Study to Evaluate SAGE-324 in Participants With Essential Tremor

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the dose-response relationship of different doses of SAGE-324 on upper extremity tremor in participants with essential tremor (ET) in the monotherapy cohort.

Official Title
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A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Dose-Response Study of SAGE-324 for the Treatment of Essential Tremor

Conditions
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Essential Tremor

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of ET, as defined by all of the following criteria: Isolated tremor syndrome consisting of bilateral upper limb action tremor At least 3 years duration With or without tremor in other locations (eg, head, voice, or lower limbs) Absence of other neurological signs, such as dystonia, ataxia, or parkinsonism, isolated focal tremors (eg, voice, head), task- and position-specific tremors, sudden tremor onset, or evidence of stepwise deterioration of tremor. Participant has the following: Scores of at least 12 in the combined TETRAS Performance Subscale Item 4 (upper limb tremor) at both Screening and pre-dose on Day 1 Scores of at least 6 in the total TETRAS Performance Subscale Item 4 score for the dominant upper limb (the sum of the three items for either the right or left upper limb, whichever is dominant) at both Screening and pre-dose on Day 1 Participant has a baseline TETRAS ADL Subscale score of at least 20 at Screening. Willing to discontinue medications taken for the treatment of ET except propranolol at least 14 days or 5 half-lives (whichever is longer) prior to receiving the investigational product (IP). Medications taken for the treatment of ET that were discontinued prior to receiving IP may be resumed following Day 97. Participants in the adjunct therapy cohort must be on a stable dose of propranolol (maximum total daily propranolol dose up to 320 mg allowed) for the treatment of ET from 3 months prior to Screening through Day 97 of the 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 Day 97 of the study. Participant is willing to maintain prestudy consumption of products that contain nicotine starting at least 1 week prior to Day 1 and through Day 97 of the study. Exclusion Criteria: Presence of known causes of enhanced physiological tremor. Participant has had newly administered tremorgenic drugs (14 days or 5 half-lives [whichever is longer] prior to Day 1) or presence of alcohol withdrawal state. Direct or indirect injury or trauma to the nervous system within 3 months before the onset of tremor. Previous procedure for the treatment of ET, deep brain stimulation, brain lesioning, or magnetic resonance (MR) guided procedure, eg, MR-guided focused ultrasound. Use of Cala Trio bracelet for the treatment of ET from two weeks prior to Day 1 through Day 97 is prohibited. Participant has had botulinum toxin for treatment of ET within 6 months of Screening. Historical or clinical evidence of tremor with functional neurological syndrome origin. Participant currently requires propranolol treatment for a medical condition other than ET. Participant has history of substance abuse or dependence prior to Screening, has a positive screen for drugs of abuse at Screening or predose on Day 1. Participants with nicotine use disorder that impacts their tremor are excluded.

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Placebo Comparator: SAGE-324 Matched Placebo<br>Participants will receive SAGE-324 matched placebo, stratified by baseline propranolol use. Monotherapy: Participants will receive SAGE-324 matched placebo, oral tablets, once daily (QD), in the evening, from Day 1 to Day 90 in a double-blind treatment period. Adjunct therapy: Participants will receive SAGE-324 matched placebo, oral tablets, QD, in the evening, from Day 1 to Day 90 along with a stable dose of up to 320 milligrams (mg) of propranolol from 3 months prior to Screening up to Day 90 in a double-blind treatment period. | Drug: SAGE-324 Matched Placebo<br>* SAGE-324 matched placebo oral tablets.<br>|
| Experimental: SAGE-324 15 mg<br>Participants will receive SAGE-324, 15 mg, stratified by baseline propranolol use. Monotherapy: Participants will receive SAGE-324, 15 mg, oral tablets, QD, in the evening, from Day 1 to Day 90 in a double-blind treatment period. Adjunct therapy: Participants will receive SAGE-324, 15 mg, oral tablets, QD, in the evening, from Day 1 to Day 90 along with a stable dose of up to 320 mg of propranolol from 3 months prior to Screening up to Day 90 in a double-blind treatment period. | Drug: SAGE-324<br>* SAGE-324 oral tablets.<br>|
| Experimental: SAGE-324 30 mg<br>Participants will receive SAGE-324, 30 mg, stratified by baseline propranolol use. Monotherapy: Participants will receive SAGE-324, 30 mg, oral tablets, QD, in the evening, from Day 1 to Day 90 in a double-blind treatment period. Adjunct therapy: Participants will receive SAGE-324, 30 mg, oral tablets, QD, in the evening, from Day 1 to Day 90 along with a stable dose of up to 320 mg of propranolol from 3 months prior to Screening up to Day 90 in a double-blind treatment period. | Drug: SAGE-324<br>* SAGE-324 oral tablets.<br>|
| Experimental: SAGE-324 60 mg<br>Participants will receive SAGE-324: 15 mg, 30 mg, 45 mg, and 60 mg, stratified by baseline propranolol use. Monotherapy: Participants will receive SAGE-324, 15 mg from Day 1 to 14, followed by up-titration to 30 mg from Day 15 to 28, then to 45 mg from Day 29 to 42, and then to 60 mg from Day 43 to 90, oral tablets, QD, in the evening, from Day 1 to Day 90 in a double-blind treatment period. Adjunct therapy: Participants will receive SAGE-324, 15 mg from Day 1 to 14, followed by up-titration to 30 mg from Day 15 to 28, then to 45 mg from Day 29 to 42, and then to 60 mg from Day 43 to 90, oral tablets, QD, in the evening, from Day 1 to Day 90 along with a stable dose of up to 320 mg of propranolol from 3 months prior to Screening up to Day 90 in a double-blind treatment period. | Drug: SAGE-324<br>* SAGE-324 oral tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in The Essential Tremor Rating Assessment Scale (TETRAS) Performance Subscale Item 4 (Upper Limb) Total Score on Day 91 in the Monotherapy Cohort | TETRAS is a validated, comprehensive clinical assessment of essential tremor. For the performance subscale item 4 upper limb (UL) tremor score, all 3 maneuvers in the UL assessments of item 4 (subscale 4a, 4b, and 4c) will be completed for both arms, first for the left arm and then for the right. The item 4 subscale ordinally rates postural (limbs extended forward and wing-beating [elbows flexed]), and kinetic (finger-nose-finger maneuver) tremor on a 0 to 4 severity scale in 0.5-point increments. TETRAS Item 4 score for each upper limb ranges from 0 to 12 and for both upper limbs from 0 to 24. | Baseline up to Day 91 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in TETRAS Activities of Daily Living (ADL) Composite Score in the Monotherapy Cohort | TETRAS ADL subscale assesses how ET affects typical ADL (i.e., speech, eating, drinking, dressing, personal hygiene, writing, occupational impairment, social impact, and activities affected by upper limb tremor). It consists of 12 items, each item rated on a scale from 0 (normal activity) to 4 (severe abnormality). The performance subscale assesses the overall rating of tremor in the voice, limbs, head, face, trunk, while performing prespecified tasks, and also measures functional task capabilities, i.e., handwriting, spirography, and holding a pen over a dot. It consists of 16 items, each item rated on a scale from 0 (no tremor) to 4 (severe tremor). The ADL composite score comprises items 1 to 11 of the ADL subscale and item 6 of the performance subscale, each item rated on a scale from 0 (normal/slightly abnormal) to 3 (severely abnormal) and the overall score range is 0 to 36. A negative change from baseline will indicate improvement. | Baseline up to Day 91 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Essential Tremor, SAGE-324