Cognitive Dysfunction, Parkinson Disease
Conditions
Brief summary
The primary purpose of this study is to evaluate the effect of SAGE-718 on cognitive performance in participants with Parkinson's disease mild cognitive impairment (PD-MCI).
Interventions
Oral capsules
DRUGSAGE-718
Oral capsules
Sponsors
Supernus Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Meet the following criteria for PD-MCI: Have a confirmed diagnosis of idiopathic Parkinson's disease (PD) according to 2015 Movement Disorder Society (MDS) clinical diagnostic criteria and meet MDS Task Force criteria for MCI in PD (excluding requirement for United Kingdom PD Brain Bank diagnostic criteria). 2. Meet the following criteria for Montreal Cognitive Assessment (MoCA): For participants meeting Level 1 PD-MCI criteria, have a MoCA score of 20 to 25 (inclusive) at Screening; For participants meeting Level 2 PD-MCI criteria (within the past year), have a MoCA score of 18 to 25 (inclusive) at Screening. 3. Meet criteria for modified Hoehn & Yahr Stage I to III (mild to moderate motor severity) at Screening. 4. Have stable motor symptoms for at least 4 weeks prior to Screening, in the opinion of the investigator. 5. Must be able to complete the Color Trails Test 1 (including the ability to follow rater redirection and correct errors), and, based on participant's performance and investigator's opinion, participant is expected to be capable of engaging in prolonged cognitive testing for the duration of the study.
Exclusion criteria
1. Have a diagnosis of dementia of any etiology, including but not limited to: Dementia with Lewy bodies, Alzheimer's dementia, and vascular dementia. 2. Have any parkinsonism other than PD, including secondary parkinsonism or atypical parkinsonism. 3. In the opinion of the investigator, be experiencing fluctuations in motor symptoms associated with PD that will interfere with completing study procedures. 4. Have an ongoing central nervous system condition other than PD that in the opinion of the investigator could influence the outcome of the study. 5. Have experienced significant psychotic symptoms, including hallucinations or delusions, within the past 3 months, in the opinion of the investigator. 6. Have a history of brain surgery, deep brain stimulation, or any history of hospitalization due to a brain injury. 7. Have a history, presence, and/or current evidence clinically relevant intracranial abnormality (e.g., stroke, hemorrhage, space-occupying lesion).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Wechsler Adult Intelligence Scale-IV (WAIS-IV) Coding Test Score | Baseline, Day 42 | The WAIS-IV coding test is a valid and sensitive measure of cognitive dysfunction that correlates with real-world functional outcomes (e.g., the ability to accomplish everyday tasks) and recovery from functional disability used to assess processing speed. The participant is required to identify the symbols matched to numbers using a key and write in the symbol beneath the associated number. The total score ranges from 0 to 135 and is based on the total number of codes correctly completed over a 120-second time limit. Higher scores indicate better processing speed. Positive change from baseline indicates better processing speed. Least Squares (LS) Means were calculated using a mixed-effects model for repeated measures (MMRM) approach. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | Up to Day 70 | An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal (investigational) product. A TEAE is defined as any AE on or after the first dose of IP or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study. |
| Number of Participants With at Least One TEAE by Severity | Up to Day 70 | A TEAE is defined as any AE on or after the first dose of IP or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study. Severity was assessed as: * Mild: symptoms barely noticeable to participant or does not make participant uncomfortable; does not influence performance or functioning; prescription drug not ordinarily needed for relief of symptoms * Moderate: symptoms of a sufficient severity to make participant uncomfortable; performance of daily activity is influenced; participant is able to continue in study; treatment for symptoms may be needed * Severe: symptoms cause severe discomfort; symptoms cause incapacitation or significant impact on participant's daily life; severity may cause cessation of treatment with IP; treatment for symptoms may be given and/or participant hospitalized. Participant with multiple instances of events is counted only once using maximum intensity. |
| Number of Participants Who Withdrew From Study Due to TEAEs | Up to Day 70 | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal (investigational) product. A TEAE is defined as any AE on or after the first dose of IP or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at 38 investigative sites in the United States from 06 June 2022 to 23 February 2024.
