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. 2023 Oct 1;80(10):1062-1069.
doi: 10.1001/jamaneurol.2023.2679.

IPX203 vs Immediate-Release Carbidopa-Levodopa for the Treatment of Motor Fluctuations in Parkinson Disease: The RISE-PD Randomized Clinical Trial

Robert A Hauser  1 , Alberto J Espay  2 , Aaron L Ellenbogen  3 , Hubert H Fernandez  4 , Stuart H Isaacson  5 , Peter A LeWitt  6 , William G Ondo  7 , Rajesh Pahwa  8 , Johannes Schwarz  9 , Fabrizio Stocchi  10 , Leonid Zeitlin  11 , Ghazal Banisadr  12 , Stanley Fisher  12 , Hester Visser  12 , Richard D'Souza  12
Affiliations

IPX203 vs Immediate-Release Carbidopa-Levodopa for the Treatment of Motor Fluctuations in Parkinson Disease: The RISE-PD Randomized Clinical Trial

Robert A Hauser et al. JAMA Neurol. .

Abstract

Importance: Levodopa has a short half-life and a limited window of opportunity for absorption in the proximal small intestine. IPX203 is an oral, extended-release formulation of carbidopa-levodopa developed to address these limitations.

Objective: To assess the efficacy and safety of IPX203 vs immediate-release carbidopa-levodopa in patients with Parkinson disease who are experiencing motor fluctuations.

Design, setting, and participants: RISE-PD was a 20-week, randomized, double-blind, double-dummy, active-controlled, phase 3 clinical trial. The study was conducted between November 6, 2018, and June 15, 2021, at 105 academic and clinical centers in the US and Europe. Patients with Parkinson disease taking a total daily dose of 400 mg or more of levodopa and experiencing an average of 2.5 hours or more daily off-time were included in the study. A total of 770 patients were screened, 140 were excluded (those taking controlled-release carbidopa-levodopa apart from a single daily bedtime dose, Rytary (Amneal Pharmaceuticals), additional carbidopa or benserazide, or catechol O-methyl transferase inhibitors or who had a history of psychosis within the past 10 years), and 630 were enrolled in the trial.

Interventions: Following open-label immediate-release carbidopa-levodopa dose adjustment (3 weeks) and conversion to IPX203 (4 weeks), patients were randomized in a 1:1 ratio to double-blind, double-dummy treatment with immediate-release carbidopa-levodopa or IPX203 for 13 weeks.

Main outcome and measures: The primary end point was mean change in daily good on-time (ie, on-time without troublesome dyskinesia) from baseline to the end of the double-blind treatment period.

Results: A total of 630 patients (mean [SD] age, 66.5 [8.95] years; 396 [62.9%] men) were enrolled, and 506 patients were randomly assigned to receive IPX203 (n = 256) or immediate-release carbidopa-levodopa (n = 250). The study met its primary end point, demonstrating statistically significant improvement in daily good on-time for IPX203 compared to immediate-release carbidopa-levodopa (least squares mean, 0.53 hours; 95% CI, 0.09-0.97; P = .02), with IPX203 dosed a mean 3 times per day vs 5 times per day for immediate-release carbidopa-levodopa. Good on-time per dose increased by 1.55 hours with IPX203 compared to immediate-release carbidopa-levodopa (95% CI, 1.37-1.73; P < .001). IPX203 was well tolerated. The most common adverse events in the double-blind phase (IPX203 vs immediate-release carbidopa-levodopa) were nausea (4.3% vs 0.8%) and anxiety (2.7% vs 0.0%).

Conclusions and relevance: In this study, IPX203 provided more hours of good on-time per day than immediate-release carbidopa-levodopa, even as IPX203 was dosed less frequently.

