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ADS-5102 (Amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia in Parkinson Disease (EASE LID Study)A Randomized Clinical Trial

Educational Objective To determine via a randomized clinical trial whether 274 mg of ADS-5102 (amantadine) extended-release capsules can safely and effectively treat levodopa-induced dyskinesia in patients with Parkinson disease.
1 Credit CME
Key Points

Question  Are 274-mg ADS-5102 (amantadine) extended-release capsules safe and effective for the treatment of levodopa-induced dyskinesia in Parkinson disease?

Findings  In this randomized clinical trial, ADS-5102 was associated with a significantly greater reduction in the duration, severity, and impact of dyskinesia at 12 weeks compared with placebo, as measured by the least-squares mean change in the Unified Dyskinesia Rating Scale score (treatment difference, –7.9); this reduction in the duration, severity, and impact of dyskinesia was maintained through week 24 (treatment difference, –9.3). Adverse events led to treatment discontinuation for 13 of 63 patients receiving ADS-5102 (20.6%) vs 4 of 58 patients receiving placebo (6.9%).

Meaning  ADS-5102 may be an effective treatment for levodopa-induced dyskinesia.

Abstract

Importance  Medical treatment of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) is an unmet need.

Objective  To evaluate the efficacy and safety of ADS-5102 (amantadine) extended-release 274-mg capsules for treatment of LID in patients with PD.

Design, Setting, and Participants  A randomized, double-blind, placebo-controlled clinical trial was conducted between May 7, 2014, and July 22, 2015, at 44 North American sites among patients with PD treated with levodopa who experienced at least 1 hour of troublesome dyskinesia per day with at least mild functional impact.

Interventions  Patients were randomized to receive placebo or 274 mg of ADS-5102 administered orally at bedtime for up to 25 weeks.

Main Outcomes and Measures  The primary efficacy analysis was the change from baseline to week 12 in the Unified Dyskinesia Rating Scale total score for ADS-5102 vs placebo in the modified intent-to-treat population. OFF time (amount of time the PD medication is not controlling motor symptoms) was a key secondary end point. Safety analyses included all patients who received the study drug (ADS-5102 or placebo).

Results  A total of 189 patients were screened, and 126 were randomized; the modified intent-to-treat population included 121 patients (51 women and 70 men; mean [SD] age, 64.7 [9.1] years). At week 12, the least-squares mean (SE) change in the Unified Dyskinesia Rating Scale score was –15.9 (1.6) for ADS-5102 (n = 63) and –8.0 (1.6) for placebo (n = 58) (treatment difference, –7.9; 95% CI, –12.5 to –3.3; P < .001). OFF time decreased by a mean (SE) of 0.6 (0.3) hours for ADS-5102 and increased by 0.3 (0.3) hours for placebo (treatment difference, –0.9 hours; 95% CI, –1.6 to –0.2; P = .02). Common adverse events for ADS-5102 vs placebo included visual hallucinations (15 [23.8%] vs 1 [1.7%]), peripheral edema (15 [23.8%] vs 0), and dizziness (14 [22.2%] vs 0). Adverse events led to treatment discontinuation for 13 patients receiving ADS-5102 (20.6%) vs 4 patients receiving placebo (6.9%).

Conclusions and Relevance  ADS-5102, 274 mg at bedtime, may be an effective treatment for LID. An additional benefit is reduced OFF time. To our knowledge, this is the first demonstration of an oral treatment reducing both LID and OFF time in patients with PD with dyskinesia.

Trial Registration  clinicaltrials.gov Identifier: NCT02136914

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Article Information

Accepted for Publication: April 15, 2017.

Corresponding Author: Rajesh Pahwa, MD, Department of Neurology, University of Kansas Medical Center, 3599 Rainbow Blvd, Mailstop 3042, Kansas City, KS 66160 (rpahwa@kumc.edu).

Correction: This article was corrected on September 11, 2017, to add the Open Access paragraph to the acknowledgments section.

Published Online: June 12, 2017. doi:10.1001/jamaneurol.2017.0943

Open Access: This article is published under the JN-OA license and is free to read on the day of publication.

Author Contributions: Dr Pahwa had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Pahwa, Tanner, Hauser, Johnson.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Pahwa, Hull, Lyons, Johnson.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Isaacson, Nausieda, Truong, Agarwal, Johnson.

Study supervision: Pahwa, Isaacson, Nausieda, Hull, Johnson, Stempien.

