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Futility
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pre-randomization Valbenazine | Experimental | Participants received valbenazine once daily for up to 12 weeks, depending on if and when randomization occured. 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 participants <50 kg and 80 mg for participants ≥50 kg to achieve an optimal dose of valbenazine for each participant. |
|
| Randomized Placebo | Placebo Comparator | 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. |
|
| Randomized Valbenazine | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Valbenazine | Drug | vesicular monoamine transporter 2 (VMAT2) inhibitor |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Randomization (Week 8, 10 or 12) through Week 36 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Clinical Development Lead | Neurocrine Biosciences | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Neuricrine Clinical Site | Sun City | Arizona | 85351 | United States | ||
| Neurocrine Clinical Site |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Pre-randomization Valbenazine | Participants received valbenazine once daily for up to 12 weeks, depending on if and when randomization occurred. 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 participants <50 kg and 80 mg for participants ≥50 kg to achieve an optimal dose of valbenazine for each participant. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Pre-randomization |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Dec 3, 2018 | Jan 27, 2022 |
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open-label study drug treatment period followed by blinded randomization into treatment arm or placebo arm
| Placebo oral capsule | Drug | non-active dosage form |
|
| Randomization Baseline (Week 8, 10 or 12); 8 weeks post-randomization |
| 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. | Randomization Baseline (Week 8, 10 or 12); Week 36 |
| 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. | Randomization Baseline (Week 8, 10 or 12); 8 weeks post-randomization |
| 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. | Randomization Baseline (Week 8, 10 or 12); Week 36 |
| Little Rock |
| Arkansas |
| 72205 |
| United States |
| Neurocrine Clinical Site | Rogers | Arkansas | 72758 | United States |
| Neurocrine Clinical Site | Anaheim | California | 92805 | United States |
| Neurocrine Clinical Site | Fullerton | California | 92835 | United States |
| Neurocrine Clinical Site | San Diego | California | 92108 | United States |
| Neurocrine Clinical Site | Santa Ana | California | 92705 | United States |
| Neurocrine Clinical Site | Pueblo | Colorado | 81003 | United States |
| Neurocrine Clinical Site | Stamford | Connecticut | 06905 | United States |
| Neurocrine Clinical Site | Washington D.C. | District of Columbia | 22207 | United States |
| Neurocrine Clinical Site | Gulf Breeze | Florida | 32561 | United States |
| Neurocrine Clinical Site | Hialeah | Florida | 33012 | United States |
| Neurocrine Clinical Site | Miami | Florida | 33125 | United States |
| Neurocrine Clinical Site | Miami | Florida | 33136 | United States |
| Neurocrine Clinical Site | North Miami | Florida | 33161 | United States |
| Neurocrine Clinical Site | Orlando | Florida | 32803 | United States |
| Neurocrine Clinical Site | Palmetto Bay | Florida | 33157 | United States |
| Neurocrine Clinical Site | Spring Hill | Florida | 34609 | United States |
| Neurocrine Clinical Site | St. Petersburg | Florida | 33701 | United States |
| Neurocrine Clinical Site | Tallahassee | Florida | 32308 | United States |
| Neurocrine Clinical Site | Atlanta | Georgia | 30338 | United States |
| Neurocrine Clinical Site | Fayetteville | Georgia | 30214 | United States |
| Neurocrine Clinical Site | Savannah | Georgia | 31406 | United States |
| Neurocrine Clinical Site | Chicago | Illinois | 60634 | United States |
| Neurocrine Clinical Site | South Bend | Indiana | 46617 | United States |
| Neurocrine Clinical Site | Boston | Massachusetts | 02114 | United States |
| Neurocrine Clinical Site | Ann Arbor | Michigan | 48015 | United States |
| Neurocrine Clinical Site | Bloomfield Hills | Michigan | 48302 | United States |
| Neurocrine Clinical Site | West Bloomfield | Michigan | 48322 | United States |
| Neurocrine Clinical Site | Lincoln | Nebraska | 68526 | United States |
| Neurocrine Clinical Site | Nashua | New Hampshire | 03060 | United States |
| Neurocrine Clinical Site | Cherry Hill | New Jersey | 08002 | United States |
| Neurocrine Clinical Site | Mount Arlington | New Jersey | 07856 | United States |
| Neurocrine Clinical Site | New York | New York | 10036 | United States |
| Neurocrine Clinical Site | South Setauket | New York | 11720 | United States |
| Neurocrine Clinical Site | Charlotte | North Carolina | 29141 | United States |
| Neurocrine Clinical Site | Mason | Ohio | 45040 | United States |
| Neurocrine Clinical Site | Oklahoma City | Oklahoma | 73112 | United States |
| Neurocrine Clinical Site | Dallas | Texas | 75243 | United States |
| Neurocrine Clinical Site | DeSoto | Texas | 75115 | United States |
| Neurocrine Clinical Site | Houston | Texas | 77030 | United States |
| Neurocrine Clinical Site | Houston | Texas | 77058 | United States |
| Neurocrine Clinical Site | Irving | Texas | 75062 | United States |
| Neurocrine Clinical Site | San Antonio | Texas | 78249 | United States |
| Neurocrine Clinical Site | Charlottesville | Virginia | 22903 | United States |
| Neurocrine Clinical Site | Bothell | Washington | 98011 | United States |
