Tardive Dyskinesia
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy, safety, and tolerability of two doses (50 and 100 mg) of NBI-98854 administered once daily for the treatment of Tardive Dyskinesia (TD) symptoms.
Detailed description
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy, safety, and tolerability of two doses (50 and 100 mg) of NBI-98854 administered once daily for up to 2 weeks. The study will also allow for an evaluation of the efficacy of NBI-98854 50 mg once daily for up to 6 weeks and the safety and tolerability of NBI 98854 50 mg once daily for up to 12 weeks. The double-blind placebo-controlled treatment period the study has three arms: * NBI-98854 50 mg once daily for 6 weeks * NBI-98854 100 mg once daily for 2 weeks followed by 50 mg once daily for the remaining 4 weeks * placebo At the end of the 6-week placebo-controlled double-blind treatment period, subjects will continue in the study for an additional 6-week open-label period where all subjects who have completed the double-blind treatment period will receive NBI-98854 50 mg once daily. Two and four weeks after the last dose of study drug, follow-up assessments will be performed.
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 a clinical diagnosis of schizophrenia or schizoaffective disorder and 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. The primary efficacy endpoint was the change from baseline in the AIMS dyskinesia total score at Week 6 between the pooled NBI-98854 50+100 mg group and placebo group analyzed using the ANCOVA model (LOCF, ITT analysis set). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression - Global Improvement of TD (CGI-TD) | 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). The ANOVA analysis of CGI-TD was conducted for the pooled NBI-98854 50+100 mg group and placebo group. |
| Clinical Global Impression - Global Improvement of TD (CGI-TD) at Week 2 | Week 2 | 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). |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
This study enrolled patients with a clinical diagnosis of schizophrenia or schizoaffective disorder with moderate or severe tardive dyskinesia (TD) from 35 centers in the United States and Puerto Rico. The last patient completed in October 2013.
Participants by arm
| Arm | Count |
|---|---|
| Double-Blind Placebo, Then Open-Label 50mg Double-Blind Period: Participants first received Placebo capsule (matching valbenazine capsule) once daily for 6 weeks.
Open-Label Period: Participants received valbenazine 50mg capsule once daily for 6 weeks. | 54 |
| Double-Blind 50mg, Then Open-Label 50mg Double-Blind Period: Participants first received valbenazine 50mg capsule once daily for 6 weeks.
Open-Label Period: Participants received valbenazine 50mg capsule once daily for 6 weeks. | 28 |
| Double-Blind 100mg/50mg, Then Open-Label 50mg Double-Blind Period: Participants first received valbenazine 100mg capsule once daily for 2 weeks, then they received valbenazine 50mg capsule once daily for 4 weeks.
Open-Label Period: Participants received valbenazine 50mg capsule once daily for 6 weeks. | 27 |
| Total | 109 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-Blind Period (Week 0 to 6) | Adverse Event | 1 | 0 | 1 |
| Double-Blind Period (Week 0 to 6) | Lost to Follow-up | 1 | 0 | 1 |
| Double-Blind Period (Week 0 to 6) | Non-compliance | 1 | 2 | 3 |
| Double-Blind Period (Week 0 to 6) | Physician Decision | 0 | 1 | 0 |
| Double-Blind Period (Week 0 to 6) | Withdrawal by Subject | 4 | 0 | 1 |
| Follow-up Period (Week 12 to 16) | Withdrawal by Subject | 0 | 1 | 0 |
| Open-Label Period (Week 6 to 12) | Adverse Event | 4 | 1 | 1 |
| Open-Label Period (Week 6 to 12) | Lost to Follow-up | 0 | 0 | 1 |
| Open-Label Period (Week 6 to 12) | Non-compliance | 0 | 0 | 2 |
