Safety, Tolerability, and Efficacy of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome

• Sponsor: Neurocrine Biosciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03325010
• Collaborator: (none)
• Enrollment: 127
• Locations: 35
• Arms: 2
• Actual Duration (Months): 13.4
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Tourette Syndrome	Drug: Valbenazine; Drug: Placebo oral capsule	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 127 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Dose Optimization Study to Assess the Safety, Tolerability, and Efficacy of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome
• Actual Study Start Date: Oct 5, 2017
• Actual Primary Completion Date: Nov 1, 2018
• Actual Study Completion Date: Nov 16, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received placebo (matching valbenazine) once daily for 12 weeks.	Drug: Placebo oral capsule; non-active dosage form
Experimental: 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.	Drug: Valbenazine; vesicular monoamine transporter 2 (VMAT2) inhibitor; Other Names: Ingrezza NBI-98854

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Neurocrine Clinical Site	Sun City	Arizona	United States	85351
2	Neurocrine Clinical Site	Rogers	Arkansas	United States	72758
3	Neurocrine Clinical Site	Anaheim	California	United States	92805
4	Neurocrine Clinical Site	San Diego	California	United States	92108
5	Neurocrine Clinical Site	Santa Clarita	California	United States	91321
6	Neurocrine Clinical Site	New Haven	Connecticut	United States	06519
7	Neurocrine Clinical Site	Hialeah	Florida	United States	33012
8	Neurocrine Clinical Site	Hialeah	Florida	United States	33013
9	Neurocrine Clinical Site	Hialeah	Florida	United States	33018
10	Neurocrine Clinical Site	Loxahatchee Groves	Florida	United States	33470
11	Neurocrine Clinical Site	Orange City	Florida	United States	32763
12	Neurocrine Clinical Site	Orlando	Florida	United States	32801
13	Neurocrine Clinical Site	Orlando	Florida	United States	32803
14	Neurocrine Clinical Site	Tampa	Florida	United States	33609
15	Neurocrine Clinical Site	Chicago	Illinois	United States	60634
16	Neurocrine Clinical Site	Chicago	Illinois	United States	60637
17	Neurocrine Clinical Site	Naperville	Illinois	United States	60563
18	Neurocrine Clinical Site	Iowa City	Iowa	United States	52242
19	Neurocrine Clinical Site	Leawood	Kansas	United States	66206
20	Neurocrine Clinical Site	Boston	Massachusetts	United States	02114
21	Neurocrine Clinical Site	Lincoln	Nebraska	United States	68526
22	Neurocrine Clinical Site	Nashua	New Hampshire	United States	03060
23	Neurocrine Clinical Site	Mount Arlington	New Jersey	United States	07856
24	Neurocrine Clinical Site	Voorhees	New Jersey	United States	08043
25	Neurocrine Clinical Site	Bronx	New York	United States	10467
26	Neurocrine Clinical Site	New York	New York	United States	10036
27	Neurocrine Clinical Site	Durham	North Carolina	United States	27705
28	Neurocrine Clinical Site	Memphis	Tennessee	United States	38119
29	Neurocrine Clinical Site	Dallas	Texas	United States	75243
30	Neurocrine Clinical Site	Houston	Texas	United States	77058
31	Neurocrine Clinical Site	Irving	Texas	United States	75062
32	Neurocrine Clinical Site	Everett	Washington	United States	98201
33	Neurocrine Clinical Site	Seattle	Washington	United States	98105
34	Neurocrine Clinical Site	Spokane	Washington	United States	99204
35	Neurocrine Clinical Site	San Juan		Puerto Rico	00926

Sponsors and Collaborators

• Neurocrine Biosciences

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 31, 2018
• Statistical Analysis Plan - Sep 25, 2018

More Information

Additional Information:

• Go to TForceGOLD.com to get information regarding the study and participating sites.

Publications

None provided.

• Responsible Party: Neurocrine Biosciences
• ClinicalTrials.gov Identifier: NCT03325010
• Other Study ID Numbers: NBI-98854-TS2003
• First Posted: Oct 30, 2017
• Last Update Posted: Jun 28, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Tourette Syndrome; Syndrome

Study Results

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.

