A Study to Evaluate SAGE-217 in Participants With Essential Tremor

• ClinicalTrials.gov Identifier: NCT02978781
• Recruitment Status: Completed
• First Posted: December 1, 2016
• Results First Posted: February 17, 2021
• Last Update Posted: February 17, 2021
• Sponsor: Sage Therapeutics
• Information provided by (Responsible Party): Sage Therapeutics

Study Description

Brief Summary:

This study is a three-part, multicenter, Phase 2a study to evaluate the efficacy, safety, tolerability, and pharmacokinetics of SAGE-217 in adult participants with essential tremor.

Condition or disease	Intervention/treatment	Phase
Essential Tremor	Drug: SAGE-217; Drug: Placebo	Phase 2

Detailed Description:

Part A of the study was an open-label design with morning dosing of SAGE-217 for 7 days and included 16 participants, 8 of whom qualified for, and entered, Part B.

Part B had a double-blind, placebo-controlled, randomized withdrawal design with morning dosing for 7 days.

Part C was an open-label design with morning and evening dosing for 14 days and included a different set of 18 participants.

Parts A and B were stopped early (in advance of the planned sample size).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2a, Double-Blind, Placebo-Controlled, Randomized Withdrawal Study Evaluating the Efficacy, Safety, Tolerability, and Pharmacokinetics of SAGE-217 in the Treatment of Subjects With Essential Tremor
• Actual Study Start Date: March 24, 2017
• Actual Primary Completion Date: November 22, 2017
• Actual Study Completion Date: December 5, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part A: SAGE-217 Oral Solution; Participants received SAGE-217 10 mg oral solution on Day 1, 20 mg on Day 2 and 30 mg on Days 3 to 7 with food in the morning.	Drug: SAGE-217; SAGE-217 Oral Solution
Experimental: Part A: SAGE-217 Capsules; Participants received SAGE-217 10 mg capsules on Day 1, 20 mg on Day 2 and 30 mg on Days 3 to 7, orally, with food in the morning.	Drug: SAGE-217; SAGE-217 Capsules
Placebo Comparator: Part B: Placebo; Participants who received maximum tolerated dose of SAGE-217 in Part A and achieved response on Day 8 were randomized to receive to SAGE-217 matching placebo for 7 days beginning on Day 8 with food in the morning.	Drug: Placebo; SAGE-217 matching placebo capsules
Experimental: Part B: SAGE-217 Capsules; Participants who received maximum tolerated dose of SAGE-217 in Part A and achieved response on Day 8 were randomized to receive to SAGE-217 for 7 days beginning on Day 8 with food in the morning.	Drug: SAGE-217; SAGE-217 Capsules
Experimental: Part C: SAGE-217 Capsules; Participants received SAGE-217 10 mg capsules on Day 1, 20 mg on Day 2, 30 mg on Day 3, orally, with food in the evening. Beginning on Day 4 through Day 14, participants received a 40-mg total daily dose (administered as 10 mg with food in the morning and 30 mg with food in the evening).	Drug: SAGE-217; SAGE-217 Capsules

Outcome Measures

Primary Outcome Measures :

1. Part A: Change From Baseline in Accelerometer-based Kinesia Kinetic Tremor Combined Score at Day 7 [ Time Frame: Baseline (Day 1) and Day 7 (8 hours postdose) ]
   The accelerometer-based Kinesia kinetic tremor combined score is the sum of Kinesia kinetic tremor scores across both sides of the body. Tremor is measured using a motion sensor that transmits raw data to a computer where it converts the tremor amplitude to a Kinesia score of 0 to 4 based on validated algorithms; the total score ranges from 0 to 8, higher scores indicate more severe tremor. A negative change from Baseline indicates improvement.
2. Part B: Change From Randomization in Accelerometer-based Kinesia Kinetic Tremor Combined Score at Day 14 [ Time Frame: Randomization (Day 8, predose) and Day 14 (predose) ]
   The accelerometer-based Kinesia kinetic tremor combined score is the sum of Kinesia kinetic tremor scores across both sides of the body. Tremor is measured using a motion sensor that transmits raw data to a computer where it converts the tremor amplitude to a Kinesia score of 0 to 4 based on validated algorithms; the total score ranges from 0 to 8, higher scores indicate more severe tremor. A negative change from Randomization indicates improvement.
3. Part C: Change From Baseline in the Accelerometer-based Kinesia Upper Limb Tremor Combined Score at Day 15 [ Time Frame: Baseline (Day 1) and Day 15 ]
   The accelerometer-based Kinesia upper limb total score is the sum of the individual item scores across both sides of the body. The individual items included forward outstretched postural tremor (FOPT), lateral "wing beating" postural tremor (LWBPT), and kinetic tremor (KT) scores from both sides of the body. Each upper limb individual item question score for each side of the body ranges from 0 to 4. The Kinesia upper limb total score ranges from 0 to 24, with higher scores indicating more tremors/greater tremor amplitude. A negative change from Baseline indicates improvement.

