Pharmacy & Therapeutics - December 2008 - (Page 693)

DRUG FORECAST UHDRS chorea scores decreased by 42.4% ± 17.8% with a tendency to improve but then worsened over several hours. The mean duration of effect lasted for 5.4 ± 1.3 hours. This study supported the efficacy of tetrabenazine in the treatment of chorea and the findings of inter individual variation in effects. It also demonstrated the rapid onset of action of tetrabenazine, because the rater was able to visualize improvement within 90 minutes in each patient. full UHDRS assessment, which included motor, cognitive, behavioral, and functional components, was performed at baseline, at the end of the titration phase, and at the end of the maintenance phase. The investigators piloted a new instrument—the Functional Impact Scale (FIS)—to assess the degree of difficulty involved in certain activities of daily living, namely, bathing, dressing, feeding, social isolation, and toileting. The information was obtained from the accompanying caregivers. Each item was scored on a scale of 0 (zero) to 3, with a maximum score of 15, indicating complete dependence on others for daily activities. The impact of tetrabenazine treatment on chorea severity (–5.0 ± 0.7 UHDRS units; P < 0.0001) was greater than the effect of placebo, but there was a mild reduction from baseline in that group as well. The adjusted effect size of –3.5 UHDRS units represents a 23.5% average reduction in chorea severity attributed to tetrabenazine. Whereas only 20% of subjects in the placebo group had a reduction of at least three UHDRS units in chorea, 69% of subjects in the tetrabenazine group had at least that much reduction in chorea (P < 0.0001). Tetrabenazine was also superior to placebo, according to the Clinical Global Impressions (CGI) Improvement Scale. Twenty-four percent of the placebo subjects achieved a score of 3 or lower (corresponding to at least minimal improvement), compared with 69% of the tetrabenazine subjects (P = 0.0001). Only two participants receiving placebo had more than minimal improvement compared with 23 subjects receiving tetrabenazine (P = 0.0004). No differences were found between tetrabenazine and placebo at the end of the washout phase compared with baseline values in motor, cognitive, behavioral, or global measures of illness severity. After discontinuation of treatment, chorea worsened further in those subjects who had received tetrabenazine compared with those who had received placebo (P < 0.0001). Tetrabenazine was fairly well tolerated, but it was associated with a significant increase in reports of drowsiness and insomnia. Other adverse events that limited dosing included depressed mood in two patients, parkinsonism in two, and akathisia in four. These effects resolved with a dosage reduction. No significant differences were observed in the number of adverse events reported between the tetrabenazine and placebo groups. Investigators also noted no adverse impact on Barnes Akathisia Scale scores or on measures of parkinsonism, dysphagia, or dysarthria. According to Hamilton Depression Scale (HAM-D) results, no evidence of tetrabenazine-related depression was found, although subjects receiving placebo had better scores in this scale. One subject in the tetrabenazine group committed suicide during this trial, although HAM-D scores had been in the normal range during previous assessments. Overall, tetrabenazine demonstrated statistically significant reductions in chorea and improvement on the CGI scale in ambulatory patients in doses of up to 100 mg/day. However, it did not offer improvement in other functional outcome measures, suggesting that chorea is only one aspect of the disability seen in HD. Huntington Study Group18 The Huntington Study Group conducted the first multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, dosing, tolerability, and safety of tetrabenazine in two parallel groups of HD subjects with clinically manifested chorea. The study enrolled 84 subjects with HD (range, 25 to 77 years of age). The diagnosis of HD was confirmed by presence of a characteristic movement disorder (e.g., chorea), a family history, and an expanded CAG repeat of 37 or more. The inclusion criteria consisted of being independently ambulatory, having a screening Total Functional Capacity (TFC) Scale score of greater than 5, and a total maximal chorea score of 10 or higher based upon motor subscales of the UHDRS. Patients were not permitted to enroll in the study if they had disabling depression, dysphagia, or dysarthria. Each patient was randomly assigned to receive either a 12.5-mg tetrabenazine tablet or placebo for 12 weeks. During the first seven weeks of the study, patients received one tablet on the first day; the dosage was then increased to twice daily for the rest of the first week. The number of tablets was increased by one tablet each week until a dose of eight tablets (100 mg) per day was reached in three divided doses, the desired antichoreic effect was achieved, or intolerable adverse effects occurred. During the last five weeks, the dose remained unchanged (in the maintenance phase) unless intolerable adverse effects occurred. At the end of the 12 weeks, the study drugs were stopped and the subjects returned one week later for follow-up. At each visit, the investigator rated the UHDRS total maximal chorea score to assess changes in severity of chorea. A Frank et al.19 Frank and colleagues performed a randomized, double-blind study to confirm the efficacy of tetrabenazine by showing that chorea re-emerged when the drug was withdrawn from chronically treated patients. They also sought to determine the safety of withdrawal from short-term tetrabenazine treatment. Thirty subjects with HD, ranging in age from 39 to 75 years, participated in this five-day study. HD was confirmed by clinical diagnosis and an expanded CAG repeat of 37 or more. Subjects also had to have been taking a stable dose of tetrabenazine for at least two months, and they had to have chorea that was determined to be responsive to the medication. Eligible subjects were randomly assigned to a withdrawal group, a partialwithdrawal group (on the third day), or a no-withdrawal group. Withdrawal from tetrabenazine was performed in a doubleblind manner, with the medication replaced by placebo tablets. The primary analysis compared the mean change from the baseline visit to the evaluation of UHDRS chorea scores on day three between the withdrawal group and the other two groups. The secondary outcome measure was the change in TFC Vol. 33 No. 12 • December 2008 • P&T® 693

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - December 2008

Pharmacy & Therapeutics - December 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Interpreting Estimates of Treatment Effects Chemotherapy Foundation Symposium XXVI: Innovative Cancer Therapy for Tomorrow Third Annual Onmark National Payor/Provider Forum Fourth Annual Ophthalmic Drug Development and Delivery Summit Classification and Pharmacological Management Of Obesity CE Test and Forms Season’s Greetings: Thanks to Our Readers and Reviewers

Pharmacy & Therapeutics - December 2008

For optimal viewing of this digital publication, please enable JavaScript and then refresh the page. If you would like to try to load the digital publication without using Flash Player detection, please click here.