A Study to Evaluate the Long-term Safety and Tolerability of SAGE-324 in Participants With Essential Tremor

Study Overview
=================
Brief Summary
-----------------
The primary purpose of this study is to evaluate the long-term safety and tolerability of SAGE-324 in participants with essential tremor (ET).

Official Title
-----------------
An Open-label Study of the Long-term Safety and Tolerability of SAGE-324 in Participants With Essential Tremor

Conditions
-----------------
Essential Tremor

Intervention / Treatment
-----------------
* Drug: SAGE-324


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant is in good physical health and has no clinically significant findings (excluding ET) that may impact their ability to participate in the study, as determined by the investigator, on physical examination, 12-lead ECG, or clinical laboratory tests. Participant has a clinician-confirmed diagnosis of ET in compliance with all the following criteria: Duration of at least 3 years Absence of other neurological signs, such as dystonia, ataxia, parkinsonism, task- and position-specific tremors, sudden tremor onset, or evidence of stepwise deterioration of tremor Absence of historical or clinical evidence of tremor with psychogenic origin (including, but not limited to, eating disorders and major depression) Participant has completed the planned EOT visit and was not early terminated during the planned Treatment Period in another SAGE-324 study. Participant is willing to limit use of alcohol to 2 units per day for males and 1 unit per day for females starting at least 1 week prior to Day 1 and through the End of Study (EOS) Visit. Participant will limit alcohol use to at least 2 hours before self-administration of IP in the evening. Participant will not use alcohol starting 24 hours prior to scheduled in-clinic study visits until all assessments have been completed. Participant is willing to maintain prestudy consumption of products that contain nicotine starting at least 1 week prior to Day 1 and through EOS Visit. Exclusion Criteria: Participant has presence of alcohol withdrawal state. Participant has had direct or indirect injury or trauma to the nervous system within 3 months before the onset of tremor. Participant is taking and unable to discontinue the use of primidone at least 7 days prior to administration of the first dose of SAGE-324. Participant has a history (within 3 years of Screening) or ongoing oncologic disease, excluding skin cancers (squamous or basal cell carcinoma) for which treatment has been completed and any carcinoma in situ. Participant has an ongoing clinically relevant medical or psychiatric condition that, in the judgment of the investigator, is not well managed and poses a risk for participation in the study. Participant has history of substance dependence and/or abuse prior to Screening, has a positive screen for drugs of abuse at Screening or predose on Day 1, (unless prescribed) or has a positive screen for alcohol or cotinine predose on Day 1. Participants with nicotine use disorder that impacts their tremor are excluded. Participant has a known allergy to SAGE-324 or any excipient. Female participant has a positive pregnancy test or confirmed pregnancy or is breastfeeding. Participant has had exposure to another investigational drug or device within 30 days or 5 half-lives of the other investigational drug, whichever is longer, prior to the Day 1 visit and for the duration of the study. Participant has a history of suicidal behavior within 2 years or answers YES to questions 3, 4, or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk of suicide in the opinion of the investigator. Participant has any condition or comorbidity that in the opinion of the investigator would limit or interfere with the participant's ability to complete or partake in the study. Participant has used any known moderate or strong cytochrome P450 3A4 inhibitors and/or inducers within 14 days or 5 half-lives (whichever is longer) prior to Day 1 or consumed grapefruit juice, grapefruit, Seville oranges, or St. John's Wort or products containing these within 30 days prior to Day 1 and is unwilling to refrain from taking these medications or foods for the duration of dosing. Use of mild cytochrome inhibitors and/or inducers may be permitted.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAGE-324 60 mg<br>Participants will receive SAGE-324 oral tablets from Day 1 to the End of Treatment (EOT) Period at a starting dose of 15 milligrams (mg). The dose will be up titrated in 15 mg increments to 60 mg. In case of intolerable adverse events, the dose will be down titrated in 15 mg decrements. | Drug: SAGE-324<br>* SAGE-324 oral tablets<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With at least One Treatment-Emergent Adverse Events (TEAEs) | An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. A TEAE is defined as an AE with onset after the first dose of an investigational product (IP). | Up to approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Change from Baseline in Vital Sign Parameters | Vital signs assessment will include heart rate, respiratory rate, temperature, and blood pressure. | Baseline up to approximately 5 years | 
| Percentage of Participants With Change from Baseline in Electrocardiogram (ECG) Parameters |  | Baseline up to approximately 5 years | 
| Percentage of Participants With Change from Baseline in Clinical Laboratory Parameters | The clinical laboratory parameters will include biochemistry, coagulation, hematology, urinalysis assessments. | Baseline up to approximately 5 years | 
| Percentage of Participants With Change from Baseline in Epworth Sleepiness Scale (ESS) Score | The ESS is a quick, 8-item, self-administered questionnaire where participants rate, on a 4-point scale (0 low to 3 high), their usual chances of dozing off or falling asleep while engaged in 8 different activities. The total ESS score estimates the participant's average sleep propensity, across a range of activities in their daily lives. The ESS score can range from 0 to 24. ESS score ≥ 10 will be used to indicate excessive daytime sleepiness. A higher score indicates more severe excessive daytime sleepiness. | Baseline up to approximately 5 years | 
| Percentage of Participants With Change from Baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) Responses | This C-SSRS scale consists of a baseline evaluation that assesses the lifetime experience of the participant with suicidal ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last study visit. The C-SSRS includes 'yes' or 'no' responses for assessment of suicidal ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe). A higher score indicates more severe symptom. | Baseline up to approximately 5 years | 
| Physician Withdrawal Checklist (PWC-20) Scale Score | The Physician Withdrawal Checklist (PWC) is based on the 35-item Penn Physician Withdrawal Checklist that was developed to measure benzodiazepine and benzodiazepine-like discontinuation symptoms. The PWC-20 is made up of a list of 20 symptoms (eg, loss of appetite, nausea-vomiting, diarrhea, anxiety-nervousness, irritability) that are rated on a scale of 0 (not present) to 3 (severe). Total scores can range from 0 to 60 with higher scores indicating more severe symptoms. A higher score indicates more severe symptom. | Baseline up to approximately 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SAGE-324