Tourette Syndrome
Conditions
Keywords
Tourette Syndrome, adolescents, children
Brief summary
This is a study to evaluate the efficacy and safety of deutetrabenazine (TEV-50717) tablets for the reduction of motor and phonic tics associated with TS in children and adolescents 6 through 16 years of age.
Interventions
DRUGTEV-50717
6, 9, 12, 15, and 18 mg oral tablets
DRUGPlacebo
Placebo matched to TEV-50717 tablets will be taken BID for 12 weeks.
Sponsors
Nuvelution TS Pharma, Inc.
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 16 Years
Healthy volunteers
No
Inclusion criteria
* Participant is 6 to 16 years of age, inclusive. * Participant weighs at least 44 pounds (20 kilograms \[kg\]). * The participant's active tics are causing distress or impairment. * Participant is able to swallow study medication whole. * Participant is in good general health. * Women/girls of childbearing potential whose male partners are of childbearing potential must use contraception for the duration of the study. * Additional criteria apply, please contact the investigator for more information
Exclusion criteria
* Participant has a neurologic disorder other than TS that could obscure the evaluation of tics. * Participant has a confirmed diagnosis of bipolar disorder, schizophrenia, or another psychotic disorder. * Participant has clinically significant depression at screening or baseline. * Participant has a history of suicidal intent or related behaviors within 2 years of screening. * Participant has a history of a previous actual, interrupted, or aborted suicide attempt. * Participant has a first-degree relative who has completed suicide. * Participant has received comprehensive behavioral intervention for tics (CBIT) for TS or cognitive behavioral therapy (CBT) for obsessive-compulsive disorder (OCD) within 4 weeks of screening. * Participant has an unstable or serious medical illness at screening or baseline. * Participant is pregnant or breastfeeding. * Additional criteria apply, please contact the investigator for more information.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the TTS of the YGTSS at Week 12 | Baseline, Week 12 | YGTSS rating scale is a semi-structured clinician rating instrument that provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic tics. YGTSS is composed of 11 items: 5 items for motor tic severity, 5 items for vocal tic severity, and 1 item for impairment. Each item for motor tic severity and vocal is rated on a 6-point scale (0 for none to 5 to severe). MTSS is the sum of the 5 items for motor tic severity and VTSS is the sum of the 5 items for vocal tic severity. TTS is the sum of MTSS and VTSS, ranges from 0 (none/absent) to 50 (severe). Higher scores indicate greater severity/worse outcome. Least square (LS) mean and standard error (SE) was calculated using mixed-model repeated-measures (MMRM) with treatment group, week (5 levels: weeks 2, 4, 6, 9, and 12), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) Score at Week 12 | Baseline, Week 12 | The TS-CGI scale is a 7-point Likert scale that allows the clinician to use all available information to assess the impact of tics on the participant's quality of life. The TS-CGI is rated as follows: 1 (normal or no tics at all), 2 (borderline), 3 (mild), 4 (moderate), 5 (marked), 6 (severe), and 7 (extreme, incapacitating tics). Lower scores indicate better quality of life. LS mean and SE was calculated using MMRM with treatment group, week (5 levels: weeks 2, 4, 6, 9, and 12), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates. |
| Change From Baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) Score at Week 12 | Baseline, Week 12 | The TS-PGII is a single-item questionnaire that asks the participant to assess the degree of impact due to current tics (How much do your current tics disrupt things in your life?). The TS-PGII uses a 5-point scale, ranging from not at all (1) to very much (5), to assess overall response to therapy. |
| Change From Baseline in the Child and Adolescent Gilles de la Tourette Syndrome - Quality of Life (C&A-GTS-QOL) Activities of Daily Living (ADL) Subscale Score at Week 12 | Baseline, Week 12 | C&A-GTS-QOL is a 27-item questionnaire that asks participant to assess the extent to which their quality of life is impacted by their symptoms. C&A-GTS-QOL contains 6 subscales (cognitive, coprophenomena, psychological, physical, obsessive-compulsive, and ADL) and uses a 5-point Likert scale ranging from no problem to extreme problem. Following 3 questions from 27-item questionnaire were assessed in ADL C&A-GTS-QOL subscale: Question 2 (Had difficulty with school or sport activities?), 24 (Felt you needed more help or support from other people?), and 26 (Had difficulty going out with other people?). Total score of ADL subscale ranged from 0 (no problem) to 12 (extreme problem). Lower score indicated better quality of life. LS mean and SE was calculated using MMRM with treatment group, week (5 levels: weeks 2, 4, 6, 9, and 12), and treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6-11 years, 12-16 years) as covariates. |
| Percentage of Participants With Adverse Events | Baseline (Day 1) to follow-up (Week 14) | An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
Countries
Canada, Denmark, Russia, Serbia, Spain, United States
Participant flow
Pre-assignment details
A total of 119 participants were randomized in a 1:1 ratio to either TEV-50717 or placebo group.
