A Study to Evaluate the Efficacy, Safety, and Tolerabilit... | NCT04305275

Label	Type	Description	Intervention Names
SAGE-324 60 mg	Experimental	Participants received SAGE-324, 60 milligrams (mg), oral tablets, once daily (QD), in the morning for 28 days.	Drug: SAGE-324
SAGE-324 Matched Placebo	Placebo Comparator	Participants received SAGE-324 matched placebo, oral tablets, QD, in the morning for 28 days.	Drug: SAGE-324 Placebo

Name	Type	Description	Arm Group Labels	Other Names
SAGE-324	Drug	SAGE-324 oral tablet	SAGE-324 60 mg
SAGE-324 Placebo

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change From Baseline Compared to Placebo in TETRAS Performance Subscale Part 4 Upper Limb Tremor Score on Day 29	The Essential Tremor Rating Assessment Scale (TETRAS) is a clinical evaluation of essential tremor. The TETRAS performance subscale upper limb tremor score is a component of TETRAS. The TETRAS performance subscale upper limb tremor total score is the sum of the TETRAS individual item scores from both arms of the body. The TETRAS individual item score included TETRAS Performance Subscale items 4a, 4b, and 4c scores [4a: limbs extended forward maneuver, 4b: wing-beating (elbows flexed) maneuver, and 4c: kinetic (finger-nose-finger) maneuver] scores from both arms of the body. Each individual item score ranges from 0 to 4; with 0 to 12 being the score range for each arm of the body. The total upper limb score combined for both arms ranges from 0 to 24. Higher scores=more severe tremor. A negative change from baseline =improvement. Mixed model repeated measures (MMRM) was used for the analysis.	Baseline, Day 29

Secondary Outcomes

Measure	Description	Time Frame
Change From Baseline Compared to Placebo in TETRAS Performance Subscale Part 4 Upper Limb Tremor Score at Days 8, 15, 22, and 42	TETRAS is a clinical evaluation of essential tremor. The TETRAS performance subscale upper limb tremor score is a component of TETRAS. The TETRAS performance subscale upper limb tremor total score is the sum of the TETRAS individual item scores from both arms of the body. The TETRAS individual item score included TETRAS Performance Subscale items 4a, 4b, and 4c scores [4a: limbs extended forward maneuver, 4b: wing-beating (elbows flexed) maneuver, and 4c: kinetic (finger-nose-finger) maneuver] scores from both arms of the body. Each individual item score ranges from 0 to 4; with 0 to 12 being the score range for each arm of the body. The total upper limb score combined for both arms ranges from 0 to 24. Higher scores=more severe tremor. A negative change from baseline =improvement. MMRM was used for the analysis.

Eligibility Module

Eligibility Criteria

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 (e.g., 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 the essential tremor rating assessment scale (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 pre-dose 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 investigational product (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, e.g., 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 organic anion transporting polypeptide 1B1 (OATP1B1) transporter.

Facility	Status	City	State	ZIP	Country	Contacts
Sage Investigational Site		Phoenix	Arizona	85258	United States
Sage Investigational Site

ID	Title	Description
FG000	SAGE-324 60 mg	Participants received SAGE-324, 60 milligrams (mg), oral tablets, once daily (QD), in the morning for 28 days.
FG001	SAGE-324 Matched Placebo	Participants received SAGE-324 matched placebo, oral tablets, QD, in the morning for 28 days.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Dec 18, 2020	Jan 30, 2024

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

- ParticipantsBG00034
- ParticipantsBG00135
- ParticipantsBG00269

Title	Measurements

Sex: Female, Male

Count of Participants

Participants

Title	Denominators	Categories
	ParticipantsBG00034 ParticipantsBG00135 ParticipantsBG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title	Denominators	Categories
	ParticipantsBG00034 ParticipantsBG00135 ParticipantsBG002

Race (NIH/OMB)

Count of Participants

Participants

Title	Denominators	Categories
	ParticipantsBG00034 ParticipantsBG00135 ParticipantsBG002

Region of Enrollment

Number

participants

Title	Denominators	Categories
United States	ParticipantsBG00034 ParticipantsBG00135 ParticipantsBG002

Tremor Rating Assessment Scale (TETRAS) Performance Subscale Item 4 Upper Limb Tremor Score

The TETRAS performance subscale upper limb tremor total score is the sum of the TETRAS individual item scores from both arms of the body. The TETRAS individual item score included TETRAS Performance Subscale items 4a, 4b, and 4c scores [4a:limbs extended forward maneuver, 4b:wing-beating (elbows flexed) maneuver, and 4c: kinetic (finger-nose-finger) maneuver]scores from both arms of the body. Each item score ranges from 0 to 4;with 0 to 12 being the score range for each arm of the body. The total upper limb score combined for both arms ranges from 0 to 24.Higher scores=more severe tremor.

