A Study to Evaluate the Effects of SAGE-718 in Participants With Mild Cognitive Impairment or Mild Dementia Due to Alzheimer's Disease (AD)

Phase 2

Completed

Conditions: Mild Cognitive Impairment
Alzheimer's Disease
Mild Dementia

Interventions: Drug: SAGE-718
Drug: SAGE-718-matching Placebo

Registration Number: NCT05619692

Lead Sponsor: Sage Therapeutics

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 174

Inclusion Criteria

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
Have a score of 15 to 25 (inclusive) on the Montreal Cognitive Assessment (MoCA) with years of education adjustment at Screening.

Exclusion Criteria

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
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
Have any medical or neurological condition (other than AD) that might be contributing to the participant's cognitive impairment or history of cognitive decline
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
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
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)
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
Have a positive pregnancy test, or be lactating, or intend to breastfeed during the study
Is known to be allergic to any of SAGE-718 excipients, including soy lecithin

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
SAGE-718	SAGE-718	Participants will receive SAGE-718, 1.2 milligrams (mg), orally, once daily (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.
Placebo	SAGE-718-matching Placebo	Participants will receive SAGE-718-matching placebo, orally, QD, throughout the treatment period up to Day 84.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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 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.
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.