Levodopa-Carbidopa Intraintestinal Infusion: Benefits in Advanced Parkinson's Disease
Abstract & Commentary
By Claire Henchcliffe, MD
Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College
Dr. Henchcliffe reports she is on the speakers bureau and advisory board for GE, Teva Pharmaceutical Industries, and UCB; advisory board for Allergan and USWorldmeds; receives grant/research support from Biogen and Kaneka; and does CME program development and presentation for MedIQ.
Synopsis: In this 12-week, randomized, double-blind and double-dummy trial, intrajejunal infusion of levodopa-carbidopa gel decreased "off" time by almost 2 hours more than oral levodopa-carbidopa in individuals with Parkinson's disease suffering motor fluctuations.
Source: Olanow CW, et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: A randomized, controlled, double-blind, double-dummy study. Lancet Neurol 2014;13:141-149.
This 12-week multicenter, double-blind, double-dummy clinical trial assessed efficacy and safety of direct intrajejunal delivery of levodopa-carbidopa intestinal gel (LCIG) in advanced Parkinson's disease (PD). The primary outcome was change in daily motor "off" time measured by home diaries, i.e., time when PD symptoms were not controlled by medications. Seventy-one individuals with PD and levodopa-associated motor complications underwent placement of a percutaneous gastrojejunostomy tube attached to a pump and a cassette containing either LCIG or placebo gel. They were then randomized to receive either: 1) immediate-release oral levodopa-carbidopa (LC) plus placebo intestinal gel (n = 34), or 2) LCIG plus oral placebo tablets (n = 37). Participants in the two groups were well matched for age (63.7 ± 9.5 vs 65.1 ± 6.8 years for LCIG vs oral LC), PD disease duration (10.0 ± 4.6 and 11.8 ± 5.6 years for LCIG vs oral LC), and "off" time (6.3 ± 1.7 and 7.0 ± 2.1 hours daily for LCIG vs oral LC). "On" time with troublesome dyskinesias was approximately 1 hour in each group. Baseline daily levodopa doses were 1005 ± 374 mg (LCIG) and 1124 ± 478 mg (oral LC), and dopamine agonists, catechol-O-methyl transferase inhibitors, and monoamine oxidase B inhibitors were allowed. Subjects were started at their regular levodopa dose but were converted to immediate-release tablets containing 25 mg carbidopa and 100 mg levodopa. In those receiving LCIG, a morning bolus of 5-10 cc gel was followed by continuous infusion through waking hours and was stopped overnight. Investigators were allowed to adjust doses over the first 4 weeks. The study successfully met its primary outcome by reducing daily "off" time by -4.04 ± 0.65 hours (LCIG) vs -2.14 ± 0.66 hours (oral LC) (P = 0.0015). In parallel, "on" time without troublesome dyskinesias increased by 4.11 ± 0.75 hours (LCIG), and 2.24 ± 0.76 hours (oral LC) (P = 0.0059). "On" time without dyskinesias increased by 3.37 ± 1.04 hours (LCIG) vs 1.09 ± 1.05 hours (oral LC) (P = 0.0142). Serious adverse events occurred in 5/37 receiving LCIG and in 7/34 receiving oral LC. Many were related to the surgical procedure and device complications, but were mostly mild-to-moderate. Procedural pain was reported in 32%, wound infection in 17%, and post-procedural discharge in 10%. Intestinal tube malfunction included dislocation (24%) and occlusion (13%), and the tube was unintentionally removed in one subject. Pump malfunction occurred in 8%. Three subjects discontinued due to peritonitis and pneumonia (n = 1), psychosis (n = 1, LCIG group), or post-procedural discharge (n = 1), and two patients discontinued due to surgical complications.
Oral levodopa-carbidopa has been the "gold standard" of pharmacologic treatment of PD, but treatment results in dose- and duration-related motor complications in the majority of patients. Motor complications typically comprise end-of-dose wearing off (loss of benefit prior to the next scheduled dose) and dyskinesias that are often associated with peak dose. As PD progresses, patients are increasingly affected by fluctuating plasma levels of levodopa (which has a half-life of only 60-90 minutes) and erratic gastrointestinal absorption. Therefore, a need to "smooth out" levodopa delivery underpins the rationale for infusion technology tested in this trial. Results demonstrate clear superiority in reduction of "off" time for LCIG administration compared with oral LC. Although dopamine agonists, monoamine oxidase B inhibitors, and catechol-O-methyl transferase inhibitors decrease "off" time, a simultaneous increase in dyskinesia and other side effects limit benefit in some patients. In such situations, deep brain stimulation may be an option, but is not suitable for all patients and is associated with rare but potentially serious complications. The authors raise the intriguing point of whether smoother levodopa delivery will improve dyskinesias, but proving this will require a longer study. In the meantime, it is encouraging that plasma levodopa levels were less variable in those receiving LCIG vs oral LC. The majority of adverse events were related to either placement or function of the percutaneous gastrojejunostomy tube and pump, and patients and caregivers will need to be well counseled, educated, and trained when starting LCIG. Common levodopa-associated side effects, such as nausea, were also recorded in both groups. One group has previously reported polyneuropathy and Guillain-Barré syndrome in association of LCIG use, but no such instances were found in this study. In summary, this is the first double-blind study to demonstrate LCIG superiority over oral LC in PD. LCIG is currently in use for PD with motor complications in more than 40 countries, so there is ample experience to further support its use. If and when LCIG reaches the market in the United States, it should provide an important new treatment in selected patients struggling to manage fluctuating symptoms of advanced PD.