Spinocerebellar Ataxias, Spinocerebellar Ataxia Type 1, Spinocerebellar Ataxia Type 2, Spinocerebellar Ataxia Type 3, Spinocerebellar Ataxia Type 6, Spinocerebellar Ataxia Type 7, Spinocerebellar Ataxia Type 8, Spinocerebellar Ataxia Type 10
Conditions
Keywords
Ataxia, SCA, Spinocerebellar Ataxia
Brief summary
The purpose of this study is to compare the efficacy of Troriluzole (200 mg once daily) versus placebo after 48 weeks of treatment in subjects with spinocerebellar ataxia (SCA).
Interventions
DRUGtroriluzole
Administered orally
DRUGPlacebo
Administered orally
Sponsors
Biohaven Pharmaceuticals, Inc.
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 75 Years
Healthy volunteers
No
Inclusion criteria
1. Participants with a known or suspected diagnosis of the following specific hereditary ataxias: SCA1, SCA2, SCA3, SCA6, SCA7, SCA8 and SCA10. 1. A participant should have a confirmed genotypic diagnosis from a Clinical Laboratory Improvement Amendments (CLIA) certified lab (can produce test results); or, 2. A participant has a family member that has a confirmed genotypic diagnosis from a CLIA certified lab (can produce test results) and must be willing to undergo genetic testing to confirm underlying SCA diagnosis; or, 3. A participant has a confirmed genotypic diagnosis from a lab that is not CLIA certified and must be willing to undergo genetic testing to confirm underlying SCA diagnosis; or, 4. A participant has clinical evidence that supports diagnosis of one of the aforementioned SCA genotypes but does not have producible test results from a CLIA certified lab from either a family member or for his or herself and the participant must be willing to undergo such testing to confirm the SCA diagnosis (in this case, site must wait for results of genotypic testing prior to randomization) 2. Ability to ambulate 8 meters without human assistance (canes and other devices allowed) 3. Screening Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) total score ≥3. 4. Score of ≥1 on gait subsection of the f-SARA 5. Determined by the investigator to be medically stable at Baseline/randomization as assessed by medical history, physical examination, laboratory test results, and electrocardiogram testing.
Exclusion criteria
1. A ≥ 2-point difference on the Modified Functional SARA score between screening and baseline 2. Mini Mental State Exam (MMSE) score \<24 3. Any medical condition other than one of the hereditary ataxias specified in the inclusion criteria that could predominantly explain or contribute significantly to the participants' symptoms of ataxia. 4. A prominent spasticity or dystonia that, in the opinion of the investigator, will compromise the ability of the SARA instrument to assess underlying ataxia severity. 5. A score of 4 on any individual item (Items 1-4) of the f-SARA 6. Participants should be excluded at screening or baseline if medical conditions have arisen or there is a change in disease status that could confound the ability of the SARA to accurately reflect changes in ataxia severity. 7. Active liver disease or a history of hepatic intolerance to medications that in the investigator's judgment, is medically significant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Randomization Phase: Change From Baseline in the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) Total Score at Week 48 in SCA Participants | Randomization Baseline; Week 48 | The f-SARA was a 4-item performance based scale: 1-gait, 2-stance, 3-sitting, 4-speech disturbance (0:normal (no impairment), 1: mildly impaired function, but no assistance required, 2: moderately impaired function, but needs assistance for certain parts of task, 3: severely impaired function to degree that assistance is needed for all parts of the task, 4: unable to perform function). Total score was derived as sum of individual items; ranged from 0 to 16. Higher score indicated worst outcome. A negative change in score showed improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Randomization Phase: Change From Baseline in Patient Impression of Function and Activities of Daily Living Scale (PIFAS) Total Score at Week 48 in SCA Participants | Randomization Baseline, Week 48 | PIFAS was a 17-item instrument designed to assess the level of functional disability. The scale was rater administered and the items were selected to encompass domains of relevance to SCA (i.e., mobility, speech/swallowing, and fatigue), and to capture function and activities of daily living within these domains. Statements were rated on a 5-point Likert scale ranging from 0 reflecting not at all to 4 reflecting very much. The total score was derived as the sum of the individual items, ranged between 0 to 68. Higher score indicated a worst outcome. A negative change in score showed improvement. |