Pre-assignment details
A total of 190 participants were screened, of which 86 participants were randomized to receive either SAGE-718 or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received SAGE-718-matching placebo, oral capsules, QD in the morning for 42 days. | 43 |
| SAGE-718 Participants received SAGE-718, 1.2 mg, oral capsules, QD in the morning for 42 days. | 43 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-Compliance with Study Drug | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | SAGE-718 |
|---|---|---|---|
| Age, Continuous | 68.5 years STANDARD_DEVIATION 4.76 | 68.3 years STANDARD_DEVIATION 5.59 | 68.2 years STANDARD_DEVIATION 6.37 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 17 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 69 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 41 Participants | 81 Participants | 40 Participants |
| Sex: Female, Male Female | 9 Participants | 23 Participants | 14 Participants |
| Sex: Female, Male Male | 34 Participants | 63 Participants | 29 Participants |
| Wechsler Adult Intelligence Scale-IV (WAIS-IV) Coding Test Score | 40.5 score on a scale STANDARD_DEVIATION 13.27 | 40.1 score on a scale STANDARD_DEVIATION 13.1 | 39.7 score on a scale STANDARD_DEVIATION 13.06 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 43 | 0 / 43 |
| other Total, other adverse events | 4 / 43 | 5 / 43 |
| serious Total, serious adverse events | 2 / 43 | 3 / 43 |
Outcome results
Primary
Change From Baseline in the Wechsler Adult Intelligence Scale-IV (WAIS-IV) Coding Test Score
The WAIS-IV coding test is a valid and sensitive measure of cognitive dysfunction that correlates with real-world functional outcomes (e.g., the ability to accomplish everyday tasks) and recovery from functional disability used to assess processing speed. The participant is required to identify the symbols matched to numbers using a key and write in the symbol beneath the associated number. The total score ranges from 0 to 135 and is based on the total number of codes correctly completed over a 120-second time limit. Higher scores indicate better processing speed. Positive change from baseline indicates better processing speed. Least Squares (LS) Means were calculated using a mixed-effects model for repeated measures (MMRM) approach.
Time frame: Baseline, Day 42
Population: FAS included all participants in the safety set (which included all participants who were administered at least one dose of the IP) who had baseline and at least 1 post-baseline efficacy evaluation. Here, 'overall number of participants analyzed' signifies the number of participants with data available for analysis at specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Wechsler Adult Intelligence Scale-IV (WAIS-IV) Coding Test Score | 2.0 score on a scale | Standard Error 1.44 |
| SAGE-718 | Change From Baseline in the Wechsler Adult Intelligence Scale-IV (WAIS-IV) Coding Test Score | 2.0 score on a scale | Standard Error 1.48 |
p-value: 0.993495% CI: [-4.13, 4.09]MMRM
Secondary
Number of Participants Who Withdrew From Study Due to TEAEs
An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal (investigational) product. A TEAE is defined as any AE on or after the first dose of IP or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study.
Time frame: Up to Day 70
Population: The safety set included all participants who were administered at least one dose of the IP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Withdrew From Study Due to TEAEs | 0 Participants |
| SAGE-718 | Number of Participants Who Withdrew From Study Due to TEAEs | 0 Participants |
Secondary
Number of Participants With at Least One TEAE by Severity
A TEAE is defined as any AE on or after the first dose of IP or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study. Severity was assessed as: * Mild: symptoms barely noticeable to participant or does not make participant uncomfortable; does not influence performance or functioning; prescription drug not ordinarily needed for relief of symptoms * Moderate: symptoms of a sufficient severity to make participant uncomfortable; performance of daily activity is influenced; participant is able to continue in study; treatment for symptoms may be needed * Severe: symptoms cause severe discomfort; symptoms cause incapacitation or significant impact on participant's daily life; severity may cause cessation of treatment with IP; treatment for symptoms may be given and/or participant hospitalized. Participant with multiple instances of events is counted only once using maximum intensity.
Time frame: Up to Day 70
Population: The safety set included all participants who were administered at least one dose of the IP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With at Least One TEAE by Severity | Mild | 15 Participants |
| Placebo | Number of Participants With at Least One TEAE by Severity | Moderate | 10 Participants |
| Placebo | Number of Participants With at Least One TEAE by Severity | Severe | 2 Participants |
| SAGE-718 | Number of Participants With at Least One TEAE by Severity | Mild | 14 Participants |
| SAGE-718 | Number of Participants With at Least One TEAE by Severity | Moderate | 5 Participants |
| SAGE-718 | Number of Participants With at Least One TEAE by Severity | Severe | 2 Participants |
Secondary
Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE)
An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal (investigational) product. A TEAE is defined as any AE on or after the first dose of IP or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study.
Time frame: Up to Day 70
Population: The safety set included all participants who were administered at least one dose of the IP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | 27 Participants |
| SAGE-718 | Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | 21 Participants |