Tardive Dyskinesia
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy, safety, and tolerability of NBI-98854 (titrated to a subject's optimal dose in the range of 25 to 75 mg) administered once daily for the treatment of Tardive Dyskinesia (TD) symptoms.
Detailed description
This is a Phase 2, randomized, double-blind, placebo-controlled, dose-titration study to evaluate the efficacy, safety, and tolerability of NBI-98854 (titrated to subject's optimal dose in the range of 25 to 75 mg) compared to placebo, administered once daily (q.d.) for a total of 6 weeks of treatment. Approximately 90 medically stable male and female subjects with one of the following clinical diagnoses will be enrolled: schizophrenia or schizoaffective disorder with neuroleptic-induced TD; mood disorder with neuroleptic-induced TD; or gastrointestinal disorder with metoclopramide-induced TD. For subjects randomized to active treatment, the starting dose will be 25 mg NBI 98854, which may be escalated in increments of 25 mg every 2 weeks to a maximum of 75 mg to achieve an optimal dose of NBI-98854 for each subject
Interventions
DRUGNBI-98854
25 mg capsule
DRUGPlacebo
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
* Have one of the following clinical diagnoses for at least 3 months prior to screening a) schizophrenia or schizoaffective disorder; b) mood disorder; or c) gastrointestinal disorder (e.g., gastroparesis, gastroesophageal reflux disease) * Have a clinical diagnosis of neuroleptic-induced tardive dyskinesia for at least 3 months prior to screening. * Be receiving a stable dose of antipsychotic medication for a minimum of 30 days before study start. Subjects who are not using antipsychotic medication must have stable psychiatric status. * Have the doses of concurrent medications and the conditions being treated be stable for a minimum of 30 days before study start and be expected to remain stable during the study. * Subjects of childbearing potential must agree to use hormonal or two forms of nonhormonal birth control during the study. * Female subjects must not be pregnant. * Be in good general health and expected to complete the clinical study as designed. * Have a body mass index (BMI) of 18 to 38 kg/m2 (both inclusive). * Have a negative urine drug screen (negative for amphetamines, barbiturates, benzodiazepine, phencyclidine, cocaine, opiates, or cannabinoids) at screening and study start, except for any subject receiving a stable dose of benzodiazepine. * Have a negative alcohol breath test at screening and study start.
Exclusion criteria
* Have an active clinically significant unstable medical condition within 1 month (30 days) prior to screening. * Have a history of substance dependence or substance (drug) or alcohol abuse within the 3 months before study start(nicotine and caffeine dependence are not exclusionary). * Have a known history of neuroleptic malignant syndrome. * Have a significant risk of suicidal or violent behavior. * Receiving any excluded concomitant medication such as reserpine, metoclopramide, stimulants, or tetrabenazine. * Receiving medication for the treatment of tardive dyskinesia. * Have a positive human immunodeficiency virus antibody, (HIV-Ab), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody result at screening or have a history of positive result. * 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 an allergy, hypersensitivity, or intolerance to tetrabenazine. * Have had previous exposure with NBI-98854.
