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

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.

Conflict of interest statement

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.

Figures

Figure 1.. Trial Flowchart

aFour additional patients discontinued the study drug owing to adverse events but continued the study. bTwo patients did not have a postbaseline Unified Dyskinesia Rating Scale assessment (predefined criterion) and thus were excluded from the modified intent-to-treat (mITT) population.

Figure 2.. Change in Primary Efficacy Analysis and Key Secondary End Points

A, Change in Unified Dyskinesia Rating Scale (UDysRS) score over time in the modified intent-to-treat population. Ranges in parentheses indicate 95% CIs. B, Change in Parkinson disease (PD) home diary data over time in the modified intent-to-treat population. Least-squares mean changes in PD diary data from baseline through week 24 are summarized for the modified intent-to-treat population. The shaded areas represent the difference (in hours) between placebo and ADS-5102 across time for amount of time the PD medication was not controlling motor symptoms (OFF time) and amount of time the PD medication provided good benefit for motor symptoms (ON time) without troublesome dyskinesia. Error bars indicate SE.