Tardive Dyskinesia (TD)
Conditions
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.
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 85 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 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
Countries
Puerto Rico, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 58 |
| 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. | 59 |
| Total | 117 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Open-label Period | Adverse Event | 2 | 0 | 0 |
| Open-label Period | Death | 1 | 0 | 0 |
| Open-label Period | Lost to Follow-up | 2 | 0 | 0 |
| Open-label Period | Protocol Violation | 5 | 0 | 0 |
| Open-label Period | Withdrawal by Subject | 6 | 0 | 0 |
| Placebo-controlled Period and Follow-up | Adverse Event | 0 | 1 | 1 |
| Placebo-controlled Period and Follow-up | Lost to Follow-up | 0 | 2 | 0 |
| Placebo-controlled Period and Follow-up | Protocol Violation | 0 | 2 | 1 |
| Placebo-controlled Period and Follow-up | Withdrawal by Subject | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Placebo-controlled Valbenazine | Placebo-controlled Placebo |
|---|---|---|---|
| Abnormal Involuntary Movement Scale at Study Baseline | 10.7 Score on scale STANDARD_DEVIATION 3.9 | 11.0 Score on scale STANDARD_DEVIATION 4.1 | 10.3 Score on scale STANDARD_DEVIATION 3.7 |
| Age, Continuous | 58.6 Years STANDARD_DEVIATION 8.1 | 58.0 Years STANDARD_DEVIATION 8 | 59.2 Years STANDARD_DEVIATION 8.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 64 Participants | 32 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 53 Participants | 27 Participants | 26 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 37 Participants | 16 Participants | 21 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 79 Participants | 43 Participants | 36 Participants |
| Sex: Female, Male Female | 57 Participants | 30 Participants | 27 Participants |
| Sex: Female, Male Male | 60 Participants | 29 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 132 | 0 / 59 | 0 / 59 |
| other Total, other adverse events | 17 / 132 | 11 / 59 | 7 / 59 |
| serious Total, serious adverse events | 3 / 132 | 2 / 59 | 1 / 59 |
Outcome results
Primary
Change From Randomization (Week 8) in Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score at 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.
Time frame: Week 8, Week 16
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo-controlled Placebo | Change From Randomization (Week 8) in Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score at Week 16 | 0.6 Score on scale |
| Placebo-controlled Valbenazine | Change From Randomization (Week 8) in Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score at Week 16 | -1.6 Score on scale |
Secondary
Change From Baseline in the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Health State Index Score at 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.
Time frame: Baseline, Week 16
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo-controlled Placebo | Change From Baseline in the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Health State Index Score at Week 16 | 0.09 Score on scale | Standard Error 0.03 |
| Placebo-controlled Valbenazine | Change From Baseline in the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Health State Index Score at Week 16 | 0.16 Score on scale | Standard Error 0.03 |
Secondary
Change From Baseline in the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) at 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).
Time frame: Baseline, Week 16
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo-controlled Placebo | Change From Baseline in the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) at Week 16 | 4.5 Score on scale | Standard Error 2.5 |
| Placebo-controlled Valbenazine | Change From Baseline in the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) at Week 16 | 6.5 Score on scale | Standard Error 2.8 |