Levodopa Intestinal Gel Reduces 'Off' Time in Parkinson's

Pauline Anderson

April 18, 2012

April 18, 2012 — Continuous delivery of levodopa directly into the small intestine is showing promise as a treatment for patients with advanced Parkinson's disease (PD).

A phase 3 study, to be released at the upcoming 64th Annual Meeting of the American Academy of Neurology, showed that a levodopa-carbidopa intestinal gel (LCIG) (Duodopa, Abbott) was better than levodopa-carbidopa immediate-release (IR) tablets at improving "off" time, without increasing dyskinesia.

The double-blind, double-dummy trial, which included 71 patients with PD, also showed that adverse events were similar in the 2 groups and were generally related to the placement of the intrajejunal tube.

Levodopa has been an effective drug for half a century, but as PD progresses, the drug is associated with side effects, including a tendency to wear off, and for patients to develop dyskinesia during periods of response, said lead researcher C. Warren Olanow, MD, professor of neurology and neuroscience, Mount Sinai School of Medicine, New York.

"This is a terrific drug for treating Parkinson disease, but the benefit becomes complicated by periods where parkinsonism returns and is not controlled, and periods where it is controlled but there are these involuntary movements, and patients cycle between these periods," he told Medscape Medical News.

These side effects occur because levodopa is being restored "in a non-physiologic way", said Dr. Olanow. "We have argued for a long time that if we could find a way to give levodopa more continuously, it would be more physiologic and would avoid these side effects."

Continuous administration of a levodopa gel through the intestine appears to address these issues, said Dr. Olanow.

Discreet Pump

For the study, patients with advanced PD and severe motor fluctuations despite optimized oral treatment were randomly assigned to receive LCIG infusion (n = 37) plus placebo capsules or encapsulated levodopa-carbidopa IR tablets (n = 34) plus placebo gel infusion. The infused drug was delivered through a tube inserted into the intestine.

"It's very similar to a feeding tube," explained Dr. Olanow. The portable pump connected to the tube is discreet, he added. "It's not like you're running around with a big machine attached to you."

The mean duration of PD for study patients was 10.9 years. Baseline mean "off" time and "on" time without TD were 6.6 and 8.3 hours per day, respectively.

For the primary endpoint — change from baseline to 12 weeks in "off" time normalized to 16 waking hours — researchers used the Parkinson's Disease Diary–derived measures. To assess a key secondary outcome of "on" time without troublesome dyskinesia, they used the Parkinson's Disease Questionnaire, Clinical Global Impression-Improvement, and Unified Parkinson's Disease Rating Scale scores.

The rate of premature discontinuation in the study due to adverse events was similar between treatment groups. Of the enrolled patients, 93% (n = 66) completed the trial.

The results showed the intestinal gel offered significant improvements. Mean "off" time decreased by 4.0 hours per day in patients receiving LCIG, an average of 1.91 fewer hours compared with the time in those taking the levodopa tablets (P = .0015). As well, mean "on" time improved by 4.1 hours with LCIG, an average of 1.86 more hours compared with the time for the tablets (P = .0059). There was no significant change in "on" time with TD.

Adverse events occurred in 35 (95%) patients receiving LCIG compared with 34 (100%) in the placebo group. The most common events were complications of device insertion (51%), abdominal pain (42%), procedural pain (32%), and nausea (25%). Other side effects included constipation (21%), orthostatic hypotension (18%), postoperative wound infection (17%), and incision site erythema (16%).

Treatment-related serious adverse events were reported in 5 patients (14%) in the LCIG group and in 7 patients (21%) in the levodopa-carbidopa IR tablets group.

Similar to Deep Brain Stimulation?

The intestinal gel was "surprisingly well tolerated," commented Dr. Olanow. "For many patients, it has changed their life tremendously," he said. It's "a huge advantage" to be "on" for the bulk of the day without suffering dyskinesias, he added.

There is also evidence this could be a longer-term solution, said Dr. Olanow. He referred to an open-label study during which researchers followed 6 patients who had the intestinal pump inserted. "In those patients, we were able not only to reverse the 'off' time, without worsening dyskinesia, but we were also able to actually reverse the dyskinesia," he noted. "These benefits persisted for many, many years."

Dr. Olanow likened the effects of the intestinal gel to those seen with deep brain stimulation (DBS). "The magnitude of benefit you see with Duodopa is very similar to the magnitude of benefit you see with deep brain stimulation — there are pluses and minuses to each."

Among the "minuses" of the gel is that it requires an operation to insert the tube and the tube could become blocked or cause local inflammation. But DBS also comes with possible complications, including inflammation, infection, or brain damage caused during needle insertion.

As well, not all patients are good candidates for DBS — for example, those who are cognitively impaired, have an anatomic impairment, or merely prefer a gastrointestinal procedure over a brain operation.

Patients who would not be good candidates for this new intestinal gel include those who don't respond to levodopa, said Dr. Olanow. "Sadly, that's a meaningful number."

Another open-label study of this approach was presented last June at the Movement Disorders Society 15th International Congress of Parkinson's Disease and Movement Disorders, and reported by Medscape Medical News at that time.

Specialized Treatment

Invited to comment on this research, Jens Volkmann, MD, PhD, chairman and professor of neurology, Department of Neurology, University Clinic of Würzburg, Germany, said the study results are not surprising, given the clinical experience with LCIG in Germany and other European countries.

In Germany, LCIG, along with DBS and apomorphine infusion, are the 3 treatment options used when conventional oral drug therapy fails to control motor fluctuations or dyskinesia. The current study was requested by the US Food and Drug Administration to support an application for approval in the United States, he said.

Dr. Volkmann noted that the "off" time reduction reported in the study (1.91 hours) was less than expected from open-label studies and does not reflect his own clinical experience. "It must be related to restrictions within the study protocol, which probably prevented an optimal adjustment of the therapy," he told Medscape Medical News. "A well-adjusted levodopa infusion therapy provides, in most cases, an almost continuous 'on' state during daytime hours."

Important issues related to the therapy still need to be addressed, he stressed. These include the true rate of adverse events during long-term use; the drop-out rate for the therapy, which requires a certain amount of nursing care; and patient selection, he said.

LCIG will certainly not completely replace oral levodopa therapy "because of the invasive nature of the therapy, the cosmetic aspects and the practical restriction of carrying a pump system," said Dr. Volkmann. "It is a specialized treatment for patients with severe fluctuations despite optimized oral therapy, in particular for those who do not want to have DBS or who do not meet the very strict inclusion criteria for DBS."

The study was supported by Abbott. Dr. Olanow served as a consultant for Solvay and Abbott.

American Academy of Neurology's 64th Annual Meeting in New Orleans. To be presented on April 25.

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