Tourette Syndrome
Conditions
Brief summary
Phase 2, double-blind, placebo-controlled study to assess the safety and efficacy of NBI-98854 administered once daily (qd) for a total of 6 weeks of treatment. This study will enroll approximately 90 male and female pediatric subjects clinically diagnosed with Tourette Syndrome.
Interventions
DRUGNBI-98854
DRUGPlacebo
Sponsors
Neurocrine Biosciences
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 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 6 in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) | Baseline, Week 6 | 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 |
|---|---|---|
| Clinical Global Impression of Tourette Syndrome (CGI-TS) - Improvement Score at Week 6 | Week 6 | The CGI-TS-Improvement scale is used to assess overall improvement since the initiation of study drug dosing on a 7-point scale. Each of the CGI-TS-Improvement response categories was assigned a numerical score as follows: 1 = Very much improved; 2 = Much improved; 3 = Minimally improved; 4 = Not changed; 5 = Minimally worse; 6 = Much worse; 7 = Very much worse. |
| Participants Who Are a YGTSS TTS Responder at Week 6 | Baseline, Week 6 | 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. |
| Change From Baseline to Week 6 in the YGTSS Global Tic Severity Score | Baseline, Week 6 | The YGTSS Global Tic Severity score is the sum of the YGTSS TTS and the YGTSS Impairment score and ranges from 0 to 100, with higher scores representing greater severity. |
| Change From Baseline to Week 6 in the YGTSS Impairment Score | Baseline, Week 6 | The YGTSS Impairment item is used to rate impairment due to tics using the following 50-point anchored scale: 0 = None; 10 = Minimal; 20 = Mild; 30 = Moderate; 40 = Marked; 50 = Severe. |
| Change From Baseline to Week 6 in the Premonitory Urge for Tics Scale (PUTS) Total Score | Baseline, Week 6 | The PUTS is an instrument for quantifying the premonitory urge phenomena associated with tics. It consists of 9 items, each of which is scored on a 4-point scale (1=not at all true, 2=a little true, 3=pretty much true, 4=very much true). The PUTS total score is calculated as the sum of the scores for the 9 items. The total score ranges from 9 to 36, with higher scores indicating a worse outcome. |
| Change From Baseline to Week 6 in the Clinical Global Impression of Tics (CGI-Tics) - Severity Score | Baseline, Week 6 | 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 CGI-TS-Improvement Responder at Week 6 | Week 6 | A participant is classified as a CGI-TS-Improvement responder at a given visit if their CGI-TS-Improvement score is either a 1 (very much improved) or a 2 (much improved) at the visit. |
| Change From Baseline to Week 6 in the Rush Video-based Tic Rating Scale (RTRS) Total Score | Baseline, Week 6 | A modified RTRS was used in this study that includes short video recordings to measure 5 tic variables: number of body areas affected, frequency of motor and phonic tics, and severity of motor and phonic tics. The RTRS total score is calculated as the sum of the 5 domain scores, and ranges from 0 to 20, with higher scores representing greater severity. The final on-treatment visit was used in participants who discontinued prior to Week 6. |
Countries
United States
Participant flow
Recruitment details
This study enrolled participants (male and female), 6 to 17 years of age, with a diagnosis of Tourette Syndrome through Diagnostic and Statistical Manual of Mental Disorders, 4th or 5th Editions (DSM-IV or -V) from 30 study centers in the United States. The first participant was enrolled on 23 March 2016 and last participant completed the study on 14 April 2017.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received matching placebo once daily for 6 weeks. | 31 |
| NBI-98854 Low Dose Participants received valbenazine once daily for 6 weeks. Participants aged 6 to 11 years received 10 mg/day. Participants aged 12 to 17 years received 20 mg/day. | 32 |
