Preladenant As an Adjunctive Therapy with Levodopa in Parkinson Disease: Two Randomized Clinical Trials and Lessons Learned

Supplementary Online Content

Hauser RA, Stocchi F, Rascol O, et al. Preladenant as an adjunctive therapy with levodopa in Parkinson disease: two randomized clinical trials and lessons learned. JAMA Neurol. Published online October 19, 2015. doi:10.1001/jamaneurol.2015.2268.

eMethods. Sequential Testing Procedures to Control for Multiplicity in Trial-1 (A) and Trial-2 (B) eFigure 1. Estimated Mean +/- SE Change From Baseline in Average OFF Time (Hours/Day) Over Time in Trial-1 (A) and Trial-2 (B) eFigure 2. Estimated Mean +/- SE Change From Baseline in UPDRS Part-3 Scores Over Time in Trial-1 (A) and Trial-2 (B) eTable 1. Number (%) of Patients With Adverse Events (All-Patients-as-Treated) eTable 2. Comparison of Rasagiline Results and Patient Characteristics in Trial-1 versus LARGO and PRESTO Trials eTable 3. Preladenant Drug Exposure in Trial-1 Compared With Phase-2b Trial eTable 4. Post-Hoc Analysis: Differences in OFF Time (Hours/Day) at Week-12 by Enrollment Half (Trial-1, Full Analysis Set) eTable 5. Summary of Previously Published Randomized Controlled Trials of Adenosine 2a Receptor Antagonists as Adjunct Therapy in PD (With the 2 Current Trials for Comparison) eReferences. Supplemental References eAppendix. Investigators in Trial-1 and Trial-2

This supplementary material has been provided by the authors to give readers additional information about their work.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 eMethods: Sequential Testing Procedures to Control for Multiplicity in Trial-1 (A) and Trial-2 (B) A.

If all tests in Step 1 are statistically significant (p ≤0.049), testing will continue with the endpoints in Step 2, and so on. Tests of rasagiline versus placebo were not incorporated into the multiplicity strategy.

If all tests in Step 1 are statistically significant (p ≤0.049), testing will continue with the endpoints in Step 2, and so on.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 eFigure 1. Estimated Mean +/- SE Change from Baseline in Average OFF Time (Hours/Day) over Time in Trial-1 (A) and Trial-2 (B).

PRL = Preladenant, PBO = Placebo, RAS = Rasagiline.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 eFigure 2. Estimated Mean +/- SE Change from Baseline in UPDRS Part-3 Scores over Time in Trial-1 (A) and Trial-2 (B)

* nominal p-value <0.05 versus placebo. PRL = Preladenant, PBO = Placebo, RAS = Rasagiline.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 eTable 1. Number (%) of Patients with Adverse Events (All-Patients-as-Treated) Preladenanta Placebo Rasagiline Trial-1 Trial-2 Trial-1 Trial-2 Trial-1 N = 460 N = 314 N = 155 N = 159 N = 154 Any AE 250 (54) 190 (61) 87 (56) 73 (46) 84 (55) Drug-related AEb 140 (30) 115 (37) 51 (33) 43 (27) 57 (37) Serious AE 14 (3) 7 (2) 6 (4) 4 (3) 9 (6) Discontinued due to 33 (7) 16 (5) 17 (11) 4 (3) 18 (12) AE Common AEs Constipation 26 (6) 25 (8) 1 (1) 4 (3) 2 (1) Headache 17 (4) 21 (7) 16 (10) 5 (3) 4 (3) Dyskinesia 22 (5) 14 (4) 8 (5) 5 (3) 21 (14) Dizziness 15 (3) 15 (5) 4 (3) 3 (2) 3 (2) Nausea 14 (3) 13 (4) 3 (2) 2 (1) 4 (3) Fall 15 (3) 15 (5) 5 (3) 8 (5) 7 (5) aData are pooled over preladenant doses (2, 5 and 10mg BID in Trial-1, 2 and 5mg BID in Trial- 2). bInvestigator determination while blinded to treatment.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 eTable 2: Comparison of Rasagiline Results and Patient Characteristics in Trial-1 versus LARGO1 and PRESTO2 Trials Trial-1 (preladenant phase 3) LARGO PRESTO