| Randomization Phase: Change From Baseline in Friedreich's Ataxia Rating Scale - Activities of Daily Living (FARS-ADL) Total Score at Week 48 in SCA Participants | Randomization Baseline, Week 48 | FARS was a scale consisting of combined timed measures of performance, FUNC (0-6, higher score indicated worst outcome), ADL with paramount neurologic examination (0-36, higher score indicated worst outcome), FARSn (0-125, higher score indicated worst outcome). Total score was sum of these 3 subscales: 0-167, higher score indicated worst outcome. For this outcome measure, only FARS-ADL sub-scale was evaluated. It was multicomponent scale designed to assess neurological domains affected in Friedreich's Ataxia, another hereditary cerebellar ataxia disorder. This subscale had been validated in Friedreich's ataxia, was a measure of functional disability, and correlated with SARA total scores. It assessed 9 areas of ADL with response categories rated on 5-point scale with 0 reflecting normal and 4 reflecting inability to perform specific function. Total score was derived as sum of individual items, ranging 0-36, higher score indicated worst outcome. FARS-ADL was rater administered. |
| Randomization Phase: Change From Baseline in Functional Staging for Ataxia Scale From the Friedreich's Ataxia Rating Scale (FARS-FUNC) Total Score at Week 48 in SCA Participants | Randomization Baseline, Week 48 | FARS was a scale consisting of combined timed measures of performance, FUNC (0-6, higher score indicated worst outcome), ADL with paramount neurologic examination (0-36, higher score indicated worst outcome), FARSn (0-125, higher score indicated worst outcome). The total score was a sum of these 3 subscales; 0-167, higher score indicated worst outcome. For this outcome measure, only the FARS-FUNC sub-scale was evaluated. FARS-FUNC was a subscale of the FARS designed to provide functional staging for ataxia in which clinicians were asked to assess function on a 6-stage staging system, with 0 reflecting normal and 6 reflecting a stage in participant was total disabled. |
| Randomization Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (TESAEs); and AEs Leading to Treatment Discontinuation | From first dose of study drug to Week 48 plus 30 days (maximum duration: 52 weeks) | An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant that did not necessarily had a causal relationship with this treatment. An SAE was defined as any AE that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect in the offspring of the participant or was considered another important medical event. Treatment-emergent AEs (TEAEs) in the randomization phase included any AE with an onset date on or after the first day of double-blind study drug and up to the first day of open-label study drug in the extension phase (for participants entering the extension phase) or last day of the randomization phase study drug + 30 days. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Randomization Phase: Change From Baseline in the f-SARA Total Score at Week 48 in SCA3 Participants | Randomization Baseline; Week 48 | The f-SARA was a 4-item performance based scale: 1-gait, 2-stance, 3-sitting, 4-speech disturbance (0:normal (no impairment), 1:mildly impaired function, but no assistance required, 2:moderately impaired function, but needs assistance for certain parts of task, 3: severely impaired function to degree that assistance is needed for all parts of the task, 4:unable to perform function). Total score was derived as sum of individual items; ranged from 0 to 16. Higher score indicated worst outcome. A negative change in score shows improvement. |
| Falls Events in Troriluzole Compared to Placebo for All SCA Participants | Randomization Baseline, Week 48 | An AE of Fall was recorded if there was a worsening of frequency of falls or if a fall was associated with an injury. |