Trial registration: ClinicalTrials.gov Identifier: NCT03670953.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Hauser reported other from Amneal Pharmaceuticals The University of South Florida (payments to conduct the trial at the site) during the conduct of the study; consulting and/or speaking fees from AbbVie, Acorda, AgeX Therapeutics, Amneal Pharmaceuticals, Blue Rock Therapeutics, Global Kinetics, Cerevel, Inhibikase, Jazz Pharmaceuticals, Kyowa Kirin, Med Rhythms, Merz, Neurocrine Biosciences, NeuroDerm, Ovid Therapeutics, PD Neurotechnology, Pharma Two B, Regenxbio, Sage Therapeutics, Scion Neurostim, Supernus Pharmaceuticals, Tolmar, TrisPharma, UCB, and Vivifi Biotech outside the submitted work; and holds stock options in Inhibikase and Enterin; in addition, the University of South Florida holds a copyright on a Parkinson Diary for which Dr. Hauser receives fees. Dr Espay reported grants from Amneal (paid to institution) and personal fees from Amneal for serving on the scientific advisory board during the conduct of the study as well as personal fees for serving on scientific advisory boards from Neuroderm, Acadia, Avion Pharmaceuticals, Acorda, Kyowa Kirin, Sunovion, Supernus, and Herantis Pharma outside the submitted work. Dr Ellenbogen reported personal fees from Neurderm, Supernus, Kyowa Kirin, and AbbVie outside the submitted work. Dr Fernandez reported consulting fees from Amneal during the conduct of the study; grants from Biogen, Michael J Fox Foundation, National Institute of Neurological Disorders and Stroke, and Roche and consulting fees from Parkinson Study Group, Cerevel, and AbbVie outside the submitted work; a stipend from Elsevier for serving as editor in chief of Parkinsonism and Related Disorders; and honoraria from Springer Publishing for book authorship. Dr Isaacson reported grants and personal fees from Amneal during the conduct of the study as well as personal fees from Neurocrine, Bial, Neuroderm, AbbVie, Supernus, Acorda, Kyowa, and Sunovion outside the submitted work. Dr Pahwa reported other from Amneal (participation in clinical trials) and personal fees from Amneal during the conduct of the study as well as consulting fees from Abbott, AbbVie, Acadia, Acorda, Allevion, Amneal, Artemida, BioVie, CalaHealth, Convatec, Fasikl, Global Kinetics, Inbeeo, Insightec, Jazz, Kyowa, Lundbeck, Merz, Neurocrine, Neuroderm, Ono, PhotoPharmics, Regenxbio, Sage, Sunovion, Supernus, UCB, and Wren and grants from Abbott, AbbVie, Alexza, Annovis, Biogen, Bluerock, Bukwang, Cerevel, Global Kinetics, Jazz, Michael J Fox Foundation, Neuroderm, Neuraly, Parkinson’s Foundation, Praxis, Roche, Sage, Scion, Sun Pharma, UCB, and Voyager outside the submitted work. Dr Stocchi reported personal fees from Bial, Lundbeck, Zambon, Biogen, Roche, Chiesi, Britannia, Sunovion, Contera, Neuroderm, AbbVie, Lusofarmaco, and Ever Pharma outside the submitted work. Dr Zeitlin reported personal fees from Quartesian during the conduct of the study and outside the submitted work. Drs Banisadr, Fisher, and Visser are employees of Amneal Pharmaceuticals; in addition, Dr Visser reports a patent pending (WO 2022/140448 A1). Dr D’Souza reported a patent for US20230054825A1 pending (Amneal Pharmaceuticals). No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Design
EOS indicates end of study; IR CD-LD, immediate-release carbidopa-levodopa. aIPX203 was recommended to be dosed approximately every 8 hours. Participants who were taking a total daily dose of less than 125-500 mg CD-LD from IR CD-LD were advised to initially take IPX203 every 12 hours. The dosing interval could vary but could not be more frequent than every 6 hours.
Figure 2.
Figure 2.. CONSORT Diagram
IR CD-LD indicates immediate-release carbidopa-levodopa; mITT, modified intent-to-treat; PP, per-protocol.
Figure 3.
Figure 3.. Change From Baseline in Good On-Time, Least Squares Mean
Good on-time was defined as on-time without troublesome dyskinesia. EOS indicates end of study; IR CD-LD, immediate-release carbidopa-levodopa.
Figure 4.
Figure 4.. Good On-Time at Visit 7/Early Termination
Good on-time was defined as on-time without troublesome dyskinesia. IR CD-LD indicates immediate-release carbidopa-levodopa.
See this image and copyright information in PMC

References

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