The Potential for Clinical Dependence and Withdrawal Symptoms Associated With Valbenazine

• Sponsor: Neurocrine Biosciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03698331
• Collaborator: (none)
• Enrollment: 89
• Locations: 17
• Arms: 2
• Actual Duration (Months): 6.6
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This is a Phase 4, randomized, double-blind, placebo-controlled study to evaluate the potential for clinical dependence and withdrawal symptoms associated with valbenazine.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 89 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 4, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Potential for Clinical Dependence and Withdrawal Symptoms Associated With Valbenazine
• Actual Study Start Date: Sep 14, 2018
• Actual Primary Completion Date: Apr 3, 2019
• Actual Study Completion Date: Apr 3, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Valbenazine Valbenazine or placebo oral capsules administered once daily for 7 weeks.	Drug: Valbenazine; vesicular monoamine transporter 2 (VMAT2) inhibitor; Other Names: Ingrezza, NBI-98854 ; Drug: Placebo oral capsule; non-active dosage form
Placebo Comparator: Placebo Placebo oral capsules administered once daily for 7 weeks.	Drug: Placebo oral capsule; non-active dosage form

Outcome Measures

Primary Outcome Measures

1. Participants With Withdrawal-Emergent Adverse Events [3 weeks]

   A withdrawal-emergent adverse event is an adverse event that begins during the Withdrawal Period.

Secondary Outcome Measures

1. Participants Who Experience Worsening of Symptoms as Measured by the Physician Withdrawal Checklist-20 (PWC-20) [3 weeks]

   The PWC-20 is a validated 20-item physician-rated survey that assesses the severity of potential symptoms of withdrawal. Items are rated on a scale from 0 to 3, with total scores ranging from 0 to 60. Worsening of symptoms is defined by 5 new symptoms of moderate or severe degree or a worsening of symptoms by 2 points on the PWC-20 scale during Weeks 5 to 7 compared with Week 4. Note: a 2-point worsening from 0 (none) at Week 4 to 2 (moderate) post-Week 4 is counted as a worsening of symptoms.

2. Absolute Worst Total Score as Measured by the Physician Withdrawal Checklist-20 (PWC-20) [3 weeks]

   The PWC-20 is a validated 20-item physician-rated survey that assesses the severity of potential symptoms of withdrawal. Items are rated on a scale from 0 to 3, with total scores ranging from 0 to 60. Larger values indicate more severe symptoms. Rickels et al (J Clin Psychopharmacol 2008) cites PWC-20 mean scores associated with withdrawal in the range of 15 to 24.

3. Severity of Withdrawal Symptoms as Measured by the Change From Withdrawal Baseline (Week 4) to Week 7 in the Modified Cocaine Selective Severity Assessment (mCSSA) [7 weeks]

   The mCSSA is an 18-item survey based on symptoms commonly associated with early cocaine abstinence, including depression, fatigue, anhedonia, anxiety, irritability, sleep disturbance, and inability to concentrate. Items are rated on scales of 0 to 7 or 0 to 8, with separate scale descriptions for each item. Larger values indicate more severe symptoms. The scale has been modified to be specific to study drug (valbenazine or placebo) instead of cocaine.

4. Overall Improvement From Baseline of TD Symptoms as Measured by the Clinical Global Impression-Tardive Dyskinesia-Improvement (CGI-TD-I) Score [Baseline, Week 4, Week 7]

   The CGI-TD-I scale is a 7-point scale (range; 1=very much improved to 7=very much worse) used to assess overall improvement in TD symptoms since the initiation of study drug dosing.

5. Change in Severity of TD Symptoms as Measured by Change From Baseline in the Clinical Global Impression-Tardive Dyskinesia-Severity (CGI-TD-S) Scale [Baseline, Week 4, Week 7]

   The CGI-TD-S scale is a 7-point scale (range; 1=normal, not at all ill to 7=among the most extremely ill patient) used to assess the overall global severity of TD.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 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 a known history of neuroleptic malignant syndrome.

