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.
Author(s): Hauser RA(1), Hsu A, Kell S, Espay AJ, Sethi K, Stacy M, Ondo W, O'Connell M,
Gupta S; IPX066 ADVANCE-PD investigators.
Affiliation(s): Author information:
(1)University of South Florida, Tampa, FL, USA. rhauser@health.usf.edu
Publication date & source: 2013, Lancet Neurol. , 12(4):346-56
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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