A Controlled Trial of Rotigotine Monotherapy in Early Parkinson's Disease FREE

CLINICAL TRIALS have demonstrated efficacy of oral dopamine agonists in early Parkinson's disease (PD) and have shown a lower incidence of dyskinesias and motor fluctuations in subjects treated initially with an oral dopamine agonist compared with subjects treated initially with levodopa.^1- 2 Rotigotine (SPM 962) (Loh-mann Therapy System AG, Andernoch, Germany) is a novel, nonergot, selective D₂-dopamine receptor agonist, which has been formulated in a silicone-based transdermal system.^3- 4 Pharmacokinetic data of this transdermal delivery system in healthy volunteers have shown that steady-state plasma levels of active drug are reached after 24 hours, and a stable drug release profile is maintained throughout the 24-hour period while the patch is in place.⁴ The rationale behind developing this transdermal delivery system is 2-fold: to provide a nonoral route of dopamine agonist administration and, by maintaining relatively stable blood levels of a dopamine agonist for 24 hours, to potentially avoid pulsatile stimulation of the dopamine receptors (which may contribute to the development of motor fluctuations and dyskinesias). Thus far, rotigotine has been shown to be safe and well tolerated in phase 1 and 2a studies in patients with early and advanced PD.^3- 4 We, therefore, conducted a study to determine the efficacy, safety, and tolerability of rotigotine in patients with early PD who required but were not yet receiving other dopaminergic therapy.

This randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-ranging study was designed to determine the efficacy, safety, and tolerability of rotigotine in patients with early PD who were not yet receiving dopaminergic therapy. This study included a 4-week maximum screening period, during which the last 4 to 7 days included a placebo patch run-in period, a 4-week double-blind dose titration period, a 7-week dose maintenance phase, a 1-week dose de-escalation period, and a 2-week safety follow-up period without study drug. The placebo patch run-in period was used to ensure that subjects could apply and remove patches appropriately and to evaluate subjects for any immediate cutaneous hypersensitivity reactions.

The study was reviewed and approved by the institutional review board at each of the participating sites, and all subjects gave written informed consent. Two hundred forty-two eligible subjects were randomized in the trial at 36 Parkinson Study Group (PSG) sites between November 29, 1999, and August 10, 2000. Eligible subjects included men and women older than 30 years who were diagnosed as having idiopathic PD and had a Hoehn and Yahr stage of 3 or less.⁵ Subjects were permitted to take selegiline, amantadine, or anticholinergic agents if maintained at stable dosages for 28 days before baseline and throughout the trial. Subjects were excluded if they had cognitive impairment defined by a Mini-Mental State Examination⁶ score of less than 24; were unable to appropriately apply and remove the patches; had a history of skin sensitivity to adhesives or other transdermal medications; had taken a dopamine agonist or levodopa within 28 days of the baseline visit or had ever taken levodopa for longer than 6 months; had an atypical parkinsonian syndrome; had a clinically unstable medical or psychiatric condition; had cardiac abnormalities such as arrhythmias, conduction blocks, congestive heart failure, QT-corrected interval of 500 milliseconds or more, unexplained syncope, symptomatic orthostatic hypotension, or a recent myocardial infarction; or had recent exposure to monoamine oxidase type A inhibitors, amphetamines, dopamine-depleting antihypertensive agents, neuroleptics, or antipsychotics or antiemetics that blocked central dopamine activity.

Subjects were randomized with equal allocation to 1 of 5 treatment groups: placebo, 4.5 mg of rotigotine, 9.0 mg of rotigotine, 13.5 mg of rotigotine, or 18.0 mg of rotigotine. The computer-generated randomization plan included stratification by center and blocking to ensure approximate balance among the treatment groups within each center. The plan was generated by a programmer (A.W.) in the PSG Biostatistics Center (Rochester, NY) and implemented with the Q-Tone Interactive Voice Response System (IVRS) (Quintiles Inc, Research Triangle Park, NC), which required the site staff to telephone to receive the appropriately assigned study drug kit number. Only designated staff members in the Biostatistics Center, Q-Tone IVRS, and Schwarz Pharma (Schwarz Pharma Manufacturing Inc, Seymour, Ind, and Schwarz Pharma Inc, Mequon, Wis), who packaged and labeled the drug, were potentially aware of the individual treatment assignments.

