Tardive Dyskinesia (TD)
Conditions
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.
Interventions
DRUGValbenazine
vesicular monoamine transporter 2 (VMAT2) inhibitor
DRUGPlacebo oral capsule
non-active dosage form
Sponsors
Neurocrine Biosciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Withdrawal-Emergent Adverse Events | 3 weeks | A withdrawal-emergent adverse event is an adverse event that begins during the Withdrawal Period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Valbenazine/Placebo Valbenazine administered once daily for 4 weeks, followed by placebo administered once daily for 3 weeks. | 44 |
| Placebo/Placebo Placebo administered once daily for 7 weeks. | 45 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Non-compliance with study drug | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo/Placebo | Total | Valbenazine/Placebo |
|---|---|---|---|
| Age, Continuous | 53.6 years STANDARD_DEVIATION 9.5 | 54.1 years STANDARD_DEVIATION 8.5 | 54.7 years STANDARD_DEVIATION 7.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 36 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 53 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 32 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 25 Participants | 55 Participants | 30 Participants |
| Sex: Female, Male Female | 18 Participants | 37 Participants | 19 Participants |
| Sex: Female, Male Male | 27 Participants | 52 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 45 |
| other Total, other adverse events | 12 / 44 | 19 / 45 |
| serious Total, serious adverse events | 1 / 44 | 1 / 45 |
Outcome results
Primary
Participants With Withdrawal-Emergent Adverse Events
A withdrawal-emergent adverse event is an adverse event that begins during the Withdrawal Period.
Time frame: 3 weeks
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Valbenazine/Placebo | Participants With Withdrawal-Emergent Adverse Events | 9 Participants |
| Placebo/Placebo | Participants With Withdrawal-Emergent Adverse Events | 13 Participants |
Secondary
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.
Time frame: 3 weeks
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Valbenazine/Placebo | Absolute Worst Total Score as Measured by the Physician Withdrawal Checklist-20 (PWC-20) | Mean absolute score at baseline | 4.6 score on a scale | Standard Deviation 5 |
| Valbenazine/Placebo | Absolute Worst Total Score as Measured by the Physician Withdrawal Checklist-20 (PWC-20) | Mean absolute score at withdrawal baseline | 3.8 score on a scale | Standard Deviation 3.7 |
| Valbenazine/Placebo | Absolute Worst Total Score as Measured by the Physician Withdrawal Checklist-20 (PWC-20) | Mean absolute worst total score | 5.6 score on a scale | Standard Deviation 5.3 |
| Placebo/Placebo | Absolute Worst Total Score as Measured by the Physician Withdrawal Checklist-20 (PWC-20) | Mean absolute worst total score | 3.3 score on a scale | Standard Deviation 2.6 |
| Placebo/Placebo | Absolute Worst Total Score as Measured by the Physician Withdrawal Checklist-20 (PWC-20) | Mean absolute score at baseline | 3.9 score on a scale | Standard Deviation 4.5 |
| Placebo/Placebo | Absolute Worst Total Score as Measured by the Physician Withdrawal Checklist-20 (PWC-20) | Mean absolute score at withdrawal baseline | 3.1 score on a scale | Standard Deviation 3.8 |
Secondary
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.
Time frame: Baseline, Week 4, Week 7
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Valbenazine/Placebo | Change in Severity of TD Symptoms as Measured by Change From Baseline in the Clinical Global Impression-Tardive Dyskinesia-Severity (CGI-TD-S) Scale | End of Week 4 | -0.3 score on a scale | Standard Deviation 0.7 |
| Valbenazine/Placebo | Change in Severity of TD Symptoms as Measured by Change From Baseline in the Clinical Global Impression-Tardive Dyskinesia-Severity (CGI-TD-S) Scale | End of Week 5 | -0.3 score on a scale | Standard Deviation 0.6 |
| Valbenazine/Placebo | Change in Severity of TD Symptoms as Measured by Change From Baseline in the Clinical Global Impression-Tardive Dyskinesia-Severity (CGI-TD-S) Scale | End of Week 6 | -0.4 score on a scale | Standard Deviation 0.5 |
| Valbenazine/Placebo | Change in Severity of TD Symptoms as Measured by Change From Baseline in the Clinical Global Impression-Tardive Dyskinesia-Severity (CGI-TD-S) Scale | End of Week 7 | -0.4 score on a scale | Standard Deviation 0.5 |
| Placebo/Placebo | Change in Severity of TD Symptoms as Measured by Change From Baseline in the Clinical Global Impression-Tardive Dyskinesia-Severity (CGI-TD-S) Scale | End of Week 7 | -0.5 score on a scale | Standard Deviation 0.6 |
| Placebo/Placebo | Change in Severity of TD Symptoms as Measured by Change From Baseline in the Clinical Global Impression-Tardive Dyskinesia-Severity (CGI-TD-S) Scale | End of Week 4 | -0.2 score on a scale | Standard Deviation 0.6 |
| Placebo/Placebo | Change in Severity of TD Symptoms as Measured by Change From Baseline in the Clinical Global Impression-Tardive Dyskinesia-Severity (CGI-TD-S) Scale | End of Week 6 | -0.5 score on a scale | Standard Deviation 0.6 |
| Placebo/Placebo | Change in Severity of TD Symptoms as Measured by Change From Baseline in the Clinical Global Impression-Tardive Dyskinesia-Severity (CGI-TD-S) Scale | End of Week 5 | -0.3 score on a scale | Standard Deviation 0.6 |
Secondary
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.
Time frame: Baseline, Week 4, Week 7
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Valbenazine/Placebo | Overall Improvement From Baseline of TD Symptoms as Measured by the Clinical Global Impression-Tardive Dyskinesia-Improvement (CGI-TD-I) Score | End of Week 4 | 3.2 score on a scale | Standard Deviation 0.8 |
| Valbenazine/Placebo | Overall Improvement From Baseline of TD Symptoms as Measured by the Clinical Global Impression-Tardive Dyskinesia-Improvement (CGI-TD-I) Score | End of Week 7 | 3.0 score on a scale | Standard Deviation 0.7 |
| Placebo/Placebo | Overall Improvement From Baseline of TD Symptoms as Measured by the Clinical Global Impression-Tardive Dyskinesia-Improvement (CGI-TD-I) Score | End of Week 4 | 3.4 score on a scale | Standard Deviation 0.7 |
| Placebo/Placebo | Overall Improvement From Baseline of TD Symptoms as Measured by the Clinical Global Impression-Tardive Dyskinesia-Improvement (CGI-TD-I) Score | End of Week 7 | 3.0 score on a scale | Standard Deviation 0.8 |
Secondary
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.
Time frame: 3 weeks
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Valbenazine/Placebo | Participants Who Experience Worsening of Symptoms as Measured by the Physician Withdrawal Checklist-20 (PWC-20) | 9 Participants |
| Placebo/Placebo | Participants Who Experience Worsening of Symptoms as Measured by the Physician Withdrawal Checklist-20 (PWC-20) | 3 Participants |
Secondary
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.
Time frame: 7 weeks
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Valbenazine/Placebo | 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) | 1.9 score on a scale | Standard Deviation 4.1 |
| Placebo/Placebo | 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) | 0.5 score on a scale | Standard Deviation 3.2 |