Rasagiline difference from 1 mg: -0.3 1 mg: -0.8 1 mg: -0.94 placebo in change from (95% CI -0.9, 0.3) (95% CI -1.2, -0.4) (95% CI -1.36, -0.51) baseline OFF time (hour) at 12 weeks at 18 weeks 0.5 mg: -0.49 (95% CI -0.91, -0.08) at 26 weeks Mean age, years 63 64 63 Male gender, % 50-63 58-67 62-66 Median PD duration, years 8.2-8.9 8.7-9.2 8.8-9.3 Baseline median daily L-dopa 625-800 697-722 750-815 dose, mg Mean Hoehn & Yahr score 2.9 2.1 2.0 Patients taking dopamine 60-75 57-61 71-72 agonists, % Baseline OFF time, hour 5.6-6.1 5.5-5.6 6.0-6.3 Baseline ON time without 9.5-10.2 9.0-9.1 9.4-9.5 troublesome dyskinesia, hour Regions European Union, Eastern Europe, Israel, Argentina North America, Puerto Rico Europe, North America, Latin America, India, Turkey

Downloaded From: https://jamanetwork.com/ on 09/30/2021 eTable 3. Preladenant Drug Exposure in Trial-1 Compared With Phase-2b Trial3 Preladenant dose Geometric mean (80% CI) AUC, hr*ng/mL (number of patients Phase-2b/Trial-1) Phase-2b Trial-1 2 mg (47/135) 83.1 (63.2-120) 85.5 (63.0-116) 5 mg (42/134) 192 (144-263) 221 (150-344) 10 mg (53/142) 383 (236-657) 424 (271-625) AUC, area under the curve; CI, confidence intervals.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 eTable 4. Post-hoc Analysis: Differences in OFF Time (Hours/Day) at Week-12 by Enrollment Half (Trial-1, Full Analysis Set) Enrollment Model estimate Preladenant Preladenant Preladenant Placebo Rasagiline half 2 mg BID 5 mg BID 10 mg BID 1 mg QD

1st 50% Change from baseline -0.8 -1.2 -0.9 -0.03 -1.3

Difference -0.7 -1.2 -0.9 - -1.2 vs. Placebo (95% CI) (-1.55, 0.06) (-1.98, -0.36) (-1.69, -0.11) (-2.04, -0.41)

p-value 0.068 0.005 0.026 - 0.003

2nd 50% Change from baseline -1.0 -0.7 -0.7 -1.4 -1.0

Difference 0.4 0.7 0.7 - 0.4 vs. Placebo (95% CI) (-0.46, 1.17) ( -0.11, 1.53) (-0.14, 1.50) ( -0.41, 1.21)

p-value 0.391 0.089 0.106 - 0.333

Downloaded From: https://jamanetwork.com/ on 09/30/2021 eTable 5. Summary of Previously Published Randomized Controlled Trials of Adenosine 2a receptor Antagonists as Adjunct Therapy in PD (with the 2 Current Trials for Comparison)

Author Phase Dose Active No. No. Duration Region Mean Average Mean % Mean Placebo Treatment P-value (mg)* control arms randomized (weeks) age PD using baseline change change in (y) duration concomitant OFF in OFF OFF time (y) MAO-B time time (h) vs. placebo inhibitors (h) (h)#

Istradefylline Hauser 1b/2 ≤20, No 3 83 12 US 64 - 22 6.3 0.5 -1.7 0.004 20034 ≤40 LeWitt 2 40 No 2 196 12 North 64 9 16 6.3 -0.6 -1.2 0.006 20085 America Stacy 2 20, 60 No 3 395 12 North 64 8 11 5.9 -0.6 20: -0.6 0.026 20086 America 60: -0.8 0.024 Hauser 3 20 No 2 231 12 US 64 9 11 6.6 -0.9 -0.7 0.03 20087 Mizuno 2b/3 20, 40 No 3 363 12 Japan 64 8 52 6.6 -0.7 20: -0.7 0.013 20108 40: -0.9 <0.001 Pourcher 3 10, 20, No 4 610 12 North 63 9 13 6.7 -1.3 10: 0.3 NS (high 20129 40 America 20: 0.2 placebo 40: -0.2 response) Mizuno 3 20, 40 No 3 373 12 Japan 66 8 50 6.3 -0.2 20: -0.8 0.003 201310 40: -0.7 0.003 Preladenant Hauser 2 1, 2, 5, No 5 253 12 World- 62 - 24 5.7 -0.5 1: 0.2 NS 20113 10 wide 2: -0.7 NS 5: -1.0 0.049 10: -1.2 0.019 Hauser 3 2, 5, Rasagilin 5 778 12 World- 63 8 <1 5.9 -0.8 2: -0.1 NS Current 10 e 1mg wide 5:- 0.2 NS Trial-1 10: -0.0 NS Ras: -0.3 NS Hauser 3 2, 5 No 3 476 12 World- 64 8 <1 5.8 -0.8 2: -0.2 NS Current wide 5: -0.3 NS Trial-2 Tozadenant Hauser 2b 60, No 5 420 12 Americas 63 9 37 6.1 -0.8 60: -0.6 NS 201411 120, Eastern 120: -1.1 <0.001 180, Europe 180: -1.2 0.004 240 240: -0.9 NS *daily dose for istradefylline, twice-daily dose for preladenant and tozadenant

Downloaded From: https://jamanetwork.com/ on 09/30/2021 # Treatment change from baseline value minus placebo change from baseline value (i.e., the difference between treatment and placebo)  averaged across treatment groups NS = not significant

Downloaded From: https://jamanetwork.com/ on 09/30/2021 eReferences

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 eAppendix. Investigators in Trial-1 and Trial-2 Trial-1 Austria: Eduard Auff, Medizinische Universitat Wien, Wien; Regina Katzenschlager, SMZ Ost Donauspital, Wien; Werner Poewe, Univ. Klinik Innsbruck, Innsbruck; Reinhold Schmidt, Universitätsklinik für Neurologie, Graz; Brazil: Vanderici Borges, Universidade Federal de Sao Paulo - UNIFESP, Sao Paulo; Carlos Roberto De Mello Rieder, Hospital das Clinicas de Porto Alegre, Porto Alegre; Andre Luis Fernandes Palmini, Hospital Sao Lucas da PUC-RS, Porto Alegre; Vitor Tumas, Hospital das Clinicas da FMRP, Ribeirao Preto; Ana Lucia Zuma Rosso, Hospital Universitario Clementino Fraga Filho - UFRJ, Rio de Janeiro; Bulgaria: Sonya Ivanova/Ivan Milanov, SHATNP, Sofia; Latchezar Traykov, UMHAT, Sofia; Zahari Zahariev, UMHAT, Plovdiv; Milena Milanova, MHATNP, Sofia; Canada: David Grimes/Martin Cloutier, The Ottawa Hospital-Civic