Persistence of Effect and Safety of Valbenazine for the Treatment of Tardive Dyskinesia

• Sponsor: Neurocrine Biosciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03891862
• Collaborator: (none)
• Enrollment: 135
• Locations: 43
• Arms: 3
• Actual Duration (Months): 10.4
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is a Phase 4, randomized, double-blind, placebo-controlled study to evaluate the persistence of effect of valbenazine 40 mg and 80 mg.

Condition or Disease	Intervention/Treatment	Phase
Tardive Dyskinesia (TD)	Drug: Valbenazine; Drug: Placebo oral capsule	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 135 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 4, Double-Blind, Placebo-Controlled, Randomized Withdrawal Study to Evaluate the Persistence of Effect and Safety of Valbenazine for the Treatment of Tardive Dyskinesia
• Actual Study Start Date: Mar 18, 2019
• Actual Primary Completion Date: Dec 23, 2019
• Actual Study Completion Date: Jan 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Open-label Valbenazine Participants received valbenazine 40 mg once daily for 1 week, then 80 mg once daily for the remainder of the 8-week open label period.	Drug: Valbenazine; vesicular monoamine transporter 2 (VMAT2) inhibitor; Other Names: Ingrezza, NBI-98854
Placebo Comparator: Placebo-controlled Placebo Participants received placebo (matching valbenazine) once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks.	Drug: Placebo oral capsule; non-active dosage form
Experimental: Placebo-controlled Valbenazine Participants received valbenazine 80 mg once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks.	Drug: Valbenazine; vesicular monoamine transporter 2 (VMAT2) inhibitor; Other Names: Ingrezza, NBI-98854

Outcome Measures

Primary Outcome Measures

1. Change From Randomization (Week 8) in Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score at Week 16 [Week 8, Week 16]

   The AIMS rates 10 items of involuntary movement, each item ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Items assess facial, oral, extremity, and trunk movements, as well as self-awareness of abnormal movements. The AIMS Dyskinesia Total Score is the sum of items 1-7 and ranges from 0 to 28, with higher scores indicating more severe dyskinesia. Least-squares mean were estimated using a mixed-effects model for repeated measures.

Secondary Outcome Measures

1. Change From Baseline in the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Health State Index Score at Week 16 [Baseline, Week 16]

   The EQ-5D-5L assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The health state index score is based on the results of the individual health profiles using the United States value set and ranges from -0.573 to 1.0, with higher scores indicating higher health utility.

2. Change From Baseline in the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) at Week 16 [Baseline, Week 16]

   The EQ-5D-5L assesses general health-related quality of life. The second portion of the scale is a self-perceived health score assessed using a VAS that ranges from 0 ("the worst imaginable health") to 100 ("the best imaginable health").

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Subjects of childbearing potential 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.

2. Have one of the following clinical diagnoses for at least 3 months before screening: Schizophrenia, Schizoaffective Disorder, or Mood Disorder

3. Have a clinical diagnosis of neuroleptic-induced TD for at least 3 months before screening.

4. Be on stable doses if using maintenance medication(s) for schizophrenia or schizoaffective disorder, or mood disorder. Subjects with bipolar disorder must be on stable doses of a mood stabilizer.

5. Be in general good health.

6. Have adequate hearing, vision, and language skills to perform the procedures specified in the protocol.

Exclusion Criteria:

1. Have an active, clinically significant unstable medical condition within 1 month before screening.

2. Have a known history of substance (drug) dependence, or substance or alcohol abuse.

3. Have a significant risk of suicidal or violent behavior.

4. Have been hospitalized for psychiatric disorder within 6 months before Day 1.

5. Have a known history of neuroleptic malignant syndrome.

6. Have a known history of long QT syndrome or cardiac arrhythmia.

7. Have a cancer diagnosis within 3 years prior to screening (some exceptions allowed).

8. Are currently taking tetrabenazine or deutetrabenazine, or have used valbenazine (INGREZA) within 30 days of screening.

9. Have received an investigational drug within 30 days before Day 1 or plan to use an investigational drug (other than NBI-98854) during the study.