| NBI-98854 High Dose Participants received valbenazine once daily for 6 weeks. Participants aged 6 to 11 years received 10 mg/day for the first week followed by 20 mg/day for the remainder of the treatment period. Participants aged 12 to 17 years received 20 mg/day for the first week followed by 40 mg/day for the remainder of the treatment period. | 32 |
| Total | 95 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 2 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | NBI-98854 High Dose | NBI-98854 Low Dose |
|---|---|---|---|---|
| Age, Continuous | 11.5 Years | 11.7 Years | 11.6 Years | 12.0 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 11 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 84 Participants | 30 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 87 Participants | 29 Participants | 31 Participants |
| Sex: Female, Male Female | 4 Participants | 20 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 27 Participants | 75 Participants | 27 Participants | 21 Participants |
| Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) | 30.4 Score on scale | 32.1 Score on scale | 32.9 Score on scale | 32.8 Score on scale |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 32 | 0 / 33 |
| other Total, other adverse events | 9 / 32 | 15 / 32 | 19 / 33 |
| serious Total, serious adverse events | 1 / 32 | 0 / 32 | 0 / 33 |
Outcome results
Primary
Change From Baseline to Week 6 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 6
Population: The intent-to-treat (ITT) analysis set included all randomized participants who received at least one dose of study drug, had postbaseline safety data, and had a baseline (Day -1) and at least one postrandomization TTS value reported at a scheduled or mapped early termination (ET) visit during the 6-week treatment period. Dose levels based on age group were prespecified to be combined within each dose arm.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 6 in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) | -8.8 Score on scale | Standard Error 1.5 |
| NBI-98854 Low Dose | Change From Baseline to Week 6 in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) | -7.3 Score on scale | Standard Error 1.4 |
| NBI-98854 High Dose | Change From Baseline to Week 6 in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) | -9.1 Score on scale | Standard Error 1.4 |
p-value: 0.8995% CI: [-4.4, 3.8]Mixed Models Analysis
p-value: 0.4795% CI: [-2.6, 5.6]Mixed Models Analysis
Secondary
Change From Baseline to Week 6 in the Clinical Global Impression of Tics (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 6
Population: The ITT analysis set included all randomized participants who received at least one dose of study drug, had postbaseline safety data, and had a baseline (Day -1) and at least one postrandomization TTS value reported at a scheduled or mapped early termination (ET) visit during the 6-week treatment period. Dose levels based on age group were prespecified to be combined within each dose arm.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 6 in the Clinical Global Impression of Tics (CGI-Tics) - Severity Score | -1.1 Score on scale | Standard Error 0.2 |
| NBI-98854 Low Dose | Change From Baseline to Week 6 in the Clinical Global Impression of Tics (CGI-Tics) - Severity Score | -0.5 Score on scale | Standard Error 0.2 |
| NBI-98854 High Dose | Change From Baseline to Week 6 in the Clinical Global Impression of Tics (CGI-Tics) - Severity Score | -0.9 Score on scale | Standard Error 0.2 |
p-value: 0.4195% CI: [-0.3, 0.7]Mixed Models Analysis
p-value: 0.0195% CI: [0.2, 1.1]Mixed Models Analysis
Secondary
Change From Baseline to Week 6 in the Premonitory Urge for Tics Scale (PUTS) Total Score
The PUTS is an instrument for quantifying the premonitory urge phenomena associated with tics. It consists of 9 items, each of which is scored on a 4-point scale (1=not at all true, 2=a little true, 3=pretty much true, 4=very much true). The PUTS total score is calculated as the sum of the scores for the 9 items. The total score ranges from 9 to 36, with higher scores indicating a worse outcome.
