A Randomized Placebo-Controlled Trial of Rasagiline in Levodopa-Treated Patients With Parkinson Disease and Motor Fluctuations:  The PRESTO Study FREE

Motor complications, especially “on-off” fluctuations and dyskinesias, commonly occur in patients with Parkinson disease (PD) after months to years of dopaminergic therapy.¹ Despite the availability of several new treatments, the emergence and progression of these motor complications continue to represent major unmet therapeutic needs in many PD patients.²Previous studies have demonstrated that inhibitors of monoamine oxidase type B (MAO-B), the main enzyme that metabolizes dopamine in the brain, can potentiate the beneficial motor effect of levodopa^3- 5 and attenuate motor fluctuations.^6- 9Rasagiline (N-propargyl-1[R]-aminoindan) mesylate is a novel irreversible MAO-B inhibitor with high selectivity for the B isoform of the enzyme. Rasagiline, 1.0 mg/d, causes almost total inhibition of platelet MAO-B in humans.¹⁰ We recently reported a multicenter, randomized, double-blind, placebo-controlled clinical investigation of rasagiline monotherapy in 404 subjects with early, otherwise untreated, PD.^11- 12 Rasagiline was well tolerated at dosages of 1.0 and 2.0 mg/d, and patients receiving rasagiline had better function after 6 months of treatment than those receiving placebo. In the present study, we evaluated the safety, tolerability, and efficacy of rasagiline compared with placebo in levodopa-treated patients with motor fluctuations.

The study was designed, implemented, and analyzed by the Parkinson Study Group in collaboration with Teva Pharmaceutical Industries, Ltd, Netanya, Israel, and H. Lundbeck A/S, Copenhagen, Denmark. It was reviewed and approved by the institutional review boards at each of the participating centers.

Levodopa-treated patients with motor fluctuations (N = 472) were enrolled at 57 participating Parkinson Study Group sites between December 2000 and June 2002. Eligible patients included those with idiopathic PD who were in a modified Hoehn and Yahr¹³stage of less than 5 in the “off” (poor motor function) state, were 30 years or older, and experienced at least 21/2 hours in the off state daily, as confirmed by a baseline 3-day home diary. Patients must have received an optimized and stable dosage of levodopa at least 3 times daily, not including a bedtime dose, for at least 2 weeks before their screening evaluation. Concomitant treatment with stable dosages of dopamine agonists, amantadine hydrochloride, anticholinergics, and entacapone was allowed. Patients with atypical or secondary parkinsonism, pronounced cognitive impairment (Mini-Mental State Examination¹⁴ score, <24), depressive symptoms (Beck Depression Inventory¹⁵ score, >15), and unstable neurological and medical disorders were excluded.

This was a multicenter, randomized, placebo-controlled, double-blind study of parallel groups of PD subjects with motor fluctuations while receiving optimized levodopa therapy. Following a screening visit to ensure that subjects met all enrollment criteria, including the ability to complete accurate home diaries, patients were randomized to 0.5 mg/d rasagiline, 1.0 mg/d rasagiline, or matching placebo. The computer-generated randomization plan provided for stratification by center and blocking to ensure approximate balance among the treatment groups within each center. The levodopa dosage could be decreased 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 study. Subjects had visits 3, 6, 10, 14, 20, and 26 weeks after baseline for safety and efficacy monitoring. A home diary in which subjects rated themselves every half hour as “on without dyskinesias or on without troublesome dyskinesias,” “on with troublesome dyskinesias,” “off,” or “asleep” was completed for 3 days immediately before the baseline, week 6, week 14, and week 26 visits. Definitions of “on” (“relatively good overall function and mobility when you feel your medication is working”), off (“relatively poor overall function . . . which corresponds to when your medication is not working”), dyskinesias (“involuntary, nontremor movements”), and troublesome dyskinesias (those that are “painful, impair balance, or are excessive to the point of causing impairment in coordination or general function”) were explained and demonstrated using a standardized video training tape and practice diaries. Subjects monitored blood pressures before and after the main meal of the day for 7 days before the baseline, week 3, and week 26 visits using an automated device (Welch Allyn, Skaneateles, NY). Urinalysis, complete blood counts, and serum chemistry profiles were performed at screening and after 10 and 26 weeks of treatment at a central facility (ACM Laboratories, Rochester, NY). Electrocardiograms (ECGs) were performed at screening and after 26 weeks of treatment. Dermatologic examinations were performed at screening and after 14 and 26 weeks of treatment because of the increased frequency of skin cancers in PD in general^16- 17 and the occurrence of a few cases in prior rasagiline investigations.¹² Patients were not required to restrict tyramine intake at any time.