Full Analysis Set included all randomized participants who received any amount of SAGE-324 or placebo and had a baseline and at least one postbaseline efficacy assessment.

Mean

Standard Deviation

score on a scale

Title	Denominators	Categories
	ParticipantsBG00033 ParticipantsBG001

Kinesia ONE™ Accelerometer Score

Kinesia ONE™ measures three-dimensional motion converted to scores.The accelerometer-based Kinesia ONE™ individual scores is the sum of the individual item scores across both arms of the body. The individual items included forward outstretched postural tremor, lateral "wing beating" postural tremor, and kinetic tremor scores from both arms of the body. Each item score ranges from 0(none) to 4(severe tremor);with 0 to 12 being the score range for each arm of the body. The Kinesia ONE total score combined for both arms ranges from 0 to 24. Higher scores=more tremors/greater tremor amplitude.

Full Analysis Set included all randomized participants who received any amount of SAGE-324 or placebo and had a baseline and at least one postbaseline efficacy assessment. 'Number analyzed" signifies the number of participants with data available at the Baseline for the analysis of the specified parameter.

Mean

Standard Deviation

score on a scale

Title	Denominators	Categories
	ParticipantsBG00033 ParticipantsBG001

TETRAS Activities of Daily Living (ADL) Score

The ADL subscale assesses how ET impacts typical activities of daily living (speech, eating, drinking, dressing, personal hygiene, writing, occupational impairment, social impact, and activities affected by UL tremor. It consists of 12 items, each rated from 0 (normal activity) to 4 (severe abnormality). The overall ADL score calculated as the sum of subscale items ranges from 0 to 48. A higher score indicates severity.

Full Analysis Set included all randomized participants who received any amount of SAGE-324 or placebo and had a baseline and at least one postbaseline efficacy assessment.

Mean

Standard Deviation

score on a scale

Title	Denominators	Categories
	ParticipantsBG00033 ParticipantsBG001

TETRAS Total Performance Subscale Score

The total performance score is based on the overall rating of tremor amplitude in the voice, limbs, head, face, and 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, calculated as the sum of the subscale items. Higher score indicates severity.

Full Analysis Set included all randomized participants who received any amount of SAGE-324 or placebo and had a baseline and at least one postbaseline efficacy assessment.

Mean

Standard Deviation

score on a scale

Title	Denominators	Categories
	ParticipantsBG00033 ParticipantsBG001

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline Compared to Placebo in TETRAS Performance Subscale Part 4 Upper Limb Tremor Score on Day 29

The Essential Tremor Rating Assessment Scale (TETRAS) is a clinical evaluation of essential tremor. The TETRAS performance subscale upper limb tremor score is a component of TETRAS. The TETRAS performance subscale upper limb tremor total score is the sum of the TETRAS individual item scores from both arms of the body. The TETRAS individual item score included TETRAS Performance Subscale items 4a, 4b, and 4c scores [4a: limbs extended forward maneuver, 4b: wing-beating (elbows flexed) maneuver, and 4c: kinetic (finger-nose-finger) maneuver] scores from both arms of the body. Each individual item score ranges from 0 to 4; with 0 to 12 being the score range for each arm of the body. The total upper limb score combined for both arms ranges from 0 to 24. Higher scores=more severe tremor. A negative change from baseline =improvement. Mixed model repeated measures (MMRM) was used for the analysis.

Full Analysis Set included all randomized participants who received any amount of SAGE-324 or placebo and had a baseline and at least one postbaseline efficacy assessment. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline, Day 29

ID	Title	Description
OG000	SAGE-324 60 mg	Participants received SAGE-324, 60 mg, oral tablets, QD, in the morning for 28 days.
OG001	SAGE-324 Matched Placebo	Participants received SAGE-324 matched placebo, oral tablets, QD, in the morning for 28 days.

Units	Counts
Participants	OG00021 OG00133

Title

Denominators

Categories

Title	Measurements
	OG000-2.31± 0.401 OG001-1.24± 0.349

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		MMRM	MMRM model included treatment, baseline score, assessment timepoint, & timepoint-by-treatment as explanatory variables, treated as fixed effects.	0.0491		Least Squares (LS) Mean Difference	-1.07	Standard Error of the Mean	0.533	2-Sided	95	-2.14	0.00					Superiority

Secondary

Change From Baseline Compared to Placebo in TETRAS Performance Subscale Part 4 Upper Limb Tremor Score at Days 8, 15, 22, and 42

TETRAS is a clinical evaluation of essential tremor. The TETRAS performance subscale upper limb tremor score is a component of TETRAS. The TETRAS performance subscale upper limb tremor total score is the sum of the TETRAS individual item scores from both arms of the body. The TETRAS individual item score included TETRAS Performance Subscale items 4a, 4b, and 4c scores [4a: limbs extended forward maneuver, 4b: wing-beating (elbows flexed) maneuver, and 4c: kinetic (finger-nose-finger) maneuver] scores from both arms of the body. Each individual item score ranges from 0 to 4; with 0 to 12 being the score range for each arm of the body. The total upper limb score combined for both arms ranges from 0 to 24. Higher scores=more severe tremor. A negative change from baseline =improvement. MMRM was used for the analysis.