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

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

7. Have ever taken valbenazine (INGREZZA or NBI-98854) or participated in a valbenazine clinical study.

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

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

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

11. Are currently pregnant or breastfeeding.

12. Have HIV or hepatitis B.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Neurocrine Clinical Site	Anaheim	California	United States	92804
2	Neurocrine Clinical Site	Glendale	California	United States	91206
3	Neurocrine Clinical Site	Norwalk	California	United States	90650
4	Neurocrine Clinical Site	Oceanside	California	United States	92054
5	Neurocrine Clinical Site	San Bernardino	California	United States	92108
6	Neurocrine Clinical Site	Hialeah	Florida	United States	33012
7	Neurocrine Clinical Site	Hialeah	Florida	United States	33013
8	Neurocrine Clinical Site	Hialeah	Florida	United States	33018
9	Neurocrine Clinical Site	Honolulu	Hawaii	United States	96817
10	Neurocrine Clinical Site	Fort Wayne	Indiana	United States	46804
11	Neurocrine Clinical Site	Ann Arbor	Michigan	United States	48105
12	Neurocrine Clinical Site	Beechwood	Ohio	United States	44122
13	Neurocrine Clinical Site	Oklahoma City	Oklahoma	United States	73112
14	Neurocrine Clinical Site	Scranton	Pennsylvania	United States	18503
15	Neurocrine Clinical Site	DeSoto	Texas	United States	75115
16	Neurocrine Clinical Site	Irving	Texas	United States	75062
17	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)

• Statistical Analysis Plan - Oct 9, 2019
• Study Protocol - Apr 16, 2019

More Information

Publications

None provided.

• Responsible Party: Neurocrine Biosciences
• ClinicalTrials.gov Identifier: NCT03698331
• Other Study ID Numbers: NBI-98854-TD4001
• First Posted: Oct 9, 2018
• Last Update Posted: Jun 4, 2020
• Last Verified: May 1, 2020

• 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
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Dyskinesias; Tardive Dyskinesia; Substance Withdrawal Syndrome

Study Results

Participant Flow

Arm/Group Title	Valbenazine/Placebo	Placebo/Placebo
Arm/Group Description	Valbenazine administered once daily for 4 weeks, followed by placebo administered once daily for 3 weeks.	Placebo administered once daily for 7 weeks.
Period Title: Overall Study
STARTED	44	45
Entered Withdrawal Period	42	39
COMPLETED	40	39
NOT COMPLETED	4	6

Baseline Characteristics

Arm/Group Title	Valbenazine/Placebo	Placebo/Placebo	Total
Arm/Group Description	Valbenazine administered once daily for 4 weeks, followed by placebo administered once daily for 3 weeks.	Placebo administered once daily for 7 weeks.	Total of all reporting groups
Overall Participants	44	45	89
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.7 (7.5)	53.6 (9.5)	54.1 (8.5)
Sex: Female, Male (Count of Participants)
Female	19 43.2%	18 40%	37 41.6%
Male	25 56.8%	27 60%	52 58.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	19 43.2%	17 37.8%	36 40.4%
Not Hispanic or Latino	25 56.8%	28 62.2%	53 59.6%
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%	1 2.2%	1 1.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	13 29.5%	19 42.2%	32 36%
White	30 68.2%	25 55.6%	55 61.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 2.3%	0 0%	1 1.1%

Outcome Measures

1. Primary Outcome

Title	Participants With Withdrawal-Emergent Adverse Events
Description	A withdrawal-emergent adverse event is an adverse event that begins during the Withdrawal Period.
Time Frame	3 weeks

Outcome Measure Data

Analysis Population Description

Dependence and Withdrawal Analysis Set, which includes all participants who were randomized, took at least one dose of study drug, and entered the Withdrawal Period.