The prespecified primary measure of efficacy was the change from baseline in mean total daily off time, as measured by home diaries, averaged during the treatment period (from weeks 6, 14, and 26). Secondary measures of efficacy, in prespecified order for purposes of statistical analysis, included the investigator’s clinical global impression of patient improvement during the study as measured on a 7-point scale (ranging from “significantly improved” to “no change” to “significantly worsened”), as well as changes from baseline in the Unified Parkinson’s Disease Rating Scale (UPDRS)¹⁸ activities of daily living (ADL) subscale during off periods, in the UPDRS motor subscale during on periods, and in patient-rated quality of life as measured by the Parkinson Disease Quality-of-Life (PDQUALIF) scale.¹⁹ Additional prespecified end points included changes from baseline in the mean total daily on time, in the Schwab and England²⁰ ADL scale during on and off periods, and in the UPDRS ADL subscale during on periods. Measures of safety included the frequency and severity of reported adverse experiences, changes in vital signs, laboratory test results, ECGs, and dermatologic examinations. Changes in laboratory and ECG values were considered abnormal when they deviated from reference ranges established by the central laboratories. Systolic blood pressure was considered abnormal when greater than 180 mm Hg, less than 90 mm Hg, or changed by more than 30 mm Hg from baseline. Diastolic blood pressure was considered abnormal when greater than 100 mm Hg, less than 50 mm Hg, or changed by more than 20 mm Hg from baseline. Pulse rate was considered abnormal when greater than 120 beats/min, less than 45 beats/min, or changed by more than 20 beats/min from baseline. Tolerability was assessed based on the number of patients in each group who discontinued the study.

The intended sample size of 150 patients per group (total sample, 450) was chosen to provide 80% or better power to detect an improvement of 45 minutes or more in the mean total daily off time in either active treatment group compared with the placebo group. The primary analysis of efficacy used an analysis of covariance model that included the change from baseline in the mean total daily off time as the dependent variable, treatment group as the independent variable of interest, investigator (center) as a stratification factor, and baseline off time as a covariate. The treatment × center interaction was to be included if significant at P<.10. The primary statistical analysis included data from all patients with postrandomization diary data (n = 451). To determine the effect of patient withdrawals, the analyses were repeated with only patients who completed the study (n = 414) and patients who completed all procedures according to protocol (n = 359). The results of the latter analyses did not differ materially from those of the primary analyses and hence are not reported. Secondary and exploratory efficacy measures were analyzed in the same way as the primary measure of efficacy. If a patient was missing a response, the last available observation for that patient was carried forward and imputed for that visit. Frequencies of adverse experiences and abnormal laboratory test values, vital signs, and ECG results were analyzed by χ² tests, with imbalances among treatment groups flagged at a nominal P<.05.

All methods of analysis were prespecified before patient treatment assignments were revealed. Analyses were performed according to the intention-to-treat principle, and P<.05 was used for formal significance testing and interval estimation.

A hierarchical method of analysis, combined with the step-up modification to the Bonferroni method by Hochberg,²¹ was used to control for type I error. Analyses of the primary outcome measure (change in the mean total daily off time) and the 4 prespecified and ordered secondary outcome measures (clinical global impression, change in the UPDRS ADL subscale during off time, change in the UPDRS motor subscale during on time, and change in the PDQUALIF scale) were designed to use 2 types of contrasts (1.0 mg/d vs placebo and 0.5 mg/d vs placebo, for a maximum of 5 contrasts for each rasagiline dosage). The hierarchical approach for each dosage tested the 5 outcomes in their prespecified order (as listed), with the testing for that dosage to be terminated at the first nonsignificant result.²²