The transdermal system was manufactured for Schwarz Pharma by Lohmann Therapy System AG. The active drug was dissolved in a silicone adhesive spread evenly on a silicone backing to produce a concentration of 4.5 mg/10 cm². Laboratory and clinical studies demonstrated that the release of drug was uniform over the full surface of the patch, producing a dosage that is proportional to patch surface area and relatively constant over 24 hours (Schwarz Pharma, unpublished data, 1999).

Active rotigotine patches contained 4.5 mg of rotigotine per patch and were identical to the placebo patches. All subjects were instructed to wear 4 patches that contained various combinations of placebo and active drug and were applied once daily on the abdomen in a rotating scheme. All subjects, except those taking placebo, began active treatment at 4.5 mg/d, then were adjusted weekly by increments of 4.5 mg of rotigotine. Active drug starting times were staggered, so all subjects ultimately reached their maintenance dosage at the fourth week of the titration phase. A maximum of 2 dosage reductions were permitted for intolerable adverse effects during the second through fourth weeks of the dosage titration period. Subjects who required dosage reductions were not rechallenged with higher dosages of study drug.

Subjects were seen at the study centers for screening, baseline, week 2, week 4, week 7, week 11, and week 14 visits. The week 11 visit was the last visit while taking the study drug. At randomization and all follow-up visits, the investigator rated subjects using the Unified Parkinson's Disease Rating Scale (UPDRS),⁷ including the mental, activities of daily living (ADL), and motor components. Hoehn and Yahr stage was determined at screening, baseline, week 4, and week 11. Safety assessments at each visit included measurement of vital signs, 12-lead electrocardiograms (ECGs) at multiple times before and after patch application and removal, and a laboratory test panel, including a hematologic profile, basic metabolic panel, hepatic profile, and a urinalysis. Subjects were assessed for adverse experiences at each visit, and the skin was examined for any application site reactions. Medication compliance was determined at all follow-up visits by counting the unused patches returned by the subjects.

The primary outcome variable was prespecified as the change in the sum of the UPDRS parts 2 and 3 (ADL and motor components) between baseline and the week 11 visit. Secondary outcome variables for efficacy included changes in the UPDRS mental, ADL, and motor subscale scores and the change in Hoehn and Yahr stage between baseline and the week 11 visit. Safety was measured by the frequency and severity of adverse events and by changes in vital signs, ECGs, and clinical laboratory values that occurred after baseline. The primary tolerability measure was prespecified as whether the subject completed the entire 11-week study on the originally assigned treatment.

A projected sample size of 45 subjects per group (225 total) was calculated to provide approximately 90% power to detect a difference in the mean change in the sum of the motor and ADL components of the UPDRS of 5.0 units between the placebo group and the highest dosage group, using a 1-tailed t test at the .025 level of significance. Based on previous similar trials conducted by the PSG, an SD of 7.0 units was assumed for this calculation.⁸ For the primary analysis, the last available postbaseline observation was used for subjects who withdrew from the trial. The sample size estimate assumed that approximately 5% of subjects would not have postbaseline measurements.

The prespecified primary analyses of efficacy used an analysis of covariance model to compare the treatment groups regarding the primary outcome variable, with treatment group included in the model as the factor of interest and the baseline value of the motor and ADL UPDRS score included as a covariate. A closed testing procedure⁹ was used in conjunction with this model whereby a 1-tailed t test was performed of the null hypothesis of equal mean responses in the highest dosage group and the placebo group. If (and only if) this null hypothesis was rejected, a 1-tailed t test was performed of the null hypothesis of equal mean responses in the second highest dosage group and the placebo group and so on. The procedure was terminated when a null hypothesis could not be rejected. Each test was performed at the .025 level of significance. In addition, 95% confidence intervals were computed for the differences between the adjusted group means in each active treatment group and the placebo group using this analysis of covariance model. Secondary outcome variables for efficacy, as well as changes in laboratory test results, vital signs, and ECG results, were similarly analyzed. Although we performed 1-tailed t tests using a .025 level of significance, the P values reported are 2-tailed and use the conventional .05 significance level.

