A Study to Evaluate the Effect of SAGE-718 on Cognitive Function in Participants With Huntington's Disease (HD)

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the effect of SAGE-718 on cognitive performance and functioning in participants with HD.

Official Title
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A Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Effect of SAGE-718 on Cognitive Function in Participants With Huntington's Disease

Conditions
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Huntington's Disease

Intervention / Treatment
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* Drug: SAGE-718
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet all the following criteria for HD: Genetically confirmed disease with huntingtin gene CAG expansion ≥36. UHDRS-Total Functional Capacity (TFC) score >6 and <13. No features of juvenile HD. Score <26 on the Montreal Cognitive Assessment (MoCA) at screening. Be willing to invite a study partner, if available, who is reliable, competent, and at least 18 years of age to participate in the study. Be ambulatory (use of assistance devices such as a walker or cane is acceptable, as is occasional use of wheelchair, as judged by the investigator. Individuals requiring a wheelchair on a regular basis are excluded), able to travel to the study center, and, as judged by the investigator, is likely to be able to continue to travel to the study center to complete study visits for the duration of the study. Exclusion Criteria: Have participated in a previous clinical study of SAGE-718, have participated in a previous gene therapy study, or have participated in any other drug, biologic, or device trial within 30 days or 5 half-lives (whichever is longer), unless the patient participated solely in the placebo arm of the study. Additionally, participants who have received treatment with antisense oligonucleotides (ASOs) or an mRNA splicing modifier will be excluded. Have a diagnosis of an ongoing neurodegenerative condition other than HD, including but not limited to, Alzheimer's Disease, vascular dementia, dementia with Lewy bodies, or Parkinson's Disease.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAGE-718<br>Participants will receive SAGE-718, once daily for 84 days. | Drug: SAGE-718<br>* Oral capsules.<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo, once daily for 84 days. | Drug: Placebo<br>* SAGE-718-matching oral capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Huntington's Disease Cognitive Assessment Battery (HD-CAB) Composite Score | The HD-CAB evaluates cognitive function via the following subtests: Symbol Digit Modalities Test; One Touch Stockings of Cambridge; Trail Making; Hopkins Verbal Learning Test Revised; Paced Tapping Test; and the Emotion Recognition Test. The HD-CAB composite is derived by transforming individual participants' scores on each of the 6 subtests to z-scores, and averaging z-scores to represent global performance relative to the reference sample. Change from baseline will be computed using baseline mean and standard deviation, with an expected z-score distribution of approximately -3 to +3. A positive HD-CAB composite at follow-up indicates improvement in cognitive function; a negative composite score indicates worsening in cognitive function; and a composite of 0 would reflect no change relative to baseline. | Baseline and Day 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Unified Huntington's Disease Rating Scale (UHDRS) - Independence Scale | The UHDRS independence scale is a single item of independence rated from 10 to 100, with higher scores on the function scales indicating better functioning than lower scores. | Baseline and Day 84 | 
| Change From Baseline in the UHDRS - Total Motor Score (TMS) | The motor section of the UHDRS assesses motor features of HD with standardized ratings of oculomotor function, dysarthria, chorea, dystonia, gait, and postural stability. Each item is scored on a scale of 0-4, where 0 is normal, and 4 is the highest motor dysfunction. The total motor impairment score is the sum of all the individual motor ratings. The total score range is 0-24, with higher scores indicating more severe motor impairment than lower scores. | Baseline and Day 84 | 
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. A TEAE is defined as an AE with onset after the start of the investigational product, or any worsening of a pre-existing medical condition/AE with onset after the start of the investigational product and throughout the study. | Up to approximately 112 days |