Long-term safety and efficacy of levodopa-carbidopa intestinal gel in advanced Parkinson's disease: Long-Term Safety and Efficacy of LCIG

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Abstract

<p class="first" id="d4497090e245">Levodopa-carbidopa intestinal gel (designated as carbidopa-levodopa enteral suspension in the United States) provides stable plasma levodopa concentrations and reduces motor fluctuations in advanced Parkinson's disease patients through continuous delivery of levodopa via percutaneous endoscopic gastrojejunostomy. We report long-term safety and efficacy outcomes from an open-label phase 3 treatment program. </p>

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Most cited references 37

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Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study.

C Warren Olanow, C Warren Olanow, Moneeb Othman … (2014)

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. 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. 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. 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. AbbVie. Copyright © 2014 Elsevier Ltd. All rights reserved.

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Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease.

(1993)

In 1987 we began a multicenter controlled clinical trial of deprenyl (a monoamine oxidase inhibitor) and tocopherol (a component of vitamin E that traps free radicals) in the treatment of early Parkinson's disease. We randomly assigned 800 patients to one of four treatments: placebo, active tocopherol and deprenyl placebo, active deprenyl and tocopherol placebo, or both active drugs. The primary end point was the onset of disability prompting the clinical decision to begin administering levodopa. An interim analysis showed that deprenyl was beneficial (N Engl J Med 1989;321:1364-71). We report the results of tocopherol treatment after a mean (+/- SD) follow-up of 14 +/- 6 months, as well as the follow-up results for deprenyl. There was no beneficial effect of tocopherol or any interaction between tocopherol and deprenyl. The beneficial effects of deprenyl, which occurred largely during the first 12 months of treatment, remained strong and significantly delayed the onset of disability requiring levodopa therapy (hazard ratio, 0.50; 95 percent confidence interval, 0.41 to 0.62; P < 0.001). The difference in the estimated median time to the end point was about nine months. The ratings for Parkinson's disease improved during the first three months of deprenyl treatment; the motor performance of deprenyl-treated patients worsened after the treatments were withdrawn. Deprenyl (10 mg per day) but not tocopherol (2000 IU per day) delays the onset of disability associated with early, otherwise untreated Parkinson's disease. The action of deprenyl that accounts for its beneficial effects remains unclear.

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Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature.

J. Ahlskog, Manfred Muenter (2001)

There is no clear consensus regarding the frequency (and hence, the risk), of dyskinesias or motor fluctuations during chronic levodopa therapy for Parkinson's disease (PD). Multiple clinical series have tabulated these frequencies since the advent of levodopa over 30 years ago. We were interested in determining: (1) the aggregate frequency figures in the existing literature; and (2) how clinical series from the early levodopa era, which included patients with longer durations of parkinsonism, compare to more recent (modern era) series. We searched MEDLINE for all English language publications reporting the cumulative frequency of levodopa-induced dyskinesias or motor fluctuations during discrete intervals of treatment. This generated 2,478 publications spanning 1966 through September 2000. Papers with appropriate titles or abstracts were reviewed; reference lists from published clinical series were a source of additional papers for review. This ultimately yielded 74 publications with adequate data, relating to 112 intervals of levodopa treatment. Series that included patients with PD-onset well before levodopa availability (pre-levodopa era) were separately analyzed from all subsequent series. Series were grouped by duration of levodopa therapy and the median frequencies of dyskinesias and motor fluctuations were tabulated for each group. The data were analyzed both with and without adjustment for the number (N) in each series. Among series containing pre-levodopa era patients, the median dyskinesia frequency was already 50% by 5-6 months of treatment. This contrasts with the modern era series where dyskinesias were reported later in treatment. The median dyskinesia frequency was slightly less than 40% by 4-6 years of levodopa therapy among modern era patients. Motor fluctuations (wearing-off) were not tabulated in most of the early levodopa series. Among modern era reports, motor fluctuations were nil during the first year of levodopa therapy but were experienced by approximately 40% of patients by 4-6 years of treatment. Similar results were found when the analyses were restricted to only prospective studies where levodopa motor complications were targeted outcome measures. The conclusions reached were: (1) patients from the pre-levodopa era experienced dyskinesias much earlier during levodopa treatment than modern era patients, perhaps because of longer durations of pre-existing PD; (2) in the present era, patients treated with levodopa therapy for 4-6 years have approximately a 40% likelihood of experiencing motor fluctuations and a risk of dyskinesias just short of 40%; and (3) these findings represent incident data and the prevalence of clinically important morbidity may be substantially less. Copyright 2001 Movement Disorder Society.

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Author and article information

Contributors

David G. Standaert: (View ORCID Profile)

Alberto J. Espay: (View ORCID Profile)

Journal

Title: Movement Disorders

Abbreviated Title: Mov Disord.

Publisher: Wiley

ISSN: 08853185

Publication date Created: July 2018

Publication date (Print): July 2018

Publication date (Electronic): March 23 2018

Volume: 33

Issue: 6

Pages: 928-936

Affiliations

[1 ]Center for Neurological Restoration; Cleveland Clinic; Cleveland Ohio USA

[2 ]University of Vermont Larner College of Medicine, Burlington; Vermont USA

[3 ]Westmead Hospital and Sydney Medical School; Sydney Australia

[4 ]Keck/University of Southern California School of Medicine; Los Angeles California USA

[5 ]University of Florida College of Medicine, Gainesville, Florida, USA, and Orlando Veterans Affairs Medical Center; Orlando Florida USA

[6 ]University of Kentucky Medical Center; Lexington Kentucky USA

[7 ]University of Alabama at Birmingham; Birmingham; Alabama USA

[8 ]Feinberg School of Medicine; Northwestern University; Chicago Illinois USA

[9 ]AbbVie Inc.; North Chicago Illinois USA

[10 ]University of Cincinnati Academic Health Center; Cincinnati Ohio USA

Article

DOI: 10.1002/mds.27338

PubMed ID: 29570853

SO-VID: 149279e4-0e2d-4382-9963-b4af8169557c

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Most cited references 37

Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study.

Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease.

Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature.

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