| Open-Label Period (Week 6 to 12) | Withdrawal by Subject | 1 | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Double-Blind Placebo, Then Open-Label 50mg | Double-Blind 50mg, Then Open-Label 50mg | Double-Blind 100mg/50mg, Then Open-Label 50mg |
|---|---|---|---|---|
| Age at Schizophrenia/Schizoaffective Disorder Diagnosis | 29.7 years | 29.4 years | 29.7 years | 30.4 years |
| Age at TD Diagnosis | 47.5 years | 46.9 years | 48.5 years | 47.5 years |
| Age, Continuous | 55.0 years | 54.5 years | 55.5 years | 55.6 years |
| Baseline AIMS Total Dyskinesia Score | 15.0 units on a scale STANDARD_DEVIATION 4.8 | 15.3 units on a scale STANDARD_DEVIATION 4.4 | 14.6 units on a scale STANDARD_DEVIATION 5.9 | 14.6 units on a scale STANDARD_DEVIATION 4.7 |
| Body Mass Index | 28.17 kg/m^2 | 28.71 kg/m^2 | 28.85 kg/m^2 | 26.39 kg/m^2 |
| BPRS Total Score | 33.3 units on a scale | 33.8 units on a scale | 32.6 units on a scale | 33.0 units on a scale |
| Race/Ethnicity, Customized American Indian or Alaska Native, Black | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 48 Participants | 29 Participants | 12 Participants | 7 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 57 Participants | 23 Participants | 15 Participants | 19 Participants |
| Sex: Female, Male Female | 37 Participants | 20 Participants | 8 Participants | 9 Participants |
| Sex: Female, Male Male | 72 Participants | 34 Participants | 20 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 27 | 0 / 54 | 0 / 93 | 0 / 80 |
| other Total, other adverse events | 4 / 28 | 3 / 27 | 2 / 54 | 5 / 93 | 1 / 80 |
| serious Total, serious adverse events | 2 / 28 | 0 / 27 | 1 / 54 | 3 / 93 | 0 / 80 |
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. The primary efficacy endpoint was the change from baseline in the AIMS dyskinesia total score at Week 6 between the pooled NBI-98854 50+100 mg group and placebo group analyzed using the ANCOVA model (LOCF, ITT analysis set).
Time frame: Baseline and Week 6
Population: Intent to Treat (ITT) analysis set (all subjects in the safety analysis set with an evaluable AIMS dyskinesia total score value at either Week 2 or Week 6). Last observation carried forward (LOCF) imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Change From Baseline at Week 6 | -2.5 units on a scale | Standard Error 0.7 |
| All Valbenazine | Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score Change From Baseline at Week 6 | -3.3 units on a scale | Standard Error 0.7 |
p-value: 0.296695% CI: [-2.3, 0.7]ANCOVA
Secondary
Clinical Global Impression - Global Improvement of TD (CGI-TD)
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). The ANOVA analysis of CGI-TD was conducted for the pooled NBI-98854 50+100 mg group and placebo group.
Time frame: Week 6
Population: ITT analysis set (all subjects in the safety analysis set with an evaluable AIMS dyskinesia total score value at either Week 2 or Week 6).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Clinical Global Impression - Global Improvement of TD (CGI-TD) | 3.2 units on a scale | Standard Error 0.1 |
| All Valbenazine | Clinical Global Impression - Global Improvement of TD (CGI-TD) | 3.3 units on a scale | Standard Error 0.1 |
p-value: 0.74395% CI: [-0.3, 0.4]ANOVA
Secondary
Clinical Global Impression - Global Improvement of TD (CGI-TD) at Week 2
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 2
Population: ITT analysis set (all subjects in the safety analysis set with an evaluable AIMS dyskinesia total score value at Week 2).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Clinical Global Impression - Global Improvement of TD (CGI-TD) at Week 2 | 3.6 units on a scale | Standard Error 0.1 |
| All Valbenazine | Clinical Global Impression - Global Improvement of TD (CGI-TD) at Week 2 | 3.3 units on a scale | Standard Error 0.2 |
| Valbenazine 100mg | Clinical Global Impression - Global Improvement of TD (CGI-TD) at Week 2 | 3.2 units on a scale | Standard Error 0.2 |
p-value: 0.115195% CI: [-0.7, 0.1]ANOVA
p-value: 0.027795% CI: [-0.8, 0]ANOVA