The primary analyses of tolerability used a series of 1-tailed Fisher's exact tests to compare each active treatment group separately with the placebo group regarding the proportion of subjects completing the study on the originally assigned dosage. One-tailed tests were used because it was thought that a finding of poorer tolerability in the placebo group would be highly unlikely. Analyses of safety variables were mainly descriptive. Frequencies of individual adverse events and abnormal laboratory test or ECG results were analyzed in a manner similar to that for the tolerability measures, except that 2-tailed Fisher's exact tests were used.

The primary statistical analyses were performed according to the intention-to-treat principle. All subjects were included in the analyses of tolerability and adverse events. For the analyses of the efficacy variables, if a subject was missing data at a particular visit, the last available postbaseline observation for that subject was carried forward and imputed for that visit.

Of the 297 subjects who were identified as potential study participants at the screening evaluation, 55 were found to be ineligible or chose not to enroll for the following reasons: ECG abnormalities in 22 subjects; clinically active or unstable medical conditions in 12 subjects; use of exclusionary medications in 6 subjects; stringency of protocol in 2 subjects; placebo control in 2 subjects; and other reasons, including lack of interest, in 11 subjects. No subjects withdrew during the placebo patch run-in. The remaining 242 eligible subjects were randomized to 1 of the 5 treatment groups (Figure 1). There were no important differences among the 5 treatment groups in the baseline demographic and clinical variables (Table 1).

The mean (SD) changes from baseline to week 11 in the combined motor and ADL UPDRS score by intention-to-treat analysis for each group were as follows: placebo, −0.29 (7.66); 4.5 mg of rotigotine, −1.20 (6.53); 9.0 mg of rotigotine, −3.13 (6.37); 13.5 mg of rotigotine, −5.09 (7.03); and 18.0 mg of rotigotine, −5.30 (7.02) (Figure 2). Treatment effects at week 11 were statistically significant in the 13.5- and 18.0-mg groups, and a dose-response relationship was evident from 4.5 to 13.5 mg, with a plateau between 13.5 and 18.0 mg (Table 2 and Figure 2). The results for the subset of subjects completing the full 11 weeks of treatment while taking the assigned drug were similar to those from the intention-to-treat analysis. Statistically significant improvements in the sum of the motor and ADL UPDRS scores occurred in the active treatment groups by the week 4 visit and persisted throughout the maintenance phase (Figure 2). The UPDRS scores returned toward the prior baseline values in all treatment groups following withdrawal of study medications by the week 14 visit.

Ninety-one percent of all subjects reported at least 1 adverse event during the 14-week trial. The most commonly reported adverse events among all the treatment groups are listed in Table 3. Adverse events that occurred more commonly among subjects assigned to active treatment included nausea, application site reactions, dizziness, somnolence, insomnia, vomiting, and fatigue. Application site reactions were mild or moderate in most cases and severe in only 5 cases. The mild application site reactions most commonly appeared as a geographical region of erythema corresponding to the area of the removed patch. Some of the more severe cases manifested as blistering and/or ulceration of the skin previously under the patches and also including the surrounding area in some cases. When the application site reaction data were analyzed per actual dosage taken, approximately 35% of the application site reactions first occurred while subjects were taking placebo. Nausea and vomiting occurred primarily during the dosage titration phase, with a trend toward symptom onset at the time of initiation of active drug. Hallucinations were rare and mild, occurring in only 1 subject in each treatment group except for the 4.5-mg group in which no hallucinations were reported.