Time frame: Baseline, Week 6
Population: The ITT analysis set included all randomized participants who received at least one dose of study drug, had postbaseline safety data, and had a baseline (Day -1) and at least one postrandomization TTS value reported at a scheduled or mapped early termination (ET) visit during the 6-week treatment period. Excludes those with missing PUTS data. Dose levels based on age group were prespecified to be combined within each dose arm.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 6 in the Premonitory Urge for Tics Scale (PUTS) Total Score | -0.6 Score on scale | Standard Error 0.8 |
| NBI-98854 Low Dose | Change From Baseline to Week 6 in the Premonitory Urge for Tics Scale (PUTS) Total Score | -1.0 Score on scale | Standard Error 0.8 |
| NBI-98854 High Dose | Change From Baseline to Week 6 in the Premonitory Urge for Tics Scale (PUTS) Total Score | 0.3 Score on scale | Standard Error 0.8 |
p-value: 0.4595% CI: [-1.4, 3.2]Mixed Models Analysis
p-value: 0.7295% CI: [-2.7, 1.9]Mixed Models Analysis
Secondary
Change From Baseline to Week 6 in the Rush Video-based Tic Rating Scale (RTRS) Total Score
A modified RTRS was used in this study that includes short video recordings to measure 5 tic variables: number of body areas affected, frequency of motor and phonic tics, and severity of motor and phonic tics. The RTRS total score is calculated as the sum of the 5 domain scores, and ranges from 0 to 20, with higher scores representing greater severity. The final on-treatment visit was used in participants who discontinued prior to Week 6.
Time frame: Baseline, Week 6
Population: Participants with observed data in the ITT analysis set, defined as all randomized participants who received at least one dose of study drug, had postbaseline safety data, and had a baseline (Day -1) and at least one postrandomization TTS value reported at a scheduled or mapped early termination (ET) visit during the 6-week treatment period. Dose levels based on age group were prespecified to be combined within each dose arm.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 6 in the Rush Video-based Tic Rating Scale (RTRS) Total Score | -1.2 Score on scale | Standard Error 0.8 |
| NBI-98854 Low Dose | Change From Baseline to Week 6 in the Rush Video-based Tic Rating Scale (RTRS) Total Score | -1.6 Score on scale | Standard Error 0.8 |
| NBI-98854 High Dose | Change From Baseline to Week 6 in the Rush Video-based Tic Rating Scale (RTRS) Total Score | -1.7 Score on scale | Standard Error 0.7 |
p-value: 0.6495% CI: [-2.6, 1.6]ANCOVA
p-value: 0.7795% CI: [-2.5, 1.9]ANCOVA
Secondary
Change From Baseline to Week 6 in the YGTSS Global Tic Severity Score
The YGTSS Global Tic Severity score is the sum of the YGTSS TTS and the YGTSS Impairment score and ranges from 0 to 100, with higher scores representing greater severity.
Time frame: Baseline, Week 6
Population: The ITT analysis set included all randomized participants who received at least one dose of study drug, had postbaseline safety data, and had a baseline (Day -1) and at least one postrandomization TTS value reported at a scheduled or mapped early termination (ET) visit during the 6-week treatment period. Dose levels based on age group were prespecified to be combined within each dose arm.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 6 in the YGTSS Global Tic Severity Score | -17.2 Score on scale | Standard Error 3.2 |
| NBI-98854 Low Dose | Change From Baseline to Week 6 in the YGTSS Global Tic Severity Score | -14.4 Score on scale | Standard Error 3.1 |
| NBI-98854 High Dose | Change From Baseline to Week 6 in the YGTSS Global Tic Severity Score | -19.5 Score on scale | Standard Error 3.1 |
p-value: 0.695% CI: [-11.2, 6.5]Mixed Models Analysis
p-value: 0.5495% CI: [-6.1, 11.7]Mixed Models Analysis
Secondary
Change From Baseline to Week 6 in the YGTSS Impairment Score
The YGTSS Impairment item is used to rate impairment due to tics using the following 50-point anchored scale: 0 = None; 10 = Minimal; 20 = Mild; 30 = Moderate; 40 = Marked; 50 = Severe.
