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DailyMed – INGREZZA- valbenazine capsule INGREZZA- valbenazine kit


A randomized, double-blind, placebo-controlled trial of INGREZZA was conducted in patients with moderate to severe tardive dyskinesia as determined by clinical observation. Patients had underlying schizophrenia, schizoaffective disorder, or a mood disorder. Individuals at significant risk for suicidal or violent behavior and individuals with unstable psychiatric symptoms were excluded. 

The Abnormal Involuntary Movement Scale (AIMS) was the primary efficacy measure for the assessment of tardive dyskinesia severity. The AIMS is a 12-item scale; items 1 to 7 assess the severity of involuntary movements across body regions and these items were used in this study. Each of the 7 items was scored on a 0 to 4 scale, rated as: 0=no dyskinesia; 1=low amplitude, present during some but not most of the exam; 2=low amplitude and present during most of the exam (or moderate amplitude and present during some of the exam); 3=moderate amplitude and present during most of exam; or 4=maximal amplitude and present during most of exam. The AIMS dyskinesia total score (sum of items 1 to 7) could thus range from 0 to 28, with a decrease in score indicating improvement. The AIMS was scored by central raters who interpreted the videos blinded to subject identification, treatment assignment, and visit number.

The primary efficacy endpoint was the mean change from baseline in the AIMS dyskinesia total score at the end of Week 6. The change from baseline for two fixed doses of INGREZZA (40 mg or 80 mg) was compared to placebo. At the end of Week 6, subjects initially assigned to placebo were re-randomized to receive INGREZZA 40 mg or 80 mg. Subjects originally randomized to INGREZZA continued INGREZZA at their randomized dose. Follow-up was continued through Week 48 on the assigned drug, followed by a 4-week period off-drug (subjects were not blind to withdrawal).  

A total of 234 subjects were enrolled, with 29 (12%) discontinuing prior to completion of the placebo-controlled period. Mean age was 56 (range 26 to 84). Patients were 54% male and 46% female. Patients were 57% Caucasian, 38% African-American, and 5% other. Concurrent diagnoses included schizophrenia/schizoaffective disorder (66%) and mood disorder (34%). With respect to concurrent antipsychotic use, 70% of subjects were receiving atypical antipsychotics, 14% were receiving typical or combination antipsychotics, and 16% were not receiving antipsychotics.

Results are presented in Table 3, with the distribution of responses shown in Figure 4.  The change from baseline in the AIMS total dyskinesia score in the 80 mg INGREZZA group was statistically significantly different from the change in the placebo group. Subgroup analyses by gender, age, racial subgroup, underlying psychiatric diagnostic category, and concomitant antipsychotic medication did not suggest any clear evidence of differential responsiveness.

The mean changes in the AIMS dyskinesia total score by visit are shown in Figure 5. Among subjects remaining in the study at the end of the 48-week treatment (N=123 [52.6%]), following discontinuation of INGREZZA, the mean AIMS dyskinesia total score appeared to return toward baseline (there was no formal hypothesis testing for the change following discontinuation). 

Table 3:
     
Primary Efficacy Endpoint – Severity of Tardive Dyskinesia at
Baseline and the End of Week 6

LS Mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean; CI=2-sided 95% confidence interval

*Dose that was statistically significantly different from placebo after adjusting for multiplicity.

**A negative change from baseline indicates improvement.

Figure 4:
     
Percent of Patients with Specified Magnitude of AIMS Total Score Improvement at the End of Week 6

ITT=Intent to Treat; This analysis set includes all randomized patients who had a baseline and at least one post-baseline AIMS dyskinesia total score value reported.

Figure 5:
     
AIMS Dyskinesia Total Score Mean Change from Baseline – Entire Study Duration (Arithmetic Mean)

Figure 5

DB=Double-Blind; After Week 6, subjects initially receiving placebo were re-randomized to receive INGREZZA 40 mg or 80 mg until the end of Week 48. Error bars represent ±1 Standard Error of the Mean (SEM).

Efficacy of INGREZZA 60 mg

Based on modeling and simulation, the predicted mean change from baseline in the AIMS dyskinesia total score at Week 6 for INGREZZA 60 mg once daily in subjects with TD is -2.69 (95% CI: -3.30, -2.13), which is within the efficacy range for INGREZZA 40 mg and 80 mg once daily.



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