No deaths occurred. Nine serious adverse events occurred (placebo, 1 subject; 4.5 mg of rotigotine, 3 subjects; 13.5 mg of rotigotine, 3 subjects; and 18.0 mg of rotigotine, 2 subjects). Sudden onset of sleep while driving (13.5 mg) and brief loss of consciousness while driving (18.0 mg) were reported among these 9 serious adverse events and were judged by the investigator as having a highly probable and probable relationship, respectively, to the study drug. One subject in the 4.5-mg group reported tachycardia, which was thought to be possibly related to the study drug; however, a subsequent cardiac evaluation, including ambulatory monitoring, did not detect any tachyarrhythmia. Another subject in the 4.5-mg group developed eosinophilia and neutropenia while using the placebo patches in the titration phase, which normalized within 8 days after discontinuation of study drug. The other 5 serious adverse events were classified as unrelated to the study drug and included 3 events related to elective orthopedic surgery, 1 unwitnessed fall in which the subject sustained a closed head injury, and 1 case of squamous cell carcinoma of the lower lip. No clinically relevant changes in laboratory test results, vital signs, or ECG results occurred in any of the subjects undergoing active treatment after randomization.

Eighty-three percent of the subjects in the placebo group completed the study while taking their originally assigned dosage compared with 69% (P = .09) in the 4.5-mg group, 60% (P = .01) in the 9.0-mg group, 65% (P = .04) in the 13.5-mg group, and 75% (P = .22) in the 18.0-mg group. Forty-six subjects required a single dosage reduction. Two of the 11 subjects undergoing a dosage reduction in the 4.5-mg group underwent a sham dose reduction while they were still using placebo patches before the fourth week of the titration phase. Two dosage reductions were required by 4 additional subjects, 1 in each group except the 9.0-mg group.

Thirty-six subjects withdrew before completing the study (Figure 1); differences among groups were not significant. The most frequent reason for subject withdrawal was the occurrence of adverse events. Eight subjects (4.5-mg group, 1 subject; 13.5-mg group, 3 subjects; and 18.0-mg group, 4 subjects) cited a skin reaction as the reason for early withdrawal, and 2 subjects experienced sudden onset of sleep or a brief loss of consciousness while driving (13.5- and 18.0-mg groups). The other adverse events leading to withdrawal included the following: falling, somnolence and weakness, headache (n = 2), tachycardia, insomnia, confusion, orthostatic hypotension, nausea and vomiting, prolonged QT-corrected interval, severe nausea and dizziness, dry heaves, and neutropenia. The 3 subjects in the "other" category had ECGs that met exclusion criteria at baseline.

The compliance rate, as calculated from the unused patches, was determined to be approximately 97.5% in all 5 treatment groups.

Our placebo-controlled clinical trial demonstrated that rotigotine administered transdermally at dosages ranging from 4.5 to 18.0 mg/d was safe and generally well tolerated for up to 11 weeks in subjects with early PD. Our study also defined the minimum effective dosage of rotigotine in the 9.0- to 13.5-mg range and demonstrated a dose-response relationship among the active treatment groups up to 13.5 mg, with a plateau in the therapeutic effect occurring between 13.5 and 18.0 mg. Tachyphylaxis related to continuous dopamine receptor stimulation was not apparent during the 8 to 11 weeks of active treatment.

Transdermal rotigotine treatment produced clinical improvement in parkinsonian symptoms (as measured by the change in motor and ADL UPDRS score between baseline and 11 weeks of treatment) comparable to that reported after administration of the dopamine agonists pramipexole and ropinirole.^1- 2,8 This study confirms the preliminary data³ that a dopamine agonist can be effectively and safely delivered via transdermal administration.

The adverse events that were reported significantly more frequently with rotigotine (eg, nausea, vomiting, fatigue, somnolence) were qualitatively similar to those reported in other studies of dopamine agonists in patients with early PD.^8,10 The sudden onset of sleep or brief loss of consciousness while driving experienced by 2 rotigotine-treated subjects resembled the sudden "sleep attacks" reported with other dopamine agonists.¹¹

The application skin site reaction, an adverse effect that occurred with both placebo and active patches, seemed to be related in part to the transdermal delivery system but still occurred more frequently in the higher dosage groups. The risk of application site reaction may have been increased by the study requirement to apply 4 patches daily to sites limited to the abdomen. This risk could possibly be reduced by rotating the patch application sites to the limbs and other areas of the torso.

