Tourette Syndrome
Conditions
Brief summary
This is a Phase 2, double-blind, placebo-controlled, randomized withdrawal study to evaluate the safety and maintenance of efficacy of an optimized once-daily (qd) dose of NBI-98854 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)
Masking description
open-label study drug treatment period followed by blinded randomization into treatment arm or placebo arm
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 11. Have previously participated in an NBI-98854 clinical study, except for NBI-98854-1403 or NBI-98854-1501. 12. Have HIV, hepatitis B, or hepatitis C
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Loss of Treatment Response | Randomization (Week 8, 10 or 12) through Week 36 | Loss of treatment response during the withdrawal period was defined as: 2 consecutive visits with 1) an increase in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) of greater than 35% or 7 points from the randomized withdrawal period baseline and 2) an increase in CGI-Tics-Severity score of ≥2 points from the randomized withdrawal period baseline; or discontinuation due to lack of efficacy or a treatment-emergent adverse event (TEAE) of worsening of tics. Median (lower and upper quartiles) Kaplan-Meier estimates for the time to loss of treatment response were not able to be calculated because of the low incidence of loss of treatment response events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Randomization Baseline to the 8 Weeks Post-randomization Timepoint in the YGTSS TTS | Randomization Baseline (Week 8, 10 or 12); 8 weeks post-randomization | 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. Least-squares mean were estimated using a mixed-effects model for repeated measures. |
| Change From Randomization Baseline to the Week 36 Visit in the YGTSS TTS | Randomization Baseline (Week 8, 10 or 12); Week 36 | 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. |
| Change From Randomization Baseline to the 8 Weeks Post-randomization Timepoint in the CGI-Tics-Severity Score | Randomization Baseline (Week 8, 10 or 12); 8 weeks post-randomization | 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. |
| Change From Randomization Baseline to the Week 36 Visit in the CGI-Tics-Severity Score | Randomization Baseline (Week 8, 10 or 12); Week 36 | 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. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Up to 180 male and female pediatric subjects between 6 and 17 years of age (inclusive) with a DSM-IV or -V diagnosis of TS were planned to be enrolled. A total of 81 subjects were enrolled. The first and last participants were enrolled on April 17 2018 and May 7 2019, respectively.
Pre-assignment details
At the end of Weeks 8, 10, or 12, treatment responders (sufficient control of tic behaviors based on investigator assessment) were randomized in a 1:1 ratio to placebo or valbenazine. Randomization was stratified based on the subject's weight group at baseline (\<50 kg versus ≥50 kg). The visit week when subjects were randomized was blinded. At Week 12 all nonresponders were discontinued.
Participants by arm
| Arm | Count |
|---|---|
| Randomized Placebo Participants received placebo (matching valbenazine) once daily from randomization (Week 8, 10, or 12) through Week 36. Randomization into this arm occurred after treatment with valbenazine once daily through randomization. | 26 |
| Randomized Valbenazine Participants received their optimized dose of valbenazine once daily from randomization (Week 8, 10, or 12) through Week 36. Randomization into this arm occurred after treatment with valbenazine once daily through randomization. | 26 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Pre-randomization | Adverse Event | 12 | 0 | 0 |
| Pre-randomization | Protocol Violation | 2 | 0 | 0 |
| Pre-randomization | Study Terminated by Sponsor | 5 | 0 | 0 |
| Pre-randomization | Withdrawal by Subject | 5 | 0 | 0 |
| Randomized Withdrawal Period / Follow-up | Adverse Event | 0 | 2 | 4 |
| Randomized Withdrawal Period / Follow-up | Lack of Efficacy | 0 | 2 | 0 |
| Randomized Withdrawal Period / Follow-up | Protocol Violation | 0 | 0 | 1 |
| Randomized Withdrawal Period / Follow-up | Study Terminated by Sponsor | 0 | 10 | 10 |
| Randomized Withdrawal Period / Follow-up | Withdrawal by Subject | 0 | 3 | 2 |
Baseline characteristics
| Characteristic | Randomized Valbenazine | Total | Randomized Placebo |
|---|---|---|---|
| Age, Continuous | 12.8 years STANDARD_DEVIATION 3.1 | 12.8 years STANDARD_DEVIATION 2.9 | 12.7 years STANDARD_DEVIATION 2.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 14 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 38 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 24 Participants | 46 Participants | 22 Participants |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 5 Participants |
| Sex: Female, Male Male | 24 Participants | 45 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 80 | 0 / 26 | 0 / 26 |
| other Total, other adverse events | 41 / 80 | 12 / 26 | 14 / 26 |
| serious Total, serious adverse events | 1 / 80 | 2 / 26 | 2 / 26 |
Outcome results
Primary
Time to Loss of Treatment Response
Loss of treatment response during the withdrawal period was defined as: 2 consecutive visits with 1) an increase in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) of greater than 35% or 7 points from the randomized withdrawal period baseline and 2) an increase in CGI-Tics-Severity score of ≥2 points from the randomized withdrawal period baseline; or discontinuation due to lack of efficacy or a treatment-emergent adverse event (TEAE) of worsening of tics. Median (lower and upper quartiles) Kaplan-Meier estimates for the time to loss of treatment response were not able to be calculated because of the low incidence of loss of treatment response events.
