Alzheimer Disease, Cognitive Dysfunction, Mild Dementia
Conditions
Brief summary
The primary purpose of this study is to evaluate the safety and tolerability of SAGE-718 and its effects on cognitive and neuropsychiatric symptoms in participants with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease (AD).
Interventions
DRUGSAGE-718
SAGE-718 oral tablets.
Sponsors
Supernus Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Participant meets the following criteria for MCI or mild dementia due to AD at Screening: has a memory complaint, has clinical dementia rating (CDR) score of 0.5 to 1.0 (inclusive) with a memory box score ≥0.5, has essentially preserved activities of daily living 2. Participant has a score of 15 to 24 (inclusive) on the Montreal Cognitive Assessment at Screening 3. Participant has normal premorbid intelligence quotient (IQ) at Screening 4. Participant has a study partner who is reliable, competent, at least 18 years of age, willing to be available to the study center by phone, support study-specific activities, and accompany the participant to study visits as needed
Exclusion criteria
1. Participant has any medical or neurological condition (other than AD) that might be contributing to the participant's cognitive impairment or history of cognitive decline 2. Participant has a history of brain surgery, deep brain stimulation, a significant head injury causing loss of consciousness greater than 30 minutes, or hospitalization due to a brain injury 3. Participant has a history, presence, and/or current evidence of a clinically-significant intracranial abnormality (eg, stroke, hemorrhage, space-occupying lesion) that could account for the observed cognitive impairment (excluding abnormalities consistent with underlying AD pathology) 4. Participant has a history of possible or probable cerebral amyloid angiopathy, according to the Boston Criteria 5. Participant has a history of seizures or epilepsy, with the exception of a single episode of febrile seizures in childhood 6. Participant has current or recent suicidality
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From first dose of study drug up to last follow up visit (up to 28 days) | An adverse event (AE) was any untoward medical occurrence in a participant administered with a pharmaceutical product and that does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an IP whether or not related to the product. An AE can include any undesirable medical condition, even if no study treatment has been administered. TEAEs were defined as an AE with an onset date on or after the date of 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least One Potentially Clinically Significant (PCS) Change in Vital Signs Measurements | From first dose of study drug up to last follow-up visit (up to 28 days) | PCS changes for vital signs included: Supine Systolic Blood Pressure (SBP) \>180 millimeters of mercury (mmHg), SBP decrease from baseline of ≥ 30 mmHg, standing 1-minute SBP \>180 mmHg, standing 3 minutes SBP decrease from baseline of ≥ 30 mmHg, Supine diastolic BP (DBP) decrease from baseline of ≥ 20 mmHg, standing 1-minute DBP decrease from baseline of ≥ 20 mmHg, standing 1-minute DBP increase from baseline of ≥ 20 mmHg, standing 3-minute DBP increase from baseline of ≥ 20 mmHg, orthostatic SBP: supine-1 minute standing ≥ 20 mmHg and supine-3 minute standing ≥ 20 mmHg, orthostatic DBP: supine-1 minute standing ≥ 10 mmHg and supine-3 minute standing ≥ 10 mmHg. Percentage of participants with at least one PCS change in vital signs measurements were reported. |
| Percentage of Participants With at Least One Potentially Clinically Significant Change in Laboratory Assessments | From first dose of study drug up to last follow-up visit (up to 28 days) | PCS changes for laboratory assessments included: hematology: hematocrit- male low (\<0.385 fractions of 1), hemoglobin male low (\<115 grams per liter \[g/L\]) and biochemistry: glucose high (\>13.9 millimoles per liter \[mmol/L\]), potassium low (\<3.3 mmol/L), blood urea nitrogen high (\>10.71 mmol/L)., Percentage of participants with at least one PCS change in laboratory assessments were reported. |
| Percentage of Participants With at Least One Potentially Clinically Significant Change in Electrocardiogram (ECG) Measurements | From first dose of study drug up to last follow-up visit (up to 28 days) | PCS changes for ECG measurements included: QTcF Interval \>450 to ≤480 milliseconds (msec), \>480 to ≤500 msec, and ≥30 to ≤60 msec increase from baseline. Percentage of participants with at least one PCS change in ECG measurements were reported. |
| Percentage of Participants With Suicidal Ideation or Behavior Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS) | Up to Day 28 | The C-SSRS scale assesses the lifetime experience of participants with suicidal ideation (SI) and suicidal behavior (SB). The C-SSRS included yes or no responses for assessment of suicidal ideation and behavior as well as numeric ratings for the severity of ideation, if present (with score range from 1 to 5, with 5 being the most severe). The C-SSRS SI items involved wish to be dead, non-specific active suicidal thoughts, active SI with any methods, active SI with some intent and active SI with a specific plan. The C-SSRS SB items involved preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt (non-fatal) and completed suicide. Percentage of participants with a response of 'yes' for suicidal ideation or behavior were reported. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at investigative sites in the United States from 07 December 2020 to 28 September 2021.