Treatment groups had no significant differences at baseline with regard to demographic and clinical characteristics (Table 1). Figure 1 tracks all evaluated patients, by treatment group, through the study. Overall, 414 patients (87.7% of enrolled) completed 26 weeks of treatment. A subset of 359 patients (76.1% of enrolled) completed the study without deviating from the protocol. The most common deviations were premature termination (12%), fewer than 6 acceptable daily diaries (10%, mainly in patients who terminated prematurely), and change in daily levodopa or other anti-PD medication dosage by more than 20% from baseline during the last 20 weeks of the study (4%). Compliance was high, as measured by pill counts, with 95% of patients taking at least 90% of scheduled doses. Between baseline and the week 26 visit, patients receiving placebo decreased their mean ± SD daily levodopa dosages by 12 ± 142 mg, patients receiving 0.5 mg/d of rasagiline decreased their dosages by 32 ± 122 mg, and patients receiving 1.0 mg/d rasagiline decreased their dosages by 36 ± 133 mg. In each group, the median change in levodopa dosage was 0 mg. Most patients were taking additional PD medications, including dopamine agonists, entacapone, and amantadine (Table 1).

During the treatment period, the mean adjusted total daily off time decreased from baseline by 1.85 hours (29%) in patients treated with 1.0 mg/d of rasagiline, 1.41 hours (23%) with 0.5 mg/d rasagiline, and 0.91 hour (15%) with placebo (Table 2). Patients treated with 1.0 mg/d of rasagiline had 0.94 hour (95% confidence interval, 0.51-1.36 hours; P<.001) less off time per day compared with placebo. Patients treated with 0.5 mg/d of rasagiline had 0.49 hour (95% confidence interval, 0.08-0.91 hour; P = .02) less off time compared with placebo. Changes from baseline and differences between groups were sustained throughout the treatment period (Figure 2). There was no evidence for differences in treatment effects at different sites (P = .58, treatment × center interaction).

Secondary efficacy measures were assessed using a prespecified hierarchical analysis. Compared with placebo, the clinical global impression, UPDRS ADL score during off time, and UPDRS motor score during on time improved significantly during treatment in patients receiving either dosage of rasagiline (Table 2). Quality of life, as measured by the PDQUALIF summary score, showed a trend toward improvement in patients treated with 0.5 mg/d of rasagiline (P = .07) but not with 1.0 mg/d of rasagiline. The social subscale of the PDQUALIF scale showed a benefit of both rasagiline dosages over placebo, the outlook subscale showed a benefit for the 0.5-mg/d dosage only, and the function, image, independence, sleep, and urinary subscales showed no difference from placebo.

Prespecified exploratory analyses (Table 2) demonstrated significant increases in the amount of on time per day during treatment with both dosages of rasagiline, corresponding to the decreases in off time. In the 0.5-mg/d rasagiline group, all of the increase in on time was without troublesome dyskinesias. In the 1.0-mg/d rasagiline group, 32% of the increase in on time included troublesome dyskinesias. Rasagiline, 1.0 mg/d, produced significant improvement in the Schwab and England²⁰ ADL scale during off times (P = .02), but 0.5 mg/d did not. Post hoc analysis of UPDRS subscores during on times revealed significant improvements in rigidity, bradykinesia, and tremor in patients treated with 1.0 mg/d of rasagiline (as rated on the UPDRS) and in postural instability and gait and tremor in patients treated with 0.5 mg/d.

The number of patients discontinuing for any reason, or because of an adverse event, was not significantly different between treatment groups (P = .85, χ² test) (Figure 1). Adverse events were reported in 87% of patients receiving placebo, 91% receiving 0.5 mg/d of rasagiline, and 95% receiving 1.0 mg/d of rasagiline. Adverse events that were significantly more common in patients treated with either dosage of rasagiline compared with placebo are listed in Table 3. These mostly involved the gastrointestinal system and appeared to be dose related. Dyskinesias were reported as an adverse event in 10% of patients receiving placebo and 18% of patients receiving either dosage of rasagiline (P = .03, χ² test for combined rasagiline groups vs placebo). Balance difficulty occurred more often in patients receiving rasagiline, but it did not appear to be dose related. Depression was significantly less common in patients receiving 0.5 mg/d of rasagiline compared with placebo (P = .04). There were 22 serious adverse events in 14 patients receiving placebo, 42 in 21 patients receiving 0.5 mg/d of rasagiline, and 27 in 18 patients receiving 1.0 mg/d of rasagiline. The most common serious adverse events (all 3 groups combined) were related to accidental injury (n = 6), arthritis, worsening PD, melanoma, stroke (n=3), and urinary tract infection (n = 3); none were significantly more common in patients receiving rasagiline compared with placebo.

Rasagiline did not have adverse effects on blood pressure or pulse rate. Flagging group differences in the incidence of abnormalities at P<.05 revealed more patients with low systolic (20 patients vs 8 patients) or diastolic (9 patients vs 1 patient) blood pressure while standing, but not while supine, during treatment with 0.5 mg/d of rasagiline compared with placebo. Analogous comparisons between 1.0 mg/d of rasagiline and placebo did not demonstrate significant differences. More patients receiving placebo had increases in systolic blood pressure compared with baseline (standing: 28 patients receiving placebo, 12 patients receiving 0.5 mg/d of rasagiline, and 13 patients receiving 1.0 mg/d of rasagiline; and supine: 27 patients receiving placebo, 17 patients receiving 0.5 mg/d of rasagiline, and 10 patients receiving 1.0 mg/d of rasagiline). There were no significant group differences in the incidence of decreased blood pressure compared with baseline. There were no significant group differences in the incidence of observed changes in blood pressure from supine to standing or in reports of symptomatic orthostasis as an adverse event. There were no significant group differences in laboratory values or ECG results during treatment. Home blood pressure monitoring before and after the main meal of the day (4809 observations at baseline, 4645 observations at week 3, and 4069 observations at week 26) showed no significant group differences. During treatment, dermatologic examinations revealed 3 patients with melanomas (1 patient receiving 0.5 mg/d rasagiline and 2 patients receiving 1.0 mg/d rasagiline). In addition, 1 patient was identified as having a melanoma before initiating study medication.

Rasagiline treatment was well tolerated and was associated with several therapeutic benefits in PD patients with motor fluctuations, despite optimized levodopa, including decreased off time on home diaries completed by patients and improvement in clinical global impression performed by blinded examiners. Neurological function improved during off times (ADL scores based on patient reports) and during on times (overall motor, postural instability and gait, rigidity, bradykinesia, and tremor scores based on patient reports and direct examination). These benefits were measurable at the first efficacy assessment 6 weeks after treatment was initiated and were sustained throughout the treatment period. Benefits tended to be greater in patients treated with 1.0 mg/d of rasagiline compared with 0.5 mg/d of rasagiline, but differences between the 2 rasagiline dosages were not significant for most end points. These results demonstrate a benefit of adding rasagiline to the regimens of patients who were already optimally treated with levodopa, dopamine agonists, amantadine, anticholinergics, and entacapone before enrolling in the study.

The lack of benefit demonstrated by the PDQUALIF scale does not override the benefits seen using patient-derived and examination-based end points. Although the PDQUALIF scale strives to assess the effects of PD on the patient’s quality of life from the patient’s point of view, it is not clear from existing research that this scale or any other existing quality-of-life scale has adequate psychometric properties to be considered a prerequisite for meaningful benefits.¹⁹ To date, most phase 3 studies in PD have used data from patient diaries or neurological examinations as their primary end points.

Observed decreases in daily off time were associated with nearly equal increases in on time. Patients treated with 0.5 mg/d of rasagiline experienced this benefit without extra time spent with troublesome dyskinesias. In patients treated with 1.0 mg/d of rasagiline, the increase in on time was greater and most of the increase was without troublesome dyskinesias, but 32% of the increase included troublesome dyskinesias. The UPDRS rating of dyskinesias also suggested that patients treated with 1.0 mg/d rasagiline experienced more dyskinesias than those treated with 0.5 mg/d rasagiline, but both groups reported increased dyskinesias as adverse events in 18% of patients compared with 10% of the placebo group. Together with hints of a dose response favoring the higher dosage of rasagiline, these results suggest that the higher dosage of rasagiline used in this study may have benefits that are partially offset by increased dyskinesias. In clinical practice, some of the dyskinesias might have been avoided by adjusting levodopa and other antiparkinsonian medications, but such changes were prohibited in the research setting because they might have confounded interpretation of rasagiline effects. Despite these restrictions, dyskinesias did not lead to early terminations. Other adverse effects, including gastrointestinal effects, may also be dose related. Psychiatric adverse effects that occur with dopaminergic therapies, such as hallucinations, somnolence, and confusion,^23- 26 were not increased by rasagiline.

The incidence of melanomas appears to be increased in PD patients based on epidemiological studies.^16- 17 On noting a few melanomas during the rasagiline development program,¹² routine dermatological examinations were incorporated into the study activities to improve surveillance. This may have resulted in an apparent increase in melanoma incidence because of improved ascertainment compared with other studies. Although the melanomas detected after starting the study drug occurred in patients receiving rasagiline, this is not particularly revealing because only one third were receiving placebo. Furthermore, the fact that 1 patient had a melanoma detected before starting the study drug supports the interpretation that these results were affected by increased surveillance of a disorder common to this patient group rather than being related to rasagiline exposure.

Other adjunctive, antiparkinsonian medications have been studied in similar trials, providing comparable results. Changes in on and off time as measured by patient diaries have been a standard measure of drug efficacy in these patients.²⁷ The catechol-O-methyl-transferase inhibitor entacapone, for example, improved on time by approximately 1 hour in PD patients with motor fluctuations when taken with each dose of levodopa.²³ Dopamine agonists, including pergolide mesylate,²⁴ pramipexole,²⁵ and ropinirole hydrochloride,²⁶ have added 1 to 2 hours of on time, although adverse effects have been more limiting than with rasagiline. Common adverse effects with these agents include gastrointestinal intolerance, hallucinations, edema, somnolence, and orthostatic hypotension, often resulting in discontinuation of the drug. The MAO inhibitor selegiline hydrochloride has not been carefully studied with respect to on-off fluctuations in PD.

Given the improvements in PD signs and symptoms during rasagiline monotherapy in patients with early PD^11- 12and during adjunctive therapy in patients with motor fluctuations, rasagiline appears to be a promising new treatment for PD. The simplicity of administration (once-daily dosing with no titration required) and excellent tolerability of rasagiline are additional advantages. In addition to these short-term effects, rasagiline appears to have more long-lasting benefits, suggesting that it may modify the course of PD progression. Preclinical studies^28- 29 have shown that MAO-B inhibitors can protect neurons from oxidative stress, apoptosis, and other forms of injury in multiple experimental models. Furthermore, in a blinded study of 404 patients with early PD, those who were randomized to rasagiline treatment for 12 months had better UPDRS scores than patients who were randomized to delay rasagiline treatment for the first 6 months.¹² Both groups were examined while taking the same dosage of rasagiline, so they should have been receiving the same symptomatic benefits; the sustained difference observed may be related to protective effects associated with long-term use. Further studies are warranted to explore this possibility.

The following members of the Parkinson Study Group participated in this study and were authors of this report:

STEERING COMMITTEE

University of Rochester, Rochester: Steven R. Schwid MD, (medical director), Ira Shoulson MD, (principal investigator); University of Pennsylvania, Philadelphia: Matthew Stern MD, (coprincipal investigator); University of Rochester: David Oakes PhD, (chief biostatistician), Karl Kieburtz MD, (director, Clinical Trials Coordination Center); Columbia-Presbyterian Medical Center, New York, NY: Stanley Fahn MD; Medical College of Wisconsin, Milwaukee: Karen Blindauer MD; University of Connecticut, Farmington: Antoinelle deMarcaida MD.