Campus, Ottawa, Ontario; Mark Guttman, Centre for Movement Disorders, Markham, Ontario; Anne-Louise LaFontaine, Montreal General Hospital, Montreal, QC; Tilak Mendis, Parkinson's and Neurodegenerative Disorders Clinic, Ottawa, Ontario; Oksana Suchowersky, University of Alberta Hospital, Edmonton, Alberta; Czech Republic: Edvard Ehler, Pardubicka krajska nemocnice a s, Pardubice; Jiri Polivka, Neurologicka klinika, Plzen – Lochotin; Jindra Svatova, Neurologicka ordinace, Praha; Martin Valis, Poliklinika Chocen, Chocen; Ladislav Pazdera, CTC Rychnov nad Kneznou s.r.o., Rychnov nad Knezou; Petr Docekal/Radoslav Bembenek, Clintrial s r o, Praha; Stanislav Vohanka, Fakultni nemocnice Brno, Brno; Katerina Zarubova, Neurologie – EEG, Praha; Finland: Juha- Pekka Eralinna, Suomen Terveystalo Clinical Research Oy, Turku; Vilho Myllylä, Terveystalo Oulu, Oulu; France: Jean Philippe Azulay, CHU de la Timone, Marseille; Olivier Rascol, CHRU de Touluse, Toulouse; Francois Viallet, Centre Hospitalier du Pays d'Aix, Aix-en-Provence; Sophie Drapier/Marc Verin, Hopital Pontchaillou, Rennes; Pascal Derkinderen, CHU de Nantes - Hopital Laennec, NANTES; Giovanni Castelnovo, CHU de Nimes, Nimes; Germany: Johann Hagenah, Universitaetsklinikum Schleswig Holstein, Luebeck; Siegfried Muhlack, St. Josef-Hospital, Bochum; Per Odin, Zentralkrankenhaus Reinkenheide, Bremerhaven; Christian Oehlwein, Gera; Wolfgag Oertel, Universitatsklinikum Marburg, Marburg; Martin Sommer, Universitaetsklinikum Goettingen, Goettingen; Reinhard Ehret, Neurologie Berlin, Berlin; Fabian Klostermann, Charite – Campus Benjamin Franklin, Berlin; India: Mohit Bhatt, Kokilaben Dhirubhai Ambani Hosp.& Med. Research Inst., Mumbai; Asha Kishore, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Kerala; Meena Angamuthu, Nizam's Institute of Medical Sciences, Hyderabad; Uday Muthane, Parkinsons and Aging Research Foundation, Karna; Charulata Sankhla, P.D. Hinduja Nat. Hospital & Med. Research Centre,Mumbai; G.R.K. Sharma, St. John's Medical College Hospital, Bangalore; Suresh Kumar, Vijaya Health Centre, Chennai; Israel: Tanya Gurevich, Tel- Aviv Sourasky Medical Center, Tel Aviv; Sharon Hassin, Chaim Sheba Medical Center, Ramat Gan; Radi Shahien, Ziv Medical Center, Zefat; Ilana Schlesinger, Rambam Health Care Campus, Haifa; Italy: Anna Rite Bentivoglio, Policlinico Universitario Agostino Gemelli, Rome; Paolo Del Dotto /Ubaldo Bonuccelli, Ospedale Verilia, Lucca; Roberto