Participants by arm
| Arm | Count |
|---|---|
| TEV-50717 Participants received TEV-50717 as oral tablets at a starting dose of 6 mg/day, with the dose titrated weekly for 7 weeks to an optimal level. The target maximum daily dose was determined by body weight and CYP2D6 impairment status at baseline. Maximum total daily dose for participants ≥40 kg was 48 mg/day (24 mg BID), 30 to \<40 kg was 42 mg/day (21 mg BID), and 20 to \<30 kg was 30 mg/day (15 mg BID). For those considered CYP2D6 impaired, maximum daily dose for participants ≥40 kg was 36 mg/day, 30 to \<40 kg was 24 mg/day, and 20 to \<30 kg was 18 mg/day. Total daily doses of ≥12 mg/day was divided into a BID administration. Depending on the dose, TEV-50717 tablets and/or placebo tablets were taken to maintain the blind. Participants then received TEV-50717 at the optimal level as maintenance therapy daily for 5 weeks. | 59 |
| Placebo Participants received placebo matched to TEV-50717 BID for a total of 12 weeks. | 60 |
| Total | 119 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Maintenance Period (5 Weeks) | Adverse Event | 1 | 0 |
| Maintenance Period (5 Weeks) | Withdrawal by Subject | 2 | 0 |
| Titration Period (7 Weeks) | Adverse Event | 1 | 1 |
| Titration Period (7 Weeks) | Lost to Follow-up | 1 | 0 |
| Titration Period (7 Weeks) | Protocol Violation | 0 | 1 |
| Titration Period (7 Weeks) | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Total | TEV-50717 | Placebo |
|---|---|---|---|
| Age, Continuous | 11.5 years STANDARD_DEVIATION 2.54 | 11.5 years STANDARD_DEVIATION 2.52 | 11.5 years STANDARD_DEVIATION 2.59 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 5 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 101 Participants | 51 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 6 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Multiple | 4 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Native American | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 102 Participants | 49 Participants | 53 Participants |
| Sex: Female, Male Female | 15 Participants | 6 Participants | 9 Participants |
| Sex: Female, Male Male | 104 Participants | 53 Participants | 51 Participants |
| Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) | 32.3 units on a scale STANDARD_DEVIATION 5.89 | 31.7 units on a scale STANDARD_DEVIATION 5.81 | 33.0 units on a scale STANDARD_DEVIATION 5.96 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 58 | 0 / 59 |
| other Total, other adverse events | 22 / 58 | 23 / 59 |
| serious Total, serious adverse events | 0 / 58 | 0 / 59 |
Outcome results
Primary
Change From Baseline in the TTS of the YGTSS at Week 12
YGTSS rating scale is a semi-structured clinician rating instrument that provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic tics. YGTSS is composed of 11 items: 5 items for motor tic severity, 5 items for vocal tic severity, and 1 item for impairment. Each item for motor tic severity and vocal is rated on a 6-point scale (0 for none to 5 to severe). MTSS is the sum of the 5 items for motor tic severity and VTSS is the sum of the 5 items for vocal tic severity. TTS is the sum of MTSS and VTSS, ranges from 0 (none/absent) to 50 (severe). Higher scores indicate greater severity/worse outcome. Least square (LS) mean and standard error (SE) was calculated using mixed-model repeated-measures (MMRM) with treatment group, week (5 levels: weeks 2, 4, 6, 9, and 12), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates.
