NEW ORLEANS – Advanced Parkinson’s disease patients had significantly less "off" time – without increased dyskinesia – when they were treated with levodopa-carbidopa intestinal gel rather than immediate-release oral levodopa-carbidopa in a phase III, randomized trial sponsored by the gel’s maker, Abbott Laboratories.
The trial is part of Abbott’s phase III development program for the drug; the company plans to submit an approval package to the Food and Drug Administration this year. The gel has been on the market for several years in Europe and elsewhere, where it has been sold under the name Duodopa.
Commenting on his blog, the medical director of the National Parkinson Foundation, Dr. Michael Okun, wrote, "Duodopa will likely be a great choice for many patients with on-off fluctuations, and will in most cases allow discontinuation of oral PD drugs."
"However, Duodopa does require a very attentive caregiver who will need to attend to device management, skin management (for the tube), and also attend to medication refills. Early studies of Duodopa have revealed high rates of device-related problems with the intestinal tube," such as clogging, kinking, and moving out of the correct location, said Dr. Okun, codirector of the center for movement disorders and neurorestoration at the University of Florida, Gainesville.
The idea is that by infusing levodopa-carbidopa continuously, patients can avoid the fluctuating plasma levodopa levels associated with oral formulations.
Perhaps those fluctuating levels induce molecular and physiological changes in dopamine receptors "that ultimately result in motor complications. This has led to the theory that if you can deliver levodopa more continuously, it would be more physiologic and might avoid these problems," said lead investigator Dr. Warren Olanow, director of the Bendheim Parkinson Center at the Mount Sinai Medical Center in New York City. He presented the findings on behalf of Abbott.
The gel is delivered through a surgically placed gastrojejunostomy tube, which is connected to a portable pump that is worn around the waist for 16 hours a day.
In the 12-week trial, 37 patients with motor complications that were inadequately controlled by oral medications were randomized to levodopa-carbidopa intestinal gel (LCIG) plus placebo capsules; 34 were randomized to levodopa-carbidopa immediate release (LC-IR) tablets plus placebo gel infusions.
The LCIG group had a mean 1.91 hours less "off" time each day than did the LC-IR group (P = .0015), and a mean 1.86 hours more daily "on" time without troublesome dyskinesia (P = .0059).
But the tube placement caused complications in about half of the patients, and 23 (32.4%) had pain with the procedure. In all, 19 (51%) LCIG patients and 11 (32%) LC-IR patients complained of abdominal pain; 11 (30%) LCIG patients and 7 (21%) LC-IR patients complained of nausea. Although common, the side effects were mostly transient, Dr. Olanow said.
Overall, the benefits of the gel "in a patient group that cannot be satisfactorily controlled with standard levodopa represent an important step forward in our efforts to treat advanced PD patients," he said.
With several years of use in Europe and elsewhere, the gel already has a fairly robust body of published literature. In a small, randomized, pharmacokinetics study that compared it to sustained-release oral levodopa-carbidopa, the gel patients had steadier levodopa plasma concentrations and greater "on" time (Clin. Neuropharmacol. 2003;26:156-63).
Another trial compared subthalamic nucleus deep brain stimulation (DBS) in 20 patients to Duodopa in 20 others who were unsuitable for DBS neurosurgery. Both groups had a significant improvement in Unified Parkinson’s Disease Rating Scale scores and considerable off-time reduction. Only the DBS group had a significant improvement in dyskinesia duration and disability, but also a significant drop in verbal fluency that was not seen with Duodopa. Duodopa, however, had more procedure-related complications (Mov. Disord. 2011;26:664-70).
Dr. Olanow has received personal compensation for activities with Abbott, Teva/Lundbeck, Novartis/Orion, Ceregene, Merck Serono, Ipsen, and Impax. He holds stock or stock options in Clintrex and Ceregene. Dr. Okun has no current, relevant disclosures.