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Levodopa Gel Reported to Reduce Parkinson Disease “Off Time”

Continuous infusion of a levodopa gel into the small intestine beat out levodopa-carbidopa immediate-release (IR) tablets at reducing “off” time in patients with advanced Parkinson disease (PD), without increasing dyskinesia.

That's according to results of a phase 3 randomized, double-blind, double-dummy trial presented as part of the emerging science program at the AAN annual meeting in New Orleans in April.

“Levodopa is still the best drug we have [for Parkinson disease], but after a long period of time, many patients develop motor complications, dyskinesias, during periods of response. Additionally, there is tendency of the drug to wear off, and Parkinson symptoms to return,” said lead researcher C. Warren Olanow, MD, professor of neurology and neuroscience at Mount Sinai School of Medicine in New York.

“Patients begin cycling between periods when parkinsonism is controlled but there are involuntary movements and periods when parkinsonism is not controlled,” he said.

“A growing body of evidence suggests cycling occurs because levodopa is being restored in a non-physiologic way,” Dr. Olanow continued. “And a number of studies have shown that continuous infusion of levodopa into the intestine could prevent this cycling, but the studies have been small and open label in design,” he said.

So the researchers designed what Dr. Olanow believes is the first double-blind, double-dummy trial pitting a continuous infusion of levodopa-carbidopa intestinal gel (LCIG) against standard levodopa-carbidopa immediate-release tablets in patients with advanced Parkinson disease and motor complications on optimized oral treatment.

A total of 37 patients were randomly assigned to receive LCIG infusion plus placebo capsules and 34 patients were randomized to encapsulated levodopa-carbidopa IR tablets plus placebo gel infusion. The infused drug was delivered through an intrajejunal percutaneous gastrostomy tube that Dr. Olanow compared to a feeding tube.

Patients in the trial had PD for a mean of 10.9 yrs. Baseline mean “off” time and “on” time without troublesome dyskinesia were 6.6 hours daily and 8.3 hours daily, respectively.

The primary endpoint was change from baseline to week 12 in “off” time normalized to 16 waking hours, as assessed using patient diaries. “On” time without troublesome dyskinesia was a key secondary outcome, assessed using the Parkinson's Disease Questionnaire and the Unified Parkinson's Disease Rating Scale.

A total of 66 patients (93 percent) completed the trial, which was supported by Abbott.


Among the findings: mean “off” time decreased by four hours daily in patients receiving LCIG, an average of 1.91 fewer hours compared with the time in those taking levodopa tablets (p =.0015).

Mean “on” time without troublesome dyskinesia increased by 4.1 hours in patients receiving LCIG, an average of 1.86 more hours compared with the time in those taking tablets (p =.0059). There was no significant change in “on” time with troublesome dyskinesia.

Adverse events occurred in 35 (95 percent) patients receiving LCIG and 34 patients (100 percent) in the control group. The most common adverse events were complications of device insertion (51 percent) abdominal pain (42 percent), procedural pain (32 percent), and nausea (25 percent).

Dr. Olanow said the researchers hope there will be fewer side effects as clinicians grow more comfortable with the procedure.


Stanley Fahn, MD, the H. Houston Merritt professor of neurology at Columbia University and director of the movement disorder division of the Neurological Institute in New York, said there appears to be “a definite advantage” of the continuous infusion of levodopa over tablets in terms of clinical benefit.

“This is another way to smooth patients out if it can't be done by oral medication. And it allows us to avoid [brain] surgery,” Dr. Fahn said.

He noted that LCIG is already in use in many European countries. “The FDA required a double-dummy study for approval in the United States, which is why the current trial was done,” he said.

The clinical benefit is similar to what can be achieved with deep brain stimulation (DBS), “but most patients don't want electrodes in their brain,” he said.

Dr. Fahn conceded that inserting the tube into the intestine can cause mechanical problems such as blockage, inflammation or infection.

“But inserting a needle into the brain for DBS is probably much more dangerous, carrying potential risk of brain inflammation, infection, or damage,” he said.

A word of caution: Not all patients are candidates for the intestinal gel, Dr. Fahn said. “This is not meant for someone who doesn't respond to levodopa, which can include patients who are very far advanced or who don't really have PD or who have intractable disease beyond what levodopa can do,” he said.



What are the advantages or limitations of using an intrajejunal gastronomy tube to deliver continuous levodopa? Watch here as Neurology Today Editor-in-chief Steven P. Ringel, MD, and Associate Editor Robert Holloway, MD, weigh in: