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A Randomized Placebo-Controlled Trial of Rasagiline in Levodopa-Treated Patients with Parkinson Disease and Motor Fluctuations the PRESTO Study

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A Randomized Placebo-Controlled Trial of Rasagiline in Levodopa-Treated Patients with Parkinson Disease and Motor Fluctuations the PRESTO Study ORIGINAL CONTRIBUTION A Randomized Placebo-Controlled Trial of Rasagiline in Levodopa-Treated Patients With Parkinson Disease and Motor Fluctuations The PRESTO Study Parkinson Study Group Background: Rasagiline (N-propargyl-1[R]- completing 26 weeks of treatment, and adverse event fre- aminoindan) mesylate is a novel irreversible selective quency. monoamine oxidase type B inhibitor, previously dem- onstrated to improve symptoms in early Parkinson dis- Results: During the treatment period, the mean ad- ease (PD). justed total daily off time decreased from baseline by 1.85 hours (29%) in patients treated with 1.0 mg/d of rasagi- Objective: To determine the safety, tolerability, and ef- line, 1.41 hours (23%) with 0.5 mg/d rasagiline, and 0.91 ficacy of rasagiline in levodopa-treated patients with PD hour (15%) with placebo. Compared with placebo, pa- and motor fluctuations. tients treated with 1.0 mg/d rasagiline had 0.94 hour less off time per day, and patients treated with 0.5 mg/d rasagi- Design: Multicenter, randomized, placebo-controlled, line had 0.49 hour less off time per day. Prespecified sec- double-blind, parallel-group study. ondary end points also improved during rasagiline treat- ment, including scores on an investigator-rated clinical Patients: Parkinson disease patients (N=472) with at global impression scale and the Unified Parkinson’s Dis- least 21⁄2 hours of daily “off” (poor motor function) time, ease Rating Scale (activities of daily living in the off state despite optimized treatment with other anti-PD medi- and motor performance in the “on” state). Rasagiline was cations. well tolerated. Interventions: Rasagiline, 1.0 or 0.5 mg/d, or match- Conclusions: Rasagiline improves motor fluctuations and ing placebo. PD symptoms in levodopa-treated PD patients. In light of recently reported benefits in patients with early ill- Main Outcome Measures: Change from baseline in ness, rasagiline is a promising new treatment for PD. total daily off time measured by patients’ home diaries during 26 weeks of treatment, percentage of patients Arch Neurol. 2005;62:241-248 OTOR COMPLICATIONS, brain, can potentiate the beneficial mo- especially “on-off” tor effect of levodopa3-5 and attenuate mo- fluctuations and dys- tor fluctuations.6-9 kinesias, commonly Rasagiline (N -propargyl-1[R]- occur in patients with aminoindan) mesylate is a novel irrevers- Parkinson disease (PD) after months to ible MAO-B inhibitor with high selectiv- M 1 years of dopaminergic therapy. Despite the ity for the B isoform of the enzyme. availability of several new treatments, the Rasagiline, 1.0 mg/d, causes almost total emergence and progression of these mo- inhibition of platelet MAO-B in hu- tor complications continue to represent mans.10 We recently reported a multi- center, randomized, double-blind, pla- cebo-controlled clinical investigation of CME course available at rasagiline monotherapy in 404 subjects www.archneurol.com with early, otherwise untreated, PD.11,12 Rasagiline was well tolerated at dosages of Group Information: A list of major unmet therapeutic needs in many 1.0 and 2.0 mg/d, and patients receiving the members of the Parkinson 2 Study Group who participated PD patients. Previous studies have dem- rasagiline had better function after 6 in this study and were authors onstrated that inhibitors of monoamine months of treatment than those receiv- of this report appears on page oxidase type B (MAO-B), the main en- ing placebo. In the present study, we evalu- 246. zyme that metabolizes dopamine in the ated the safety, tolerability, and efficacy of (REPRINTED) ARCH NEUROL / VOL 62, FEB 2005 WWW.ARCHNEUROL.COM 241 ©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 rasagiline compared with placebo in levodopa-treated pa- istry profiles were performed at screening and after 10 and 26 tients with motor fluctuations. weeks of treatment at a central facility (ACM Laboratories, Roch- ester, NY). Electrocardiograms (ECGs) were performed at screening and after 26 weeks of treatment. Dermatologic ex- METHODS aminations were performed at screening and after 14 and 26 weeks of treatment because of the increased frequency of skin ORGANIZATION cancers in PD in general16,17 and the occurrence of a few cases in prior rasagiline investigations.12 Patients were not required The study was designed, implemented, and analyzed by the Par- to restrict tyramine intake at any time. kinson Study Group in collaboration with Teva Pharmaceutical Industries, Ltd, Netanya, Israel, and H. Lundbeck A/S, Copen- OUTCOME MEASURES hagen, Denmark. It was reviewed