| Neurocrine Clinical Site | Everett | Washington | 98201 | United States |
| Neurocrine Clinical Site | Spokane | Washington | 99202 | United States |
| Neurocrine Clinical Site | San Juan | 00926 | Puerto Rico |
| FG001 | 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. |
| FG002 | 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. |
| Safety Analysis Set | The safety analysis set includes all enrolled subjects who received at least one dose of study drug and had any safety data collected after the first dose of study drug. |
|
| COMPLETED |
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| NOT COMPLETED |
|
|
| Randomized Withdrawal Period / Follow-up |
|
|
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.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Median | 95% Confidence Interval | Days | Randomization (Week 8, 10 or 12) through Week 36 |
|
|
| ||||||||||||||||||||||||||||
| 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. | 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. | Posted | Least Squares Mean | Standard Error | units on a scale | Randomization Baseline (Week 8, 10 or 12); 8 weeks post-randomization |
| ||||||||||||||||||||||||||||||
| 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. | 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. | Posted | Mean | Standard Deviation | units on a scale | Randomization Baseline (Week 8, 10 or 12); Week 36 |
| ||||||||||||||||||||||||||||||
| 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. | 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. | Posted | Least Squares Mean | Standard Error | units on a scale | Randomization Baseline (Week 8, 10 or 12); 8 weeks post-randomization |
| ||||||||||||||||||||||||||||||
| 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. | 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. | Posted | Mean | Standard Deviation | units on a scale | Randomization Baseline (Week 8, 10 or 12); Week 36 |
|
Pre-randomization valbenazine group: from baseline up to randomization (Week 8, 10 or 12) or end of participation in subjects who did not randomize, up to 16 weeks. Randomized placebo and valbenazine groups: from randomization (Week 8, 10 or 12) up to Week 40
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Pre-randomization Valbenazine | Participants received valbenazine once daily for up to 12 weeks, depending on if and when randomization occurs. 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. Valbenazine: vesicular monoamine transporter 2 (VMAT2) inhibitor | 0 | 80 | 1 | 80 | 41 | 80 |
| EG001 | 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. Placebo oral capsule: non-active dosage form | 0 | 26 | 2 | 26 | 12 | 26 |
| EG002 | 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. Valbenazine: vesicular monoamine transporter 2 (VMAT2) inhibitor | 0 | 26 | 2 | 26 | 14 | 26 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Enterovirus infection | Infections and infestations | MedDRA 12.0 | Systematic Assessment |
| |
| Akathisia | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Tic | Psychiatric disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Obsessive-compulsive disorder | Psychiatric disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Tourette's disorder | Congenital, familial and genetic disorders | MedDRA 12.0 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Irritability | General disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Gastroenteritis viral | Infections and infestations | MedDRA 12.0 | Systematic Assessment |
| |
| Upper respiratory tract infection | Infections and infestations | MedDRA 12.0 | Systematic Assessment |
| |
| Weight increased | Investigations | MedDRA 12.0 | Systematic Assessment |
| |
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Somnolence | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Aggression | Psychiatric disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Anxiety | Psychiatric disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Suicidal ideation | Psychiatric disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Tic | Psychiatric disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Haematuria | Renal and urinary disorders | MedDRA 12.0 | Systematic Assessment |
| |
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 12.0 | Systematic Assessment |
|
Generally, the PI has the right to publish results provided such publication does not violate confidentiality or IP provisions within the contract with the Sponsor. Prior to submission for publication or presentation of results, the PI must provide the Sponsor time for review. The Sponsor can request the PI to withhold or remove information from all publications. For a multi-center study, any publication of results by the PI shall not be made before the first multi-center publication.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Neurocrine Medical Information | Neurocrine Biosciences | 877-641-3461 | medinfo@neurocrine.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Aug 2, 2019 | Jan 27, 2022 | SAP_001.pdf |
Not provided
| ID | Term |
|---|---|
| D005879 | Tourette Syndrome |
| ID | Term |
|---|---|
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D013981 | Tic Disorders |
| D009069 | Movement Disorders |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
Not provided
Not provided
| ID | Term |
|---|---|
| C000603978 | valbenazine |
Not provided
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Not provided
| Withdrawal by Subject |
|
| Lack of Efficacy |
|
| Study Terminated by Sponsor |
|
| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
|
|
|
|
|
|
| Units | Counts |
|---|---|
| Participants |
|
|