| Randomization Phase: Change From Baseline in PIFAS Total Score at Week 48 in SCA3 Participants | Randomization Baseline, Week 48 | PIFAS was a 17-item instrument designed to assess the level of functional disability. The scale is rater administered and the items were selected to encompass domains of relevance to SCA (i.e., mobility, speech/swallowing, and fatigue), and to capture function and activities of daily living within these domains. Statements are rated on a 5-point Likert scale ranging from 0 reflecting not at all to 4 reflecting very much. The total score is derived as the sum of the individual items, ranged between 0 to 68. Higher score indicated a worst outcome. A negative change in score showed improvement. |
| Randomization Phase: Change From Baseline in FARS-ADL Total Score at Week 48 in SCA3 Participants | Randomization Baseline, Week 48 | FARS was a scale consisting of combined timed measures of performance, FUNC (0-6, higher score indicated worst outcome), ADL with paramount neurologic examination (0-36, higher score indicated worst outcome), FARSn (0-125, higher score indicated worst outcome). Total score was sum of these 3 subscales: 0-167, higher score indicated worst outcome. For this outcome measure, only FARS-ADL sub-scale was evaluated. It was multicomponent scale designed to assess neurological domains affected in Friedreich's Ataxia, another hereditary cerebellar ataxia disorder. This subscale had been validated in Friedreich's ataxia, was a measure of functional disability, and correlated with SARA total scores. It assessed 9 areas of ADL with response categories rated on 5-point scale with 0 reflecting normal and 4 reflecting inability to perform specific function. Total score was derived as sum of individual items, ranging 0-36, higher score indicated worst outcome. FARS-ADL was rater administered. |
| Randomization Phase: Change From Baseline in FARS-FUNC Total Score at Week 48 in SCA3 Participants | Randomization Baseline, Week 48 | FARS was a scale consisting of combined timed measures of performance, FUNC (0-6, higher score indicated worst outcome), ADL with paramount neurologic examination (0-36, higher score indicated worst outcome), FARSn (0-125, higher score indicated worst outcome). The total score was a sum of these 3 subscales; 0-167, higher score indicated worst outcome. For this outcome measure, only the FARS-FUNC sub-scale was evaluated. FARS-FUNC was a subscale of the FARS designed to provide functional staging for ataxia in which clinicians were asked to assess function on a 6-stage staging system, with 0 reflecting normal and 6 reflecting a stage in participant was total disabled. |
| Change From Baseline in Clinical Global Impression - Global Improvement Scale (CGI-I) in SCA3 Participants | Randomization Baseline; Week 48 | The CGI-I was a 7-point scale that required the clinician to assess how much the participant's illness had improved or worsened relative to the baseline visit and it was rated on a 7 point scale: 1= Very much improved, 2= Much improved, 3= Minimally improved, 4= No change, 5= Minimally worse, 6= Much worse and 7= Very much worse. Higher scores indicated greater impairment. |
Countries
China, United States
Participant flow
Recruitment details
The study was conducted at 23 sites in 2 countries (21 sites in the US and 2 sites in China).
Pre-assignment details
A total of 299 participants were enrolled, of which 218 participants were randomized in a 1:1: ratio to receive troriluzole or placebo. Study consisted of double-blind randomization phase (up to Week 48) and open-label extension phase (up to Week 192). The study is ongoing, and results are reported only for randomization phase (up to Week 48).
Participants by arm
| Arm | Count |
|---|---|
| Troriluzole Randomization phase (Randomization through Week 48):
Participants received starting dose of troriluzole 140 milligrams (mg) capsules orally once daily for first 4 weeks, followed by 200 mg once daily for the remaining 44 weeks of 48 week duration of the double-blind randomization phase.
Open-label extension (OLE) phase (OLE Week 1 up to Week 192): Participants who were eligible and agreed to enroll in an OLE phase, will receive troriluzole 200 mg capsules orally once daily for 4 weeks in a blinded manner. After OLE Week 4, all participants will then receive open label troriluzole 200 mg up to Week 192. | 108 |
| Placebo Randomization phase (Randomization through Week 48):
Participants received troriluzole matching placebo capsules orally once daily for 48 weeks duration of the double-blind randomization phase.
