. NTB includes Cogstate Detection test (DET), Cogstate Identification test (IDN), Cogstate One Card Learning test (OCL), Cogstate One Back test (ONB), Letter Fluency Test (LFT). 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 subjects compared to placebo recipients. | Demonstrate that neflamapimod improves global (cognition, function and behavior) disease status evaluated by a clinician with caregiver input, compared to placebo, 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DLB