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

Robert A. Hauser, Ann Hsu, Sherron Kell, Alberto J. Espay, Kapil Sethi, Mark Stacy, William Ondo, Martin O'Connell, Suneel Gupta

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)346-356
Number of pages11
JournalThe Lancet Neurology
Volume12
Issue number4
DOIs
StatePublished - Apr 1 2013

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Parkinson Disease
levodopa drug combination carbidopa
Maintenance
Sleep Initiation and Maintenance Disorders
Levodopa
North America
Double-Blind Method
Nausea
Capsules
Therapeutics
Placebos

ASJC Scopus subject areas

  • Clinical Neurology

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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. / Hauser, Robert A.; Hsu, Ann; Kell, Sherron; Espay, Alberto J.; Sethi, Kapil; Stacy, Mark; Ondo, William; O'Connell, Martin; Gupta, Suneel.

In: The Lancet Neurology, Vol. 12, No. 4, 01.04.2013, p. 346-356.

Research output: Contribution to journalArticle

Hauser, Robert A. ; Hsu, Ann ; Kell, Sherron ; Espay, Alberto J. ; Sethi, Kapil ; Stacy, Mark ; Ondo, William ; O'Connell, Martin ; Gupta, Suneel. / 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. In: The Lancet Neurology. 2013 ; Vol. 12, No. 4. pp. 346-356.
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abstract = "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.",
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T1 - Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations

T2 - A phase 3 randomised, double-blind trial

AU - Hauser, Robert A.

AU - Hsu, Ann

AU - Kell, Sherron

AU - Espay, Alberto J.

AU - Sethi, Kapil

AU - Stacy, Mark

AU - Ondo, William

AU - O'Connell, Martin

AU - Gupta, Suneel

PY - 2013/4/1

Y1 - 2013/4/1

N2 - 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.

AB - 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.

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