Secondary Outcome Measures :

1. Part A: Change From Baseline in Kinesia Upper Limb Total Score at Day 7 [ Time Frame: Baseline (Day 1) and Day 7 (8 hours postdose) ]
   The accelerometer-based Kinesia upper limb total score is the sum of Kinesia kinetic tremor scores across both sides of the body. The individual items included forward outstretched postural tremor (FOPT), lateral "wing beating" postural tremor (LWBPT), and kinetic tremor (KT) scores from both sides of the body. Each upper limb individual item question score for each side of the body ranges from 0 to 4. The Kinesia upper limb total score ranges from 0 to 24, with higher scores indicating more tremors/greater tremor amplitude. A negative change from Baseline indicates improvement.
2. Part A: Change From Baseline in Kinesia Upper Limb Individual Item Score at Day 7 [ Time Frame: Baseline (Day 1) and Day 7 (8 hours [hr] postdose [pd]) ]
   The accelerometer-based Kinesia upper limb total score is the sum of Kinesia kinetic tremor scores across both sides of the body. The individual items included forward outstretched postural tremor (FOPT), lateral "wing beating" postural tremor (LWBPT), and kinetic tremor (KT) scores from both sides of the body. Each upper limb individual item question score for each side of the body ranges from 0 to 4, with higher scores indicating more tremors/greater tremor amplitude. The Kinesia upper limb total score ranges from 0 to 24, with higher scores indicating more tremors/greater tremor amplitude. A negative change from Baseline indicates improvement.
3. Part A: Change From Baseline in the Tremor Research Group (TRG) Essential Tremor Rating Assessment Scale (TETRAS) Upper Limb Total Score at Day 7 [ Time Frame: Baseline (Day 1) and Day 7 (8 hours postdose) ]
   The TETRAS performance subscale upper limb total score is the sum of the TETRAS individual item scores from both sides of the body. The TETRAS individual item score included TETRAS Performance Subscale item 4a, 4b and 4c scores [4a: forward outstretched postural tremor (FOPT) and 4b: lateral "wing beating" postural tremor (LWBPT) scores and 4c: Kinetic tremor (KT) score] from both sides of the body. Each individual item score ranges from 0 to 4; The total upper limb score ranges from 0 to 24, higher scores indicate more severe tremor. A negative change indicates improvement.
4. Change From Baseline in the TETRAS Upper Limb Individual Items (Performance Subscale Items 4a, 4b, or 4c) Scores at Day 7 [ Time Frame: Baseline (Day 1) and Day 7 (8 hours postdose) ]
   The TETRAS individual item score is the sum of the TETRAS Performance Subscale items 4a, 4b, or 4c scores [4a: forward outstretched postural tremor (FOPT), 4b: lateral "wing beating" postural tremor (LWBPT), 4c: kinetic tremor] from both sides of the body. Each TETRAS score ranges from 0 to 4; the total score ranges from 0 to 16; higher scores indicate more severe tremor. A negative change from Baseline indicates improvement.
5. Part A: Change From Baseline in TETRAS Performance Subscale Score (Items 6, 7, and 8) at Day 7 [ Time Frame: Baseline (Day 1) and Day 7 (predose) ]
   The TETRAS Performance Subscale score includes 9 items. Out of these 9 items, Item 6 is Archimedes spirals (AS), Item 7 is Handwriting, and Item 8 is Dot approximation task (DAT). Each item was scored from 0 to 4, for both sides of the body, each item has a total score of 0 to 8, where higher scores indicate more severe tremor. A negative change from Baseline indicates improvement.
6. Part B: Change From Randomization in the Kinesia Upper Limb Total Score at Day 14 [ Time Frame: Randomization (Day 8, predose) and Day 14 (predose) ]
   The accelerometer-based Kinesia upper limb total score is the sum of Kinesia kinetic tremor scores across both sides of the body. The individual items included forward outstretched postural tremor (FOPT), lateral "wing beating" postural tremor (LWBPT), and kinetic tremor (KT) scores from both sides of the body. Each upper limb individual item question score for each side of the body ranges from 0 to 4. The Kinesia upper limb total score ranges from 0 to 24, with higher scores indicating more tremors/greater tremor amplitude. A negative change from Randomization indicates improvement.
