Tardive Dyskinesia
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy, safety, and tolerability of NBI-98854 administered once daily for the treatment of Tardive Dyskinesia (TD) symptoms.
Detailed description
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel, fixed-dose study to evaluate the efficacy, safety, and tolerability of two doses of NBI-98854 (40 mg and 80 mg) compared to placebo, administered once daily. The study design includes a double-blind, placebo-controlled treatment period for 6 weeks and a double-blind NBI-98854 treatment period for an additional 42 weeks, for a total of 48 weeks of treatment. Final follow-up assessments will be conducted 4 weeks after the last dose of the study drug.
Interventions
DRUGNBI-98854
NBI-98854 40 mg capsules
DRUGPlacebo
NBI-98854 placebo capsules
Sponsors
Neurocrine Biosciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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. Female subjects must not be pregnant. 3. Have one of the following clinical diagnoses for at least 3 months prior to screening: Schizophrenia or Schizoaffective Disorder, or Mood Disorder. 4. Have a clinical diagnosis of neuroleptic-induced TD for at least 3 months prior to screening. 5. Have moderate or severe TD. 6. If using maintenance medication(s) for schizophrenia or schizoaffective disorder, or mood disorder, be on stable doses. 7. Be in good general health. 8. Have adequate hearing, vision, and language skills to perform the procedures specified in the protocol. 9. Have a negative drug screen for amphetamines,barbiturates, benzodiazepines, phencyclidine, cocaine, opiates, or cannabinoids
Exclusion criteria
1. Have an active, clinically significant unstable medical condition within 1 month prior to screening. 2. Have a known history of substance dependence, or substance (drug) 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 tachy-arrhythmia. 6. Have a cancer diagnosis within 3 years of screening (some exceptions allowed) 7. Have received an investigational drug within 30 days prior to screening or plan to use an investigational drug (other than NBI-98854) during the study. 8. Have a blood loss ≥550 mL or donated blood within 30 days prior to Baseline. 9. Have an allergy, hypersensitivity, or intolerance to tetrabenazine. 10. Have had previous exposure with NBI-98854 or had previously participated in an NBI-98854 clinical study. 11. Are currently pregnant or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Change From Baseline at Week 6 | Baseline and Week 6 | Severity of TD symptoms assessed by AIMS dyskinesia total score (sum of items 1 through 7), as assessed by blinded central AIMS video raters. The AIMS Total Dyskinesia Score rates a total of 7 items, rating involuntary movement from 0 (no dyskinesia) to 4 (severe dyskinesia). Items 1 through 7 include facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). The AIMS dyskinesia total score for Items 1-7 ranges from 0 to 28; a higher score reflects increased severity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression of Change - TD (CGI-TD) at Week 6 | Week 6 | Clinician's perspective of the participant's overall improvement of TD symptoms over time. The CGI-TD is based on a 7-point scale (range: 1=very much improved to 7=very much worse). |
| Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Responder Analysis at Week 6 | Week 6 | Percentage of AIMS responders (subjects who had at least a 50 percent reduction in AIMS score from baseline) |
Countries
Canada, Puerto Rico, United States
Participant flow
Recruitment details
This study enrolled patients with schizophrenia or schizoaffective disorder with tardive dyskinesia (TD) or mood disorder with TD from 63 centers in North America and Puerto Rico. The last patient completed in August 2016.
Participants by arm
| Arm | Count |
|---|---|
| Placebo-Controlled Placebo Participants received Placebo capsule (matching valbenazine capsules) once daily for 6 weeks. | 76 |
| Placebo-Controlled Valbenazine 40mg Participants received valbenazine 40mg capsule once daily for 6 weeks. | 72 |
| Placebo-Controlled Valbenazine 80mg Participants received valbenazine 40mg capsule once daily for 1 week, then 80mg capsule once daily for 5 weeks. | 79 |
| Total | 227 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 | 2 |
| Overall Study | Death | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 1 | 1 |
| Overall Study | Non-compliance | 2 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 5 | 4 |
Baseline characteristics
| Characteristic | Total | Placebo-Controlled Valbenazine 80mg | Placebo-Controlled Valbenazine 40mg | Placebo-Controlled Placebo |
|---|---|---|---|---|
| Age at TD Diagnosis | 48.2 years | 47.6 years | 47.8 years | 49.4 years |
| Age, Continuous | 56.1 years | 56.0 years | 55.3 years | 57.0 years |
| Baseline AIMS Total Dyskinesia Score | 10.0 units on a scale STANDARD_DEVIATION 4 | 10.4 units on a scale STANDARD_DEVIATION 3.6 | 9.7 units on a scale STANDARD_DEVIATION 4.1 | 9.9 units on a scale STANDARD_DEVIATION 4.3 |
| Body Mass Index | 28.13 kg/m^2 | 27.78 kg/m^2 | 28.64 kg/m^2 | 28.03 kg/m^2 |
| BPRS Total Score | 29.7 units on a scale | 29.1 units on a scale | 30.6 units on a scale | 29.3 units on a scale |
