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

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

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

Study Overview

• Status: Completed
• Conditions: Huntington's Disease
• Intervention / Treatment: Drug: SAGE-718; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 189
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Sage Investigational Site
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Sage Investigational Site
  • Victoria
    • Bethlehem, Victoria, Australia, 3162
      • Sage Investigational Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sage Investigational Site
• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3S 1N2
      • Sage Investigational Site
  • Ontario
    • North York, Ontario, Canada, M2K 1E1
      • Sage Investigational Site
  • Quebec
    • Montreal, Quebec, Canada, H2X 0A9
      • Sage Investigational Site
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZA
    • Sage Investigational Site
  • Birmingham, United Kingdom, B15 2FG
    • Sage Investigational Site
  • Cardiff, United Kingdom, CF10 3AX
    • Sage Investigational Site
  • Leeds, United Kingdom, LS7 4SA
    • Sage Investigational Site
  • Newcastle upon Tyne, United Kingdom, NE6 4QD
    • Sage Investigational Site
  • Plymouth, United Kingdom, PL6 8BT
    • Sage Investigational Site
  • Southampton, United Kingdom, SO16 6YD
    • Sage Investigational Site
  • London
    • Tooting, London, United Kingdom, SW17 0QT
      • Sage Investigational Site
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Sage Investigational Site
  • California
    • La Jolla, California, United States, 92037
      • Sage Investigational Site
    • Los Angeles, California, United States, 90095
      • Sage Investigational Site
    • Sacramento, California, United States, 95817
      • Sage Investigational Site
  • Colorado
    • Englewood, Colorado, United States, 80113
      • Sage Investigational Site
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Sage Investigational Site
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Sage Investigational Site
    • Boca Raton, Florida, United States, 33431
      • Sage Investigational Site
    • Tampa, Florida, United States, 33612
      • Sage Investigational Site
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Sage Investigational Site
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Sage Investigational Site
    • Chicago, Illinois, United States, 60612
      • Sage Investigational Site
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Sage Investigational Site
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Sage Investigational Site
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Sage Investigational Site
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Sage Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Sage Investigational Site
    • Boston, Massachusetts, United States, 02129
      • Sage Investigational Site
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Sage Investigational Site
  • New York
    • Buffalo, New York, United States, 14221
      • Sage Investigational Site
    • New York, New York, United States, 10032
      • Sage Investigational Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Sage Investigational Site
    • Durham, North Carolina, United States, 27705
      • Sage Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Sage Investigational Site
    • Toledo, Ohio, United States, 43614
      • Sage Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Sage Investigational Site
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Sage Investigational Site
  • Tennessee
    • Memphis, Tennessee, United States, 38157
      • Sage Investigational Site
    • Nashville, Tennessee, United States, 37212
      • Sage Investigational Site
  • Texas
    • Houston, Texas, United States, 77030
      • Sage Investigational Site
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Sage Investigational Site
  • Washington
    • Kirkland, Washington, United States, 98034
      • Sage Investigational Site
    • Spokane, Washington, United States, 99202
      • Sage Investigational Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Sage Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Meet all the following criteria for HD at Screening (Days -28 to -2):

   1. Genetically confirmed disease with huntingtin gene CAG expansion greater than or equal to (≥) 36.
   2. At screening, Unified Huntington's Disease Rating Scale (UHDRS)-Total Functional Capacity (TFC) score greater than (>) 6 and less than (<)13, suggesting no more than a moderate level of functional impairment.
   3. No features of juvenile HD.
2. Score of 15 to 25 (inclusive) on the Montreal Cognitive Assessment (MoCA) at screening indicating the presence of cognitive impairment.
3. 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.
4. 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.
5. Completion of Huntington's Disease Cognitive Assessment Battery (HD-CAB) Trail Making-B Test in less than 240 seconds at Screening (Days -28 to -2).

Exclusion Criteria:

1. Have participated in a previous clinical study of SAGE-718, have previous exposure to gene therapy, have participated in any HD investigational drug, biologic, or device trial within 180 days, or a non-HD drug, biologic, or device trial within 30 days or 5 half-lives (whichever is longer).

   (Note: Participants with confirmation of enrollment in the placebo arm of these trials would not be excluded.)

2. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants will receive SAGE-718-matching placebo, orally, once daily (QD) for up to Day 84.	Drug: Placebo; SAGE-718-matching oral capsules.
Experimental: SAGE-718; Participants will receive SAGE-718, 1.2 milligrams (mg), capsules, orally, QD for Days 1 to 27, followed by 0.9 mg for the remainder of the treatment period up to Day 84.	Drug: SAGE-718; Oral capsules.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the SDMT	The SDMT evaluates the tracking of cognitive function over time and for the early detection of cognitive impairment. The test assesses sustained attention, processing speed, visual scanning, and psychomotor speed, with the total score reflecting the number of correct pairings (out of 110 possible) completed within 90 seconds. Scores range from 0 to 110, with higher scores indicating better cognitive performance.	Baseline, 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 is a multi-domain clinical rating scale for assessment of functional capacity in HD. Independence Scale, Part V of the UHDRS, is a single-item measure to assess a participant's ability to function independently in daily activities across all stages of HD. Total score ranges from 10 to 100, with higher scores indicating better functioning. Negative change from baseline indicates worsening in functional ability.	Baseline, Day 84
Change From Baseline in the Trail Making Test Part B	The Trail Making test is a speeded graphomotor test of visual attention and task switching. Part B includes a set-switching component that requires participants to connect a series of alternating numbers and letters in order from lowest to highest (i.e., 1-A-2-B-3-C) in the shortest time possible. The time limit to complete the task is 240 seconds, at which point the test is stopped and scored using the maximum allowable time if not yet completed. Greater time indicates greater impairment. Negative change from baseline indicates less impairment.	Baseline, Day 84
Change From Baseline in the One Touch Stockings of Cambridge (OTS-Mean Latency Until Correct Response)	The OTS is a computerized test of executive function to assess problem-solving and planning ability. In this task, participants are shown a set of colored balls and must determine the minimum number of moves required to match a target arrangement by moving one ball at a time into one of two available locations. The goal is to perform the task using the smallest number of moves possible. The participant selects the correct number of moves from the options shown on the screen. The time to correct response is measured. Longer times indicate greater impairment. Negative change from baseline indicates an improvement in performance.	Baseline, Day 84
Change From Baseline in the Paced Tapping Test (PTAP)	The PTAP is a test of motor timing in which participants synchronize their finger taps with auditory pacing tones during an initial paced phase. This is followed by a self-paced phase, where the tones are removed, and the participant continues tapping until a final auditory cue signals the end of the test. The primary outcome is paced tapping consistency, calculated as the inverse of the standard deviation of the intertap intervals per millisecond (1/msec), with no range specified. Higher values indicate greater timing accuracy.	Baseline, Day 84
Change From Baseline in the Huntington's Disease Everyday Functioning (Hi-DEF) Home Subdomain Score	Hi-DEF Scale: self-reported measure to capture difficulties experienced in daily life due to HD across 4 areas of functioning: At home, At work, Driving, & Relationships. Full scale comprises 40 items which ask participants to rate their functioning difficulty using 5-point Likert scale from 1 (No Difficulty) to 5 (Cannot do this anymore) on first 3 domains (home, work & driving), & 4-point scale from 1 (Never) to 4 (Always)for Relationships. Hi-DEF total score ranges from 0-154, higher score=greater difficulty. For Home subdomain, before scores can be calculated, data from item responses should be rescored so as: lowest item-level score=0 & highest item-level score= 4. Hence, Home subdomain has 15 items scored on 5-point Likert scale, 0 indicating no difficulty & 4 indicating cannot be done anymore, where total raw score of 0-60 are transformed to 0-100. Higher score=greater difficulty. Negative change from baseline=improvement in daily functioning.	Baseline, Day 84
Change From Baseline in the Clinical Global Impression - Severity (CGI-S) Cognitive Status Subdomain Score	The CGI-S scale is a validated instrument developed by the National Institute of Mental Health specifically for use in clinical studies. Cognitive Status Subdomain is one of clinical global impression severity scales domains, for which clinicians generate ratings of the severity of the participant's condition over the past 7 days (including the day of the clinic visit). The responses are scored on a scale ranging from 0 (normal - no symptoms present) to 6 (severely disabled; helpless; complete assistance needed). Higher scores indicate greater disease symptom severity. Negative change from baseline indicates an improvement in the participant's condition.	Baseline, 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 IP, or any worsening of a pre-existing medical condition/AE with onset after the start of the IP and throughout the study.	Up to last follow-up visit (up to Day 112)

Collaborators and Investigators

• Sponsor: Supernus Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): January 26, 2022
• Primary Completion (Actual): September 4, 2024
• Study Completion (Actual): October 3, 2024

Study Registration Dates

• First Submitted: October 25, 2021
• First Submitted That Met QC Criteria: November 3, 2021
• First Posted (Actual): November 4, 2021

Study Record Updates

• Last Update Posted (Estimated): September 15, 2025
• Last Update Submitted That Met QC Criteria: September 11, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Genetic Diseases, Inborn; Neurocognitive Disorders; Cognition Disorders; Dementia; Neurodegenerative Diseases; Movement Disorders; Heredodegenerative Disorders, Nervous System; Basal Ganglia Diseases; Dyskinesias; Chorea; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Huntington Disease; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs
• Other Study ID Numbers: 718-CIH-201; 2021-005577-16 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data sharing will be consistent with the results submission policy of ClinicalTrials.gov.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No