Full Analysis Set included all randomized participants who received any amount of SAGE-324 or placebo and had a baseline and at least one postbaseline efficacy assessment. 'Number analyzed' indicates the number of participants with data available for analysis at the specified time point.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline, Days 8, 15 (pre-dose, 5, and 8 hours post-dose), 22, and 42

ID	Title	Description
OG000	SAGE-324 60 mg	Participants received SAGE-324, 60 mg, oral tablets, QD, in the morning for 28 days.
OG001	SAGE-324 Matched Placebo

Secondary

Change From Baseline Compared to Placebo in Kinesia ONE™ Accelerometer Score at Days 8, 15, 22, 29, and 42

Kinesia ONE™ measures three-dimensional motion converted to scores. Motion in both arms were captured. The accelerometer-based Kinesia ONE individual scores is the sum of the individual item scores across both arms of the body. The individual items included forward outstretched postural tremor, lateral "wing beating" postural tremor, and kinetic tremor scores from both arms of the body. Each individual item score ranges from 0 (no tremor) to 4 (severe tremor); with 0 to 12 being the score range for each arm of the body. The Kinesia ONE total score combined for both arms ranges from 0 to 24. Higher scores=more tremors/greater tremor amplitude. A negative change from baseline indicates improvement. MMRM was used for the analysis.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline, Days 8, 15 (pre-dose, 5, and 8 hours post-dose), 22, 29, and 42

ID	Title	Description
OG000	SAGE-324 60 mg	Participants received SAGE-324, 60 mg, oral tablets, QD, in the morning for 28 days.
OG001	SAGE-324 Matched Placebo

Secondary

Change From Baseline Compared to Placebo in TETRAS ADL Score at Days 8, 15, 22, 29, and 42

The ADL subscale assesses how ET impacts typical activities of daily living (speech, eating, drinking, dressing, personal hygiene, writing, occupational impairment, social impact, and activities affected by UL tremor. It consists of 12 items, each rated from 0 (normal activity) to 4 (severe abnormality). The overall ADL score, calculated as the sum of subscale items ranges from 0 to 48. Higher scores indicate greater tremor severity, while a negative change from baseline indicates improvement. MMRM was used for the analysis.

Full Analysis Set included all randomized participants who received any amount of SAGE-324 or placebo and had a baseline and at least one postbaseline efficacy assessment. 'Number analyzed' indicates the number of participants with data available for analysis at the specified time point.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline, Days 8, 15, 22, 29, and 42

ID	Title	Description
OG000	SAGE-324 60 mg	Participants received SAGE-324, 60 mg, oral tablets, QD, in the morning for 28 days.
OG001	SAGE-324 Matched Placebo	Participants received SAGE-324 matched placebo, oral tablets, QD, in the morning for 28 days.

Secondary

Change From Baseline Compared to Placebo in TETRAS Total Performance Score at Days 8, 15, 22, 29, and 42

The total performance score is based on the overall rating of tremor amplitude in the voice, limbs, head, face, and 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, calculated as the sum of subscale items. Higher scores indicate greater tremor severity. A negative change from baseline indicates improvement. MMRM was used for the analysis.

Full Analysis Set included all randomized participants who received any amount of SAGE-324 or placebo and had a baseline and at least one postbaseline efficacy assessment. 'Number analyzed' indicates the number of participants with data available for analysis at the specified time point.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline, Days 8, 15 (pre-dose, 5, and 8 hours post-dose), 22, 29, and 42

ID	Title	Description
OG000	SAGE-324 60 mg	Participants received SAGE-324, 60 mg, oral tablets, QD, in the morning for 28 days.
OG001	SAGE-324 Matched Placebo	Participants received SAGE-324 matched placebo, oral tablets, QD, in the morning for 28 days.

Secondary

Number of Participants With Treatment-emergent Adverse Events (TEAEs)

An AE was any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have a causal relationship with the treatment. A TEAE was defined as an AE with onset after the start of investigational product (IP), or any worsening of a preexisting medical condition/AE with onset after the start of IP and throughout the study.