PARTICIPATING INVESTIGATORS AND COORDINATORS

Medical College of Ohio, Toledo: Lawrence Elmer MD, PhD, Kathy Davis; New York University Medical Center, New York: Enrico Fazzini MD, Linda Chin RN; Duke University Medical Center, Durham, NC: Burton Scott MD, Carroll Wilcox RN; University of Pennsylvania: Amy Colcher MD, Sue Reichwein CCRC; University of South Florida, Tampa: Robert Hauser MD, Lisa Gauger BA; University of Colorado Health Sciences Center, Denver: Maureen Leehey MD; Baylor College of Medicine, Houston, Tex: William Ondo MD; Clinical Neuroscience Center, Southfield, Mich: Peter Lewitt MD, Patricia Kaminski RN; University of Virginia, Charlottesville: Madaline Harrison MD, Elke Rost-Ruffner RN, BSN; Washington University, St Louis, Mo: Brad Racette MD, Patti Cooper; The Parkinson’s & Movement Disorder Institute, Fountain Valley, Calif: Karen Frei MD, Nancy Luong BS; University of Kansas Medical Center, Kansas City: Rajesh Pahwa MD, Jovianna Dicarlo CMA; University of Southern California, Los Angeles: Mark F. Lew MD, Connie Kawai RN, BSN, CCRC; Institute for Neurodegenerative Disorders, New Haven, Conn: Danna Jennings MD, Karen Caplan MSW; Boston University, Boston, Mass: J. Stephen Fink MD, PhD, Peter Novak MD, Cathi-Ann Thomas RN; Hotel-Dieu Hospital, Centre Hospitalier de l’Université de Montreal, Montreal, Quebec: Sylvain Chouinard MD, Chantale Beauvais RN; University of Arkansas for Medical Sciences, Little Rock: Samer Tabbal MD, Ergun Uc MD, Jana Patterson RN; Brown University, Pawtucket, RI: Hubert Fernandez MD; Creighton University, Omaha, Neb: John M. Bertoni MD, Larisa Skrypnik BS; McGill Centre for Studies in Aging, Verdun, Quebec: Michel Panisset MD, Marie Josee Fortin; Albany Medical College, Albany, NY: Eric Molho MD, Jacqueline Nash; University of Cincinnati/Cincinnati Children’s Hospital, Cincinnati, Ohio: Arif Dalvi MD, Donna Schwieterman MA, CCRC; Rush-Presbyterian/St Luke’s Medical Center, Chicago, Ill: Christopher Goetz MD, Kimberly Janko RN, BSN; Ottawa Hospital Civic Site, Ottawa, Ontario: Tilak Mendis MD, Davoud Mahtat, Peggy Gray BSCN; University of Alberta, Edmonton: Richard Camicioli MD, Pamela King RN, BSN; Indiana University School of Medicine, Indianapolis: Joanne Wojcieszek MD; Colorado Neurological Institute, Englewood: Rajeev Kumar MD, Deborah Judd RN; Margolin Brain Institute, Fresno, Calif: David Margolin MD, PhD, J. J. Margolin RN, FNP, Karen Clem RN; University of New Mexico, Albuquerque: Paul Gordon MD; University of Rochester: Frederick Marshall MD, Debra Berry MSN, NP; University of Minnesota/Minneapolis VA Medical Center, Minneapolis: David Rottenberg MD, Joy Hansen RN; Long Island Jewish Medical Center, New Hyde Park, NY: Mark Forrest Gordon MD; University of Connecticut, Hartford: Mohamed Hassan MD, Patricia Keltonic RN; University of California, Irvine: Neal Hermanowicz MD, Shari Niswonger RN; London Health Sciences Centre, London, Ontario: Mandar Jog MD, PhD, Cheryl Horn RN; University of Maryland School of Medicine, Baltimore: Lisa Shulman MD, Michelle Cines RN; University of Calgary, Calgary, Alberta: Oksana Suchowersky MD, Sarah Furtado MD, PhD, Lorelei Derwent RN; Barrow Neurological Institute, Phoenix, Ariz: Johan Samanta MD, Kelli Williamson RN; University of Puerto Rico School of Medicine, San Juan: Carmen Serrano Ramos MD, Laritza Berrios RN, Sandra Roque RN; California Medical Center for Movement Disorders, Oxnard: James Sutton MD, Juanita Young CCRC; Columbia-Presbyterian Medical Center: Cheryl Waters MD, Reina Benabou MD, PhD; University of Miami, Miami, Fla: Carlos Singer MD, William Koller MD, Doris Martin; Medical College of Georgia, Augusta: Kapil Sethi MD, Joan Carpenter RN; Louisiana State University Medical Center, New Orleans: Jayaraman Rao MD, Maureen Cook RN, BSN; North Shore University Hospital, Manhassett, NY: Andrew Feigin MD, Margaret Cox RN; University Hospitals of Cleveland, Cleveland, Ohio: David Riley MD; Hunter Homes McGuire Veterans Medical Center, Richmond, Va: Vincent Calabrese MD; Massachusetts General Hospital, Boston: David Standaert MD, PhD, Marsha Tennis RN; Scott & White Hospital/Texas A&M University, Temple: Bala Manyam MD, Jacqueline Whetteckey, Brian Wulbrecht BA, CCRP; Saskatoon District Health Board Royal University Hospital, Saskatoon, Saskatchewan: Alexander Rajput MD; University of Medicine and Dentistry, New Brunswick, NJ: Lawrence Golbe MD, Debbie Caputo RN, MSN; Emory University School of Medicine, Atlanta, Ga: Alan Freeman MD, Linda McGinn; Cleveland Clinic, Cleveland: Thyagarajan Subramanian MD; McFarland Neurosciences, Ames, Iowa: Todd Ajax MD; University of California, San Francisco: Michael Aminoff MD, FRCP, Julie Hevezi RN; Toronto Western Hospital, Toronto, Ontario: Julie So RN.