OLE phase (Week 1 up to Week 192): Participants who were eligible and agreed to enroll in an OLE phase, will receive troriluzole 140 mg capsules orally once daily for the first 4 weeks in a blinded manner. After OLE Week 4, all participants will then receive open label troriluzole 200 mg up to Week 192. | 109 |
| Total | 217 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 5 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Investigators decision | 1 | 2 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Randomized but not treated | 1 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 3 |
Baseline characteristics
| Characteristic | Troriluzole | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 47.7 years STANDARD_DEVIATION 13.16 | 47.6 years STANDARD_DEVIATION 12.48 | 47.6 years STANDARD_DEVIATION 12.79 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 11 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 95 Participants | 98 Participants | 193 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Number of Participants with Spinocerebellar ataxia (SCA) Genotype SCA1 | 15 participants | 11 participants | 26 participants |
| Number of Participants with Spinocerebellar ataxia (SCA) Genotype SCA10 | 3 participants | 5 participants | 8 participants |
| Number of Participants with Spinocerebellar ataxia (SCA) Genotype SCA2 | 32 participants | 35 participants | 67 participants |
| Number of Participants with Spinocerebellar ataxia (SCA) Genotype SCA3 | 44 participants | 45 participants | 89 participants |
| Number of Participants with Spinocerebellar ataxia (SCA) Genotype SCA6 | 6 participants | 6 participants | 12 participants |
| Number of Participants with Spinocerebellar ataxia (SCA) Genotype SCA7 | 5 participants | 5 participants | 10 participants |
| Number of Participants with Spinocerebellar ataxia (SCA) Genotype SCA8 | 3 participants | 2 participants | 5 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 21 Participants | 40 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 14 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 74 Participants | 74 Participants | 148 Participants |
| Sex: Female, Male Female | 50 Participants | 56 Participants | 106 Participants |
| Sex: Female, Male Male | 58 Participants | 53 Participants | 111 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 109 | 1 / 109 |
| other Total, other adverse events | 54 / 108 | 58 / 109 |
| serious Total, serious adverse events | 6 / 108 | 8 / 109 |
Outcome results
Primary
Randomization Phase: Change From Baseline in the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) Total Score at Week 48 in SCA Participants
The f-SARA was a 4-item performance based scale: 1-gait, 2-stance, 3-sitting, 4-speech disturbance (0:normal (no impairment), 1: mildly impaired function, but no assistance required, 2: moderately impaired function, but needs assistance for certain parts of task, 3: severely impaired function to degree that assistance is needed for all parts of the task, 4: unable to perform function). Total score was derived as sum of individual items; ranged from 0 to 16. Higher score indicated worst outcome. A negative change in score showed improvement.
Time frame: Randomization Baseline; Week 48
Population: The modified intent-to-treat (mITT) analysis set in randomization phase included randomized participants who received at least one dose of double-blind study medication (troriluzole or placebo) during the randomization phase and provided a non-missing baseline measurement and at least one non-missing post-baseline efficacy measurement during the randomization phase. Participants with available data were included. Pre-specified randomization strata by SCA genotype.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Troriluzole | Randomization Phase: Change From Baseline in the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) Total Score at Week 48 in SCA Participants | All SCA | 0.20 score on a scale | Standard Error 0.19 |
| Troriluzole | Randomization Phase: Change From Baseline in the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) Total Score at Week 48 in SCA Participants | SCA3 | -0.03 score on a scale | Standard Error 0.2 |
| Placebo | Randomization Phase: Change From Baseline in the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) Total Score at Week 48 in SCA Participants | All SCA | 0.27 score on a scale | Standard Error 0.18 |
| Placebo | Randomization Phase: Change From Baseline in the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) Total Score at Week 48 in SCA Participants | SCA3 | 0.53 score on a scale | Standard Error 0.19 |
Comparison: All SCA participantsp-value: 0.758195% CI: [-0.47, 0.34]Mixed Models Analysis
Comparison: SCA3 genotype participantsp-value: 0.04595% CI: [-1.11, -0.01]Mixed Models Analysis
Secondary
Randomization Phase: Change From Baseline in Friedreich's Ataxia Rating Scale - Activities of Daily Living (FARS-ADL) Total Score at Week 48 in SCA Participants
FARS was a scale consisting of combined timed measures of performance, FUNC (0-6, higher score indicated worst outcome), ADL with paramount neurologic examination (0-36, higher score indicated worst outcome), FARSn (0-125, higher score indicated worst outcome). Total score was sum of these 3 subscales: 0-167, higher score indicated worst outcome. For this outcome measure, only FARS-ADL sub-scale was evaluated. It was multicomponent scale designed to assess neurological domains affected in Friedreich's Ataxia, another hereditary cerebellar ataxia disorder. This subscale had been validated in Friedreich's ataxia, was a measure of functional disability, and correlated with SARA total scores. It assessed 9 areas of ADL with response categories rated on 5-point scale with 0 reflecting normal and 4 reflecting inability to perform specific function. Total score was derived as sum of individual items, ranging 0-36, higher score indicated worst outcome. FARS-ADL was rater administered.