Safety Set included all participants who were administered SAGE-324 or placebo.

Posted

Count of Participants

Participants

From the first dose of the study drug up to the end of the study (i.e., up to approximately 42 days)

ID	Title	Description
OG000	SAGE-324 60 mg	Participants received SAGE-324, 60 mg, oral tablets, QD, in the morning for 28 days.
OG001	SAGE-324 Matched Placebo	Participants received SAGE-324 matched placebo, oral tablets, QD, in the morning for 28 days.

Units	Counts
Participants

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Somnolence	Nervous system disorders	23.0	Systematic Assessment	EG00023 affected34 at risk EG0012 affected35 at risk
Dizziness	Nervous system disorders	23.0	Systematic Assessment	EG00013 affected34 at risk EG0014 affected35 at risk
Fatigue	General disorders	23.0	Systematic Assessment	EG0005 affected34 at risk EG0014 affected35 at risk
Balance disorder	Nervous system disorders	23.0	Systematic Assessment	EG0005 affected34 at risk EG0010 affected35 at risk
Diplopia	Eye disorders	23.0	Systematic Assessment	EG0004 affected34 at risk EG0010 affected35 at risk
Dysarthria	Nervous system disorders	23.0	Systematic Assessment	EG0004 affected34 at risk EG0010 affected35 at risk
Gait disturbance	General disorders	23.0	Systematic Assessment	EG0004 affected34 at risk EG0010 affected35 at risk
Disturbance in attention	Nervous system disorders	23.0	Systematic Assessment	EG0003 affected34 at risk EG0013 affected35 at risk
Myoclonus	Nervous system disorders	23.0	Systematic Assessment	EG0003 affected34 at risk EG0010 affected35 at risk
Diarrhoea	Gastrointestinal disorders	23.0	Systematic Assessment	EG0002 affected34 at risk EG0013 affected35 at risk
Paraesthesia	Nervous system disorders	23.0	Systematic Assessment	EG0002 affected34 at risk EG0012 affected35 at risk
Lethargy	Nervous system disorders	23.0	Systematic Assessment	EG0002 affected34 at risk EG0010 affected35 at risk
Speech disorder	Nervous system disorders	23.0	Systematic Assessment	EG0002 affected34 at risk EG0010 affected35 at risk
Headache	Nervous system disorders	23.0	Systematic Assessment	EG0001 affected34 at risk EG0016 affected35 at risk
Coordination abnormal	Nervous system disorders	23.0	Systematic Assessment	EG0001 affected34 at risk EG0013 affected35 at risk
Asthenia	General disorders	23.0	Systematic Assessment	EG0001 affected34 at risk EG0012 affected35 at risk
Insomnia	Psychiatric disorders	23.0	Systematic Assessment	EG0001 affected34 at risk EG0012 affected35 at risk
Urinary tract infection	Infections and infestations	23.0	Systematic Assessment	EG0001 affected34 at risk EG0012 affected35 at risk
Irritability	Psychiatric disorders	23.0	Systematic Assessment	EG0000 affected34 at risk EG0012 affected35 at risk
Myalgia	Musculoskeletal and connective tissue disorders	23.0	Systematic Assessment	EG0000 affected34 at risk EG0012 affected35 at risk

ID	Term
D009069	Movement Disorders
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases

ID	Title	Description
BG000	SAGE-324 60 mg	Participants received SAGE-324, 60 mg, oral tablets, QD, in the morning for 28 days.
BG001	SAGE-324 Matched Placebo	Participants received SAGE-324 matched placebo, oral tablets, QD, in the morning for 28 days.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	SAGE-324 60 mg	Participants received SAGE-324, 60 mg, oral tablets, QD, in the morning for 28 days.	0	34	3	34	29	34
EG001	SAGE-324 Matched Placebo	Participants received SAGE-324 matched placebo, oral tablets, QD, in the morning for 28 days.	0	35	1	35	15	35

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Mental status changes	Psychiatric disorders	23.0	Systematic Assessment	EG0002 affected34 at risk EG0010 affected35 at risk
Dehydration	Metabolism and nutrition disorders	23.0	Systematic Assessment	EG0001 affected34 at risk EG0010 affected35 at risk
Headache	Nervous system disorders	23.0	Systematic Assessment	EG0001 affected34 at risk EG0010 affected35 at risk
Transient ischaemic attack	Nervous system disorders	23.0	Systematic Assessment	EG0001 affected34 at risk EG0010 affected35 at risk
Angina pectoris	Cardiac disorders	23.0	Systematic Assessment	EG0000 affected34 at risk EG0011 affected35 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	23.0	Systematic Assessment	EG0000 affected34 at risk EG0011 affected35 at risk