The Potential for Clinical Dependence and Withdrawal Symptoms Associated With Valbenazine

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

Official Title
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A Phase 4, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Potential for Clinical Dependence and Withdrawal Symptoms Associated With Valbenazine

Conditions
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Tardive Dyskinesia (TD)

Intervention / Treatment
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* Drug: Valbenazine
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Have one of the following clinical diagnoses for at least 3 months before screening: Schizophrenia, Schizoaffective Disorder, or Mood Disorder Have a clinical diagnosis of neuroleptic-induced TD for at least 3 months before screening. 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. Be in general good health. Have adequate hearing, vision, and language skills to perform the procedures specified in the protocol. Exclusion Criteria: Have an active, clinically significant unstable medical condition within 1 month before screening. Have a known history of substance (drug) dependence, or substance or alcohol abuse. Have a significant risk of suicidal or violent behavior. Have a known history of neuroleptic malignant syndrome. Have a known history of long QT syndrome or cardiac arrhythmia. Have a cancer diagnosis within 3 years prior to screening (some exceptions allowed). Have ever taken valbenazine (INGREZZA or NBI-98854) or participated in a valbenazine clinical study. Have received an investigational drug within 30 days before screening or plan to use an investigational drug (other than NBI-98854) during the study. Have a blood loss ≥550 mL or donated blood within 30 days prior to Baseline. Have an allergy, hypersensitivity, or intolerance to VMAT2 inhibitors (eg, tetrabenazine, deutetrabenazine). Are currently pregnant or breastfeeding. Have HIV or hepatitis B.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants Who Experience Worsening of Symptoms as Measured by the Physician Withdrawal Checklist-20 (PWC-20) | 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. | 3 weeks | 
| Absolute Worst Total Score as Measured by the Physician Withdrawal Checklist-20 (PWC-20) | 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 weeks | 
| 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) | 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. | 7 weeks | 
| Overall Improvement From Baseline of TD Symptoms as Measured by the Clinical Global Impression-Tardive Dyskinesia-Improvement (CGI-TD-I) Score | 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. | Baseline, Week 4, Week 7 | 
| Change in Severity of TD Symptoms as Measured by Change From Baseline in the Clinical Global Impression-Tardive Dyskinesia-Severity (CGI-TD-S) Scale | 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. | Baseline, Week 4, Week 7 |