Study 1 

The efficacy of tetrabenazine as a treatment for the chorea of Huntington’s disease was established primarily in a randomized, double-blind, placebo-controlled multi-center trial (Study 1) conducted in ambulatory patients with a diagnosis of HD. The diagnosis of HD was based on family history, neurological exam, and genetic testing. Treatment duration was 12 weeks, including a 7-week dose titration period and a 5-week maintenance period followed by a 1-week washout. Tetrabenazine tablets were started at a dose of 12.5 mg per day, followed by upward titration at weekly intervals, in 12.5 mg increments until satisfactory control of chorea was achieved, intolerable side effects occurred, or until a maximal dose of 100 mg per day was reached. 

The primary efficacy endpoint was the Total Chorea Score, an item of the Unified Huntington’s Disease Rating Scale (UHDRS). On this scale, chorea is rated from 0 to 4 (with 0 representing no chorea) for 7 different parts of the body. The total score ranges from 0 to 28. 

As shown in Figure 1, Total Chorea Scores for patients in the drug group declined by an estimated 5.0 units during maintenance therapy (average of Week 9 and Week 12 scores versus baseline), compared to an estimated 1.5 units in the placebo group. The treatment effect of 3.5 units was statistically significant. At the Week 13 follow-up in Study 1 (1 week after discontinuation of the study medication), the Total Chorea Scores of patients receiving tetrabenazine returned to baseline.

Figure 1: Mean ± s.e.m. Changes from Baseline in Total Chorea Score in 84 HD Patients Treated with Tetrabenazine (n=54) or Placebo (n=30)

(error bars are ± s.e.m.)

*p<0.05

Figure 2 illustrates the cumulative percentages of patients from the tetrabenazine and placebo treatment groups who achieved the level of reduction in the Total Chorea Score shown on the X axis. The left-ward shift of the curve (toward greater improvement) for the tetrabenazine-treated patients indicates that these patients were more likely to have any given degree of improvement in chorea score. For example, about 7% of placebo patients had a 6-point or greater improvement compared to 50% of tetrabenazine-treated patients. The percentage of patients achieving reductions of at least 10, 6, and 3 points from baseline to Week 12 are shown in the inset table. 

Figure 2: Cumulative Percentage of Patients with Specified Changes from Baseline in Total Chorea Score. The Percentages of Randomized Patients within each treatment group who completed Study 1 were: Placebo 97%, Tetrabenazine 91%.

A Physician-rated Clinical Global Impression (CGI) favored tetrabenazine statistically. In general, measures of functional capacity and cognition showed no difference between tetrabenazine and placebo. However, one functional measure (Part 4 of the UHDRS), a 25-item scale assessing the capacity for patients to perform certain activities of daily living, showed a decrement for patients treated with tetrabenazine compared to placebo, a difference that was nominally statistically significant. A 3-item cognitive battery specifically developed to assess cognitive function in patients with HD (Part 2 of the UHDRS) also showed a decrement for patients treated with tetrabenazine compared to placebo, but the difference was not statistically significant. 

Study 2 

A second controlled study was performed in patients who had been treated with open-label tetrabenazine for at least 2 months (mean duration of treatment was 2 years). They were randomized to continuation of tetrabenazine at the same dose (n=12) or to placebo (n=6) for three days, at which time their chorea scores were compared. Although the comparison did not reach statistical significance (p=0.1), the estimate of the treatment effect was similar to that seen in Study 1 (about 3.5 units).