Arm/Group Title	Placebo	Valbenazine
Arm/Group Description	Participants received placebo (matching valbenazine) once daily for 12 weeks.	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.
Period Title: Overall Study
STARTED	64	63
Safety Analysis Set	62	59
Full Analysis Set	61	58
COMPLETED	55	43
NOT COMPLETED	9	20

Baseline Characteristics

Arm/Group Title	Placebo	Valbenazine	Total
Arm/Group Description	Participants received placebo (matching valbenazine) once daily for 12 weeks.	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.	Total of all reporting groups
Overall Participants	61	58	119
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	12.4 (2.6)	12.2 (2.7)	12.3 (2.6)
Sex: Female, Male (Count of Participants)
Female	9 14.8%	10 17.2%	19 16%
Male	52 85.2%	48 82.8%	100 84%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	15 24.6%	14 24.1%	29 24.4%
Not Hispanic or Latino	46 75.4%	44 75.9%	90 75.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	3 4.9%	1 1.7%	4 3.4%
Black or African American	8 13.1%	1 1.7%	9 7.6%
White	49 80.3%	53 91.4%	102 85.7%
Native Hawaiian or Other Pacific Islander	1 1.6%	0 0%	1 0.8%
Other	0 0%	1 1.7%	1 0.8%
Multiple	0 0%	2 3.4%	2 1.7%
Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) (score on scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on scale]	31.2 (9.0)	29.3 (8.7)	30.3 (8.9)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 12 in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Valbenazine
Arm/Group Description	Participants received placebo (matching valbenazine) once daily for 12 weeks.	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.
Measure Participants	61	58
Least Squares Mean (Standard Error) [score on a scale]	-6.8 (1.0)	-8.9 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Valbenazine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1768
	Comments	Nominal p-value is considered statistically significant if less than 0.05. To control for multiplicity, comparisons were tested sequentially.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.1
	Confidence Interval	(2-Sided) 95%; -5.2 to 1.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.5
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Week 12 in the Clinical Global Impression of Tics Severity (CGI-Tics-Severity) Score
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Valbenazine
Arm/Group Description	Participants received placebo (matching valbenazine) once daily for 12 weeks.	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.
Measure Participants	61	58
Least Squares Mean (Standard Error) [Score on scale]	-0.7 (0.1)	-1.0 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Valbenazine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1095
	Comments	To control for multiplicity, comparisons were tested sequentially. Nominal p-value for this outcome measure would only be evaluated for statistical significance if the primary outcome measure was statistically significant.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2
	Estimation Comments

3. Secondary Outcome

Title	Participants Who Are a Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) Responder at Week 12
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Valbenazine
Arm/Group Description	Participants received placebo (matching valbenazine) once daily for 12 weeks.	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.
Measure Participants	54	43
Count of Participants [Participants]	21 34.4%	18 31%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Valbenazine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8190
	Comments	To control for multiplicity, comparisons were tested sequentially. Nominal p-value for this outcome measure would only be evaluated for statistical significance if the primary and preceding secondary outcome measures were statistically significant.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by baseline weight group (<50 kg, ≥50 kg).
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	3.0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Participants Who Are a Clinical Global Impression of Tourette Syndrome Improvement (CGI-TS-Improvement) Responder at Week 12
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Valbenazine
Arm/Group Description	Participants received placebo (matching valbenazine) once daily for 12 weeks.	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.
Measure Participants	54	43
Count of Participants [Participants]	12 19.7%	24 41.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Valbenazine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments	To control for multiplicity, comparisons were tested sequentially. Nominal p-value for this outcome measure would only be evaluated for statistical significance if the primary and preceding secondary outcome measures were statistically significant.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by baseline weight group (<50 kg, ≥50 kg)
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	33.6
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Up to 14 Weeks
Arm/Group Title	Placebo		Valbenazine
Arm/Group Description	Participants received placebo (matching valbenazine) once daily for 12 weeks.		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.
All Cause Mortality
	Placebo		Valbenazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/62 (0%)		0/59 (0%)
Serious Adverse Events
	Placebo		Valbenazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/62 (1.6%)		0/59 (0%)
Skin and subcutaneous tissue disorders
Rash	1/62 (1.6%)		0/59 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Valbenazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/62 (27.4%)		32/59 (54.2%)
Gastrointestinal disorders
Abdominal pain upper	2/62 (3.2%)		3/59 (5.1%)
Gastrooesophageal reflux disease	0/62 (0%)		3/59 (5.1%)
Nausea	2/62 (3.2%)		3/59 (5.1%)
Vomiting	4/62 (6.5%)		6/59 (10.2%)
General disorders
Fatigue	5/62 (8.1%)		6/59 (10.2%)
Irritability	2/62 (3.2%)		3/59 (5.1%)
Infections and infestations
Influenza	1/62 (1.6%)		3/59 (5.1%)
Musculoskeletal and connective tissue disorders
Pain in extremity	0/62 (0%)		3/59 (5.1%)
Nervous system disorders
Headache	5/62 (8.1%)		11/59 (18.6%)
Somnolence	0/62 (0%)		11/59 (18.6%)
Psychiatric disorders
Anxiety	2/62 (3.2%)		3/59 (5.1%)
Restlessness	0/62 (0%)		3/59 (5.1%)
Suicidal ideation	1/62 (1.6%)		5/59 (8.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.