Time frame: Baseline, Week 6
Population: The ITT analysis set included all randomized participants who received at least one dose of study drug, had postbaseline safety data, and had a baseline (Day -1) and at least one postrandomization TTS value reported at a scheduled or mapped early termination (ET) visit during the 6-week treatment period. Dose levels based on age group were prespecified to be combined within each dose arm.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 6 in the YGTSS Impairment Score | -8.5 Score on scale | Standard Error 2.1 |
| NBI-98854 Low Dose | Change From Baseline to Week 6 in the YGTSS Impairment Score | -7.1 Score on scale | Standard Error 2.1 |
| NBI-98854 High Dose | Change From Baseline to Week 6 in the YGTSS Impairment Score | -10.4 Score on scale | Standard Error 2 |
p-value: 0.5295% CI: [-7.7, 3.9]Mixed Models Analysis
p-value: 0.6495% CI: [-4.5, 7.2]Mixed Models Analysis
Secondary
Clinical Global Impression of Tourette Syndrome (CGI-TS) - Improvement Score at Week 6
The CGI-TS-Improvement scale is used to assess overall improvement since the initiation of study drug dosing on a 7-point scale. Each of the CGI-TS-Improvement response categories was assigned a numerical score as follows: 1 = Very much improved; 2 = Much improved; 3 = Minimally improved; 4 = Not changed; 5 = Minimally worse; 6 = Much worse; 7 = Very much worse.
Time frame: Week 6
Population: The ITT analysis set included all randomized participants who received at least one dose of study drug, had postbaseline safety data, and had a baseline (Day -1) and at least one postrandomization TTS value reported at a scheduled or mapped early termination (ET) visit during the 6-week treatment period. Dose levels based on age group were prespecified to be combined within each dose arm.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Clinical Global Impression of Tourette Syndrome (CGI-TS) - Improvement Score at Week 6 | 3.4 Score on scale | Standard Error 0.2 |
| NBI-98854 Low Dose | Clinical Global Impression of Tourette Syndrome (CGI-TS) - Improvement Score at Week 6 | 3.5 Score on scale | Standard Error 0.2 |
| NBI-98854 High Dose | Clinical Global Impression of Tourette Syndrome (CGI-TS) - Improvement Score at Week 6 | 3.0 Score on scale | Standard Error 0.2 |
p-value: 0.2195% CI: [-1, 0.2]Mixed Models Analysis
p-value: 0.6795% CI: [-0.5, 0.8]Mixed Models Analysis
Secondary
Participants Who Are a CGI-TS-Improvement Responder at Week 6
A participant is classified as a CGI-TS-Improvement responder at a given visit if their CGI-TS-Improvement score is either a 1 (very much improved) or a 2 (much improved) at the visit.
Time frame: Week 6
Population: Participants with observed data in the ITT analysis set, defined as all randomized participants who received at least one dose of study drug, had postbaseline safety data, and had a baseline (Day -1) and at least one postrandomization TTS value reported at a scheduled or mapped early termination (ET) visit during the 6-week treatment period. Dose levels based on age group were prespecified to be combined within each dose arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Participants Who Are a CGI-TS-Improvement Responder at Week 6 | 6 Participants |
| NBI-98854 Low Dose | Participants Who Are a CGI-TS-Improvement Responder at Week 6 | 6 Participants |
| NBI-98854 High Dose | Participants Who Are a CGI-TS-Improvement Responder at Week 6 | 11 Participants |
p-value: 0.18Cochran-Mantel-Haenszel
p-value: 0.95Cochran-Mantel-Haenszel
Secondary
Participants Who Are a YGTSS TTS Responder at Week 6
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 6
Population: Participants with observed data in the ITT analysis set, defined as all randomized participants who received at least one dose of study drug, had postbaseline safety data, and had a baseline (Day -1) and at least one postrandomization TTS value reported at a scheduled or mapped early termination (ET) visit during the 6-week treatment period. Dose levels based on age group were prespecified to be combined within each dose arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Participants Who Are a YGTSS TTS Responder at Week 6 | 10 Participants |
| NBI-98854 Low Dose | Participants Who Are a YGTSS TTS Responder at Week 6 | 9 Participants |
| NBI-98854 High Dose | Participants Who Are a YGTSS TTS Responder at Week 6 | 15 Participants |
p-value: 0.24Cochran-Mantel-Haenszel
p-value: 0.71Cochran-Mantel-Haenszel