7. Part B: Change From Randomization in the Kinesia Upper Limb Individual Item Score at Day 14 [ Time Frame: Randomization (Day 8, predose) and Day 14 (predose) ]
   The accelerometer-based Kinesia upper limb total score is the sum of Kinesia kinetic tremor scores across both sides of the body. The individual items included forward outstretched postural tremor (FOPT), lateral "wing beating" postural tremor (LWBPT), and kinetic tremor (KT) scores from both sides of the body. Each upper limb individual item question score for each side of the body ranges from 0 to 4. The Kinesia upper limb total score ranges from 0 to 24, with higher scores indicating more tremors/greater tremor amplitude. A negative change from Randomization indicates improvement.
8. Part B: Change From Randomization in the TETRAS Upper Limb Total Score at Day 14 [ Time Frame: Randomization (Day 8, predose) and Day 14 (predose) ]
   The TETRAS performance subscale upper limb total score is the sum of the TETRAS individual item scores from both sides of the body. The TETRAS individual item score included TETRAS Performance Subscale item 4a, 4b and 4c scores [4a: forward outstretched postural tremor (FOPT) and 4b: lateral "wing beating" postural tremor (LWBPT) scores and 4c: Kinetic tremor (KT) score] from both sides of the body. Each individual item score ranges from 0 to 4; The total upper limb score ranges from 0 to 24, higher scores indicate more severe tremor. A negative change from Randomization indicates improvement.
9. Part B: Change From Randomization in the TETRAS Upper Limb Individual Item (Performance Subscale Items 4a and 4b) Score at Day 14 [ Time Frame: Randomization (Day 8, predose) and Day 14 (predose) ]
   The TETRAS individual item score is the sum of the TETRAS Performance Subscale item 4a and 4b scores [4a: forward outstretched postural tremor (FOPT) and 4b: lateral "wing beating" postural tremor (LWBPT) scores] from both sides of the body. Each TETRAS score ranges from 0 to 4; the total score ranges from 0 to 16, higher scores indicate more severe tremor. A negative change from Randomization indicates improvement.
10. Part B: Change From Randomization in the TETRAS Performance Subscale Item 4c (Kinetic Tremor) Combined Score at Day 14 [ Time Frame: Randomization (Day 8, predose) and Day 14 (predose) ]
    The TETRAS kinetic tremor combined score is the sum of the TETRAS Performance Subscale item 4c (kinetic tremor) scores from both sides of the body. The TETRAS kinetic tremor score ranges from 0 to 4, the total score for both sides of the body ranges from 0 to 8, higher scores indicate more severe tremor. A negative change from Randomization indicates improvement.
11. Part B: Change From Baseline in TETRAS Performance Subscale (Items 6, 7, and 8) Score at Day 14 [ Time Frame: Baseline (Day 1) and Day 14 (predose) ]
    The TETRAS Performance Subscale score includes 9 items. Out of these 9 items, Item 6 is Archimedes spirals (AS), Item 7 is Handwriting, and Item 8 is Dot approximation task (DAT). Each item was scored from 0 to 4, for both sides of the body, each item has a total score of 0 to 8, where higher scores indicate more severe tremor. A negative change from Baseline indicates improvement.
12. Part C: Change From Baseline in the Kinesia Upper Limb Individual Item Score at Day 15 [ Time Frame: Baseline (Day 1) and Day 15 ]
    The accelerometer-based Kinesia upper limb total score is the sum of Kinesia kinetic tremor scores across both sides of the body. The individual items included forward outstretched postural tremor (FOPT), lateral "wing beating" postural tremor (LWBPT), and kinetic tremor (KT) scores from both sides of the body. Each upper limb individual item question score for each side of the body ranges from 0 to 4. The Kinesia upper limb total score ranges from 0 to 24, with higher scores indicating more tremors/greater tremor amplitude. A negative change from Baseline indicates improvement.
