ArticlesContinuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study
Introduction
Parkinson's disease is characterised by degeneration of dopamine neurons in the substantia nigra pars compacta with resultant depletion of striatal dopamine leading to the core motor features of the disease. The mainstay of treatment is levodopa, the aminoacid precursor of dopamine. Nearly all patients with Parkinson's disease have a beneficial response, and no present medical or surgical therapy has been shown in controlled trials to provide greater antiparkinsonian benefit. However, chronic oral levodopa therapy is associated with development of potentially disabling motor complications (motor fluctuations and dyskinesia) in most patients.1 Motor fluctuations consist of an initial benefit after a dose of levodopa (on-time) followed by a return of parkinsonian features (off-time) before onset of benefit from the subsequent dose. Dyskinesias are involuntary movements induced by levodopa that typically occur during on-time. Raised doses of levodopa can reduce off-time but tend to increase dyskinesia, whereas a reduction in levodopa dose can reduce dyskinesia but tends to worsen off-time. In patients with advanced Parkinson's disease, provision of a dose of levodopa that satisfactorily controls off-time without inducing dyskinesia can be difficult. Several classes of medication (eg, dopamine agonists, catechol-O-methyl transferase [COMT] inhibitors, and monoamine oxidase B [MAO-B] inhibitors) have been developed to try to reduce off-time, but these drugs typically provide only modest benefit and are frequently worsen dyskinesia.2 Deep brain stimulation is widely used in advanced patients to improve off-time and rates of dyskinesia, but requires a neurosurgical intervention that is associated with potentially serious complications.3, 4 Development of a levodopa formulation that provides benefits without inducing or worsening motor complications is a major unmet need in Parkinson's disease.
Clinical and laboratory evidence suggests that levodopa-induced motor complications are related to the non-physiological restoration of brain dopamine with intermittent doses of standard oral levodopa.5 Striatal dopamine concentrations are normally maintained at a fairly constant level. However, in Parkinson's disease, in which there is a loss of nigrostriatal terminals, striatal dopamine levels are dependent on the peripheral availability of levodopa. Intermittent dosing with standard oral levodopa formulations provides fluctuating plasma levels due to erratic gastric emptying, variable jejunal absorption, and the short half-life of the drug (60–90 min).6, 7 In the dopamine-depleted state, this variability in plasma concentrations of levodopa is translated into abnormal, fluctuating, striatal dopamine concentrations,8, 9 which in turn are associated with non-physiological intermittent or pulsatile stimulation of dopamine receptors. This intermittent stimulation results in gene and molecular changes in striatal neurons, neurophysiological changes in the firing pattern of pallidal output neurons, and the development of motor complications.5
Continuous delivery of levodopa might restore brain dopamine in a more physiological way, and thereby avoid or reduce motor complications associated with traditional levodopa therapy.5, 10 Continuous levodopa infusion has been reported to reduce both off-time and dyskinesia in open-label studies in patients with advanced Parkinson's disease.11, 12, 13 However, development of oral or patch formulations that deliver levodopa in a continuous way has been problematic.
Levodopa-carbidopa intestinal gel (AbbVie, North Chicago, IL, USA) is a carboxymethylcellulose aqueous gel that can be delivered continuously to the proximal jejunum via a percutaneous gastrojejunostomy tube connected to a portable infusion pump (CADD-Legacy, Smiths Medical, Minneapolis, MN, USA; appendix). Pharmacokinetic studies show jejunal infusion of levodopa-carbidopa intestinal gel provides fairly constant plasma levodopa levels with less variability than oral formulations,14, 15 and open-label studies suggest a notable reduction (improvement) in off-time without worsening of dyskinesias.16, 17, 18, 19 Despite the absence of double-blind trials, levodopa-carbidopa intestinal gel is approved for use in 43 countries. However, open-label interventional studies in patients with advanced Parkinson's disease have frequently not been confirmed in double-blind trials.20 Thus, we aimed to assess safety and efficacy of continuous levodopa-carbidopa intestinal gel infusion in patients with advanced Parkinson's disease in a prospective, double-blind, placebo-controlled setting.
Section snippets
Study design and participants
We undertook a 12-week, prospective, multicentre, placebo-controlled, parallel group, double-blind, double-dummy, double-titration study. We enrolled adults (aged ≥30 years) with advanced Parkinson's disease consistent with UK Brain Bank criteria that was complicated by off-periods which could not be satisfactorily controlled with optimised medical therapy. Optimised therapy was defined as an adequate trial in the judgment of the investigator of levodopa-carbidopa, a dopamine agonist, and at
Results
We enrolled 71 participants at 26 centres in Germany, New Zealand, and the USA (table 1). The mean number of patients per centre was 2·7 (median 2, IQR 1–3), and 34 patients were enrolled at the five largest sites. 35 patients in the levodopa-carbidopa intestinal gel group and 31 patients in the immediate-release oral levodopa-carbidopa group completed the trial and were included in the full-analysis set (figure 1). Titration to stable dose was achieved in a mean of 7 days (SD 2·5) for
Discussion
In our study, continuous intrajejunal infusion of levodopa gel provided a clinically significant reduction in off-time in patients with advanced Parkinson's disease compared with intermittent doses of immediate-release oral levodopa. Notably, this benefit was also associated with a significant increase in on-time without troublesome dyskinesia. Off-time in patients treated with levodopa-carbidopa intestinal gel was reduced by 1·91 h compared with standard oral levodopa, and by 4·04 h from
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