Time frame: Baseline, Week 12
Population: mITT analysis set included all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TEV-50717 | Change From Baseline in the TTS of the YGTSS at Week 12 | -9.1 units on a scale | Standard Error 1.28 |
| Placebo | Change From Baseline in the TTS of the YGTSS at Week 12 | -8.4 units on a scale | Standard Error 1.25 |
p-value: 0.69295% CI: [-4.1, 2.8]Mixed Models Analysis
Secondary
Change From Baseline in the Child and Adolescent Gilles de la Tourette Syndrome - Quality of Life (C&A-GTS-QOL) Activities of Daily Living (ADL) Subscale Score at Week 12
C&A-GTS-QOL is a 27-item questionnaire that asks participant to assess the extent to which their quality of life is impacted by their symptoms. C&A-GTS-QOL contains 6 subscales (cognitive, coprophenomena, psychological, physical, obsessive-compulsive, and ADL) and uses a 5-point Likert scale ranging from no problem to extreme problem. Following 3 questions from 27-item questionnaire were assessed in ADL C&A-GTS-QOL subscale: Question 2 (Had difficulty with school or sport activities?), 24 (Felt you needed more help or support from other people?), and 26 (Had difficulty going out with other people?). Total score of ADL subscale ranged from 0 (no problem) to 12 (extreme problem). Lower score indicated better quality of life. LS mean and SE was calculated using MMRM with treatment group, week (5 levels: weeks 2, 4, 6, 9, and 12), and treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6-11 years, 12-16 years) as covariates.
Time frame: Baseline, Week 12
Population: mITT analysis set included all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TEV-50717 | Change From Baseline in the Child and Adolescent Gilles de la Tourette Syndrome - Quality of Life (C&A-GTS-QOL) Activities of Daily Living (ADL) Subscale Score at Week 12 | -9.9 units on a scale | Standard Error 2.37 |
| Placebo | Change From Baseline in the Child and Adolescent Gilles de la Tourette Syndrome - Quality of Life (C&A-GTS-QOL) Activities of Daily Living (ADL) Subscale Score at Week 12 | -8.8 units on a scale | Standard Error 2.27 |
Secondary
Change From Baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) Score at Week 12
The TS-CGI scale is a 7-point Likert scale that allows the clinician to use all available information to assess the impact of tics on the participant's quality of life. The TS-CGI is rated as follows: 1 (normal or no tics at all), 2 (borderline), 3 (mild), 4 (moderate), 5 (marked), 6 (severe), and 7 (extreme, incapacitating tics). Lower scores indicate better quality of life. LS mean and SE was calculated using MMRM with treatment group, week (5 levels: weeks 2, 4, 6, 9, and 12), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates.
Time frame: Baseline, Week 12
Population: mITT analysis set included all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TEV-50717 | Change From Baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) Score at Week 12 | -0.7 units on a scale | Standard Error 0.13 |
| Placebo | Change From Baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) Score at Week 12 | -0.7 units on a scale | Standard Error 0.12 |
Secondary
Change From Baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) Score at Week 12
The TS-PGII is a single-item questionnaire that asks the participant to assess the degree of impact due to current tics (How much do your current tics disrupt things in your life?). The TS-PGII uses a 5-point scale, ranging from not at all (1) to very much (5), to assess overall response to therapy.
Time frame: Baseline, Week 12
Population: mITT analysis set included all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TEV-50717 | Change From Baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) Score at Week 12 | -0.7 units on a scale | Standard Error 0.18 |
| Placebo | Change From Baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) Score at Week 12 | -0.4 units on a scale | Standard Error 0.14 |
Secondary
Percentage of Participants With Adverse Events
An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time frame: Baseline (Day 1) to follow-up (Week 14)
Population: Safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TEV-50717 | Percentage of Participants With Adverse Events | Any AEs | 65.5 percentage of participants |
| TEV-50717 | Percentage of Participants With Adverse Events | Treatment-related AEs | 50.0 percentage of participants |
| TEV-50717 | Percentage of Participants With Adverse Events | Serious AEs | 0 percentage of participants |
| TEV-50717 | Percentage of Participants With Adverse Events | AEs leading to discontinuation | 1.7 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events | AEs leading to discontinuation | 1.7 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events | Any AEs | 55.9 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events | Serious AEs | 0 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events | Treatment-related AEs | 20.3 percentage of participants |