Alzheimer's Disease, Mild Cognitive Impairment, Mild Dementia
Conditions
Keywords
SAGE-718, Cognitive dysfunction, N-methyl-D-aspartate (NMDA)
Brief summary
The primary purpose of this study is to evaluate the effect of SAGE-718 on cognitive performance in participants with Alzheimer's Disease.
Interventions
Softgel lipid capsules.
DRUGSAGE-718
Softgel lipid 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 80 Years
Healthy volunteers
No
Inclusion criteria
1. Meet the following criteria for mild cognitive impairment (MCI) or mild dementia due to Alzheimer's Disease (AD) at Screening: 1. A memory complaint reported by the participant or their study partner 2. A Clinical Dementia Rating (CDR) score of 0.5 to 1.0 (inclusive) with a memory box score ≥ 0.5 3. Essentially preserved activities of daily living, in the opinion of the investigator 4. Brain Magnetic Resonance Imaging (MRI) report, obtained within the 2 years preceding the Baseline Period, that is consistent with the diagnosis of AD with no clinically significant findings of non-AD pathology that could account for the observed cognitive impairment 2. Have a score of 15 to 25 (inclusive) on the Montreal Cognitive Assessment (MoCA) with years of education adjustment at Screening.
Exclusion criteria
1. Have participated in a previous clinical study of SAGE-718, have participated in a previous gene therapy study, or have received study treatment in any other drug, biologic, or device trial within 30 days or 5 half-lives (whichever is longer), unless the participant participated solely in the placebo arm of the study. Additionally, participants who have received treatment with antisense oligonucleotides (ASO) will be excluded 2. Have a condition that precludes undergoing an MRI, in accordance with standard operating procedures at the imaging facility (eg, ferromagnetic metal in the body, claustrophobia), in a participant requiring MRI during Screening 3. Have any medical or neurological condition (other than AD) that might be contributing to the participant's cognitive impairment or history of cognitive decline 4. Have a history, presence, and/or current evidence of 1. Brain surgery, deep brain stimulation, or any history of hospitalization due to a brain injury 2. Possible or probable cerebral amyloid angiopathy, according to the Boston Criteria 3. Treatment with an anti-amyloid therapy (including biologics) without subsequent MRI demonstrating the absence of amyloid-related imaging abnormalities 4. Seizures or epilepsy, with the exception of childhood febrile seizures 5. Participants has a history of suicidal behavior within 2 years or answers YES to Questions 3, 4, or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening or at Day 1 or is currently at risk of suicide in the opinion of the investigator 6. Have any of the following medical conditions: 1. Any clinically significant finding on 12-lead electrocardiogram (ECG) during Screening in the opinion of the investigator 2. Any clinically significant supine vital signs (heart rate, systolic and diastolic blood pressure) during Screening (note: vital sign measurements may be repeated once) 7. Have a history, presence, and/or current evidence of serologic positive results for human immunodeficiency virus (HIV)-1 or HIV-2, or hepatitis B or C 8. Have a positive pregnancy test, or be lactating, or intend to breastfeed during the study 9. Is known to be allergic to any of SAGE-718 excipients, including soy lecithin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Wechsler Adult Intelligence Scale-IV (WAIS-IV) Coding Test Score | Baseline, Day 84 | 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 112 | 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 112 | 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 112 | 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
Puerto Rico, United States
Participant flow
Recruitment details
Participants were enrolled at 40 investigative sites in the United States and Puerto Rico from 29 November 2022 to 09 July 2024.
Pre-assignment details
174 participants were randomized to receive either SAGE-718 or placebo, of which 4 participants were not treated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received SAGE-718-matching placebo, orally, QD, throughout the treatment period up to Day 84. | 86 |
| SAGE-718 Participants received SAGE-718, 1.2 mg, orally, QD for the first 6 weeks (Days 1 to 42), followed by 0.9 mg of SAGE-718 for the remainder of the treatment period up to Day 84. | 84 |
| Total | 170 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Randomized but not treated | 1 | 3 |
| Overall Study | Withdrawal by Participant | 3 | 4 |
Baseline characteristics
| Characteristic | Placebo | Total | SAGE-718 |
|---|---|---|---|
| Age, Continuous | 69.5 years STANDARD_DEVIATION 6.8 | 69.6 years STANDARD_DEVIATION 6.8 | 69.6 years STANDARD_DEVIATION 6.83 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 40 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 62 Participants | 129 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Race American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Race Asian | 5 Participants | 10 Participants | 5 Participants |
| Race (NIH/OMB) Race Black or African American | 14 Participants | 20 Participants | 6 Participants |
| Race (NIH/OMB) Race More than one race | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Race Native Hawaiian or Other Pacific Islander | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Race Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Race White | 62 Participants | 133 Participants | 71 Participants |
| Sex: Female, Male Female | 51 Participants | 103 Participants | 52 Participants |
| Sex: Female, Male Male | 35 Participants | 67 Participants | 32 Participants |
| Wechsler Adult Intelligence Scale-IV (WAIS-IV) Coding Test Score | 43.9 score on a scale STANDARD_DEVIATION 14.44 | 45.2 score on a scale STANDARD_DEVIATION 15.26 | 46.5 score on a scale STANDARD_DEVIATION 16.04 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 86 | 0 / 84 |
| other Total, other adverse events | 17 / 86 | 10 / 84 |
| serious Total, serious adverse events | 5 / 86 | 4 / 84 |
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 84
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. Overall number of participants analyzed indicates number of participants with data available for analysis at a 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 | 3.8 score on a scale | Standard Error 0.77 |
| SAGE-718 | Change From Baseline in the Wechsler Adult Intelligence Scale-IV (WAIS-IV) Coding Test Score | 5.3 score on a scale | Standard Error 0.79 |
p-value: 0.164295% CI: [-0.64, 3.73]MRMM
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 112
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 | 2 Participants |
| SAGE-718 | Number of Participants Who Withdrew From Study Due to TEAEs | 2 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 112
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 | 29 Participants |
| Placebo | Number of Participants With at Least One TEAE by Severity | Moderate | 19 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 | 20 Participants |
| SAGE-718 | Number of Participants With at Least One TEAE by Severity | Moderate | 20 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 112
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) | 50 Participants |
| SAGE-718 | Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) | 42 Participants |