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

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the effect of SAGE-718 on cognitive performance in participants with Alzheimer's Disease.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effects of SAGE-718 in Participants With Mild Cognitive Impairment or Mild Dementia Due to Alzheimer's Disease

Conditions
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Mild Cognitive Impairment, Mild Dementia, Alzheimer's Disease

Intervention / Treatment
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* Drug: SAGE-718
* Drug: SAGE-718-matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet the following criteria for mild cognitive impairment (MCI) or mild dementia due to Alzheimer's Disease (AD) at Screening: A memory complaint reported by the participant or their study partner A Clinical Dementia Rating (CDR) score of 0.5 to 1.0 (inclusive) with a memory box score ≥0.5 Essentially preserved activities of daily living, in the opinion of the investigator 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) 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 Brain surgery, deep brain stimulation, or any history of hospitalization due to a brain injury Possible or probable cerebral amyloid angiopathy, according to the Boston Criteria Treatment with an anti-amyloid therapy (including biologics) without subsequent MRI demonstrating the absence of amyloid-related imaging abnormalities Seizures or epilepsy, with the exception of childhood febrile seizures Be at risk for suicidal ideation as per Columbia-Suicide Severity Rating Scale (C-SSRS) and/or in the opinion of the investigator Have any of the following medical conditions: Any clinically significant finding on 12-lead electrocardiogram (ECG) during Screening in the opinion of the investigator Supine vital signs outside of the following ranges during Screening (vital sign measurements may be repeated once if initial values exceed these ranges): i. Heart rate <50 or >100 bpm ii. Systolic blood pressure <100 or >160 mmHg iii. Diastolic blood pressure <60 or >100 mmHg 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

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAGE-718<br>Participants will receive 1.2mg of SAGE-718 orally once daily for the first 6 weeks Days 1 to 42 [±2 days]), followed by 0.9 mg of SAGE-718 for the remainder of the Treatment period up to Day 84. | Drug: SAGE-718<br>* Softgel lipid capsules.<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo-matching capsule once daily orally throughout the treatment period for up to Day 84. | Drug: SAGE-718-matching Placebo<br>* Softgel lipid capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in the Wechsler Adult Intelligence Scale Fourth Edition-IV (WAIS-IV) Coding Test | The WAIS-IV Coding Test is a valid and sensitive measure of cognitive dysfunction. Administration of the WAIS-IV Coding Test will use the traditional paper-and-pen format, in which the participant is required to identify the symbols matched to numbers using a key and write in the symbol beneath the associated number. The score will be based on the total number of codes correctly completed over a 120-second time limit. | Baseline to Day 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With At least One or More Treatment-emergent Adverse Events (TEAEs) and by Severity | An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. A TEAE is defined as an AE with onset after the start of IP, or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study. | From the inform consent signing up to end of the study (Up to approximately Day 116) | 
| Number of Participants Who Withdraw Due to Adverse Events (AEs) |  | From the inform consent signing up to end of the study (Up to approximately Day 116) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SAGE-718, Cognitive dysfunction, NMDA