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 8 weeks of treatment. This study will enroll approximately 90 male and female 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
18 Years to 64 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. Have a negative urine drug screen for amphetamines, barbiturates, benzodiazepine, phencyclidine, cocaine, or opiates, 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 tachy-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 known history of substance dependence, substance (drug) or alcohol abuse 7. Have a significant risk of suicidal or violent behavior 8. Are currently pregnant or breastfeeding 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 a blood loss ≥550 mL or donated blood within 30 days prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 8 in the YGTSS TTS | Baseline, Week 8 | 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 Change Tourette Syndrome (CGI-TS)-Improvement Score at Week 8 | Week 8 | 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. |
| Change From Baseline to Week 8 in the Clinical Global Impression of Tics (CGI-Tics)-Severity Score | Baseline, Week 8 | 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 Baseline to Last Visit in the Rush Video-based Tic Rating Scale (RTRS) Total Score | Baseline, Week 8 | 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 subjects who discontinued prior to Week 8. |
| Change From Baseline to Week 8 in the YGTSS Global Tic Severity Score | Baseline, Week 8 | 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 8 in the Premonitory Urge for Tics Scale (PUTS) Total Score | Baseline, Week 8 | 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 maximum possible total score is 36. |
Countries
United States
Participant flow
Recruitment details
This study enrolled participants (male and female) with a diagnosis of Tourette Syndrome through Diagnostic and Statistical Manual of Mental Disorders, 4th or 5th Editions (DSM-IV or -V) from approximately 40 study centers in the United States
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo administered once daily for 8 weeks | 39 |
| NBI-98854 40 mg Fixed dose of NBI-98854 40 mg administered once daily for 8 weeks | 41 |
| NBI-98854 80 mg NBI-98854 80 mg dose will be titrated in a blinded fashion (subjects will receive 40 mg for the first week followed by 80 mg for the remainder of the 8-week treatment period) | 40 |
| Total | 120 |
Baseline characteristics
| Characteristic | NBI-98854 40 mg | Placebo | NBI-98854 80 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 34.1 years | 37.2 years | 34.1 years | 35.1 years |
| Body mass index (BMI) at Screening | 28.75 kg/m^2 (kilogram/meter^2) | 28.69 kg/m^2 (kilogram/meter^2) | 29.01 kg/m^2 (kilogram/meter^2) | 28.82 kg/m^2 (kilogram/meter^2) |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 36 Participants | 36 Participants | 111 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native, White | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Black or African American | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Race Black or African American, White | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other: Thai/White | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 39 Participants | 34 Participants | 34 Participants | 107 Participants |
| Race/Ethnicity, Customized Race White, Other: German | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 9 Participants | 16 Participants | 15 Participants | 40 Participants |
| Sex: Female, Male Male | 32 Participants | 23 Participants | 25 Participants | 80 Participants |
| Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) | 31.6 Score on scale | 32.1 Score on scale | 30.0 Score on scale | 31.2 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 / 40 | 0 / 42 | 0 / 42 |
| other Total, other adverse events | 8 / 40 | 22 / 42 | 32 / 42 |
| serious Total, serious adverse events | 1 / 40 | 1 / 42 | 2 / 42 |
Outcome results
Primary
Change From Baseline to Week 8 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: Baseline, Week 8
Population: The intent-to-treat (ITT) analysis set, that includes all randomized subjects who received at least one dose of study drug, have postbaseline safety data \& have at least one post randomization Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) value at a scheduled visit or mapped early termination (ET) visit during 8-week treatment period
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 8 in the YGTSS TTS | -6.1 Least Squares Mean (Standard Error) | Standard Error 1.1 |
| NBI-98854 40 mg | Change From Baseline to Week 8 in the YGTSS TTS | -7.4 Least Squares Mean (Standard Error) | Standard Error 1.7 |
| NBI-98854 80 mg | Change From Baseline to Week 8 in the YGTSS TTS | -8.0 Least Squares Mean (Standard Error) | Standard Error 1.1 |
p-value: 0.432695% CI: [-4.9, 2.1]Mixed Models Analysis
p-value: 0.183595% CI: [-6.2, 1.2]Mixed Models Analysis
Secondary
Change From Baseline to Last Visit 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 subjects who discontinued prior to Week 8.