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Marconi, U.O. di Neurologia, Grosseto; Giampietro Nordera, Casa di Cura Villa Margherita S r l, Arcugnano, Vicenza; Marco Onofrj, Fondazionne Universita Gabriele Dannunzio, Chieti; Fabrizio Stocchi, IRCCS San Raffaele Pisana, Rome; Alessandra Monge, l’ospedale San Giovanni Battista, Rome; Francesca DePandis, IRCCS San Raffaele Cassino, Frosinone; Stefano Ruggieri, I.R.C.C.S. Neuromed-Istituto Neurologico Mediterraneo, Isernia; Netherlands: Hank Berendese, VU Medisch Centrum, Amsterdam; Wijnand Rutgers/Martini Ziekenhuis, Groningen; Ad Vermeij, / K. Keizer, Catharina Ziekenhuis Eindhoven, Eindhove; Peru: Juan Altamirano, Clinica Anglo Americana, Lima; Cesar Abel Castañeda Diaz, Clinica Medavan, Lima; Carlos Cosentino, Clinica San Pablo, Lima; Edwin Javier Pretell, Policlinico Especializado en Neurologia, Lima; Liliana Elizabeth Rodriguez Kadota, Clinica Centenario Peruano Japonesa Neurology, Lima; Poland: Krzysztof Czyzewski, Centralny Szpital, Warszawa; Tomasz Hasiec, WSS im Stefana K Wyszynskiego SPZOZ, Lublin; Robert Kucharski, Regionalny Zespol Opieki Paliatywnej, Bydgoszcz; Maciej Maciejowski, Diagnomed Clinical Research, Katowice; Walenty Nyka, Uniwersyteckie Centrum Kliniczne, Gdansk; Grezegorz Opala, Specjalistyczna Praktyka Lekarska, Katowice; Danuta Pruchnik-Wolinska, Indywidualna Specjalistyczna Praktyka Lekarska, Poznania; Maria Sygitowicz, Indywidualna Specjalistyczna Praktyka Lekarska, Gdansk; Bozena Zaleska, Klinika Nasze Zdrowie, Warszawa; Portugal: Miguel Coelho/Mario Rosa, Hospital de Santa Maria, Lisboa; Cristina Costa, Hospital Professor Doutor Fernando Fonseca, Amadora; Luis Cunha, AIBILI – Associação para a Investigação Biomédica e Inovação, Coimbra; Rosas Rosas,Hospital de Sao Joao, Porto; Russia: Valentina Alifirova, Siberian State Medical University, Tomsk; Natalia Federova, SHI of city of M City Clinical Hospital, Moscow; Marina Nesterova, Sverdlovsk Regional Psychoneurological Hospital for War Veterans, Ekaterinburg; Dmitry Pokhabov, Krasnoyarsk State Medical Academy, Krasnoyarsk; Mikhail Sherman, MHI Kirov City Clinical Hospital, Kirov; Alexander Skoromets, SEIHPE Saint Petersburg SMU RosZdrav n a I I Pavlov, St. Petersburg; Elena Strachunskaya, Smolensk State Medical Academy of Roszdrav, Smolensk; Elena Vostrikova, SEIHPE Novosibirsk State Medical University of RosZdrav, Novosibirsk; Eduard Yakupov, LLC Medical Scientific-research Complex Your Health, Kazan; Spain: Ernest Balaguer, HG de Catalunya, Barcelona; Maria Jose Martí Domenach, HU Clinic I Provincial de Barcelona, Barcelona; Jaime H Kulisevsky Bojarski, de La Santa Creu I Sant Pau, Barcelona; Gurutz Linazasoro, Policlinica Guipuzcoa, San Sebastian; Juan J. Lopez Lozano, Clinica Ruber S A, Madrid; Sweden: Wojiech Duzynski, Skånes Universitetssjukhus, Malmö; Yngve Hallstrom, Stockholms Neuro Center AB, Stockholm; Jaan Albo, Neurologi Jaan Albo AB, Vällingby; Marianne Hartford, Sahlgrenska Universitetssjukhuset, Göteborg; Turkey: Raif Cakmur, Dokuz Eylul University Medicine Faculty, Izmir; Bulent Elibol, Hacettepe University, Ankara; Sibel Ozkaynak, Akdeniz Univesity, Antalya; Ayse Bora Tokcaer, Gazi University, Ankara; Huseyin Sahin, Ondokuz Mayis University, Samsun; Serhat Ozkan, Osmangazi Universitesi, Eskisehir; United Kingdom: David Burn, New Castle University - Campus for Ageing and Vitality, New Castle upon Tyne; Anthony Schapira, Royal Free Hospital, London; Malcolm Steiger, Walton Centre for Neurology and Neurosurgery Clinical