Time frame: Randomization Baseline, Week 48
Population: Participants in mITT analysis set with available data were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Troriluzole | Randomization Phase: Change From Baseline in Friedreich's Ataxia Rating Scale - Activities of Daily Living (FARS-ADL) Total Score at Week 48 in SCA Participants | All SCA | 0.453 score on a scale | Standard Error 0.502 |
| Troriluzole | Randomization Phase: Change From Baseline in Friedreich's Ataxia Rating Scale - Activities of Daily Living (FARS-ADL) Total Score at Week 48 in SCA Participants | SCA3 | 0.918 score on a scale | Standard Error 0.523 |
| Placebo | Randomization Phase: Change From Baseline in Friedreich's Ataxia Rating Scale - Activities of Daily Living (FARS-ADL) Total Score at Week 48 in SCA Participants | All SCA | -0.017 score on a scale | Standard Error 0.48 |
| Placebo | Randomization Phase: Change From Baseline in Friedreich's Ataxia Rating Scale - Activities of Daily Living (FARS-ADL) Total Score at Week 48 in SCA Participants | SCA3 | 1.130 score on a scale | Standard Error 0.506 |
Secondary
Randomization Phase: Change From Baseline in Functional Staging for Ataxia Scale From the Friedreich's Ataxia Rating Scale (FARS-FUNC) Total Score at Week 48 in SCA Participants
FARS was a scale consisting of combined timed measures of performance, FUNC (0-6, higher score indicated worst outcome), ADL with paramount neurologic examination (0-36, higher score indicated worst outcome), FARSn (0-125, higher score indicated worst outcome). The total score was a sum of these 3 subscales; 0-167, higher score indicated worst outcome. For this outcome measure, only the FARS-FUNC sub-scale was evaluated. FARS-FUNC was a subscale of the FARS designed to provide functional staging for ataxia in which clinicians were asked to assess function on a 6-stage staging system, with 0 reflecting normal and 6 reflecting a stage in participant was total disabled.
Time frame: Randomization Baseline, Week 48
Population: Participants in mITT analysis set with available data were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Troriluzole | Randomization Phase: Change From Baseline in Functional Staging for Ataxia Scale From the Friedreich's Ataxia Rating Scale (FARS-FUNC) Total Score at Week 48 in SCA Participants | All SCA | 0.266 score on a scale | Standard Error 0.075 |
| Troriluzole | Randomization Phase: Change From Baseline in Functional Staging for Ataxia Scale From the Friedreich's Ataxia Rating Scale (FARS-FUNC) Total Score at Week 48 in SCA Participants | SCA3 | 0.216 score on a scale | Standard Error 0.079 |
| Placebo | Randomization Phase: Change From Baseline in Functional Staging for Ataxia Scale From the Friedreich's Ataxia Rating Scale (FARS-FUNC) Total Score at Week 48 in SCA Participants | All SCA | 0.226 score on a scale | Standard Error 0.072 |
| Placebo | Randomization Phase: Change From Baseline in Functional Staging for Ataxia Scale From the Friedreich's Ataxia Rating Scale (FARS-FUNC) Total Score at Week 48 in SCA Participants | SCA3 | 0.328 score on a scale | Standard Error 0.077 |
Secondary
Randomization Phase: Change From Baseline in Patient Impression of Function and Activities of Daily Living Scale (PIFAS) Total Score at Week 48 in SCA Participants
PIFAS was a 17-item instrument designed to assess the level of functional disability. The scale was rater administered and the items were selected to encompass domains of relevance to SCA (i.e., mobility, speech/swallowing, and fatigue), and to capture function and activities of daily living within these domains. Statements were rated on a 5-point Likert scale ranging from 0 reflecting not at all to 4 reflecting very much. The total score was derived as the sum of the individual items, ranged between 0 to 68. Higher score indicated a worst outcome. A negative change in score showed improvement.
