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

Abstract

Background Levodopa is the most effective therapy for Parkinson's disease (PD), but chronic treatment is associated with the development of potentially disabling motor complications. Experimental studies suggest that motor complications are due to non-physiologic, intermittent administration of the drug, and can be reduced with continuous delivery. Levodopa-carbidopa intestinal gel (LCIG) is a form of levodopa that can be delivered continuously through an intrajejunal percutaneous tube. Methods We performed a 12-week double-blind, double-dummy, double-titration, multi-center trial to evaluate the efficacy and safety of LCIG compared to optimized, oral, immediate-release levodopa-carbidopa (LC-IR) in advanced PD patients with motor complications. The primary endpoint was change from baseline to final visit in motor “Off” time. Motor “On” time without troublesome dyskinesia was the key secondary endpoint. Findings 71 patients with advanced PD were randomized to receive continuous LCIG infusion plus placebo LC-IR capsules (n=37) or to receive LC-IR capsules plus continuous placebo LCIG infusion (n=34). Both groups were titrated to optimal effect. 93% of subjects (n=66) completed the trial. In comparison to LC-IR, LCIG significantly reduced “Off” time by a mean (±SE) of 1·91±0·57 hours (P=0·0015) and increased “On” time without troublesome dyskinesia by a mean of 1·86±0·65 hours (P=0·006). Adverse events were primarily related to the surgical procedure and the device, and while potentially serious, were not associated with residual deficit or mortality. Interpretation In comparison to standard oral LC-IR, LCIG significantly reduced “Off” time and increased “On” time without troublesome dyskinesia in patients with advanced PD. Adverse events were largely due to the procedure and the device. Benefits are of greater magnitude than have been obtained with medical therapies to date, and represent the first demonstration of the benefit of continuous levodopa delivery in a double-blind controlled study.

l‐Dopa/carbidopa intestinal gel and subthalamic nucleus stimulation: Effects on cognition and behavior

“…There is limited information on the effects of LCIG on behavior and cognition; most studies have focused on its effects in motor disability, nonmotor symptoms, and quality of life (Olanow et al., 2014). A study on 17 patients showed that, after LCIG, 41% patients developed cognitive deterioration over time in memory functions, attention, visual‐motor speed, and executive functions (Zibetti et al., 2013), but it could not be excluded that cognitive changes were related to disease progression.…”

Effects of levodopa/carbidopa intestinal gel versus oral levodopa/carbidopa on B vitamin levels and neuropathy

“…Continuous jejunal infusion of levodopa/carbidopa intestinal gel (LCIG) via a percutaneous pump leads to more constant plasma levels of levodopa (Nyholm et al., 2003), and it results in significant reduction in off‐time and on‐time with troublesome dyskinesias (Antonini et al., 2007; Eggert et al., 2008; Fernandez et al., 2013; Olanow et al., 2014). Common side effects of LCIG treatment are surgical‐ or device‐related complications (Olanow et al., 2014), but there are also anecdotal reports on neuropathy in LCIG‐treated patients.…”

Algorithms for the treatment of motor problems in Parkinson's disease

“…Levodopa‐carbidopa intestinal gel infusion is also safe and well documented, with a good long‐term effect on PD motor symptoms and reduced risk of motor fluctuations 60, 61, 62, 63, 64. Most adverse effects are device‐related.…”