A transdermal delivery system offers potential applications for patients who are unable to swallow or tolerate orally administered medications. Additionally, this delivery system should not be affected by food or gastric emptying, unlike oral formulations. Furthermore, the once-daily dosing is convenient and may enhance subject compliance compared with the oral formulations of dopamine agonists.

Transdermal rotigotine may also have the advantage of maintaining constant blood levels of a dopamine agonist over a 24-hour period. This potentially could lower the long-term risk of developing motor fluctuations or dyskinesias and could make rotigotine beneficial for smoothing out motor fluctuations in patients with advanced PD. An initial trial of rotigotine in patients with advanced PD with motor fluctuations showed a reduction in off time in treated subjects, but the magnitude of change failed to reach statistical significance when compared with placebo.¹² Future studies of rotigotine are warranted to further define its role in the treatment of motor fluctuations in levodopa-treated patients with more advanced PD and also to determine its potential in patients with early PD for reducing the incidence of motor complications compared with levodopa and orally administered dopamine agonists.

The following members of the Parkinson Study Group participated in the PATCH I (PArkinson's disease Transdermal Clinical trial Helping to assess SPM-962 TDS in patients not receiving dopaminergic therapy) study and were authors of this report.

Medical College of Wisconsin, Milwaukee: Karen Blindauer, MD (coprincipal investigator); University of Rochester, Rochester, NY: Ira Shoulson, MD (principal investigator); Karl Kieburtz, MD, MPH (director, Clinical Trials Coordination Center); Michael McDermott, PhD (chief biostatistician); Irenita Gardiner, RN, CCRC (project coordinator); Cornelia Kamp, MBA, CCRC (director research operations, Clinical Trials Coordination Center); Frederick Marshall, MD; Lin Zhang, MD, PhD (medical monitor); M. Aileen Shinaman, JD (PSG executive director); Columbia-Presbyterian Medical Center, New York, NY: Stanley Fahn, MD; University of Calgary, Calgary, Alberta: Oksana Suchowersky, MD; University of Virginia Health Sciences Center, Charlottesville: Frederick G. Wooten, MD.

The Parkinson's & Movement Disorder Institute, Fountain Valley, Calif: Karen Frei, MD, Mayank Pathak, MD, Nancy Luong, BS; University of Minnesota, Minneapolis: Paul Tuite, MD, Robyn Schacherer, RN; Yale University, New Haven, Conn: Danna Jennings, MD, Karen Stavris, RN, MSN; Indiana University School of Medicine, Indianapolis: Joanne Wojcieszek, MD, Jo Ann Belden, RN; Medical College of Ohio, Toledo: Lawrence Elmer, MD, PhD, Lisa Aiken, RN, MSN; Saskatoon District Health Board Royal University