BIOSTATISTICS AND COORDINATION CENTERS STAFF

University of Rochester: Janice Bausch BS, Alicia Brocht BA, Chris Chadwick MPH, Susan DaigneaultShirley Eberly MS, Michele Goldstein BS, Karen HodgemanCarrie Irvine BS, Debbie Johnsen BS, (project coordinator), Cornelia Kamp MBA, CCRC, (director of research operations, Clinical Trials Coordination Center), Dee KampMargot Lutz RN, (senior project coordinator), Sandra Plumb BS, (senior project coordinator), Aileen Shinaman JD, (executive director, Parkinson Study Group), Chris Weaver.

SAFETY MONITORING COMMITTEE

University of Rochester: Pierre Tariot MD, (chair), Christopher Cox PhD, ; Medical College of Georgia: L. Michael Prisant MD; University of Iowa, Iowa City: Robert Rodnitzky MD.

SPONSORS

Teva Pharmaceutical Industries, Ltd: Sheila Oren MD, Ruth Levy PhD, Eli Eyal MSc, Tamar Goren PhD, Shoshi Friedman; Teva Neuroscience LLC, North Wales, Pa: Phyllis Salzman PhD, Bruce Schwartz PhD; H. Lundbeck A/S: Misser Forrest MD.

Correspondence: Steven R. Schwid, MD, Department of Neurology, University of Rochester Medical Center, 601 Elmwood Ave, Box 605, Rochester, NY 14642 (steven_schwid@urmc.rochester.edu).

Accepted for Publication: June 8, 2004.