10. Have a blood loss ≥550 mL or donated blood within 30 days prior to Baseline.

11. Have an allergy, hypersensitivity, or intolerance to VMAT2 inhibitors (eg, tetrabenazine, deutetrabenazine).

12. Are currently pregnant or breastfeeding.

13. Have HIV or hepatitis B.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Neurocrine Clinical Site	Little Rock	Arkansas	United States	72211
2	Neurocrine Clinical Site	Anaheim	California	United States	92804
3	Neurocrine Clinical Site	Anaheim	California	United States	92805
4	Neurocrine Clinical Site	Costa Mesa	California	United States	92627
5	Neurocrine Clinical Site	Escondido	California	United States	92056
6	Neurocrine Clinical Site	Fountain Valley	California	United States	92708
7	Neurocrine Clinical Site	Glendale	California	United States	91206
8	Neurocrine Clinical Site	La Habra	California	United States	90631
9	Neurocrine Clinical Site	Lemon Grove	California	United States	91945
10	Neurocrine Clinical Site	Norwalk	California	United States	90650
11	Neurocrine Clinical Site	San Bernardino	California	United States	92408
12	Neurocrine Clinical Site	San Diego	California	United States	92108
13	Neurocrine Clinical Site	Torrance	California	United States	90502
14	Neurocrine Clinical Site	Pueblo	Colorado	United States	81003
15	Neurocrine Clinical Site	Hialeah	Florida	United States	33012
16	Neurocrine Clinical Site	Hialeah	Florida	United States	33013
17	Neurocrine Clinical Site	Hialeah	Florida	United States	33018
18	Neurocrine Clinical Site	Miami	Florida	United States	33183
19	Neurocrine Clinical Site	North Miami	Florida	United States	33161
20	Neurocrine Clinical Site	Orlando	Florida	United States	32803
21	Neurocrine Clinical Site	South Bend	Indiana	United States	46601
22	Neurocrine Clinical Site	Bloomfield Hills	Michigan	United States	48302
23	Neurocrine Clinical Site	East Lansing	Michigan	United States	48824
24	Neurocrine Clinical Site	Grand Rapids	Michigan	United States	49503
25	Neurocrine Clinical Site	Kansas City	Missouri	United States	64108
26	Neurocrine Clinical Site	Saint Louis	Missouri	United States	63109
27	Neurocrine Clinical Site	Lincoln	Nebraska	United States	68526
28	Neurocrine Clinical Site	Las Vegas	Nevada	United States	89102
29	Neurocrine Clinical Site	New York	New York	United States	10029
30	Neurocrine Clinical Site	Beachwood	Ohio	United States	44122
31	Neurocrine Clinical Site	Mason	Ohio	United States	45040
32	Neurocrine Clinical Site	Oklahoma City	Oklahoma	United States	73112
33	Neurocrine Clinical Site	Conshohocken	Pennsylvania	United States	19428
34	Neurocrine Clinical Site	Scranton	Pennsylvania	United States	18503
35	Neurocrine Clinical Site	Franklin	Tennessee	United States	37067
36	Neurocrine Clinical Site	DeSoto	Texas	United States	75115
37	Neurocrine Clinical Site	Houston	Texas	United States	44030
38	Neurocrine Clinical Site	Houston	Texas	United States	77058
39	Neurocrine Clinical Site	Irving	Texas	United States	75062
40	Neurocrine Clinical Site	Richmond	Texas	United States	77407
41	Neurocrine Clinical Site	Petersburg	Virginia	United States	23805
42	Neurocrine Clinical Site	Spokane	Washington	United States	99202
43	Neurocrine Clinical Site	San Juan		Puerto Rico	00926

Sponsors and Collaborators

• Neurocrine Biosciences

Investigators

• Study Director: Chief Medical Officer, Chief Medical Officer

Study Documents (Full-Text)

• Study Protocol - May 14, 2019
• Statistical Analysis Plan - Aug 2, 2020

More Information

Publications

None provided.