Hospital, Saskatoon, Saskatchewan: Alexander Rajput, MD, Ali Rajput, MD, Marianne Ewanishin, RN, Theresa Shirley, RN; University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical Center, New Brunswick: Lawrence Golbe, MD, Debbie Caputo, RN, MSN; The University of Texas Southwestern Medical Center, Dallas: Richard Dewey, Jr, MD, Barbara Estes, RN; University of Rochester: Toni DeMarcaida, MD, Timothy Counihan, MD, Cheryl Deeley, MS, RNC; Baylor College of Medicine, Houston, Tex: Joseph Jankovic, MD, Christine Hunter, RN; Brown University/Memorial Hospital of Rhode Island, Pawtucket: Hubert H. Fernandez, MD, Margaret C. Lannon, RN, MS; The Ohio State University, Columbus: Jean Hubble, MD; University of Calgary, Calgary, Alberta: Anne-Louise La Fontaine, MD, Carol Pantella, RN, Lorelei Derwent, RN; Hunter Homes McGuire Veterans Medical Center, Richmond, Va: Vincent Calabrese, MD, Peggy Roberge, RN; Oregon Health & Science University, Portland: Jau-Shin Lou, MD, PhD, Pamela Andrews, BS; Toronto Western Hospital, University Health Network, Toronto, Ontario: Anette Nieves, MD, Elspeth Sime, RN; University of California, San Diego: Cliff Shults, MD, Deborah Fontaine, RNC, GNP; Washington University, St Louis, Mo: Brad Racette, MD, Patti Cooper, RN; University of Southern California, Los Angeles: Mickie Welsh, RN, DNSc, Connie Kawai, RN, BSN, CCRC; North Shore University Hospital, Manhassett, NY: Andrew Feigin, MD, Barbara Shannon, RN; Columbia-Presbyterian Medical Center, New York, NY: Maria SanGiorgio, MD, Cheryl Waters, MD; University of South Florida, Tampa: Robert Hauser, MD, Lisa Gauger, BA; McGill Centre for Studies in Aging, Verdun, Quebec: Michel Panisset, MD, Jean Hall, RN; Colorado Neurological Institute, Englewood: Christopher O'Brien, MD, Deborah Judd, RN; University of Cincinnati/University Neurology, Inc, Cincinnati, Ohio: Arif Dalvi, MD, Donna Schwieterman, MA, CCRC; Barrow Neurological Institute, Phoenix, Ariz: Padma Mahant, MD, Kelli Williamson, RN; University of California, San Francisco: Chadwick Christine, MD, Julie Hevezi, RN; The University of Chicago, Chicago: Un Jung Kang, MD, Judy Richman, RN; Rush-Presbyterian-St Luke's Medical Center, Chicago: Katie Kompoliti, MD, Jeana Jaglin, RN; University of Virginia Health Sciences Center, Charlottesville: Joel Trugman, MD, Elke Rost-Ruffner, RN, BSN; Ottawa Hospital Civic Site, Ottawa, Ontario: David Grimes, MD; University of Pennsylvania, Philadelphia: Amy Colcher, MD, Suzanne Reichwein, CCRC; Beth Israel Deaconess Medical Center, Boston, Mass: Daniel Tarsy, MD, Patricia Ryan, MS, MPH; Creighton University, Omaha, Neb: John Bertoni, MD, PhD, Carolyn Peterson, RN; University of Alabama at Birmingham: Paul Atchison, MD, Cathy Allen, RN, BSN; Movement Disorder Clinic, Vernon, British Columbia: Terry Curran, MD, Suzanne Bailey, RN.