Arm/Group Title	Valbenazine/Placebo	Placebo/Placebo
Arm/Group Description	Valbenazine administered once daily for 4 weeks, followed by placebo administered once daily for 3 weeks.	Placebo administered once daily for 7 weeks.
Measure Participants	42	39
Count of Participants [Participants]	9 20.5%	13 28.9%

2. Secondary Outcome

Title	Participants Who Experience Worsening of Symptoms as Measured by the Physician Withdrawal Checklist-20 (PWC-20)
Description	The PWC-20 is a validated 20-item physician-rated survey that assesses the severity of potential symptoms of withdrawal. Items are rated on a scale from 0 to 3, with total scores ranging from 0 to 60. Worsening of symptoms is defined by 5 new symptoms of moderate or severe degree or a worsening of symptoms by 2 points on the PWC-20 scale during Weeks 5 to 7 compared with Week 4. Note: a 2-point worsening from 0 (none) at Week 4 to 2 (moderate) post-Week 4 is counted as a worsening of symptoms.
Time Frame	3 weeks

Outcome Measure Data

Analysis Population Description

Dependence and Withdrawal Analysis Set, which includes all participants who were randomized, took at least one dose of study drug, and entered the Withdrawal Period.

Arm/Group Title	Valbenazine/Placebo	Placebo/Placebo
Arm/Group Description	Valbenazine administered once daily for 4 weeks, followed by placebo administered once daily for 3 weeks.	Placebo administered once daily for 7 weeks.
Measure Participants	42	39
Count of Participants [Participants]	9 20.5%	3 6.7%

3. Secondary Outcome

Title	Absolute Worst Total Score as Measured by the Physician Withdrawal Checklist-20 (PWC-20)
Description	The PWC-20 is a validated 20-item physician-rated survey that assesses the severity of potential symptoms of withdrawal. Items are rated on a scale from 0 to 3, with total scores ranging from 0 to 60. Larger values indicate more severe symptoms. Rickels et al (J Clin Psychopharmacol 2008) cites PWC-20 mean scores associated with withdrawal in the range of 15 to 24.
Time Frame	3 weeks

Outcome Measure Data

Analysis Population Description

Dependence and Withdrawal Analysis Set, which includes all participants who were randomized, took at least one dose of study drug, and entered the Withdrawal Period.

Arm/Group Title	Valbenazine/Placebo	Placebo/Placebo
Arm/Group Description	Valbenazine administered once daily for 4 weeks, followed by placebo administered once daily for 3 weeks.	Placebo administered once daily for 7 weeks.
Measure Participants	42	39
Mean absolute score at baseline	4.6 (5.0)	3.9 (4.5)
Mean absolute score at withdrawal baseline	3.8 (3.7)	3.1 (3.8)
Mean absolute worst total score	5.6 (5.3)	3.3 (2.6)

4. Secondary Outcome

Title	Severity of Withdrawal Symptoms as Measured by the Change From Withdrawal Baseline (Week 4) to Week 7 in the Modified Cocaine Selective Severity Assessment (mCSSA)
Description	The mCSSA is an 18-item survey based on symptoms commonly associated with early cocaine abstinence, including depression, fatigue, anhedonia, anxiety, irritability, sleep disturbance, and inability to concentrate. Items are rated on scales of 0 to 7 or 0 to 8, with separate scale descriptions for each item. Larger values indicate more severe symptoms. The scale has been modified to be specific to study drug (valbenazine or placebo) instead of cocaine.
Time Frame	7 weeks

Outcome Measure Data

Analysis Population Description

Dependence and Withdrawal Analysis Set, which includes all participants who were randomized, took at least one dose of study drug, and entered the Withdrawal Period.

Arm/Group Title	Valbenazine/Placebo	Placebo/Placebo
Arm/Group Description	Valbenazine administered once daily for 4 weeks, followed by placebo administered once daily for 3 weeks.	Placebo administered once daily for 7 weeks.
Measure Participants	42	39
Mean (Standard Deviation) [score on a scale]	1.9 (4.1)	0.5 (3.2)

5. Secondary Outcome

Title	Overall Improvement From Baseline of TD Symptoms as Measured by the Clinical Global Impression-Tardive Dyskinesia-Improvement (CGI-TD-I) Score
Description	The CGI-TD-I scale is a 7-point scale (range; 1=very much improved to 7=very much worse) used to assess overall improvement in TD symptoms since the initiation of study drug dosing.
Time Frame	Baseline, Week 4, Week 7

Outcome Measure Data

Analysis Population Description

Efficacy analysis set was defined as all participants who were randomized to a treatment group, took at least one dose of study drug, and had a CGI-TD-I assessment at Week 4.