Author Contributions:Study concept and design: Schwid, Shoulson, Stern, Oakes, Kieburtz, Fahn, Blindauer, deMarcaida, Fazzini, Chin, Hauser, Gauger, Ondo, Lewitt, Racette, Frei, Luong, Pahwa, Jennings, Fink, Tabbal, Uc, Panisset, Molho, Schwieterman, Mahtat, Camiciolo, King, Wojcieszek, Judd, Berry, F. Gordon, Hermanowicz, Shulman, Cines, Suchowersky, Williamson, Serrano Ramos, Roque, Benabou, Carpenter, Feigin, Riley, Calabrese, Standaert, Tennis, Manyam, Whetteckey, Wulbrecht, McGinn, Aminoff, Hevezi, Bausch, Chadwick, Irvine, Johnsen, C. Kamp, Plumb, Shinaman, Weaver, Oren, Levy, Eyal, and Salzman. Acquisition of data: Schwid, Shoulson, Kieburtz, deMarcaida, Fazzini, Chin, Scott, Wilcox, Colcher, Reichwein, Hauser, Gauger, Leehey, Lewitt, Kaminski, Harrison, Rost-Ruffner, Racette, Cooper, Frei, Luong, Pahwa, DiCarlo, Lew, Kawai, Jennings, Caplan, Novak, Thomas, Chouinard, Beauvais, Tabbal, Uc, Patterson, Fernandez, Bertoni, Skrypnik, Panisset, Fortin, Molho, Nash, Dalvi, Schwieterman, Goetz, Janko, Mendis, Mahtat, Gray, Camiciolo, King, Wojcieszek, Kumar, Judd, D. Margolin, J. J. Margolin, Clem, P. Gordon, Marshall, Berry, Rottenberg, Hansen, F. Gordon, Hassan, Keltonic, Hermanowicz, Niswonger, Jog, Horn, Shulman, Cines, Suchowersky, Furtado, Durwent, Samanta, Williamson, Serrano Ramos, Berrios, Roque, Sutton, Young, Waters, Benabou, Singer, Koller, Martin, Sethi, Carpenter, Rao, Cook, Feigin, M. Cox, Riley, Calabrese, Standaert, Tennis, Manyam, Whetteckey, Wulbrecht, Rajput, Golbe, Caputo, Freeman, McGinn, Subramanian, Ajax, Aminoff, Hevezi, So, Brocht, Chadwick, Daigneault, Goldstein, Hodgeman, Irvine, Johnsen, C. Kamp, Lutz, Plumb, Weaver, Oren, Levy, Eyal, Salzman, Schwartz, and Forrest. Analysis and interpretation of data: Schwid, Oakes, Fahn, Blindauer, deMarcaida, Elmer, Davis, Hauser, Bertoni, Panisset, Goetz, Kumar, Marshall, Suchowersky, Singer, Koller, Calabrese, Subramanian, Bausch, Brocht, Eberly, Tariot, C. Cox, Prisant, Rodnitzky, Eyal, Goren, Friedman, and Salzman. Drafting of the manuscript: Schwid, Shoulson, Oakes, Fahn, DiCarlo, Fink, Fernandez, Bertoni, Camiciolo, Rottenberg, Jog, Singer, Calabrese, McGinn, C. Kamp, and Schwartz. Critical revision of the manuscript for important intellectual content: Shoulson, Stern, Oakes, Kieburtz, Fahn, Blindauer, deMarcaida, Elmer, Davis, Fazzini, Chin, Scott, Wilcox, Colcher, Reichwein, Hauser, Gauger, Leehey, Ondo, Lewitt, Kaminski, Harrison, Rost-Ruffner, Racette, Cooper, Frei, Luong, Pahwa, Lew, Kawai, Jennings, Caplan, Novak, Thomas, Chouinard, Beauvais, Tabbal, Uc, Patterson, Fernandez, Bertoni, Skrypnik, Panisset, Fortin, Molho, Nash, Dalvi, Schwieterman, Goetz, Janko, Mendis, Mahtat, Gray, Camiciolo, King, Wojcieszek, Kumar, Judd, D. Margolin, J. J. Margolin, Clem, P. Gordon, Marshall, Berry, Hansen, F. Gordon, Hassan, Keltonic, Hermanowicz, Niswonger, Horn, Shulman, Cines, Suchowersky, Furtado, Durwent, Samanta, Williamson, Serrano Ramos, Berrios, Roque, Sutton, Young, Waters, Benabou, Koller, Martin, Sethi, Carpenter, Rao, Cook, Feigin, M. Cox, Riley, Calabrese, Standaert, Tennis, Manyam, Whetteckey, Wulbrecht, Rajput, Golbe, Caputo, Freeman, Subramanian, Ajax, Aminoff, Hevezi, So, Bausch, Brocht, Chadwick, Daigneault, Eberly, Goldstein, Hodgeman, Irvine, Johnsen, D. Kamp, Lutz, Plumb, Shinaman, Weaver, Tariot, C. Cox, Prisant, Rodnitzky, Oren, Levy, Eyal, Goren, Friedman, Salzman, and Forrest. Statistical analysis: Oakes, Eberly, Irvine, C. Cox, and Eyal. Obtained funding: Shoulson, Kieburtz, Rajput, Shinaman, and Levy. Administrative, technical, and material support: Schwid, Stern, Blindauer, Fazzini, Chin, Wilcox, Colcher, Gauger, Ondo, Lewitt, Harrison, Rost-Ruffner, Racette, Frei, Luong, Pahwa, DiCarlo, Chouinard, Tabbal, Uc, Patterson, Fernandez, Bertoni, Skrypnik, Panisset, Fortin, Nash, Dalvi, Schwieterman, Mahtat, Gray, Wojcieszek, Judd, D. Margolin, J. J. Margolin, Clem, P. Gordon, Marshall, Rottenberg, Hansen, F. Gordon, Keltonic, Horn, Shulman, Durwent, Serrano Ramos, Roque, Sutton, Young, Singer, Martin, Rao, Cook, Feigin, M. Cox, Calabrese, Tennis, Manyam, Whetteckey, Wulbrecht, Golbe, Caputo, Subramanian, Ajax, Hevezi, So, Brocht, Chadwick, Daigneault, Goldstein, Hodgeman, Irvine, C. Kamp, D. Kamp, Plumb, Shinaman, Weaver, Tariot, Prisant, Goren, and Salzman. Study supervision: Schwid, Shoulson, Oakes, Fahn, Blindauer, Fink, Dalvi, Kumar, Berrios, Sutton, Koller, Golbe, C. Kamp, Plumb, Tariot, Levy, Salzman, and Forrest.

Funding/Support: This study was supported by Teva Pharmaceutical Industries, Ltd, and by H. Lundbeck A/S.