Time frame: Randomization Baseline, Week 48
Population: Participants in mITT analysis set with available data were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Troriluzole | Randomization Phase: Change From Baseline in Patient Impression of Function and Activities of Daily Living Scale (PIFAS) Total Score at Week 48 in SCA Participants | All SCA | -0.93 score on a scale | Standard Error 1.49 |
| Troriluzole | Randomization Phase: Change From Baseline in Patient Impression of Function and Activities of Daily Living Scale (PIFAS) Total Score at Week 48 in SCA Participants | SCA3 | 0.56 score on a scale | Standard Error 1.65 |
| Placebo | Randomization Phase: Change From Baseline in Patient Impression of Function and Activities of Daily Living Scale (PIFAS) Total Score at Week 48 in SCA Participants | All SCA | 1.03 score on a scale | Standard Error 1.43 |
| Placebo | Randomization Phase: Change From Baseline in Patient Impression of Function and Activities of Daily Living Scale (PIFAS) Total Score at Week 48 in SCA Participants | SCA3 | 2.96 score on a scale | Standard Error 1.67 |
Secondary
Randomization Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (TESAEs); and AEs Leading to Treatment Discontinuation
An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant that did not necessarily had a causal relationship with this treatment. An SAE was defined as any AE that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect in the offspring of the participant or was considered another important medical event. Treatment-emergent AEs (TEAEs) in the randomization phase included any AE with an onset date on or after the first day of double-blind study drug and up to the first day of open-label study drug in the extension phase (for participants entering the extension phase) or last day of the randomization phase study drug + 30 days.
Time frame: From first dose of study drug to Week 48 plus 30 days (maximum duration: 52 weeks)
Population: The treated analysis set (TAS) included all randomized/enrolled participants who received at least one dose of study medication (blinded or open label troriluzole, or blinded placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Troriluzole | Randomization Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (TESAEs); and AEs Leading to Treatment Discontinuation | TEAEs | 87 participants |
| Troriluzole | Randomization Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (TESAEs); and AEs Leading to Treatment Discontinuation | TESAEs | 6 participants |
| Troriluzole | Randomization Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (TESAEs); and AEs Leading to Treatment Discontinuation | AEs Leading to Treatment Discontinuation | 5 participants |
| Placebo | Randomization Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (TESAEs); and AEs Leading to Treatment Discontinuation | TEAEs | 92 participants |
| Placebo | Randomization Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (TESAEs); and AEs Leading to Treatment Discontinuation | TESAEs | 8 participants |
| Placebo | Randomization Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (TESAEs); and AEs Leading to Treatment Discontinuation | AEs Leading to Treatment Discontinuation | 5 participants |
Other Pre-specified
Change From Baseline in Clinical Global Impression - Global Improvement Scale (CGI-I) in SCA3 Participants
The CGI-I was a 7-point scale that required the clinician to assess how much the participant's illness had improved or worsened relative to the baseline visit and it was rated on a 7 point scale: 1= Very much improved, 2= Much improved, 3= Minimally improved, 4= No change, 5= Minimally worse, 6= Much worse and 7= Very much worse. Higher scores indicated greater impairment.
Time frame: Randomization Baseline; Week 48
Population: Participants in mITT analysis set with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Troriluzole | Change From Baseline in Clinical Global Impression - Global Improvement Scale (CGI-I) in SCA3 Participants | 4.14 score on a scale | Standard Error 0.17 |
| Placebo | Change From Baseline in Clinical Global Impression - Global Improvement Scale (CGI-I) in SCA3 Participants | 4.68 score on a scale | Standard Error 0.17 |
Other Pre-specified
Falls Events in Troriluzole Compared to Placebo for All SCA Participants
An AE of Fall was recorded if there was a worsening of frequency of falls or if a fall was associated with an injury.
Time frame: Randomization Baseline, Week 48
Population: All randomized participants who received at least one dose of study medication during the randomization phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Troriluzole | Falls Events in Troriluzole Compared to Placebo for All SCA Participants | 20 Number of events |
| Placebo | Falls Events in Troriluzole Compared to Placebo for All SCA Participants | 42 Number of events |
Other Pre-specified
Randomization Phase: Change From Baseline in FARS-ADL Total Score at Week 48 in SCA3 Participants
FARS was a scale consisting of combined timed measures of performance, FUNC (0-6, higher score indicated worst outcome), ADL with paramount neurologic examination (0-36, higher score indicated worst outcome), FARSn (0-125, higher score indicated worst outcome). Total score was sum of these 3 subscales: 0-167, higher score indicated worst outcome. For this outcome measure, only FARS-ADL sub-scale was evaluated. It was multicomponent scale designed to assess neurological domains affected in Friedreich's Ataxia, another hereditary cerebellar ataxia disorder. This subscale had been validated in Friedreich's ataxia, was a measure of functional disability, and correlated with SARA total scores. It assessed 9 areas of ADL with response categories rated on 5-point scale with 0 reflecting normal and 4 reflecting inability to perform specific function. Total score was derived as sum of individual items, ranging 0-36, higher score indicated worst outcome. FARS-ADL was rater administered.
