TY - JOUR
T1 - IPX203 vs Immediate-Release Carbidopa-Levodopa for the Treatment of Motor Fluctuations in Parkinson Disease
T2 - The RISE-PD Randomized Clinical Trial
AU - Hauser, Robert A.
AU - Espay, Alberto J.
AU - Ellenbogen, Aaron L.
AU - Fernandez, Hubert H.
AU - Isaacson, Stuart H.
AU - Lewitt, Peter A.
AU - Ondo, William G.
AU - Pahwa, Rajesh
AU - Schwarz, Johannes
AU - Stocchi, Fabrizio
AU - Zeitlin, Leonid
AU - Banisadr, Ghazal
AU - Fisher, Stanley
AU - Visser, Hester
AU - D'Souza, Richard
N1 - Publisher Copyright:
© 2023 American Medical Association. All rights reserved.
PY - 2023/10/1
Y1 - 2023/10/1
N2 - 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.
AB - 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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U2 - 10.1001/jamaneurol.2023.2679
DO - 10.1001/jamaneurol.2023.2679
M3 - Article
C2 - 37578800
AN - SCOPUS:85177693372
SN - 2168-6149
VL - 80
SP - 1062
EP - 1069
JO - JAMA Neurology
JF - JAMA Neurology
IS - 10
ER -