Abstract
Background: Levodopa is the most effective therapy for Parkinson's disease, but chronic treatment is associated with the development of potentially disabling motor complications. Experimental studies suggest that motor complications are due to non-physiological, intermittent administration of the drug, and can be reduced with continuous delivery. We aimed to assess efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube. Methods: In our 12-week, randomised, double-blind, double-dummy, double-titration trial, we enrolled adults (aged ≥30 years) with advanced Parkinson's disease and motor complications at 26 centres in Germany, New Zealand, and the USA. Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube, and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. Randomisation was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. We assessed change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome. We assessed efficacy in a full-analysis set of participants with data for baseline and at least one post-baseline assessment, and imputed missing data with the last observation carried forward approach. We assessed safety in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. This study is registered with ClinicalTrials.gov, numbers NCT00660387 and NCT0357994. Findings: From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4·04 h (SE 0·65) for 35 patients allocated to the levodopa-carbidopa intestinal gel group compared with a decrease of 2·14 h (0·66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference -1·91 h [95% CI -3·05 to -0·76]; p=0·0015). Mean on-time without troublesome dyskinesia increased by 4·11 h (SE 0·75) in the intestinal gel group and 2·24 h (0·76) in the immediate-release oral group (difference 1·86 [95% CI 0·56 to 3·17]; p=0·0059). In the safety analyses 35 (95%) of 37 patients allocated to the levodopa-carbidopa intestinal gel group had adverse events (five [14%] serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven [21%] serious), mainly associated with the percutaneous gastrojejunostomy tube. Interpretation: Continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson's disease with motor complications. Benefits noted with intestinal gel delivery were of a greater magnitude than were those obtained with medical therapies to date, and our study is, to our knowledge, the first demonstration of the benefit of continuous levodopa delivery in a double-blind controlled study. Funding: AbbVie.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 141-149 |
| Number of pages | 9 |
| Journal | The Lancet Neurology |
| Volume | 13 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2014 |
Funding
CWO has received consultancy fees from Abbott (AbbVie), Novartis/Orion, Impax, Ceregene, Teva/Lundbeck, AstraZeneca, Biotie/Synosia, CHDI, Civitas, LZ Therapeutics, Medivation, Neuroderm, Pharma2B, Phytopharm, Siena, Synagile, UCB, Otsuka, Upsher Smith, and US World Med, has stock in Clintrex, and is on the scientific advisory board of the Michael J Fox Foundation. KK has been a consultant to the National Institutes of Health (NINDS), the US FDA, the USVA, Abbott (AbbVie), Acorda, Aptiv, AstraZeneca, Auspex, Biogen Idec, Biotie, Biovail, Boehringer Ingelheim, Ceregene, CHDI, Civitas, Clintrex, Cynapsus, Endo, EMD Merck Serono, Genzyme, Impax, Intec, Ipsen, Isis, Knopp, Lilly, Link Medicine, Lundbeck, LZ Therapeutics, Medivation, Merck, Merz, Neotope/Elan Pharmaceuticals, Novartis, Orion, Otsuka, Pharm2B, Phytopharm, Roche, Schering-Plough, Siena Biotech, Synosia, Solvay, Synagile, Sofinnova, Teva, UCB Pharma, Upsher-Smith, Vaccinex, Vectura, and Xenoport, has received grant or research support from Medivation, Michael J Fox Foundation, National Institutes of Health (NEI, NINDS, NIA, NICHD), Neurosearch, and Pfizer, and has acted as a legal consultant for Pfizer, Thompson Hine, and the Welding Rod Litigation Defendants. PO has acted as a study investigator in AbbVie-sponsored studies, has received compensation from AbbVie, Boehringer Ingelheim, Britannia, Cephalon, GSK, Ipsen, Lundbeck, Nordic Infucare, and UCB for serving as a consultant or lecturer, and has received honoraria from the Movement Disorder Society. AJE is supported by the K23 Research Scholars mentored career development awards (NIMH, 1K23MH092735), has received grant support from CleveMed/Great Lakes Neurotechnologies, Davis Phinney Foundation, and Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board for Solvay, Abbott (AbbVie), Chelsea Therapeutics, TEVA, Eli Lilly, Impax, and Solstice Neurosciences; and honoraria from Novartis, the American Academy of Neurology, and the Movement Disorders Society. DGS is an investigator in studies funded by Abbott Laboratories, the American Parkinson Disease Association, the Michael J Fox Foundation, the National Multiple Sclerosis Society, the RJG Foundation, and NIH grants 5F30NS065661, 1F31NS076017, 5K08NS060948, 5R01MH082304, 5K01NS069614, 1R01NS064934, 5P50–NS037406, 1F31NS081963, 1K23NS080912, 1U18NS082132, 2U10NS044547, and 1R25NS079188; has a clinical practice and is compensated for these activities through the University of Alabama Health Services Foundation; has served as a consultant for or received honoraria from Teva Neurosciences, Serina Therapeutics, Lundbeck, Solvay, Abbott (AbbVie), the Michael J Fox Foundation, Partners Healthcare, the University of Michigan, the University of Virginia, The University of Pittsburg, the Mayo Clinic, The Pennington Research Center, the University of Kansas, the University of Arizona, the National Institutes of Health, Balch and Bingham LLC, the American Academy of Neurology, North Shore Hospital, the Thomas Hartman Foundation, the Bachmann-Strauss Foundation, Nupathe, Bradley Arrant Boult Cummings, and he has received royalties for publications from McGraw Hill. HHF has received research support from Abbott (AbbVie), Acadia, Biotie Therapeutics, EMD-Serono, Huntington Study Group, Ipsen, Merz Pharmaceuticals, Michael J Fox Foundation, Movement Disorders Society, National Parkinson Foundation, NIH/NINDS, Novartis, Parkinson Study Group, and Teva, but has no owner interest in any pharmaceutical company; and has received honoraria from Cleveland Clinic CME, Northwestern University CME, Ipsen, Merz Pharmaceuticals, and US World Meds. AV is a paid consultant for CVS Caremark's Pharmacy & Therapeutics committee and Abbott (AbbVie), and has been a scientific advisory board member for Abbott (AbbVie). AA has received honoraria for consulting services and symposia from Abbott (AbbVie), Boheringer Ingelheim, GSK, Lundbeck, UCB, Novartis and Merck Serono. AAO, WZR, KC, and JB are current employees of AbbVie and own AbbVie stock or stock options. YP is a current employee of Astellas Pharma, but was an employee of Abbott (now AbbVie) when these studies were completed and owns Abbott and AbbVie stock. KLW and RL are current employees of Amgen, but were employees of Abbott (now AbbVie) when these studies were completed and own Abbott and AbbVie stock.
ASJC Scopus subject areas
- Clinical Neurology