13. Part C: Change From Baseline in the TETRAS Upper Limb Total Score at Day 15 [ Time Frame: Baseline (Day 1) and Day 15 ]
    The TETRAS performance subscale upper limb total score is the sum of the TETRAS individual item scores from both sides of the body. Each individual item score ranges from 0 to 4; The total upper limb score ranges from 0 to 24, higher scores indicate more severe tremor. A negative change indicates improvement.
14. Part C: Change From Baseline in the TETRAS Upper Limb Individual Item (Performance Subscale Items 4a and 4b) Score at Day 15 [ Time Frame: Baseline (Day 1) and Day 15 ]
    The TETRAS individual item score is the sum of the TETRAS Performance Subscale item 4a and 4b scores [4a: forward outstretched postural tremor (FOPT) and 4b: lateral "wing beating" postural tremor (LWBPT) scores] from both sides of the body. Each TETRAS score ranges from 0 to 4; the total score ranges from 0 to 16, higher scores indicate more severe tremor. A negative change from Baseline indicates improvement.
15. Part C: Change From Baseline in TETRAS Performance Subscale (Items 6, 7, and 8) Scores at Day 15 [ Time Frame: Baseline (Day 1) and Day 15 ]
    The TETRAS Performance Subscale score includes 9 items. Out of these 9 items, Item 6 is Archimedes spirals (AS), Item 7 is Handwriting, and Item 8 is Dot approximation task (DAT). Each item was scored from 0 to 4, for both sides of the body, each item has a total score of 0 to 8, where higher scores indicate more severe tremor. A negative change from Baseline indicates improvement.
16. Parts A, B and C: Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) or Serious Adverse Event (SAE) [ Time Frame: From first dose of study drug through 14 days after the last dose (Up to 28 days) ]
    An Adverse Event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. Adverse events that occurred after the first administration of study drug were denoted as TEAEs. A Serious Adverse Event (SAE) was an AE occurring during any study phase and at any dose of the study drug, comparator, or placebo, that fulfilled the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
17. Part A, B and C: Number of Participants With Suicidal Ideation as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) Score [ Time Frame: Baseline and post-baseline (up to 28 days) ]
    The C-SSRS consists of a baseline and post-baseline (PB) evaluation that assesses the lifetime experience of the participants with suicidal ideation and behavior. The data for suicidal ideation were summarized for participants who answered 'Yes'. Suicide ideation was categorized as 1) wish to be dead and 2) non-specific active suicidal thoughts.
18. Number of Participants With Clinically Significant Vital Signs [ Time Frame: Up to 28 days ]
    Vital signs included heart rate, respiratory rate, temperature, and blood pressure.
19. Number of Participants With Clinically Significant Laboratory Parameters [ Time Frame: Up to 28 days ]
    Laboratory parameters included hematology, blood chemistry, and urinalysis.
20. Number of Participants With Clinically Significant Electrocardiogram (ECG) Values [ Time Frame: Up to 28 days ]
    A 12-lead ECG was performed.
21. Parts A and B: Change From Baseline in Stanford Sleepiness Scale (SSS) [ Time Frame: Baseline (Day 1), Day 7 (predose) for Part A, Day 14 (predose) for Part B ]
    The SSS was designed to quickly assess how alert a subject is feeling. Degrees of sleepiness and alertness are rated on a scale of 1 to 7, where the lowest score of 1 indicates the subject is "feeling active, vital, alert, or wide awake" and the highest score of 7 indicates the participant is "no longer fighting sleep, sleep onset soon; having dream-like thoughts". Greater changes from baseline indicate greater sedation. A positive change from baseline indicates improvement.
22. Parts A, B and C: Change From Baseline in Bond-Lader Visual Analogue Scale (VAS) Score [ Time Frame: Baseline (Day 1), Day 7 (predose) for Part A, Day 14 (predose) for Part B and Day 15 for Part C ]