| Psychiatric Diagnosis Category Mood disorder | 77 Participants | 27 Participants | 24 Participants | 26 Participants |
| Psychiatric Diagnosis Category Schizophrenia/Schizoaffective disorder | 150 Participants | 52 Participants | 48 Participants | 50 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native, Caucasian | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 87 Participants | 32 Participants | 26 Participants | 29 Participants |
| Race/Ethnicity, Customized Caucasian | 128 Participants | 44 Participants | 41 Participants | 43 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other: Arabic | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other: Hispanic | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other: Mexican | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other: Mixed | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 104 Participants | 40 Participants | 30 Participants | 34 Participants |
| Sex: Female, Male Male | 123 Participants | 39 Participants | 42 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 76 | 0 / 72 | 1 / 79 |
| other Total, other adverse events | 7 / 76 | 9 / 72 | 5 / 79 |
| serious Total, serious adverse events | 3 / 76 | 4 / 72 | 6 / 79 |
Outcome results
Primary
Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Change From Baseline at Week 6
Severity of TD symptoms assessed by AIMS dyskinesia total score (sum of items 1 through 7), as assessed by blinded central AIMS video raters. The AIMS Total Dyskinesia Score rates a total of 7 items, rating involuntary movement from 0 (no dyskinesia) to 4 (severe dyskinesia). Items 1 through 7 include facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). The AIMS dyskinesia total score for Items 1-7 ranges from 0 to 28; a higher score reflects increased severity.
Time frame: Baseline and Week 6
Population: Intent to treat (ITT) analysis set (all subjects in the safety analysis set who have a baseline (Day -1) AIMS dyskinesia total score value and at least one post-randomization AIMS dyskinesia total score value reported during the placebo-controlled treatment period).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Change From Baseline at Week 6 | -0.1 scores on a scale | Standard Error 0.4 |
| Valbenazine 80mg | Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Change From Baseline at Week 6 | -3.2 scores on a scale | Standard Error 0.4 |
| Valbenazine 40mg | Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Change From Baseline at Week 6 | -1.9 scores on a scale | Standard Error 0.4 |
Comparison: Control for multiplicity was accomplished through the a fixed-sequence testing procedure for Week 6 outcomes:~* AIMS dyskinesia total score mean change from baseline (CFB): valbenazine 80 mg vs. placebo.~* CGI-TD mean score: VBZ 80 mg vs. PBO.~* AIMS: VBZ 40 mg vs. PBO.~* CGI-TD: VBZ 40 mg vs. PBO.~For a test result in the above list to be considered statistically significant, all of the test results higher in the list must have been significant at the 0.05 level of significance.p-value: <0.000195% CI: [-4.2, -2]Mixed-effect Model Repeated Measures
p-value: 0.002195% CI: [-3, -0.7]Mixed-effect Model Repeated Measures
Secondary
Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Responder Analysis at Week 6
Percentage of AIMS responders (subjects who had at least a 50 percent reduction in AIMS score from baseline)
Time frame: Week 6
Population: Intent to treat (ITT) analysis set (all subjects in the safety analysis set who have a baseline (Day -1) AIMS dyskinesia total score value and at least one post-randomization AIMS dyskinesia total score value reported during the placebo-controlled treatment period).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Responder Analysis at Week 6 | 6 Participants |
| Valbenazine 80mg | Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Responder Analysis at Week 6 | 15 Participants |
| Valbenazine 40mg | Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Responder Analysis at Week 6 | 28 Participants |
p-value: 0.02Cochran-Mantel-Haenszel
p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
Clinical Global Impression of Change - TD (CGI-TD) at Week 6
Clinician's perspective of the participant's overall improvement of TD symptoms over time. The CGI-TD is based on a 7-point scale (range: 1=very much improved to 7=very much worse).
Time frame: Week 6
Population: Intent to treat (ITT) analysis set (all subjects in the safety analysis set who have a baseline (Day -1) AIMS dyskinesia total score value and at least one post-randomization AIMS dyskinesia total score value reported during the placebo-controlled treatment period).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Clinical Global Impression of Change - TD (CGI-TD) at Week 6 | 3.2 scores on a scale | Standard Error 0.1 |
| Valbenazine 80mg | Clinical Global Impression of Change - TD (CGI-TD) at Week 6 | 2.9 scores on a scale | Standard Error 0.1 |
| Valbenazine 40mg | Clinical Global Impression of Change - TD (CGI-TD) at Week 6 | 2.9 scores on a scale | Standard Error 0.1 |
p-value: 0.074295% CI: [-0.5, 0]Mixed-effect Model Repeated Measures
p-value: 0.05695% CI: [-0.5, 0]Mixed-effect Model Repeated Measures