Essential Tremor
Conditions
Keywords
Essential Tremor, SAGE-324
Brief summary
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.
Interventions
DRUGSAGE-324
SAGE-324 oral tablets.
DRUGSAGE-324 Matched Placebo
SAGE-324 matched placebo oral tablets.
Sponsors
Biogen
Sage Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. 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) 2. 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. 3. 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 4. Participant has a baseline TETRAS ADL Subscale score of at least 20 at Screening. 5. 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. 6. 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. 7. 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
1. Presence of known causes of enhanced physiological tremor. 2. 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. 3. Direct or indirect injury or trauma to the nervous system within 3 months before the onset of tremor. 4. 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. 5. Participant has had botulinum toxin for treatment of ET within 6 months of Screening. 6. Historical or clinical evidence of tremor with functional neurological syndrome origin. 7. Participant currently requires propranolol treatment for a medical condition other than ET. 8. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline, Day 91 | TETRAS is a clinical evaluation of essential tremor. The TETRAS performance subscale upper limb tremor score is a component of TETRAS. For the TETRAS Performance Subscale Item 4 (upper limb), three maneuvers/assessments were to be completed for both arms, first for the right arm and then for the left, specifically Item 4a, limbs extended forward maneuver (postural tremor), Item 4b, wing-beating \[elbows flexed\] maneuver (postural tremor), and Item 4c finger-nose-finger maneuver (kinetic tremor). Each assessment is rated on a 0 to 4 scale of severity in 0.5-point increments, with higher scores indicating more severe tremor. The Performance Subscale Item 4 (upper limb) total score range for a given side (left or right) is 0 to 12, and for both sides combined is 0 to 24. A negative change from baseline indicates improvement. Mixed model for repeated measures (MMRM) was used for the analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in TETRAS Activities of Daily Living (ADL) Composite Score in the Monotherapy Cohort | Baseline, Day 91 | TETRAS ADL Subscale (items 1-12) assesses how ET affects typical ADL (speech, eating, drinking, dressing, personal hygiene, writing, occupational impairment, social impact, activities affected by UL tremor). TETRAS ADL composite score comprises Items 1-11 of ADL Subscale (Item 1: speech impairment; Item 10: occupational impairment; remaining 9 items: impairment in activities affected by UL tremor) and Item 6 of Performance Subscale (spiral drawing). Each of individual item is rated on a scale from 0 (normal activity) to 4 (severe abnormality); responses of 0 & 1 in TETRAS ADL Subscale Items 1 to 11 were collapsed such that scale is 0 (normal/slightly abnormal), 1 (mildly abnormal), 2 (moderately abnormal), and 3 (severely abnormal). Performance Subscale Item 6 responses were collapsed with responses having 0.5 point increments grouped with next higher integer response. ADL composite score range is 0 to 39. Higher score=greater abnormality, negative change=improvement. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at 51 investigative sites in the United States from 05 Jan 2022 to 16 May 2024.
Pre-assignment details
A total of 160 participants were planned for the study, of which 147 participants were randomized. Out of 147, 1 participant was randomized in error but was not assigned in any of the treatment group. This participant did not receive any treatment, therefore only146 participants received IP.
Participants by arm
| Arm | Count |
|---|---|
| Monotherapy: Placebo Participants received SAGE-324 matched placebo, orally, QD, in the evening, from Day 1 to Day 90 in a double-blind treatment period. | 31 |
| Monotherapy: SAGE-324 15 mg Participants received SAGE-324 15 mg, orally, QD, in the evening, from Day 1 to Day 90 in a double-blind treatment period. | 32 |
| Monotherapy: SAGE-324 30 mg Participants received SAGE-324 30 mg, orally, QD, in the evening, from Day 1 to Day 90 in a double-blind treatment period. | 32 |
| Monotherapy: SAGE-324 60 mg Participants received 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, orally, QD, in the evening, from Day 1 to Day 90 in a double-blind treatment period. | 33 |
| Adjunct Therapy: Placebo Participants received SAGE-324 matched placebo, orally, 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. | 4 |
| Adjunct Therapy: SAGE-324 15 mg Participants received 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. | 4 |
| Adjunct Therapy: SAGE-324 30 mg Participants received SAGE-324, 30 mg orally, 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. | 5 |
| Adjunct Therapy: SAGE-324 60 mg Participants received 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. | 5 |
| Total | 146 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 | 4 | 13 | 0 | 0 | 2 | 4 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Deviation | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 | 3 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Monotherapy: Placebo | Total | Adjunct Therapy: SAGE-324 60 mg | Adjunct Therapy: SAGE-324 30 mg | Adjunct Therapy: SAGE-324 15 mg | Adjunct Therapy: Placebo | Monotherapy: SAGE-324 60 mg | Monotherapy: SAGE-324 30 mg | Monotherapy: SAGE-324 15 mg |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 69.3 years STANDARD_DEVIATION 9.35 | 67.9 years STANDARD_DEVIATION 9.6 | 69.8 years STANDARD_DEVIATION 8.87 | 67.4 years STANDARD_DEVIATION 7.57 | 69.3 years STANDARD_DEVIATION 11.59 | 65.8 years STANDARD_DEVIATION 11.95 | 69.5 years STANDARD_DEVIATION 7.67 | 66.9 years STANDARD_DEVIATION 10.18 | 65.8 years STANDARD_DEVIATION 11.25 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 7 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 139 Participants | 5 Participants | 5 Participants | 4 Participants | 4 Participants | 29 Participants | 31 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 29 Participants | 139 Participants | 5 Participants | 5 Participants | 4 Participants | 3 Participants | 31 Participants | 30 Participants | 32 Participants |