• Responsible Party: Neurocrine Biosciences
• ClinicalTrials.gov Identifier: NCT03891862
• Other Study ID Numbers: NBI-98854-TD4002
• First Posted: Mar 27, 2019
• Last Update Posted: Apr 20, 2021
• Last Verified: Mar 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: Dyskinesias; Tardive Dyskinesia

Study Results

Participant Flow

Recruitment Details

The study enrolled male and female participants, 18 to 85 years of age, from 28 centers in the United States. Participants must have clinical diagnoses of schizophrenia or schizoaffective disorder with neuroleptic-induced tardive dyskinesia (TD) or mood disorder with neuroleptic-induced TD and have moderate or severe TD as assessed by an external Abnormal Involuntary Movement Scale (AIMS) Reviewer. The first and last participant was enrolled on 18 March 2019 and 3 September 2019, respectively.

Pre-assignment Detail

After receiving valbenazine 40 mg for the first week followed by valbenazine 80 mg for 7 weeks during the open-label period, participants were randomly assigned to either placebo or to continue to receive valbenazine 80 mg.

Arm/Group Title	Open-label Valbenazine	Placebo-controlled Placebo	Placebo-controlled Valbenazine
Arm/Group Description	Participants received valbenazine 40 mg once daily for 1 week, then 80 mg once daily for the remainder of the 8-week open label period.	Participants received placebo (matching valbenazine) once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks.	Participants received valbenazine 80 mg once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks.
Period Title: Open-label Period
STARTED	135	0	0
Safety Analysis Set	132	0	0
COMPLETED	119	0	0
NOT COMPLETED	16	0	0
Period Title: Open-label Period
STARTED	0	59	59
Persistence of Effect Analysis Set	0	58	59
Completed Placebo-controlled Period	0	53	56
COMPLETED	0	53	55
NOT COMPLETED	0	6	4

Baseline Characteristics

Arm/Group Title	Placebo-controlled Placebo	Placebo-controlled Valbenazine	Total
Arm/Group Description	Participants received placebo (matching valbenazine) once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks.	Participants received valbenazine 80 mg once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks.	Total of all reporting groups
Overall Participants	58	59	117
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.2 (8.3)	58.0 (8.0)	58.6 (8.1)
Sex: Female, Male (Count of Participants)
Female	27 46.6%	30 50.8%	57 48.7%
Male	31 53.4%	29 49.2%	60 51.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	32 55.2%	32 54.2%	64 54.7%
Not Hispanic or Latino	26 44.8%	27 45.8%	53 45.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	21 36.2%	16 27.1%	37 31.6%
White	36 62.1%	43 72.9%	79 67.5%
More than one race	1 1.7%	0 0%	1 0.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Abnormal Involuntary Movement Scale at Study Baseline (Score on scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score on scale]	10.3 (3.7)	11.0 (4.1)	10.7 (3.9)

Outcome Measures

1. Primary Outcome

Title	Change From Randomization (Week 8) in Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score at Week 16
Description	The AIMS rates 10 items of involuntary movement, each item ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Items assess facial, oral, extremity, and trunk movements, as well as self-awareness of abnormal movements. The AIMS Dyskinesia Total Score is the sum of items 1-7 and ranges from 0 to 28, with higher scores indicating more severe dyskinesia. Least-squares mean were estimated using a mixed-effects model for repeated measures.
Time Frame	Week 8, Week 16

Outcome Measure Data

Analysis Population Description

Persistence of effect analysis set, which includes all randomized participants who received at least one dose of randomized study drug and have at least one AIMS assessment during the placebo-controlled period. Participants who do not have an AIMS assessment at a scheduled or mapped early termination visit are not included in the analysis.

Arm/Group Title	Placebo-controlled Placebo	Placebo-controlled Valbenazine
Arm/Group Description	Participants received placebo (matching valbenazine) once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks.	Participants received valbenazine 80 mg once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks.
Measure Participants	56	58
Least Squares Mean (95% Confidence Interval) [Score on scale]	0.6	-1.6

2. Secondary Outcome

Title	Change From Baseline in the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Health State Index Score at Week 16
Description	The EQ-5D-5L assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The health state index score is based on the results of the individual health profiles using the United States value set and ranges from -0.573 to 1.0, with higher scores indicating higher health utility.
Time Frame	Baseline, Week 16

Outcome Measure Data

Analysis Population Description

Includes all participants who received at least one dose of study drug and have at least one postbaseline assessment. Missing data were imputed with last observation carried forward.