University of Rochester: Alicia Brocht, BS, Karen Hodgeman, CCRA, Lee Josephson, BS, Eric Lenio, MBA, Carolynn O'Connell, Karen Rothenburgh, Lisa Rumfola, Arthur Watts, BS, Chris Weaver.

University of Rochester: Pierre Tariot, MD (chair), Richard Raubertas, PhD; National Institute Neurological Disorders, Bethesda, Md: Thomas Chase, MD.

Sponsors: Schwarz Pharma Inc: Thomas Goodin, PhD, Joseph Bianchine, MD, PhD, Franz Woltering, PhD; Quintiles Cardiac Alert, London, England: Boaz Mendzelevski, MD.

Corresponding author and reprints: Karen Blindauer, MD, Department of Neurology, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226 (e-mail: kblindau@mcw.edu).

Accepted for publication September 4, 2003.

Author Contributions: Study concept and design (Drs Blindauer, Shoulson, Kieburtz, McDermott, Marshall, Zhang, Fahn, Suchowersky, Wooten, Goodin, Bianchine, and Woltering; Mss Gardiner, Kamp, and Shinaman); acquisition of data (Drs Frei, Pathak, Tuite, Jennings, Wojcieszek, Elmer, Alexander Rajput, Ali Rajput, Golbe, Dewey, DeMarcaida, Counihan, Jankovic, Fernandez, Hubble, Lafontaine, Calabrese, Lou, Nieves, Shults, Racette, Welsh, Feigin, SanGiorgio, Waters, Hauser, Panisset, O'Brien, Dalvi, Mahant, Christine, Kang, Kompoliti, Trugman, D. Grimes, Colcher, Tarsy, Bertoni, Atchison, Curran, and Mendzelevski; Mss Luong, Schacherer, Stavris, Belden, Aiken, Ewanishin, Shirley, Caputo, Estes, Deeley, Hunter, Lannon, Pantella, Derwent, Roberge, Andrews, Sime, Fontaine, Cooper, Kawai, Shannon, Gauger, Hall, Judd, Schwieterman, Williamson, Hevezi, Richman, Jaglin, Rost-Ruffner, Reichwein, Ryan, Peterson, Allen, Bailey, Brocht, Hodgeman, Josephson, O'Connell, Rothenburgh, Rumfola, and Weaver; and Mr Lenio); analysis and interpretation of data (Drs Blindauer, Shoulson, Kieburtz, McDermott, Marshall, Zhang, Fahn, Suchowersky, and Wooten; Mss Gardiner and Kamp; and Mr Watts); drafting of the manuscript (Drs Blindauer, Shoulson, Kieburtz, McDermott, Marshall, Fahn, Suchowersky, and Wooten; and Mss Gardiner and Kamp); critical revision of the manuscript for important intellectual content (Drs Frei, Pathak, Tuite, Jennings, Wojcieszek, Elmer, Alexander Rajput, Ali Rajput, Golbe, Dewey, DeMarcaida, Counihan, Jankovic, Fernandez, Hubble, Lafontaine, Calabrese, Lou, Nieves, Shults, Racette, Welsh, Feigin, SanGiorgio, Waters, Hauser, Panisset, O'Brien, Dalvi, Mahant, Christine, Kang, Kompoliti, Trugman, D. Grimes, Colcher, Tarsy, Bertoni, Atchison, Curran, Raubertas, Chase, Bianchine, and Mendzelevski; and Mss Luong, Schacherer, Stavris, Belden, Aiken, Ewanishin, Shirley, Caputo, Estes, Deeley, Hunter, Lannon, Pantella, Derwent, Roberge, Andrews, Sime, Fontaine, Cooper, Kawai, Shannon, Gauger, Hall, Judd, Schwieterman, Williamson, Hevezi, Richman, Jaglin, Rost-Ruffner, Reichwein, Ryan, Peterson, Allen, and Bailey); statistical expertise (Drs McDermott and Woltering and Mr Watts); obtained funding (Drs Shoulson and Kieburtz and Mss Kamp and Shinaman); administrative, technical, and material support (Drs Frei, Pathak, Tuite, Jennings, Wojcieszek, Elmer, Alexander Rajput, Ali Rajput, Golbe, Dewey, DeMarcaida, Counihan, Jankovic, Fernandez, Hubble, Lafontaine, Calabrese, Lou, Nieves, Shults, Racette, Welsh, Feigin, SanGiorgio, Waters, Hauser, Panisset, O'Brien, Dalvi, Mahant, Christine, Kang, Kompoliti, Trugman, D. Grimes, Colcher, Tarsy, Bertoni, Atchison, Curran, Bianchine, and Mendzelevski; Mss Luong, Schacherer, Stavris, Belden, Aiken, Ewanishin, Shirley, Caputo, Estes, Deeley, Hunter, Lannon, Pantella, Derwent, Roberge, Andrews, Sime, Fontaine, Cooper, Kawai, Shannon, Gauger, Hall, Judd, Schwieterman, Williamson, Hevezi, Richman, Jaglin, Rost-Ruffner, Reichwein, Ryan, Peterson, Allen, Bailey, Brocht, Hodgeman, Josephson, O'Connell, Rothenburgh, Rumfola, and Weaver; and Messrs Lenio and Watts); study supervision (Drs Blindauer, Shoulson, Kieburtz, Marshall, Zhang, Tariot, Raubertas, and Chase; and Mss Gardiner and Kamp).

This study was supported primarily by Schwarz Pharma Inc.

In keeping with the PSG conflict of interest guidelines, none of the investigators have any personal financial relationships with the sponsor. All compensation received by investigators for trial-related services was paid through a contract between the University of Rochester and the sponsor that was established before the trial began.

We thank the patients and their families who participated in this study. We acknowledge the PSG clinical research associates Lorraine Rexo, Donna Sorokti, and Ellen Wratni. Contributions from the following are acknowledged: Schwarz Pharma Inc; Theresa Thomas, MS, MT; Patricia Fischer, BS; Scott Proksch, BS; Kate Poole, MSW; Lee Anne Borden, BS; and Barbara Stegmann, MD, PhD.