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Trials Unit, Liverpool; Richard Walker, North Tyneside General Hospital, North Shields; United States of America: Victor Biton, Clinical Trials Inc., Little Rock, AR; Alessandro Di Rocco, New York University Medical Center, New York, NY; Aaron Ellenbogen, Quest Research Institute, Bingham, MI; Jerome Goldstein, San Francisco Clinical Research Center, San Francisco, CA; Robert Hauser, University of South Florida Medical Center, Tampa, FL; Keith Hull, Raleigh Neurology Associates, P.A., Raleigh, NC; Robert Hutchman, Neurosearch, Reseda, CA; Marshall Nash, DeKalb Neurology Associates, LLC., Decatur, GA; Paul Nausieda, Wisconsin Institute for Neuological and Sleep Disorders, Milwaukee, WI; Rajesh Pahwa, University of Kansas Medical Center, Kansas City, KS; Susan Criswell/Brad Racette, Washington University School of Medicine, St. Louis, MO; Arshia Sadreddin, Barrow Neurological Institute, Pheonix, AZ; Lawrence Severt, Neurology Movement Disorders, New York, NY; Michael Tuchman, Palm Beach Neurological Center Advanced Research Consultants, Inc., Palm Beach Gardens, FL; Joanne Wojcieszek, Indiana University, Indianapolis, IN; Hemanth Rao, The Neurological Institute, PA., Charlotte, NC; Stuart Isaacson, Parkinson's Disease and Movement Disorder Center of Boca Raton, Boca Raton, FL; Soitirios Parashos, Struthers Parkinson Center, Golden Valley, MN; William Grainger, Neurological Physicians of Arizona, Inc., Gilbert, AZ; Ira Goodman, Compass Research, LLC., Orlando, FL; Annette Nieves, Renstar Medical Research, Ocala, FL. Trial-2 Argentina: Nelida Susana Garretto, Instituto Argentino de Investigacion Neurologica, Ciudad Autonoma; Federico Eduard Micheli, Instituto Frenopatico, Ciudad Autonoma; Maria Peralta, Fundacion Alfredo Thomson, Buenos Aires; Chile: Carlos Juri, Hospital Clinico Pontificia Universidad Catolica de Chile, Santiago; Sergio Gloger, Psicomedica Biomedical Research Group, Santiago; Marcelo Leiva, Hospital Base Valdivia, Valdivia; Pablo Venegas, Neuroconsult Avenida Apoquindo, Santiago; Colombia: Andres Fernando Ceron Zamora, Centro de Investigacion y Atencion para la Salud Mental, Bogota; Federico Silva, Fundación Cardiovascular de Colombia, Floridablanca; Mauricio Rueda, Fundacion Centro de Investigacion Clinica CIC, Medellin; Croatia: Silvija Butkovic Soldo, Clinical Hospital Osijek, Osijek; Olivio Perkovic, Clinical Hospital Centre Rijeka, Rijeka; Sanja Hajnsek, Clinical Hospital Centre Zagreb, Zagreb; Latvia: Ligita Smeltere, Outpatient Clinic Veselibas Centrs, Riga; Lithuania: Valmantas Budrys, Vilnius University Hospital Santariskiu Clinic, Vilnius; Dalia Michevieciene, Kaunas Clinics, Kaunas; Mexico: Jose Alfonso Ontiveros Sanchez, Instituto de Informacion de Investigacion en Salud Mental, Monterrey; Jose Luis Ruiz-Sandoval, Antiguo Hospital Civil de Guadalajara, Guadalajara; Gloria de Lourd Llamosa García, CIF-BIOTEC /Médica Sur Puente de Piedra, Toriello Guerra; Russia: Alina Agafyina, City Hospital #40, St.Petersburg; Sergey Illarioshkin, SIR center of Neurology of RAMS 80, Moscow; Natalia Pizova, Clinical Hospital #8,Yaroslavl, Russia; Olga Dornina, LLC City Neurological Centre “Sibneuromed”, Novosibirsk; Maxim Novitsky, LLC “Alliance Biomedical - Russian Group”, St. Petersburg; Serbia: Vladimir Kostic, Clinical Center of Serbia, Belgrade; Svetlana Miletic Drakulic, Clinical Center Kragujevac, Kragujevac; Jagoda Potic, Clinical Center Zvezdara, Belgrade;

