Tourette Syndrome
Conditions
Brief summary
This is a Phase 2b, randomized, double-blind, placebo-controlled, dose-optimization study to evaluate the efficacy, safety, and tolerability of NBI-98854 titrated to the subject's optimal dose administered once daily (qd) for a total of 12 weeks of treatment in pediatric subjects with TS.
Interventions
DRUGValbenazine
vesicular monoamine transporter 2 (VMAT2) inhibitor
DRUGPlacebo oral capsule
non-active dosage form
Sponsors
Neurocrine Biosciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Have a clinical diagnosis of Tourette Syndrome (TS) 2. Have at least moderate tic severity 3. Have TS symptoms that impair school, occupational, and/or social function 4. If using maintenance medication(s) for TS or TS spectrum diagnoses (e.g. obsessive-compulsive disorder \[OCD\], Attention-Deficit Hyperactivity Disorder \[ADHD\]), be on stable doses 5. Be in good general health 6. Adolescent subjects (12 to 17 years of age) must have a negative urine drug screen for amphetamines, barbiturates, benzodiazepine, phencyclidine, cocaine, opiates, or cannabinoids and a negative alcohol screen 7. Subjects of childbearing potential who do not practice total abstinence must agree to use hormonal or two forms of nonhormonal contraception (dual contraception) consistently during the screening, treatment and follow-up periods of the study
Exclusion criteria
1. Have an active, clinically significant unstable medical condition within 1 month prior to screening 2. Have a known history of long QT syndrome or cardiac arrhythmia 3. Have a known history of neuroleptic malignant syndrome 4. Have a cancer diagnosis within 3 years prior to screening (some exceptions allowed) 5. Have an allergy, hypersensitivity, or intolerance to VMAT2 inhibitors 6. Have a blood loss ≥250 mL or donated blood within 30 days prior to screening 7. Have a known history of substance dependence, substance (drug) or alcohol abuse 8. Have a significant risk of suicidal or violent behavior 9. Have initiated Comprehensive Behavioral Intervention for Tics (CBIT) during the screening period or at baseline or plan to initiate CBIT during the study 10. Have received an investigational drug within 30 days before screening or plan to use an investigational drug (other than NBI-98854) during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) | Baseline, Week 12 | The YGTSS is designed to rate the overall severity of motor and phonic tic symptoms across a range of dimensions: number, frequency, intensity, complexity, and interference. The YGTSS was administered by the investigator (or qualified designee) using a computer-based structured clinical interview. The TTS is the sum of the 5 motor tic items and the 5 phonic (vocal) tic items and ranges from 0 to 50, with higher scores representing greater severity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in the Clinical Global Impression of Tics Severity (CGI-Tics-Severity) Score | Baseline, Week 12 | The CGI-Tics-Severity scale is used to assess overall severity on a 7-point scale. Each of the CGI-Tics-Severity response categories was assigned a numerical score as follows: 1 = Normal, not at all ill; 2 = Borderline ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; 7 = Among the most extremely ill patient. |
| Participants Who Are a Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) Responder at Week 12 | Baseline, Week 12 | A TTS responder is defined, on a per-visit basis, as a participant whose TTS value is reduced by at least 30% from baseline at the specified postbaseline visit. |
| Participants Who Are a Clinical Global Impression of Tourette Syndrome Improvement (CGI-TS-Improvement) Responder at Week 12 | Week 12 | The CGI-TS-Improvement scale is used to assess overall improvement since the initiation of study drug dosing on a 7-point scale. A CGI-TS-Improvement responder is defined, on a per-visit basis, as a participant whose CGI-TS-Improvement score is 1 (Very much improved) or 2 (Much improved) at the specified postbaseline visit. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
This study enrolled male and female pediatric participants, 6 to 17 years of age, with a Diagnostic and Statistical Manual of Mental Disorders, 4th or 5th Editions (DSM-IV or -V) diagnosis of Tourette Syndrome (TS) in the United States. The first and last participants were enrolled on 05 October 2017 and 19 July 2018, respectively.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo (matching valbenazine) once daily for 12 weeks. | 61 |
| Valbenazine Participants received valbenazine once daily for 12 weeks. The starting dose was 20 mg for participants \<50 kg at baseline and 40 mg for participants ≥50 kg at baseline, and could be escalated in increments of 20 mg every 2 weeks to a maximum of 60 mg for subjects \<50 kg and 80 mg for subjects ≥50 kg to achieve an optimal dose of valbenazine for each participant. | 58 |
| Total | 119 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 8 |
| Overall Study | Lack of Efficacy | 2 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 8 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Placebo | Total | Valbenazine |
|---|---|---|---|
| Age, Continuous | 12.4 Years STANDARD_DEVIATION 2.6 | 12.3 Years STANDARD_DEVIATION 2.6 | 12.2 Years STANDARD_DEVIATION 2.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 29 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants | 90 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 3 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black or African American | 8 Participants | 9 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Multiple | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 49 Participants | 102 Participants | 53 Participants |
| Sex: Female, Male Female | 9 Participants | 19 Participants | 10 Participants |
| Sex: Female, Male Male | 52 Participants | 100 Participants | 48 Participants |
| Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) | 31.2 score on scale STANDARD_DEVIATION 9 | 30.3 score on scale STANDARD_DEVIATION 8.9 | 29.3 score on scale STANDARD_DEVIATION 8.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 62 | 0 / 59 |
| other Total, other adverse events | 17 / 62 | 32 / 59 |
| serious Total, serious adverse events | 1 / 62 | 0 / 59 |
Outcome results
Primary
Change From Baseline to Week 12 in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS)
The YGTSS is designed to rate the overall severity of motor and phonic tic symptoms across a range of dimensions: number, frequency, intensity, complexity, and interference. The YGTSS was administered by the investigator (or qualified designee) using a computer-based structured clinical interview. The TTS is the sum of the 5 motor tic items and the 5 phonic (vocal) tic items and ranges from 0 to 50, with higher scores representing greater severity.
