Open-Label Surgical Trials for Parkinson Disease: Time for Reconsideration

Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY, USA.
Annals of Neurology (Impact Factor: 11.91). 07/2011; 70(1):5-8. DOI: 10.1002/ana.22453
Source: PubMed
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    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, 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.
    The Lancet Neurology 01/2013; 13(2). DOI:10.1016/S1474-4422(13)70293-X · 21.82 Impact Factor
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    ABSTRACT: Randomized controlled trials [RCTs] are recognized as the most rigorous method for evaluating the safety and efficacy of novel interventions. The fact that a series of RCTs evaluating cellular therapies for Parkinson’s disease [PD] resulted in negative outcomes has delayed the translation of stem cell research into viable treatments for people with brain damage. At present, there are a variety of strategies being followed to improve outcomes for cellular therapies, including reassessment of the theory and methodology guiding the research program. In this position paper we present an argument based on empirical and theoretical grounds that the use of double-blind, placebo controlled trials are not the best approach for testing the efficacy of cellular therapies for PD. Evidence includes the highly variable effects of neural grafts found in double blind RCTs in comparison to the much larger benefits in open-label trials for people with PD in double-blind RCT. We suggest that the ambiguity and confusion created about the actual nature of the treatment in the context of a double-blind trial compromises the efforts of participants and their Carers to make the best therapeutic use of the grafted cells. The theoretical grounds for rejecting the use of double-bind RCTs is based on the Composite Brain Theory, which postulates that to insure optimal therapeutic outcomes it is essential to integrate the intracerebral grafting of cells with an active program of neurorehabilitation. We are recommending the use of pragmatic RCTs which involve the comparison of cellular transplantation and rehabilitation with best practice pharmacotherapy or Deep Brain Stimulation as comparison groups. Using a pragmatic trial design will ensure optimal outcomes for each of the treatment groups and produce evidence applicable for identifying best available treatments for people with PD.
  • Nature Reviews Neurology 03/2014; DOI:10.1038/nrneurol.2014.45 · 14.10 Impact Factor


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