Hauser Robert A, Espay Alberto J, Ellenbogen Aaron L, Fernandez Hubert H, Isaacson Stuart H, LeWitt Peter A, Ondo William G, Pahwa Rajesh, Schwarz Johannes, Stocchi Fabrizio, Zeitlin Leonid, Banisadr Ghazal, Fisher Stanley, Visser Hester, D'Souza Richard
University of South Florida Parkinson's Disease and Movement Disorders Center/Parkinson Foundation Center of Excellence, Tampa.
James J. and Joan A. Gardner Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio.
JAMA Neurol. 2023 Oct 1;80(10):1062-1069. doi: 10.1001/jamaneurol.2023.2679.
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.
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.
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.
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.
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%).
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.
ClinicalTrials.gov Identifier: NCT03670953.
左旋多巴半衰期短，在近端小肠的吸收机会有限。IPX203是一种口服缓释卡比多巴-左旋多巴制剂，旨在解决这些局限性。
评估IPX203与速释卡比多巴-左旋多巴相比，对有运动波动的帕金森病患者的疗效和安全性。
设计、地点和参与者：RISE-PD是一项为期20周的随机、双盲、双模拟、活性对照3期临床试验。该研究于2018年11月6日至2021年6月15日在美国和欧洲的105个学术和临床中心进行。纳入了每日左旋多巴总剂量为400毫克或更多且平均每日非服药时间为2.5小时或更长时间的帕金森病患者。共筛选了770名患者，排除了140名（那些除了每日一次睡前剂量的控释卡比多巴-左旋多巴、Rytary（Amneal制药公司）、额外的卡比多巴或苄丝肼、或儿茶酚-O-甲基转移酶抑制剂之外还服用其他药物的患者，或在过去10年内有精神病病史的患者），630名患者参加了试验。
在开放标签的速释卡比多巴-左旋多巴剂量调整（3周）并转换为IPX203（4周）后，患者按1:1比例随机接受速释卡比多巴-左旋多巴或IPX203的双盲、双模拟治疗13周。
主要终点是从基线到双盲治疗期结束时每日良好服药时间（即无麻烦异动症的服药时间）的平均变化。
共纳入630名患者（平均[标准差]年龄，66.5[8.95]岁；396名[62.9%]男性），506名患者被随机分配接受IPX203（n = 256）或速释卡比多巴-左旋多巴（n = 250）。该研究达到了主要终点，与速释卡比多巴-左旋多巴相比，IPX203的每日良好服药时间有统计学意义的改善（最小二乘均值，0.53小时；95%置信区间，0.09 - 0.97；P = 0.02），IPX203平均每日给药3次，而速释卡比多巴-左旋多巴为每日5次。与速释卡比多巴-左旋多巴相比，IPX203每剂的良好服药时间增加了1.55小时（95%置信区间，1.37 - 1.73；P < 0.001）。IPX203耐受性良好。双盲阶段最常见的不良事件（IPX203与速释卡比多巴-左旋多巴相比）是恶心（4.3%对0.8%）和焦虑（2.7%对0.0%）。
在本研究中，即使IPX203给药频率较低，但与速释卡比多巴-左旋多巴相比，其每日提供的良好服药时间更多。
ClinicalTrials.gov标识符：NCT03670953。
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