Time frame: Randomization (Week 8, 10 or 12) through Week 36
Population: The full analysis set includes all subjects who were randomized to a treatment group and had at least one post-randomization visit where loss of treatment response was able to be assessed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Placebo | Time to Loss of Treatment Response | NA Days |
| Randomized Valbenazine | Time to Loss of Treatment Response | NA Days |
Secondary
Change From Randomization Baseline to the 8 Weeks Post-randomization Timepoint in the 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: Randomization Baseline (Week 8, 10 or 12); 8 weeks post-randomization
Population: The full analysis set includes all subjects who were randomized to a treatment group and had at least one post-randomization visit where loss of treatment response was able to be assessed. Participants who do not have a CGI-Tics-Severity value at a scheduled or mapped early termination visit after randomization are not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Randomized Placebo | Change From Randomization Baseline to the 8 Weeks Post-randomization Timepoint in the CGI-Tics-Severity Score | 0.7 units on a scale | Standard Error 0.2 |
| Randomized Valbenazine | Change From Randomization Baseline to the 8 Weeks Post-randomization Timepoint in the CGI-Tics-Severity Score | -0.1 units on a scale | Standard Error 0.2 |
Secondary
Change From Randomization Baseline to the 8 Weeks Post-randomization Timepoint in the YGTSS 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. Least-squares mean were estimated using a mixed-effects model for repeated measures.
Time frame: Randomization Baseline (Week 8, 10 or 12); 8 weeks post-randomization
Population: The full analysis set includes all subjects who were randomized to a treatment group and had at least one post-randomization visit where loss of treatment response was able to be assessed. Participants who do not have a TTS value at a scheduled or mapped early termination visit after randomization are not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Randomized Placebo | Change From Randomization Baseline to the 8 Weeks Post-randomization Timepoint in the YGTSS TTS | 3.8 units on a scale | Standard Error 1.6 |
| Randomized Valbenazine | Change From Randomization Baseline to the 8 Weeks Post-randomization Timepoint in the YGTSS TTS | -1.0 units on a scale | Standard Error 1.7 |
Secondary
Change From Randomization Baseline to the Week 36 Visit in the 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: Randomization Baseline (Week 8, 10 or 12); Week 36
Population: The full analysis set includes all subjects who were randomized to a treatment group and hac at least one post-randomization visit where loss of treatment response was able to be assessed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Placebo | Change From Randomization Baseline to the Week 36 Visit in the CGI-Tics-Severity Score | 0.1 units on a scale | Standard Deviation 0.78 |
| Randomized Valbenazine | Change From Randomization Baseline to the Week 36 Visit in the CGI-Tics-Severity Score | 0.2 units on a scale | Standard Deviation 1.3 |
Secondary
Change From Randomization Baseline to the Week 36 Visit in the YGTSS 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: Randomization Baseline (Week 8, 10 or 12); Week 36
Population: The full analysis set includes all subjects who were randomized to a treatment group and had at least one post-randomization visit where loss of treatment response was able to be assessed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Placebo | Change From Randomization Baseline to the Week 36 Visit in the YGTSS TTS | 0.6 units on a scale | Standard Deviation 12.06 |
| Randomized Valbenazine | Change From Randomization Baseline to the Week 36 Visit in the YGTSS TTS | 0.1 units on a scale | Standard Deviation 8.21 |