Time frame: Randomization Baseline, Week 48
Population: Participants in mITT analysis set with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Troriluzole | Randomization Phase: Change From Baseline in FARS-ADL Total Score at Week 48 in SCA3 Participants | 0.918 score on a scale | Standard Error 0.523 |
| Placebo | Randomization Phase: Change From Baseline in FARS-ADL Total Score at Week 48 in SCA3 Participants | 1.130 score on a scale | Standard Error 0.506 |
Other Pre-specified
Randomization Phase: Change From Baseline in FARS-FUNC Total Score at Week 48 in SCA3 Participants
FARS was a scale consisting of combined timed measures of performance, FUNC (0-6, higher score indicated worst outcome), ADL with paramount neurologic examination (0-36, higher score indicated worst outcome), FARSn (0-125, higher score indicated worst outcome). The total score was a sum of these 3 subscales; 0-167, higher score indicated worst outcome. For this outcome measure, only the FARS-FUNC sub-scale was evaluated. FARS-FUNC was a subscale of the FARS designed to provide functional staging for ataxia in which clinicians were asked to assess function on a 6-stage staging system, with 0 reflecting normal and 6 reflecting a stage in participant was total disabled.
Time frame: Randomization Baseline, Week 48
Population: Participants in mITT analysis set with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Troriluzole | Randomization Phase: Change From Baseline in FARS-FUNC Total Score at Week 48 in SCA3 Participants | 0.216 score on a scale | Standard Error 0.079 |
| Placebo | Randomization Phase: Change From Baseline in FARS-FUNC Total Score at Week 48 in SCA3 Participants | 0.328 score on a scale | Standard Error 0.077 |
Other Pre-specified
Randomization Phase: Change From Baseline in PIFAS Total Score at Week 48 in SCA3 Participants
PIFAS was a 17-item instrument designed to assess the level of functional disability. The scale is rater administered and the items were selected to encompass domains of relevance to SCA (i.e., mobility, speech/swallowing, and fatigue), and to capture function and activities of daily living within these domains. Statements are rated on a 5-point Likert scale ranging from 0 reflecting not at all to 4 reflecting very much. The total score is derived as the sum of the individual items, ranged between 0 to 68. Higher score indicated a worst outcome. A negative change in score showed improvement.
Time frame: Randomization Baseline, Week 48
Population: Participants in mITT analysis set with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Troriluzole | Randomization Phase: Change From Baseline in PIFAS Total Score at Week 48 in SCA3 Participants | 0.56 score on a scale | Standard Error 1.65 |
| Placebo | Randomization Phase: Change From Baseline in PIFAS Total Score at Week 48 in SCA3 Participants | 2.96 score on a scale | Standard Error 1.67 |
Other Pre-specified
Randomization Phase: Change From Baseline in the f-SARA Total Score at Week 48 in SCA3 Participants
The f-SARA was a 4-item performance based scale: 1-gait, 2-stance, 3-sitting, 4-speech disturbance (0:normal (no impairment), 1:mildly impaired function, but no assistance required, 2:moderately impaired function, but needs assistance for certain parts of task, 3: severely impaired function to degree that assistance is needed for all parts of the task, 4:unable to perform function). Total score was derived as sum of individual items; ranged from 0 to 16. Higher score indicated worst outcome. A negative change in score shows improvement.
Time frame: Randomization Baseline; Week 48
Population: Participants in mITT analysis set with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Troriluzole | Randomization Phase: Change From Baseline in the f-SARA Total Score at Week 48 in SCA3 Participants | -0.03 score on a scale | Standard Error 0.2 |
| Placebo | Randomization Phase: Change From Baseline in the f-SARA Total Score at Week 48 in SCA3 Participants | 0.53 score on a scale | Standard Error 0.19 |