Arm/Group Title	Placebo-controlled Placebo	Placebo-controlled Valbenazine
Arm/Group Description	Participants received placebo (matching valbenazine) once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks.	Participants received valbenazine 80 mg once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks.
Measure Participants	57	59
Mean (Standard Error) [Score on scale]	0.09 (0.03)	0.16 (0.03)

3. Secondary Outcome

Title	Change From Baseline in the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) at Week 16
Description	The EQ-5D-5L assesses general health-related quality of life. The second portion of the scale is a self-perceived health score assessed using a VAS that ranges from 0 ("the worst imaginable health") to 100 ("the best imaginable health").
Time Frame	Baseline, Week 16

Outcome Measure Data

Analysis Population Description

Includes all participants who received at least one dose of study drug and have at least one postbaseline assessment. Missing data were imputed with last observation carried forward.

Arm/Group Title	Placebo-controlled Placebo	Placebo-controlled Valbenazine
Arm/Group Description	Participants received placebo (matching valbenazine) once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks.	Participants received valbenazine 80 mg once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks.
Measure Participants	57	59
Mean (Standard Error) [Score on scale]	4.5 (2.5)	6.5 (2.8)

Adverse Events

Time Frame	Open-label valbenazine group: from baseline up to randomization (Week 8). Placebo-controlled placebo and valbenazine groups: from randomization (Week 8) up to Week 20
Arm/Group Title	Open-label Valbenazine		Placebo-controlled Placebo		Placebo-controlled Valbenazine
Arm/Group Description	Participants received valbenazine 40 mg once daily for 1 week, then 80 mg once daily for the remainder of the 8-week open label period.		Participants received placebo (matching valbenazine) once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks.		Participants received valbenazine 80 mg once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks.
All Cause Mortality
	Open-label Valbenazine		Placebo-controlled Placebo		Placebo-controlled Valbenazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/132 (0.8%)		0/59 (0%)		0/59 (0%)
Serious Adverse Events
	Open-label Valbenazine		Placebo-controlled Placebo		Placebo-controlled Valbenazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/132 (2.3%)		2/59 (3.4%)		1/59 (1.7%)
Infections and infestations
Cellulitis	0/132 (0%)		1/59 (1.7%)		0/59 (0%)
Sepsis	0/132 (0%)		1/59 (1.7%)		0/59 (0%)
Injury, poisoning and procedural complications
Accidental overdose	1/132 (0.8%)		0/59 (0%)		0/59 (0%)
Metabolism and nutrition disorders
Dehydration	1/132 (0.8%)		0/59 (0%)		0/59 (0%)
Nervous system disorders
Syncope	1/132 (0.8%)		0/59 (0%)		0/59 (0%)
Psychiatric disorders
Psychotic disorder	0/132 (0%)		1/59 (1.7%)		0/59 (0%)
Surgical and medical procedures
Knee arthroplasty	0/132 (0%)		0/59 (0%)		1/59 (1.7%)
Other (Not Including Serious) Adverse Events
	Open-label Valbenazine		Placebo-controlled Placebo		Placebo-controlled Valbenazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/132 (12.9%)		11/59 (18.6%)		7/59 (11.9%)
Blood and lymphatic system disorders
Anaemia	1/132 (0.8%)		2/59 (3.4%)		1/59 (1.7%)
Infections and infestations
Urinary tract infection	4/132 (3%)		6/59 (10.2%)		0/59 (0%)
Injury, poisoning and procedural complications
Fall	2/132 (1.5%)		2/59 (3.4%)		0/59 (0%)
Investigations
Blood creatine phosphokinase increased	1/132 (0.8%)		0/59 (0%)		2/59 (3.4%)
Blood glucose increased	0/132 (0%)		0/59 (0%)		2/59 (3.4%)
Weight increased	2/132 (1.5%)		0/59 (0%)		2/59 (3.4%)
Musculoskeletal and connective tissue disorders
Pain in extremity	5/132 (3.8%)		0/59 (0%)		0/59 (0%)
Nervous system disorders
Somnolence	4/132 (3%)		0/59 (0%)		0/59 (0%)
Psychiatric disorders
Suicidal ideation	1/132 (0.8%)		2/59 (3.4%)		1/59 (1.7%)

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.