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 | 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 - Global Improvement of 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). |
| AIMS Dyskinesia Total Score Change From Baseline at Week 6 | Week 6 | 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. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
This study enrolled patients with schizophrenia or schizoaffective disorder with tardive dyskinesia (TD), a mood disorder with TD, or a GI disorder with TD from 29 centers in the United States and Puerto Rico. The last patient completed in December 2013.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received Placebo capsule (matching valbenazine capsules) daily for 6 weeks. | 49 |
| Valbenazine Participants received valbenazine 25mg once daily for 2 weeks, then 50mg once daily for 2 weeks, then 75mg once daily for 2 weeks (a total of 6 weeks). | 51 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-Blind Period (Week 0 to 6) | Adverse Event | 2 | 0 |
| Double-Blind Period (Week 0 to 6) | Lost to Follow-up | 1 | 0 |
| Double-Blind Period (Week 0 to 6) | Non-compliance | 3 | 2 |
| Double-Blind Period (Week 0 to 6) | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Total | Valbenazine | Placebo |
|---|---|---|---|
| Age at TD Diagnosis | 49.2 years | 48.9 years | 49.5 years |
| Age, Continuous | 56.2 years | 56.7 years | 55.6 years |
| Baseline AIMS Total Dyskinesia Score | 8.0 units on a scale STANDARD_DEVIATION 4 | 8.0 units on a scale STANDARD_DEVIATION 3.5 | 7.9 units on a scale STANDARD_DEVIATION 4.5 |
| Body Mass Index | 28.62 kg/m^2 | 29.02 kg/m^2 | 28.19 kg/m^2 |
| BPRS Total Score | 30.1 units on a scale | 30.1 units on a scale | 30.1 units on a scale |
| Disease Category Gastrointestinal disorder | 4 Participants | 3 Participants | 1 Participants |
| Disease Category Mood disorder | 38 Participants | 20 Participants | 18 Participants |
| Disease Category Schizophrenia or schizoaffective disorder | 58 Participants | 28 Participants | 30 Participants |
| Race/Ethnicity, Customized American Indian/Alaska native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian/Alaska native, Caucasian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black/African American | 34 Participants | 18 Participants | 16 Participants |
| Race/Ethnicity, Customized Caucasian | 63 Participants | 33 Participants | 30 Participants |
| Race/Ethnicity, Customized Other/mixed | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 43 Participants | 21 Participants | 22 Participants |
| Sex: Female, Male Male | 57 Participants | 30 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 49 | 0 / 51 |
| other Total, other adverse events | 11 / 49 | 16 / 51 |
| serious Total, serious adverse events | 2 / 49 | 0 / 51 |
Outcome results
Primary
Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Change From Baseline at Week 6
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: Per protocol analysis set (subjects in the ITT analysis set that had an evaluable, blinded, central video raters' AIMS dyskinesia total score change from baseline value at Week 6, had a quantifiable NBI-98782 plasma concentration at Week 6 \[for subjects in the NBI-98854 group\], and had no efficacy-related important protocol deviations)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Change From Baseline at Week 6 | -0.3 units on a scale | Standard Error 1.1 |
| Valbenazine | Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Change From Baseline at Week 6 | -3.4 units on a scale | Standard Error 1.2 |
p-value: <0.000195% CI: [-4.5, -1.6]ANCOVA
Secondary
AIMS Dyskinesia Total Score Change From Baseline at Week 6
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: Week 6
Population: Intent to Treat (ITT) analysis set (all subjects in the safety analysis set with an evaluable, blinded, central video raters' AIMS dyskinesia total score change from baseline value at one or more scheduled assessment times during the double-blind treatment period)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | AIMS Dyskinesia Total Score Change From Baseline at Week 6 | -0.2 units on a scale |
| Valbenazine | AIMS Dyskinesia Total Score Change From Baseline at Week 6 | -2.6 units on a scale |
p-value: 0.000595% CI: [-3.7, -1.1]ANCOVA
Secondary
Clinical Global Impression - Global Improvement of 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: Per protocol analysis set (subjects in the ITT analysis set that had an evaluable, blinded, central video raters' AIMS dyskinesia total score change from baseline value at Week 6, had a quantifiable NBI-98782 plasma concentration at Week 6 \[for subjects in the NBI-98854 group\], and had no efficacy-related important protocol deviations)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Clinical Global Impression - Global Improvement of TD (CGI-TD) at Week 6 | 3.1 units on a scale |
| Valbenazine | Clinical Global Impression - Global Improvement of TD (CGI-TD) at Week 6 | 2.2 units on a scale |
p-value: <0.000195% CI: [-1.2, -0.4]ANOVA
Secondary
Clinical Global Impression - Global Improvement of 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 with an evaluable, blinded, central video raters' AIMS dyskinesia total score change from baseline value at one or more scheduled assessment times during the double-blind treatment period)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Clinical Global Impression - Global Improvement of TD (CGI-TD) at Week 6 | 3.1 units on a scale |
| Valbenazine | Clinical Global Impression - Global Improvement of TD (CGI-TD) at Week 6 | 2.2 units on a scale |
p-value: <0.000195% CI: [-1.2, -0.5]ANOVA