    Mood was assessed using the Bond-Lader VAS score. This is a 16-part self-administered questionnaire that employs a 100-mm VAS to explore different aspects of self-reported mood. Three factor scores for (alertness, contentedness, and calmness) were calculated using following equations based on normalized VAS scores:

    • Alertness = 0.827X1 + 0.618X3 + 0.755X4 + 0.642X5 + 0.776X6 + 0.635X9 + 0.792X11 + 0.593X12 + 0.614X15;
    • Contentedness = 0.677X7 + 0.697X8 + 0.823X13 + 0.738X14 + 0.594X16; and
    • Calmness = 0.845X2 + 0.677X10,

    where Xi represents a subject's item score after normalization, and i represents the item number from the entire scale (in order from 1-16). A negative change from baseline (CFB) indicated more alertness, more contentedness, and more calmness.

23. Parts A, B and C: Participant's Feeling After Taking the Study Drug as Assessed by Drug Effects Questionnaire (DEQ-5) Score [ Time Frame: Baseline (Day 1), Day 7 (2 hours postdose) for Part A, Day 14 (2 hours postdose) for Part B and Day 15 for Part C ]
    Participants responded to 5 DEQs based on how they are feeling after taking the study drug. DEQ-5 were as follows; Q1: Do you FEEL a drug effect right now? Q2: Are you HIGH right now? Q3: Do you DISLIKE any of the effects that you are feeling right now? Q4: Do you LIKE any of the effects that you are feeling right now? Q5: Would you like MORE of the drug you took, right now? The answers were recorded on a 100-mm VAS, with the answer for each being "Not at all" (0 mm) and "Extremely" (100 mm) at the extremes. There were options to record "Not applicable" for questions 3 and 4 if no drug effects were felt and for question 5 prior to administration of study medication, and these participants were excluded from the data summarization. Higher score on Q1 indicates a drug effect; on Q2 indicates feeling high; on Q3 indicates disliking the drug; and on Q4 and Q5 indicates liking the drug.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

• Participant must have a diagnosis of Essential Tremor (ET), defined as bilateral postural tremor and kinetic tremor, involving hands and forearms, that is visible and persistent and the duration is >5 years prior to screening.

Key Exclusion Criteria:

• Participant has presence of abnormal neurological signs other than tremor or Froment's sign.
• Participant has presence of known causes of enhanced physiological tremor.
• Participant has concurrent or recent exposure (14 days prior to admission visit) to tremorogenic drugs.
• Participant has had direct or indirect trauma to the nervous system within 3 months before the onset of tremor.
• Participant has historical or clinical evidence of tremor with psychogenic origin.
• Participant has convincing evidence of sudden tremor onset or evidence of stepwise deterioration of tremor.

Contacts and Locations

Locations

United States, Alabama

Sage Investigational Site

Anniston, Alabama, United States, 36207

United States, Arkansas

Sage Investigational Site

Little Rock, Arkansas, United States, 72211

Sage Investigational Site

Rogers, Arkansas, United States, 72758

United States, California

Sage Investigational Site

Cerritos, California, United States, 90703

Sage Investigational Site

Fountain Valley, California, United States, 92708

Sage Investigational Site

Oceanside, California, United States, 92056

Sage Investigational Site

San Diego, California, United States, 92103

United States, Colorado

Sage Investigational Site

Englewood, Colorado, United States, 80113

United States, Florida

Sage Investigational Site

Clearwater, Florida, United States, 33756

Sage Investigational Site

DeLand, Florida, United States, 32720

Sage Investigational Site

Lauderdale Lakes, Florida, United States, 33319

Sage Investigational Site

Orlando, Florida, United States, 32806

Sage Investigational Site

Ormond Beach, Florida, United States, 32174

Sage Investigational Site

Saint Petersburg, Florida, United States, 33713

Sage Investigational Site

Tampa, Florida, United States, 33612

United States, Georgia

Sage Investigational Site

Atlanta, Georgia, United States, 30331

Sage Investigational Site

Decatur, Georgia, United States, 30030

United States, Illinois

Sage Investigational Site

Chicago, Illinois, United States, 60612

Sage Investigational Site

Urbana, Illinois, United States, 61801

United States, Missouri

Sage Investigational Site

Saint Louis, Missouri, United States, 63141

Sage Investigational Site

Springfield, Missouri, United States, 65802

United States, North Carolina

Sage Investigational Site

Raleigh, North Carolina, United States, 27612

United States, Ohio

Sage Investigational Site

Cincinnati, Ohio, United States, 45212

Sage Investigational Site

Dayton, Ohio, United States, 45417

United States, Tennessee

Sage Investigational Site

Nashville, Tennessee, United States, 37232

United States, Texas

Sage Investigational Site

Fort Worth, Texas, United States, 76104

Sponsors and Collaborators

Sage Therapeutics

Investigators

• Study Director: Christopher Silber, MD; Sage Therapeutics

  Study Documents (Full-Text)

Documents provided by Sage Therapeutics:

Statistical Analysis Plan  [PDF] December 14, 2017

Study Protocol  [PDF] September 5, 2017

More Information

Additional Information:

Related Info 

• Responsible Party: Sage Therapeutics
• ClinicalTrials.gov Identifier: NCT02978781
• Other Study ID Numbers: 217-ETD-201
• First Posted: December 1, 2016
• Results First Posted: February 17, 2021
• Last Update Posted: February 17, 2021
• Last Verified: January 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sage Therapeutics:

Tremor

Additional relevant MeSH terms:

Tremor; Essential Tremor; Dyskinesias; Neurologic Manifestations; Nervous System Diseases; Movement Disorders; Central Nervous System Diseases