Study of BHV-4157 in Alzheimer's Disease

Study Overview
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Brief Summary
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Preclinical models suggest that riluzole, the active metabolite of BHV-4157, may protect from AD-related pathology and cognitive dysfunction. Titrated dose of BHV-4157 to 280 mg, or placebo, were administered orally once daily. Duration of treatment is 48 weeks in double-blind phase. There is also a screening period of up to 42 days; and a 4-week post-treatment observation period. Eligible participants who completed the double-blind treatment phase had the opportunity to receive open-label troriluzole for up to 48 weeks in an open-label extension (OLE) phase.

Official Title
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A Phase 2 Randomized Double-Blind Placebo-Controlled Trial to Evaluate the Efficacy and Safety of BHV-4157 in Patients With Mild to Moderate Alzheimer's Disease

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: troriluzole
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age 50 to 85 (inclusive) at screening Diagnosed with probable Alzheimer's disease dementia: Core clinical criteria in accordance with NIA/Alzheimer's Association Guidelines. Living in the community (includes assisted living facilities, but excludes long-term care nursing facilities). Ambulatory, or able to walk with an assistive device, such as a cane or walker. Participants must have a study partner who has frequent interaction with them (approximately >3-4 times per week), will be present for all clinic visits, and can assist in compliance with study procedures. An Mini-Mental State Examination score of 14 to 24, inclusive, at screening. A brain MRI scan within 6 months of screening consistent with a diagnosis of Alzheimer's disease. Participants should be treated with a stable dosage regimen of FDA-approved AD medications (acetylcholinesterase inhibitors (AchEI) and/or memantine) for at least 3 months prior to screening. Participants should be expected to remain on a stable dosage regimen of these medications for the duration of the trial. Participants who are not being treated with FDA-approved AD medications at the time of screening, because they have contraindications to these medications, or because they have previously failed treatment with these medications, are also eligible for inclusion, if it is expected that they will not be treated with these medications for the duration of the trial. Key Exclusion Criteria: Hepatic impairment defined as Child-Pugh class of A or more severe liver impairment. Other neurodegenerative diseases and causes of dementias, including Parkinson's disease and Huntington's disease, vascular dementia, CJD (Creutzfeldt-Jakob disease), LBD (Lewy Body dementia), PSP (Progressive Supranuclear Palsy), AIDS (Acquired Immunodeficiency Syndrome), or NPH (normal pressure hydrocephalus). History of a major depressive episode within the past 6 months of screening. Insulin-dependent diabetes or uncontrolled diabetes with HbA1c value >8.0 %. Cancer or a malignant tumor within the past 3 years, except patients who underwent potentially curative therapy with no evidence of recurrence for >3 years. Patients with stable prostate cancer or non-melanoma skin cancers are not excluded. Participation in another clinical trial for an investigational agent and having taken at least one dose of study medication, unless confirmed as having been on placebo, within 12 weeks prior to screening. The end of a previous investigational trial is defined as the date of the last dose of an investigational agent.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BHV-4157<br>troriluzole, 280 mg (2 x 140 mg) capsules, QD | Drug: troriluzole<br>* Oral BHV-4157 will be given daily for up to 48 weeks<br>* Other names: BHV-4157;|
| Placebo Comparator: Placebo<br>matching 280 mg (2 x 140 mg) placebo capsules, QD | Drug: Placebo oral capsule<br>* Oral matching placebo will be given daily for up to 48 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Total Score at Week 48 | The ADAS-Cog is a structured scale that evaluates memory (word recall, word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing a letter in an envelope) and constructional praxis (copying geometric designs). Ratings of spoken language, language comprehension, word finding difficulty, and ability to remember test instructions were also obtained. The test was scored in terms of errors on a scale ranging from 0 (best) to 70 (worse), with higher scores indicate poorer performance and greater impairment. | Baseline (Day 1) and Week 48 | 
| Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-Sum of Boxes) Total Score at Week 48 | The CDR-sum of boxes is a validated composite rating of cognition and everyday functioning used in longitudinal AD research which incorporates both informant input and direct assessment of performance. It assesses through semi-structured interview 3 cognitive domains including memory, orientation, and judgement/problem solving and 3 everyday functional domains including community affairs, home and hobbies and personal care. The individual domain score ranging from 0 (none) to 3 (severe) but the scores in each of these were combined to obtain a composite score (sum of boxes) ranging from 0 (best) to 18 (worst), with higher scores indicate poorer performance and greater impairment. The individual domain scores are added to create a sum of the box scores. | Baseline (Day 1) and Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Magnetic Resonance Imaging (MRI) Hippocampal Volume at Week 48 | Volumetric MRI allows the in vivo assessment of brain structure volume and provides a measure of atrophy rate. Results from MRI studies suggest that the patterns of atrophy in AD, which mirror the pathological progression of the disease, can reliably be detected and tracked across time. Hippocampal volume derived from MRI correlates with histological hippocampal volume and degree of neuronal loss and AD pathology, and entorhinal cortical thickness change appears to be an early and sensitive indicator of neurodegeneration associated with AD. | Baseline (Day 1) and Week 48 | 
| Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score at Week 48 | The ADCS-ADL inventory scale is validated questionnaire developed by the ADCS to assess instrumental and basic activities of daily living based on a 23-item structured interview of the AD study participant's partner. The scale ranging from 0 (none) to 78 (severe), with lower scores indicate greater impairment. | Baseline (Day 1) and Week 48 | 
| Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Week 48 | The NPI is a well-validated, reliable, multi-item instrument to assess psychopathology in AD dementia based on the results of an interview with the study partner. The NPI evaluates both the frequency and severity of 10 neuropsychiatric features, including delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability and lability, and aberrant motor behavior, as well as evaluates sleep and appetite/eating disorders. Frequency assessments range from 1 (occasionally, less than once per week) to 4 (very frequently, once or more per day or continuously). Severity assessments range from 1 (mild) to 3 (severe). The total score is the sum of all subscales ranging from 1 (mild) to 7 (severe), with higher scores indicate greater impairment. | Baseline (Day 1) and Week 48 | 
| Change From Baseline in Mini-Mental Status Examination (MMSE) Total Score at Week 48 | The MMSE is a frequently used screening instrument for AD drug studies. It evaluates orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy 2 intersecting pentagons. The MMSE scale ranging from 0 (worse) to 30 (best), with a lower score indicate more cognitive impairment. | Baseline (Day 1) and Week 48 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in participants or clinical investigation participants administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. A serious AE (SAE) is defined as any event that met any of the following criteria at any dose: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of a participant who received study drug; other important medical events that may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the other serious outcomes. An AE is considered Related for causality designations of possible, probable and definite. | TEAEs were reported from first dose of study drug up to end of study treatment, maximum of 96 weeks. |