Time frame: Baseline, Week 12
Population: Full analysis set, which includes all randomized participants who have at least one evaluable change from baseline value for TTS reported at a visit (either scheduled or mapped early termination visit) during the treatment period. Dose levels based on weight group and each individual participant's optimized dosing titration were prespecified to be combined within each arm.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) | -6.8 score on a scale | Standard Error 1 |
| Valbenazine | Change From Baseline to Week 12 in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) | -8.9 score on a scale | Standard Error 1.1 |
p-value: 0.176895% CI: [-5.2, 1]Mixed Models Analysis
Secondary
Change From Baseline to Week 12 in the Clinical Global Impression of Tics Severity (CGI-Tics-Severity) Score
The CGI-Tics-Severity scale is used to assess overall severity on a 7-point scale. Each of the CGI-Tics-Severity response categories was assigned a numerical score as follows: 1 = Normal, not at all ill; 2 = Borderline ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; 7 = Among the most extremely ill patient.
Time frame: Baseline, Week 12
Population: Full analysis set, which includes all randomized participants who have at least one evaluable change from baseline value for TTS reported at a visit (either scheduled or mapped early termination visit) during the treatment period. Dose levels based on weight group and each individual participant's optimized dosing titration were prespecified to be combined within each arm.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in the Clinical Global Impression of Tics Severity (CGI-Tics-Severity) Score | -0.7 Score on scale | Standard Error 0.1 |
| Valbenazine | Change From Baseline to Week 12 in the Clinical Global Impression of Tics Severity (CGI-Tics-Severity) Score | -1.0 Score on scale | Standard Error 0.1 |
p-value: 0.109595% CI: [-0.6, 0.1]Mixed Models Analysis
Secondary
Participants Who Are a Clinical Global Impression of Tourette Syndrome Improvement (CGI-TS-Improvement) Responder at Week 12
The CGI-TS-Improvement scale is used to assess overall improvement since the initiation of study drug dosing on a 7-point scale. A CGI-TS-Improvement responder is defined, on a per-visit basis, as a participant whose CGI-TS-Improvement score is 1 (Very much improved) or 2 (Much improved) at the specified postbaseline visit.
Time frame: Week 12
Population: Full analysis set, which includes all randomized participants who have at least one evaluable change from baseline value for TTS reported at a visit (either scheduled or mapped early termination visit) during the treatment period. Dose levels based on weight group and each individual participant's optimized dosing titration were prespecified to be combined within each arm. Analyses include participants with outcome data available at the specified visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Participants Who Are a Clinical Global Impression of Tourette Syndrome Improvement (CGI-TS-Improvement) Responder at Week 12 | 12 Participants |
| Valbenazine | Participants Who Are a Clinical Global Impression of Tourette Syndrome Improvement (CGI-TS-Improvement) Responder at Week 12 | 24 Participants |
p-value: 0.0008Cochran-Mantel-Haenszel
Secondary
Participants Who Are a Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) Responder at Week 12
A TTS responder is defined, on a per-visit basis, as a participant whose TTS value is reduced by at least 30% from baseline at the specified postbaseline visit.
Time frame: Baseline, Week 12
Population: Full analysis set, which includes all randomized participants who have at least one evaluable change from baseline value for TTS reported at a visit (either scheduled or mapped early termination visit) during the treatment period. Dose levels based on weight group and each individual participant's optimized dosing titration were prespecified to be combined within each arm. Analyses include participants with outcome data available at the specified visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Participants Who Are a Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) Responder at Week 12 | 21 Participants |
| Valbenazine | Participants Who Are a Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) Responder at Week 12 | 18 Participants |
p-value: 0.819Cochran-Mantel-Haenszel