Conflict of Interest Disclosures: Dr Pahwa reported receiving honoraria or payments for consulting from AbbVie, Acadia, Acorda, Adamas, Sunovion, Impax, Lundbeck, Neurocrine, Sage, St Jude Medical, Teva Neuroscience, Union Chimique Belge, US WorldMeds, and Global Kinetics; receiving research grants from Acadia, Acorda, Adamas, Avid, Biotie, Boston Scientific, Civitas, Cynapsus, Kyowa, the National Institutes of Health/National Institute of Neurological Disorders and Stroke, National Parkinson Foundation, Pfizer, and Parkinson Study Group/University of Rochester; serving on the data monitoring committee for Ionis; and receiving personal compensation as the coeditor-in-chief of the International Journal of Neuroscience. Dr Tanner reported being an employee of the University of California–San Francisco and the San Francisco Veterans Affairs Medical Center and an intermittent employee of the Parkinson’s Institute; serving on the scientific advisory boards of the Michael J. Fox Foundation and the National Spasmodic Dysphonia Association as a voluntary consultant; providing paid consulting services to Ultragenyx Pharmaceuticals, Neurocrine Biosciences, Cynapsus Therapeutics, Sage Biometrics, and Adamas Pharmaceuticals; receiving compensation for serving on data monitoring committees from Biotie Therepeutics, Voyager Therapeutics, and Intec Pharma; and receiving grant support from the Michael J. Fox Foundation, the Parkinson’s Disease Foundation, the Department of Defense, and the National Institutes of Health. Dr Hauser reported being supported in part by a center grant from the National Parkinson’s Disease Foundation; receiving payment from Adamas for participating as a steering committee member; receiving consulting fees from Teva Pharmaceuticals, Union Chimique Belge Biosciences, AbbVie, Novartis, Biotie Therapies, Lundbeck, Pfizer, Allergan Neuroscience, Neurocrine Biosciences, Chelsea Therapeutics, Auspex, Acadia Pharmaceuticals, the Michael J. Fox Foundation, Gerson Lehrman Group, AstraZeneca, Acorda Therapeutics, Impax Pharmaceuticals, Cynapsus Therapeutics, US WorldMeds, Neurospore, and Prexton; receiving salary support grants from the National Parkinson Foundation; and receiving salary from the University of South Florida. Dr Isaacson reported receiving honoraria and research grants for providing continuing medical education, serving as a consultant, and/or serving as a promotional speaker on behalf of Abbvie, Acadia, Acorda, Adamas, Addex, Allergan, Amarantus, Auspex, Avid, Axovant, AstraZeneca Therapies, Biogen, Biotie, Britannia, Cynapsus, Eisai, Eli Lilly, General Electric Healthcare, Impax, Intec Pharma, Ipsen, Kyowa, Lundbeck, Medtronics, Merz, the Michael J. Fox Foundation, Neurocrine, Neuroderm, the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Parkinson Study Group, Pfizer, Pharma2B, Prothena, Roche, Sanofi, Shire, Sunovion, Teva, Union Chimique Belge, US World Meds, and XenoPort. Dr Nausieda reported receiving honoraria from Impax Laboratories Inc for consulting services and serving as an investigator; having spoken on behalf of Novartis, Union Chimique Belge, and Teva Pharmaceuticals; holding stock in Abbott Laboratories, Bristol-Myers Squibb, Celgene, Dow Chemical, DuPont, Durata Therapeutics, Eli Lilly, Gilead, GlaxoSmithKline, Humana, Impax Laboratories Inc, Johnson and Johnson, Neogen, Phytopharm plc, Roche Holding, Sigma-Aldrich, and Teva Neuroscience; and receiving financial support from Adamas Pharmaceuticals, Aurora Health Care Foundation, Biotie Therapies, the Greater Milwaukee Foundation, the Helen Bader Foundation, Icon Clinical Research, Impax Laboratories Inc, the Milwaukee County Department of Family Care, Pharmanet LLC, PRA International, Quintiles Inc, Schwarz Biosciences/Union Chimique Belge, the Wisconsin Parkinson Association, and XenoPort. Dr Truong reported receiving research grants from Ispen, Merz, Auspex, Diichi Sankyo Pharma, AbbVie, the National Institute of Neurological Disorders and Stroke, Kyowa, and Neurocrine. Dr Hull reported serving on the speakers bureau for Acadia and receiving financial support from Teva, Campbell University, Genentech Inc, Allergan, the National Stroke Association, Lundbeck, US WorldMeds, and WakeMed. Dr Lyons reported serving as a consultant for Adamas, Medtronic, St Jude Medical, Union Chimique Belge, and US WorldMeds and receiving personal compensation as coeditor-in-chief of the International Journal of Neuroscience. Mr Johnson reported being an employee of and receiving compensation and stock options from Adamas. Dr Stempien reported serving as a consultant to receiving compensation and stock options from Adamas and receiving consultancy payments from Cymabay Therapeutics Inc and Adheron Therapeutics. No other disclosures were reported.

Funding/Support: This study was funded by Adamas Pharmaceuticals Inc.

Role of the Funder/Sponsor: In collaboration with the study investigators, the funding source participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Additional Contributions: Charles Davis, PhD, CSD Biostatistics, was a consultant to Adamas Pharmaceuticals Inc, who provided statistical analysis support during the conduct of this study. Under the direction of the authors, editorial assistance was provided by Cory Hussar, PhD, of The Curry Rockefeller Group LLC, which was funded by Adamas Pharmaceuticals Inc. We acknowledge and thank the study participants; the ADS-5102 for the Treatment of Levodopa Induced Dyskinesia (EASE LID) study investigators, including the steering committee and their staff.