Pre-assignment details
A total of 58 participants were screened, of which 26 participants were enrolled to receive SAGE-718.
Participants by arm
| Arm | Count |
|---|---|
| SAGE-718 Participants received SAGE-718 3 mg oral tablets, once daily in the morning for 14 days. | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Deviation | 1 |
| Overall Study | Withdrawal by Participant | 1 |
Baseline characteristics
| Characteristic | SAGE-718 |
|---|---|
| Age, Continuous | 67.0 years STANDARD_DEVIATION 9.11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 4 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants |
| Race/Ethnicity, Customized Race White | 21 Participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 26 |
| other Total, other adverse events | 7 / 26 |
| serious Total, serious adverse events | 0 / 26 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a participant administered with a pharmaceutical product and that does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an IP whether or not related to the product. An AE can include any undesirable medical condition, even if no study treatment has been administered. TEAEs were defined as an AE with an onset date on or after the date of 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: From first dose of study drug up to last follow up visit (up to 28 days)
Population: Safety Set included all participants who were administered IP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SAGE-718 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 7 Participants |
Secondary
Percentage of Participants With at Least One Potentially Clinically Significant Change in Electrocardiogram (ECG) Measurements
PCS changes for ECG measurements included: QTcF Interval \>450 to ≤480 milliseconds (msec), \>480 to ≤500 msec, and ≥30 to ≤60 msec increase from baseline. Percentage of participants with at least one PCS change in ECG measurements were reported.
Time frame: From first dose of study drug up to last follow-up visit (up to 28 days)
Population: Safety Set included all participants who were administered IP. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SAGE-718 | Percentage of Participants With at Least One Potentially Clinically Significant Change in Electrocardiogram (ECG) Measurements | 32.0 percentage of participants |
Secondary
Percentage of Participants With at Least One Potentially Clinically Significant Change in Laboratory Assessments
PCS changes for laboratory assessments included: hematology: hematocrit- male low (\<0.385 fractions of 1), hemoglobin male low (\<115 grams per liter \[g/L\]) and biochemistry: glucose high (\>13.9 millimoles per liter \[mmol/L\]), potassium low (\<3.3 mmol/L), blood urea nitrogen high (\>10.71 mmol/L)., Percentage of participants with at least one PCS change in laboratory assessments were reported.
Time frame: From first dose of study drug up to last follow-up visit (up to 28 days)
Population: Safety Set included all participants who were administered IP. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SAGE-718 | Percentage of Participants With at Least One Potentially Clinically Significant Change in Laboratory Assessments | Hematology | 12.0 percentage of participants |
| SAGE-718 | Percentage of Participants With at Least One Potentially Clinically Significant Change in Laboratory Assessments | Biochemistry | 16.0 percentage of participants |
Secondary
Percentage of Participants With at Least One Potentially Clinically Significant (PCS) Change in Vital Signs Measurements
PCS changes for vital signs included: Supine Systolic Blood Pressure (SBP) \>180 millimeters of mercury (mmHg), SBP decrease from baseline of ≥ 30 mmHg, standing 1-minute SBP \>180 mmHg, standing 3 minutes SBP decrease from baseline of ≥ 30 mmHg, Supine diastolic BP (DBP) decrease from baseline of ≥ 20 mmHg, standing 1-minute DBP decrease from baseline of ≥ 20 mmHg, standing 1-minute DBP increase from baseline of ≥ 20 mmHg, standing 3-minute DBP increase from baseline of ≥ 20 mmHg, orthostatic SBP: supine-1 minute standing ≥ 20 mmHg and supine-3 minute standing ≥ 20 mmHg, orthostatic DBP: supine-1 minute standing ≥ 10 mmHg and supine-3 minute standing ≥ 10 mmHg. Percentage of participants with at least one PCS change in vital signs measurements were reported.
Time frame: From first dose of study drug up to last follow-up visit (up to 28 days)
Population: Safety Set included all participants who were administered IP. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SAGE-718 | Percentage of Participants With at Least One Potentially Clinically Significant (PCS) Change in Vital Signs Measurements | 64.0 percentage of participants |
Secondary
Percentage of Participants With Suicidal Ideation or Behavior Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS scale assesses the lifetime experience of participants with suicidal ideation (SI) and suicidal behavior (SB). The C-SSRS included yes or no responses for assessment of suicidal ideation and behavior as well as numeric ratings for the severity of ideation, if present (with score range from 1 to 5, with 5 being the most severe). The C-SSRS SI items involved wish to be dead, non-specific active suicidal thoughts, active SI with any methods, active SI with some intent and active SI with a specific plan. The C-SSRS SB items involved preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt (non-fatal) and completed suicide. Percentage of participants with a response of 'yes' for suicidal ideation or behavior were reported.
Time frame: Up to Day 28
Population: Safety Set included all participants who were administered IP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SAGE-718 | Percentage of Participants With Suicidal Ideation or Behavior Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS) | 0 percentage of participants |