Arm/Group Title	Valbenazine/Placebo	Placebo/Placebo
Arm/Group Description	Valbenazine administered once daily for 4 weeks, followed by placebo administered once daily for 3 weeks.	Placebo administered once daily for 7 weeks.
Measure Participants	41	40
End of Week 4	3.2 (0.8)	3.4 (0.7)
End of Week 7	3.0 (0.7)	3.0 (0.8)

6. Secondary Outcome

Title	Change in Severity of TD Symptoms as Measured by Change From Baseline in the Clinical Global Impression-Tardive Dyskinesia-Severity (CGI-TD-S) Scale
Description	The CGI-TD-S scale is a 7-point scale (range; 1=normal, not at all ill to 7=among the most extremely ill patient) used to assess the overall global severity of TD.
Time Frame	Baseline, Week 4, Week 7

Outcome Measure Data

Analysis Population Description

Efficacy analysis set was defined as all participants who were randomized to a treatment group, took at least one dose of study drug, and had a CGI-TD-S assessment at Week 4.

Arm/Group Title	Valbenazine/Placebo	Placebo/Placebo
Arm/Group Description	Valbenazine administered once daily for 4 weeks, followed by placebo administered once daily for 3 weeks.	Placebo administered once daily for 7 weeks.
Measure Participants	41	40
End of Week 4	-0.3 (0.7)	-0.2 (0.6)
End of Week 5	-0.3 (0.6)	-0.3 (0.6)
End of Week 6	-0.4 (0.5)	-0.5 (0.6)
End of Week 7	-0.4 (0.5)	-0.5 (0.6)

Adverse Events

Time Frame	Up to 7 weeks
Arm/Group Title	Valbenazine/Placebo		Placebo/Placebo
Arm/Group Description	Valbenazine administered once daily for 4 weeks, followed by placebo administered once daily for 3 weeks.		Placebo administered once daily for 7 weeks.
All Cause Mortality
	Valbenazine/Placebo		Placebo/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/45 (0%)
Serious Adverse Events
	Valbenazine/Placebo		Placebo/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/44 (2.3%)		1/45 (2.2%)
Psychiatric disorders
Schizoaffective disorder	1/44 (2.3%)		0/45 (0%)
Psychotic disorder	0/44 (0%)		1/45 (2.2%)
Other (Not Including Serious) Adverse Events
	Valbenazine/Placebo		Placebo/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/44 (27.3%)		19/45 (42.2%)
Eye disorders
Dry eye	2/44 (4.5%)		1/45 (2.2%)
Gastrointestinal disorders
Diarrhoea	5/44 (11.4%)		2/45 (4.4%)
Salivary hypersecretion	2/44 (4.5%)		0/45 (0%)
Vomiting	2/44 (4.5%)		2/45 (4.4%)
Nausea	1/44 (2.3%)		4/45 (8.9%)
Dry mouth	0/44 (0%)		2/45 (4.4%)
General disorders
Fatigue	2/44 (4.5%)		0/45 (0%)
Infections and infestations
Nasopharyngitis	1/44 (2.3%)		2/45 (4.4%)
Upper respiratory tract infection	1/44 (2.3%)		4/45 (8.9%)
Nervous system disorders
Dizziness	2/44 (4.5%)		1/45 (2.2%)
Headache	2/44 (4.5%)		5/45 (11.1%)
Somnolence	2/44 (4.5%)		1/45 (2.2%)
Psychiatric disorders
Anxiety	1/44 (2.3%)		2/45 (4.4%)
Vascular disorders
Hypertension	0/44 (0%)		2/45 (4.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.