and approved by the institu- tional review boards at each of the participating centers. The prespecified primary measure of efficacy was the change from baseline in mean total daily off time, as measured by home PATIENTS diaries, averaged during the treatment period (from weeks 6, 14, and 26). Secondary measures of efficacy, in prespecified or- Levodopa-treated patients with motor fluctuations (N=472) der for purposes of statistical analysis, included the investiga- were enrolled at 57 participating Parkinson Study Group sites tor’s clinical global impression of patient improvement during between December 2000 and June 2002. Eligible patients in- the study as measured on a 7-point scale (ranging from “sig- cluded those with idiopathic PD who were in a modified Hoehn nificantly improved” to “no change” to “significantly wors- and Yahr13 stage of less than 5 in the “off” (poor motor func- ened”), as well as changes from baseline in the Unified Par- 18 tion) state, were 30 years or older, and experienced at least 21⁄2 kinson’s Disease Rating Scale (UPDRS) activities of daily hours in the off state daily, as confirmed by a baseline 3-day living (ADL) subscale during off periods, in the UPDRS motor home diary. Patients must have received an optimized and stable subscale during on periods, and in patient-rated quality of life dosage of levodopa at least 3 times daily, not including a bed- as measured by the Parkinson Disease Quality-of-Life time dose, for at least 2 weeks before their screening evalua- (PDQUALIF) scale.19 Additional prespecified end points tion. Concomitant treatment with stable dosages of dopamine included changes from baseline in the mean total daily on agonists, amantadine hydrochloride, anticholinergics, and en- time, in the Schwab and England20 ADL scale during on and tacapone was allowed. Patients with atypical or secondary par- off periods, and in the UPDRS ADL subscale during on peri- kinsonism, pronounced cognitive impairment (Mini-Mental ods. Measures of safety included the frequency and severity of State Examination14 score, Ͻ24), depressive symptoms (Beck reported adverse experiences, changes in vital signs, labora- Depression Inventory15 score, Ͼ15), and unstable neurologi- tory test results, ECGs, and dermatologic examinations. Changes cal and medical disorders were excluded. in laboratory and ECG values were considered abnormal when they deviated from reference ranges established by the central laboratories. Systolic blood pressure was considered abnor- PROCEDURES mal when greater than 180 mm Hg, less than 90 mm Hg, or changed by more than 30 mm Hg from baseline. Diastolic blood This was a multicenter, randomized, placebo-controlled, double- pressure was considered abnormal when greater than 100 blind study of parallel groups of PD subjects with motor fluc- mm Hg, less than 50 mm Hg, or changed by more than 20 tuations while receiving optimized levodopa therapy. Follow- mm Hg from baseline. Pulse rate was considered abnormal when ing a screening visit to ensure that subjects met all enrollment greater than 120 beats/min, less than 45 beats/min, or changed criteria, including the ability to complete accurate home dia- by more than 20 beats/min from baseline. Tolerability was as- ries, patients were randomized to 0.5 mg/d rasagiline, 1.0 mg/d sessed based on the number of patients in each group who dis- rasagiline, or matching placebo. The computer-generated ran- continued the study. domization plan provided for stratification by center and block- ing to ensure approximate balance among the treatment groups within each center. The levodopa dosage could be decreased STATISTICAL ANALYSIS during the first 6 weeks of the study at the discretion of the investigator but was held constant for the last 20 weeks of the The intended sample size of 150 patients per group (total sample, study. Subjects had visits 3, 6, 10, 14, 20, and 26 weeks after 450) was chosen to provide 80% or better power to detect an baseline for safety and efficacy monitoring. A home diary in improvement of 45 minutes or more in the mean total daily which subjects rated themselves every half hour as “on with- off time in either active treatment group compared with the pla- out dyskinesias or on without troublesome dyskinesias,” “on cebo group. The primary analysis of efficacy used an analysis with troublesome dyskinesias,” “off,” or “asleep” was com- of covariance model that included the change from baseline in pleted for 3 days immediately before the baseline, week 6, week the mean total daily off time as the dependent variable, treat- 14, and week 26 visits. Definitions of “on” (“relatively good ment group as the independent variable of interest, investiga- overall function and mobility when you feel your medication tor (center) as a stratification factor, and baseline off time as a is working”), off (“relatively poor overall function...which covariate. The
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