Huntington's Disease
Conditions
Brief summary
The primary purpose of this study is to evaluate the effect of SAGE-718 on cognitive performance and functioning in participants with HD.
Interventions
DRUGSAGE-718
Oral capsules.
DRUGPlacebo
SAGE-718-matching oral capsules.
Sponsors
Supernus Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
25 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the SDMT | Baseline, Day 84 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Trail Making Test Part B | Baseline, Day 84 | 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. |
| Change From Baseline in the One Touch Stockings of Cambridge (OTS-Mean Latency Until Correct Response) | Baseline, Day 84 | 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. |
| Change From Baseline in the Paced Tapping Test (PTAP) | Baseline, Day 84 | 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. |
| Change From Baseline in the Unified Huntington's Disease Rating Scale (UHDRS) - Independence Scale | Baseline, Day 84 | 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. |
| Change From Baseline in the Clinical Global Impression - Severity (CGI-S) Cognitive Status Subdomain Score | Baseline, Day 84 | 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. |
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Up to last follow-up visit (up to Day 112) | 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. |
| Change From Baseline in the Huntington's Disease Everyday Functioning (Hi-DEF) Home Subdomain Score | Baseline, Day 84 | 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. |
Countries
Australia, Canada, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at investigative sites from 26 January 2022 to 03 October 2024.
Pre-assignment details
A total of 309 participants with Huntington's disease (HD) were screened, of which 189 participants were randomized to receive either SAGE-718 or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received SAGE-718-matching placebo, orally, QD for up to Day 84. | 94 |
| SAGE-718 Participants received SAGE-718, 1.2 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. | 95 |
| Total | 189 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Reason Not Specified | 2 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
| Overall Study | Withdrawal of Consent | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | SAGE-718 |
|---|---|---|---|
| Age, Continuous | 52.3 years STANDARD_DEVIATION 8.71 | 51.1 years STANDARD_DEVIATION 8.94 | 50.0 years STANDARD_DEVIATION 9.07 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 16 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 87 Participants | 173 Participants | 86 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) White | 90 Participants | 177 Participants | 87 Participants |
| Sex: Female, Male Female | 48 Participants | 88 Participants | 40 Participants |
| Sex: Female, Male Male | 46 Participants | 101 Participants | 55 Participants |
| Symbol Digit Modalities Test (SDMT) Score | 27.9 score on a scale STANDARD_DEVIATION 11.86 | 28.1 score on a scale STANDARD_DEVIATION 11.52 | 28.3 score on a scale STANDARD_DEVIATION 11.24 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 94 | 0 / 95 |
| other Total, other adverse events | 29 / 94 | 18 / 95 |
| serious Total, serious adverse events | 6 / 94 | 3 / 95 |
Outcome results
Primary
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.
Time frame: Baseline, Day 84
Population: The FAS included all participants who initiated IP and had baseline and at least 1 post-baseline efficacy evaluation. The overall number of participants analyzed indicates the number of participants with data available for this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the SDMT | 2.0 score on a scale | Standard Error 0.58 |
| SAGE-718 | Change From Baseline in the SDMT | 0.8 score on a scale | Standard Error 0.57 |
p-value: 0.167595% CI: [-2.7, 0.5]MMRM
Secondary
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.
Time frame: Baseline, Day 84
Population: The FAS included all participants who initiated IP and had baseline and at least 1 post-baseline efficacy evaluation. The overall number of participants analyzed indicates the number of participants with data available for this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Clinical Global Impression - Severity (CGI-S) Cognitive Status Subdomain Score | -0.0 score on a scale | Standard Error 0.07 |
| SAGE-718 | Change From Baseline in the Clinical Global Impression - Severity (CGI-S) Cognitive Status Subdomain Score | -0.1 score on a scale | Standard Error 0.07 |
p-value: 0.292395% CI: [-0.3, 0.1]MMRM
Secondary
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.
Time frame: Baseline, Day 84
Population: The FAS included all participants who initiated IP and had baseline and at least 1 post-baseline efficacy evaluation. The overall number of participants analyzed indicates the number of participants with data available for this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Huntington's Disease Everyday Functioning (Hi-DEF) Home Subdomain Score | -4.6 score on a scale | Standard Error 1.26 |
| SAGE-718 | Change From Baseline in the Huntington's Disease Everyday Functioning (Hi-DEF) Home Subdomain Score | -0.7 score on a scale | Standard Error 1.23 |
p-value: 0.029195% CI: [0.4, 7.3]MMRM
Secondary
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.
Time frame: Baseline, Day 84
Population: The FAS included all participants who initiated IP and had baseline and at least 1 post-baseline efficacy evaluation. The overall number of participants analyzed indicates the number of participants with data available for this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the One Touch Stockings of Cambridge (OTS-Mean Latency Until Correct Response) | -4.56 seconds | Standard Error 0.9 |
| SAGE-718 | Change From Baseline in the One Touch Stockings of Cambridge (OTS-Mean Latency Until Correct Response) | -3.85 seconds | Standard Error 0.88 |
p-value: 0.576695% CI: [-1.78, 3.19]MMRM
Secondary
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.
Time frame: Baseline, Day 84
Population: The FAS included all participants who initiated IP and had baseline and at least 1 post-baseline efficacy evaluation. The overall number of participants analyzed indicates the number of participants with data available for this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Paced Tapping Test (PTAP) | 0.710 1/msec | Standard Error 0.4552 |
| SAGE-718 | Change From Baseline in the Paced Tapping Test (PTAP) | -0.157 1/msec | Standard Error 0.451 |
p-value: 0.177795% CI: [-2.13, 0.39]MMRM
Secondary
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.
Time frame: Baseline, Day 84
Population: Participants in the FAS who completed the Trail Making Test Part B at baseline within the allowable time limit (240 seconds) were included in this analysis. Participants who exceeded the 240-second limit at baseline were excluded. The overall number of participants analyzed reflects those with baseline results within the allowable time limit and at least one post-baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Trail Making Test Part B | -5.7 seconds | Standard Error 4.41 |
| SAGE-718 | Change From Baseline in the Trail Making Test Part B | -10.7 seconds | Standard Error 4.11 |
p-value: 0.408995% CI: [-17, 6.9]MMRM
Secondary
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.
Time frame: Baseline, Day 84
Population: The FAS included all participants who initiated IP and had baseline and at least 1 post-baseline efficacy evaluation. The overall number of participants analyzed indicates the number of participants with data available for this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Unified Huntington's Disease Rating Scale (UHDRS) - Independence Scale | -0.8 score on a scale | Standard Error 0.64 |
| SAGE-718 | Change From Baseline in the Unified Huntington's Disease Rating Scale (UHDRS) - Independence Scale | -1.5 score on a scale | Standard Error 0.63 |
p-value: 0.487295% CI: [-2.4, 1.1]MMRM
Secondary
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.
Time frame: Up to last follow-up visit (up to Day 112)
Population: The safety analysis set included all participants who were administered IP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 75.5 percentage of participants |
| SAGE-718 | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 62.1 percentage of participants |