Time frame: Baseline, Week 8
Population: the intent-to-treat (ITT) analysis set, that includes all randomized subjects who received at least one dose of study drug, have postbaseline safety data \& have at least one post randomization Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) value at a scheduled visit or mapped early termination (ET) visit during 8-week treatment period
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Last Visit in the Rush Video-based Tic Rating Scale (RTRS) Total Score | -1.9 score on a scale | Standard Error 0.7 |
| NBI-98854 40 mg | Change From Baseline to Last Visit in the Rush Video-based Tic Rating Scale (RTRS) Total Score | -3.0 score on a scale | Standard Error 0.6 |
| NBI-98854 80 mg | Change From Baseline to Last Visit in the Rush Video-based Tic Rating Scale (RTRS) Total Score | -3.6 score on a scale | Standard Error 0.6 |
p-value: 0.221595% CI: [-2.7, 0.6]ANCOVA
p-value: 0.056695% CI: [-3.3, 0]ANCOVA
Secondary
Change From Baseline to Week 8 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 8
Population: the intent-to-treat (ITT) analysis set, that includes all randomized subjects who received at least one dose of study drug, have postbaseline safety data \& have at least one post randomization Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) value at a scheduled visit or mapped early termination (ET) visit during 8-week treatment period
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 8 in the Clinical Global Impression of Tics (CGI-Tics)-Severity Score | -0.8 score on a scale | Standard Error 0.2 |
| NBI-98854 40 mg | Change From Baseline to Week 8 in the Clinical Global Impression of Tics (CGI-Tics)-Severity Score | -1.0 score on a scale | Standard Error 0.2 |
| NBI-98854 80 mg | Change From Baseline to Week 8 in the Clinical Global Impression of Tics (CGI-Tics)-Severity Score | -1.0 score on a scale | Standard Error 0.1 |
p-value: 0.306595% CI: [-0.6, 0.2]Mixed Models Analysis
p-value: 0.205295% CI: [-0.7, 0.2]Mixed Models Analysis
Secondary
Change From Baseline to Week 8 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 maximum possible total score is 36.
Time frame: Baseline, Week 8
Population: The analysis population include intent-to-treat (ITT):all subjects in the safety analysis set with at least one post-randomization TTS value reported at a scheduled visit or mapped Early Termination (ET) visit during the treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 8 in the Premonitory Urge for Tics Scale (PUTS) Total Score | -1.2 score on a scale | Standard Error 0.7 |
| NBI-98854 40 mg | Change From Baseline to Week 8 in the Premonitory Urge for Tics Scale (PUTS) Total Score | -0.8 score on a scale | Standard Error 0.9 |
| NBI-98854 80 mg | Change From Baseline to Week 8 in the Premonitory Urge for Tics Scale (PUTS) Total Score | -0.6 score on a scale | Standard Error 0.9 |
p-value: 0.451595% CI: [-3, 1.3]Mixed Models Analysis
p-value: 0.628995% CI: [-2.8, 1.7]Mixed Models Analysis
Secondary
Change From Baseline to Week 8 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 8
Population: the intent-to-treat (ITT) analysis set, that includes all randomized subjects who received at least one dose of study drug, have postbaseline safety data \& have at least one post randomization Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) value at a scheduled visit or mapped early termination (ET) visit during 8-week treatment period
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 8 in the YGTSS Global Tic Severity Score | -15.0 score on a scale | Standard Error 2.6 |
| NBI-98854 40 mg | Change From Baseline to Week 8 in the YGTSS Global Tic Severity Score | -16.2 score on a scale | Standard Error 3.5 |
| NBI-98854 80 mg | Change From Baseline to Week 8 in the YGTSS Global Tic Severity Score | -19.1 score on a scale | Standard Error 2.9 |
p-value: 0.568995% CI: [-9.8, 5.4]Mixed Models Analysis
p-value: 0.23295% CI: [-12.8, 3.1]Mixed Models Analysis
Secondary
Clinical Global Impression of Change Tourette Syndrome (CGI-TS)-Improvement Score at Week 8
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 8
Population: the intent-to-treat (ITT) analysis set, that includes all randomized subjects who received at least one dose of study drug, have postbaseline safety data \& have at least one post randomization Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) value at a scheduled visit or mapped early termination (ET) visit during 8-week treatment period
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Clinical Global Impression of Change Tourette Syndrome (CGI-TS)-Improvement Score at Week 8 | 3.2 score on a scale | Standard Error 0.2 |
| NBI-98854 40 mg | Clinical Global Impression of Change Tourette Syndrome (CGI-TS)-Improvement Score at Week 8 | 3.0 score on a scale | Standard Error 0.2 |
| NBI-98854 80 mg | Clinical Global Impression of Change Tourette Syndrome (CGI-TS)-Improvement Score at Week 8 | 2.6 score on a scale | Standard Error 0.1 |
p-value: 0.381295% CI: [-0.7, 0.3]ANOVA
p-value: 0.014695% CI: [-1.2, -0.1]ANOVA