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Tihomir Ilic, Military Medical Academy, Belgrade; South Africa: Stan Lipschitz, The Memory Centre, Johannesburg; Johan Smuts, Willows Medical Centre Neurology Practice, Pretoria; David Lurie, Sunninghill Hospital Cnr, Johannesburg; Mandisa Kakaza, University of Pretoria Clinical Trial Unit, Pretoria; Ukraine: Iryna Karaban, Institute of Gerontology AMS, Kiev; Nataliya Buchakchyys’ka, MI“Zapor.Reg.Clin.H osp.”, Zaporizhzhya; Sergii Moskovko, Vin.Reg.Ps.H.n.a.Yu sh., Vinnytsya; Yanosh Sanotskyy, Lviv Regional Clinical Hospital, Lviv; Tamara Mishchenko, Inst. of Neurol.,Psych.and Narcol.of the AMSU, Kharkiv; Olexandr Kozyolkin, City Clin.Hosp.#6, Zaporizhzhia; Grigory Kushnir, Crimean State Medical University, Simferopol; Igor Lutskiy, Clinical Hospital of Donetsk Station, Donetsk; Olga Shulga, Volyn Regional Clinical Hospital, Lutsk; United States of America: Rajeev Kumar, Colorado Neurological Institute, Englewood, CO; James Sutton, Pacific Neuroscience Medical Group, Oxnard, CA; Joseph Friedman, Butler Hospital, Providence, RI; James Patton, Asheville Neurology Specialists, Asheville, NC; Jeanette Wendt, NNS Clinical Research, LLC, Tucson, AZ; William McElveen, Bradenton Research Center, Inc., Bradenton, FL; Karen Frei, Parkinson's & Movement Disorder Institute, Fountain Valley CA; Peter LeWitt, Henry Ford Health System-West Bloomfield Hospital, West Bloomfield, MI; Anne-Marie Wills, Massachusetts General Hospital, Boston, MA; Stanley Fisher, Methodist Neurological Institute, Houston, TX; Joohi Jimenez-Shahed, Baylor College of Medicine, Houston, TX; Liliana Montoya, Charlotte, FL; Paul Ginsberg, Infinity Clinical Research, LLC, Hollywood, FL; Ilia Itin, Cleveland Clinic, Cleveland, OH; David Kreitzman, Parkinson's Disease and Movement Disorder Center of Long Island, Commack, NY; Gerald Ferencz, Shore Neurology, West Toms River, NJ; Burton Scott, Duke Movement Disorders Clinic, Durham, NC; Omid Omidvar, Collaborative Neuroscience Network, Inc., Long Beach, CA; Holly Shill, Banner Sun Health Research Institute, Sun City, AZ; Alan Freeman, Emory University, Atlanta, GA; Allan Bernstein, Radiant Research, Inc., Santa Rosa, CA; Ramon Rodriguez, University of Florida Center for Movement Disorders and Neurorestoration, Gainesville, FL; Matthews Gwynn, Neurotrials Research, Inc., Atlanta, GA; Barry Cutler, Neurology Clinical Research, Inc., Sunrise, FL; Ronald Wilson, Brentwood Neurology, Brentwood, TN; Perminder Bhatia, Neuro-Pain Medical Center, Fresno, CA; Walter Carlini, Providence Medical Group-Medford Neurology, Medford, OR; John Campbell, Collier Neurologic Specialists, Naples, FL; William Preston, Caring Clinical Research Corporation, Laguna Hills, CA; Paul Brownstone, Alpine Clinical Research Center, Boulder, CO; David Teeple, Center for Neurosciences, Tucson, AZ; James Goldenberg, JEM Research Institute, Atlantis, FL; Ludy Shih, Beth Israel Deaconess Medical Center, Boston, MA; Daniel Kremens, Thomas Jefferson University Hospital, Philadelphia, PA; Matt Boyce, Neurological Associates, Inc., Richmond, VA; Abraham Chamely, Infinity Clinical Research, LLC, Pompano Beach, FL; Neal Hermanowicz, University of California Irvine, Irvine, CA; Danielle Englert, Carolinas Medical Center, Charlotte, NC; Concetta Forchetti, Alexian Brothers Neurosciences Institute, Elk Grove Village, IL; Grace Liang, The Parkinson's Institute, Port Royal, SC; Anthony Ciabarra, Neurology Center of North Orange Co., Fullerton, CA; Tanya Harlow, Sanford Clinic NeuroScience,

Downloaded From: https://jamanetwork.com/ on 09/30/2021 South Fargo, ND; David Weisman, Abington Neurological Associates, Abington, PA; Karen Anderson, University of Maryland, Baltimore, MD; Stuart Isaacson, Parkinson's Disease and Movement Disorder Center of Boca Raton, Boca Raton, FL; Keith Hull, Raleigh Neurology Associates, P.A., Raleigh, NC; Hemanth Rao, The Neurological Institute, PA., Charlotte, NC.

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