Additional Information: The ADS-5102 Extended Release Capsules for the Treatment of Levodopa Induced Dyskinesia (EASE LID) principal investigators/sites that enrolled study participants included the following: Pinky Agarwal, MD, Booth Gardner Parkinson’s Care Center, Evergreen Hospital Medical Center, Kirkland, Washington; Miroslaw Brys, MD, New York University Langone Medical Center Parkinson’s and Movement Disorder Center, New York, New York; John Campbell, MD, Collier Neurologic Specialists, LLC, Naples, Florida; Susan Criswell, MD, Washington University School of Medicine, St Louis, Missouri; J. Antonelle de Marcaida, MD, Eastern Connecticut Neurology Specialists, LLC, Manchester; Andres Deik, MD, Pennsylvania Hospital Department of Neurology, Philadelphia; Rohit Dhall, MD, St Joseph’s Hospital and Medical Center/Barrow Neurology Clinics, Phoenix, Arizona; Natalie Diaz, MD, Neurosearch-Torrance, Torrance, California; Jennifer Durphy, MD, Albany Medical College, Albany, New York; Aaron Ellenbogen, DO, QUEST Research Institute, Bingham Farms, Michigan; Lawrence W. Elmer, MD, University of Toledo, Toledo, Ohio; Alberto Espay, MD, University of Cincinnati Physicians Company, LLC, Cincinnati, Ohio; Susan Fox, MRCP (UK), PhD, Toronto Western Hospital, Toronto, Ontario, Canada; Ramon Gil, MD, Parkinson’s Disease Treatment Center of SW Florida, Port Charlotte; Michal Gostkowski, DO, Cleveland Clinic, Cleveland, Ohio; Keith L. Hull Jr, MD, Raleigh Neurology Associates, Raleigh, North Carolina; Robert Hutchman, MD, Neurosearch, Inc, Reseda, California; Stuart H. Isaacson, MD, Parkinson’s Disease and Movement Disorders Center of Boca Raton Inc, Boca Raton, Florida; Joseph Jankovic, MD, Baylor College of Medicine, Houston, Texas; Jorge Juncos, MD, Emory University Department of Neurology, Atlanta, Georgia; Kevin J. Klos, MD, The Movement Disorders Clinic of Oklahoma, Tulsa; David Kreitzman, MD, David L. Kreitzman, MD, PC, Commack, New York; Maureen Leehey, MD, University of Colorado Hospital Anschutz Outpatient Pavilion, Aurora; Jerome P. Lisk, MD, Neurosearch, Pasadena, California; Ming-Jai Liu, MD, Banner-Sun Health Research Institute, Sun City, Arizona; Irene Malaty, MD, University of Florida Center for Movement Disorders and Neurorestoration, Gainesville; Shyamal Mehta, MD, Mayo Clinic Arizona, Scottsdale; Paul Nausieda, MD, Wisconsin Institute for Neurologic and Sleep Disorders, Milwaukee; Anthony Nicholas, MD, Comprehensive Parkinson Disease and Movement Disorders Clinic, University of Alabama at Birmingham; Rajesh Pahwa, MD, University of Kansas Medical Center, Kansas City; Sotirios Parashos, MD, Struthers Parkinson’s Center, Golden Valley, Minnesota; Neepa Patel, MD, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas; Ramon Rodriguez, MD, University of Florida Center for Movement Disorders and Neurorestoration, Gainesville; Marwan Sabbagh, MD, Banner-Sun Health Research Institute, Sun City, Arizona; Naomi Salins, MD, St Joseph’s Hospital and Medical Center/Barrow Neurology Clinics, Phoenix, Arizona; William Severt, MD, Beth Israel Medical Center, New York, New York; Holly Shill, MD, Banner-Sun Health Research Institute, Sun City, Arizona; Robert J. Shorr, MD, Neurosearch II, Ventura, California; Christos Sidiropoulos, MD, Henry Ford Medical Center West Bloomfield, West Bloomfield, Michigan; Richard Singer, MD, Infinity Clinical Research, LLC, Sunrise, Florida; Erin Stimming, MD, The University of Texas Professional Building, Houston; Lynn Struck, MD, Unity Point Multi-Specialty Clinic, Des Moines, Iowa; Thyagarajan Subramanian, MD, Penn State Hershey Medical Center, Clinical Research Center, Hershey, Pennsylvania; Daniel Truong, MD, Parkinson’s and Movement Disorder Institute, Fountain Valley, California; Winona Tse, MD, Bendheim Parkinson and Movement Disorders Center, Icahn School of Medicine at Mount Sinai, New York, New York; Felix Veloso, MD, Pasqua Hospital, Regina, Saskatchewan, Canada; Leonard Verhagen Metman, MD, Rush University Medical Center, Chicago, Illinois; Lin Zhang, MD, University of California, Davis Medical Center, Sacramento.

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