| Sex: Female, Male Female | 11 Participants | 54 Participants | 3 Participants | 2 Participants | 2 Participants | 1 Participants | 14 Participants | 10 Participants | 11 Participants |
| Sex: Female, Male Male | 20 Participants | 92 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 19 Participants | 22 Participants | 21 Participants |
| The Essential Tremor Rating Assessment Scale (TETRAS) Performance Subscale Item 4 (Upper Limb) Score | 13.68 score on a scale STANDARD_DEVIATION 1.249 | 13.43 score on a scale STANDARD_DEVIATION 1.492 | 13.00 score on a scale STANDARD_DEVIATION 0.935 | 13.20 score on a scale STANDARD_DEVIATION 0.758 | 14.25 score on a scale STANDARD_DEVIATION 2.843 | 12.50 score on a scale STANDARD_DEVIATION 0.577 | 13.39 score on a scale STANDARD_DEVIATION 1.633 | 13.10 score on a scale STANDARD_DEVIATION 1.625 | 13.69 score on a scale STANDARD_DEVIATION 1.43 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 32 | 0 / 32 | 0 / 33 | 0 / 4 | 0 / 4 | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 9 / 31 | 13 / 32 | 15 / 32 | 22 / 33 | 1 / 4 | 3 / 4 | 3 / 5 | 5 / 5 |
| serious Total, serious adverse events | 1 / 31 | 1 / 32 | 0 / 32 | 1 / 33 | 0 / 4 | 0 / 4 | 1 / 5 | 0 / 5 |
Outcome results
Primary
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 clinical evaluation of essential tremor. The TETRAS performance subscale upper limb tremor score is a component of TETRAS. For the TETRAS Performance Subscale Item 4 (upper limb), three maneuvers/assessments were to be completed for both arms, first for the right arm and then for the left, specifically Item 4a, limbs extended forward maneuver (postural tremor), Item 4b, wing-beating \[elbows flexed\] maneuver (postural tremor), and Item 4c finger-nose-finger maneuver (kinetic tremor). Each assessment is rated on a 0 to 4 scale of severity in 0.5-point increments, with higher scores indicating more severe tremor. The Performance Subscale Item 4 (upper limb) total score range for a given side (left or right) is 0 to 12, and for both sides combined is 0 to 24. A negative change from baseline indicates improvement. Mixed model for repeated measures (MMRM) was used for the analysis.
Time frame: Baseline, Day 91
Population: The Full Analysis Set included all randomized participants who received any amount of IP and had a baseline and at least one post-baseline TETRAS Performance Subscale Item 4 (upper limb tremor) total score. The overall number of participants analyzed indicates the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Monotherapy: Placebo | 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 | -2.53 score on a scale | Standard Error 0.445 |
| Monotherapy: SAGE-324 15 mg | 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 | -2.14 score on a scale | Standard Error 0.436 |
| Monotherapy: SAGE-324 30 mg | 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 | -2.81 score on a scale | Standard Error 0.449 |
| Monotherapy: SAGE-324 60 mg | 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 | -1.51 score on a scale | Standard Error 0.54 |
p-value: 0.532595% CI: [-0.84, 1.62]MMRM
p-value: 0.654995% CI: [-1.54, 0.97]MMRM
p-value: 0.146295% CI: [-0.36, 2.41]MMRM
Secondary
Change From Baseline in TETRAS Activities of Daily Living (ADL) Composite Score in the Monotherapy Cohort
TETRAS ADL Subscale (items 1-12) assesses how ET affects typical ADL (speech, eating, drinking, dressing, personal hygiene, writing, occupational impairment, social impact, activities affected by UL tremor). TETRAS ADL composite score comprises Items 1-11 of ADL Subscale (Item 1: speech impairment; Item 10: occupational impairment; remaining 9 items: impairment in activities affected by UL tremor) and Item 6 of Performance Subscale (spiral drawing). Each of individual item is rated on a scale from 0 (normal activity) to 4 (severe abnormality); responses of 0 & 1 in TETRAS ADL Subscale Items 1 to 11 were collapsed such that scale is 0 (normal/slightly abnormal), 1 (mildly abnormal), 2 (moderately abnormal), and 3 (severely abnormal). Performance Subscale Item 6 responses were collapsed with responses having 0.5 point increments grouped with next higher integer response. ADL composite score range is 0 to 39. Higher score=greater abnormality, negative change=improvement.
Time frame: Baseline, Day 91
Population: The Full Analysis Set included all randomized participants who received any amount of IP and had a baseline and at least one post-baseline TETRAS Performance Subscale Item 4 (upper limb tremor) total score. The overall number of participants analyzed indicates the number of participants with data available for analysis at specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Monotherapy: Placebo | Change From Baseline in TETRAS Activities of Daily Living (ADL) Composite Score in the Monotherapy Cohort | -4.51 score on a scale | Standard Error 0.951 |
| Monotherapy: SAGE-324 15 mg | Change From Baseline in TETRAS Activities of Daily Living (ADL) Composite Score in the Monotherapy Cohort | -2.48 score on a scale | Standard Error 0.921 |
| Monotherapy: SAGE-324 30 mg | Change From Baseline in TETRAS Activities of Daily Living (ADL) Composite Score in the Monotherapy Cohort | -5.29 score on a scale | Standard Error 0.948 |
| Monotherapy: SAGE-324 60 mg | Change From Baseline in TETRAS Activities of Daily Living (ADL) Composite Score in the Monotherapy Cohort | -3.51 score on a scale | Standard Error 1.08 |
p-value: 0.127195% CI: [0.59, 4.67]MMRM
p-value: 0.564295% CI: [-3.45, 1.89]MMRM
p-value: 0.48695% CI: [-1.84, 3.85]MMRM