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

Study Overview
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Brief Summary
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This is a phase 2, double-blind, placebo-controlled study to evaluate the safety and efficacy of SAGE-324 compared to placebo on upper limb tremor reduction in individuals with essential tremor (ET).

Official Title
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A Phase 2, Double-Blind, Placebo-controlled, Randomized Study Evaluating the Efficacy, Safety, and Tolerability of Sage-324 in the Treatment of Individuals With Essential Tremor

Conditions
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Essential Tremor

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has a diagnosis of ET, defined as isolated tremor syndrome consisting of bilateral upper limb action tremor for at least 3 years prior to screening, with or without tremor in other locations and 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 step-wise deterioration of tremor. Participant scores at least 1.5 for each of the six items that comprise the combined total upper limb TETRAS (total performance subscale part 4) with the total score for the dominant upper limb (the sum of the three items for either the right or left upper limb, whichever is dominant) being at least 5.5, at both Screening and predose on Day 1. Participant is willing to discontinue medications taken for the treatment of ET within 14 days or 5 half-lives prior to receiving IP. Medications taken for the treatment of ET that were discontinued prior to receiving IP may be resumed following Day 29. Participant has no clinically significant findings, as determined by the investigator, on Screening and pre-dose Day 1 physical examination including mental state examination (MSE) and neurologic examination, 12-lead electrocardiogram (ECG), or screening clinical laboratory tests. Exclusion Criteria: Participant has a presence of known causes of enhanced physiological tremor. Participant has had recent exposure (14 days prior to Day 1) to tremorgenic drugs. Participant has had direct or indirect injury or trauma to the nervous system within 3 months before the onset of tremor. Participant has had a previous procedure for the treatment of ET, deep brain stimulation, brain lesioning, or magnetic resonance (MR)-guided procedure, eg, MR-guided focused ultrasound. Participant has historical or clinical evidence of tremor with psychogenic origin (including but not limited to eating disorders, major depression, etc.). Participant has 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 for suicide in the opinion of the investigator. Participant has used any known moderate or strong cytochrome P450 3A4 and/or inducers within 14 days or 5 half-lives (whichever is longer) prior to Day 1 or consumed grapefruit juice, grapefruit, Seville oranges, pomegranates, tangelos, or St. John's Wort or products containing these within 30 days prior to Day 1. Use of mild cytochrome inhibitors and/or inducers may be permitted. Participant has concurrent or recent exposure (14 days or 5 half-lives, whichever is longer, prior to the Day 1 visit) to sedative/hypnotic drugs, stimulants, highly-caffeinated beverages or dietary supplements containing high doses of caffeine, or recent increase above regular daily consumption of caffeine. Participant currently uses or has used within 14 days or 5 half-lives (whichever is longer) prior to Day 1, any prescription or over-the-counter medication that is a substrate of the OATP1B1 transporter.

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 |
| --- | --- |
| Experimental: SAGE-324 60 mg<br>Participants will receive SAGE-324 60 mg dose (tablets) orally in the morning for 28 days. | Drug: SAGE-324<br>* SAGE-324 oral tablet<br>|
| Placebo Comparator: SAGE-324 Matched Placebo<br>Participants will receive SAGE-324 matched placebo, oral tablets for 28 days. | Drug: SAGE-324 Placebo<br>* SAGE-324 matched placebo oral tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline Compared to Placebo in The Essential Tremor Rating Assessment (TETRAS) Performance Subscale Part 4 Upper Limb Tremor Score on Day 29 | TETRAS is a validated, comprehensive clinical assessment of essential tremor. For the performance subscale part 4 upper limb (UL) tremor score, all 3 maneuvers in the UL assessments of part 4 (subscale 4a, 4b, and 4c) will be completed for both arms, first for the left arm and then for the right. The part 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 Part 4 score for each upper limb ranges from 0 to 12 and for both upper limbs from 0 to 24. | Baseline, Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline Compared to Placebo in TETRAS Performance Subscale Part 4 Upper Limb Tremor Score at all Other Timepoints | For the performance subscale part 4 upper limb (UL) tremor score, all 3 maneuvers in the UL assessments of part 4 (subscale 4a, 4b, and 4c) will be completed for both arms, first for the left arm and then for the right. The part 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 Part 4 score for each upper limb ranges from 0 to 12 and for both upper limbs from 0 to 24. | Baseline, Day 1, 8, 15, 22 and on Day 42 (or Early Termination Visit [ETV] / End of Study [EOS]) | 
| Change From Baseline Compared to Placebo in Kinesia ONE Accelerometer Scores | Kinesia ONE is a wireless motion sensor worn distally on the index finger, which utilizes 3 orthogonal accelerometers and 3 orthogonal gyroscopes to monitor three-dimensional motion. Via the Kinesia ONE software application, measures of three-dimensional motion are converted to scores ranging from 0 to 4. Higher scores indicate greater tremor severity. Motion in each arm will be captured separately. | Baseline, Day 1, 8, 15, 22, 29 and on Day 42 (or ETV / EOS) | 
| Change From Baseline Compared to Placebo in TETRAS Scale Activities of Daily Living (ADL) Score | The ADL subscale will assess how ET impacts typical activities of daily living (speech, eating, drinking, dressing, personal hygiene, writing, occupational impairment, social impact and activities affected by upper limb (UL) tremor). It consists of 12 items, each rated from 0 (normal activity) to 4 (severe abnormality) with overall ADL score range of 0 to 48. | Baseline, Day 1, 8, 15, 22, 29 and on Day 42 (or ETV / EOS) | 
| Change From Baseline Compared to Placebo in TETRAS Total Performance Score | The total performance score is based on overall rating of tremor amplitude in the voice, limbs, head, face, trunk, while performing pre-specified tasks, and functional task capabilities (handwriting, spiral drawing, and holding a pen over a dot). Each of these items is rated from 0 (no tremor) to 4 (severe tremor) with an overall performance score of 0 to 64. | Baseline, Day 1, 8, 15, 22, 29 and on Day 42 (or ETV / EOS) | 
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | A TEAE is defined as an AE with onset after the start of investigational product (IP), or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study. | Up to Day 42 | 

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