Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial

• Published in: Lancet neurology Vol. 12; no. 4; pp. 346 - 356
• Main Authors: Hauser, Robert A, Dr, Hsu, Ann, PhD, Kell, Sherron, MD, Espay, Alberto J, MD, Sethi, Kapil, MD, Stacy, Mark, MD, Ondo, William, MD, O'Connell, Martin, PhD, Gupta, Suneel, PhD
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2013; Elsevier Limited
• Subjects: Aged; Blood pressure; Carbidopa - administration & dosage; Chemistry, Pharmaceutical; Clinical trials; Delayed-Action Preparations - administration & dosage; Double-Blind Method; Drug Combinations; Drug dosages; Dyskinesia; Female; Heart rate; Humans; Laboratories; Levodopa - administration & dosage; Male; Middle Aged; Motor Skills Disorders - drug therapy; Motor Skills Disorders - epidemiology; Neurology; Parkinson Disease - drug therapy; Parkinson Disease - epidemiology; Parkinson's disease; Treatment Outcome; United States > US
• ISSN: 1474-4422; 1474-4465
• DOI: 10.1016/S1474-4422(13)70025-5

Summary Background IPX066 is an oral, extended-release, capsule formulation of carbidopa-levodopa. We aimed to assess this extended-release formulation versus immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations. Methods We did a phase 3, randomised, double-blind, double-dummy study at 68 academic and clinical centres in North America and Europe. Patients with Parkinson's disease who had at least 2·5 h per day of off-time underwent 3 weeks of open-label immediate-release carbidopa-levodopa dose adjustment followed by 6 weeks of open-label extended-release carbidopa-levodopa dose conversion. These patients were then randomly allocated (1:1), by use of an interactive web-response system, to 13 weeks of double-blind treatment with extended-release or immediate-release carbidopa-levodopa plus matched placebos. The primary efficacy measure was off-time as a percentage of waking hours in all patients randomly allocated to treatment groups, adjusted for baseline value. This study is registered with ClinicalTrials.gov , number NCT00974974. Findings Between Sept 29, 2009, and Aug 16, 2010, we enrolled 471 participants, of whom 393 (83%) were randomly allocated in the double-blind maintenance period and were included in the main efficacy analyses. As a percentage of waking hours, 201 patients treated double-blind with extended-release carbidopa-levodopa (mean 3·6 doses per day [SD 0·7]) had greater reductions in off-time than did 192 patients treated double-blind with immediate-release carbidopa-levodopa (mean 5·0 doses per day [1·2]). Covariate-adjusted end-of-study means were 23·82% (SD 14·91) for extended-release carbidopa-levodopa and 29·79% (15·81) for immediate-release carbidopa-levodopa (mean difference −5·97, 95% CI −9·05 to −2·89; p<0·0001). Extended-release carbidopa-levodopa reduced daily off-time by, on average, an extra −1·17 h (95% CI −1·69 to −0·66; p<0·0001) compared with immediate-release carbidopa-levodopa. During dose conversion with extended-release carbidopa-levodopa, 23 (5%) of 450 patients withdrew because of adverse events and 13 (3%) withdrew because of a lack of efficacy. In the maintenance period, the most common adverse events were insomnia (seven [3%] of 201 patients allocated extended-release carbidopa-levodopa vs two [1%] of 192 patients allocated immediate-release carbidopa-levodopa), nausea (six [3%] vs three [2%]), and falls (six [3%] vs four [2%]). Interpretation Extended-release carbidopa-levodopa might be a useful treatment for patients with Parkinson's disease who have motor fluctuations, with potential benefits including decreased off-time and reduced levodopa dosing frequency. Funding Impax Laboratories.