Pauline Anderson

June 15, 2011

June 15, 2011 (Toronto, Ontario) — Preliminary evidence from a phase 3 open-label, multisite study of a levodopa-carbidopa intestinal gel shows that the agent significantly decreases "off" time and increases "on" time without troublesome dyskinesia.

The agent is continuously infused during the day into the small intestine via a portable pump connected to a surgically implanted gastric tube, similar to a feeding tube.

The effect of this therapy is dramatic and on par with results from deep-brain stimulation, said one of the study's lead investigators, Alberto J. Espay, MD, assistant professor of neurology, University of Cincinnati Neuroscience Institute, and director of clinical research, Gardner Family Center for Parkinson's Disease, Ohio.

Dr. Alberto J. Espay

"The only comparable therapy that brings up the on time to the extent or the magnitude that this gel does is deep-brain stimulation, so the future of studies will require direct head-to-head comparisons between deep-brain stimulation and levodopa-carbidopa gel," he told Medscape Medical News. "It cannot be compared with any of the oral medications for Parkinson's disease."

Patients are generally very pleased with the improvements they experience with the intestinal gel, and many can return to previous activities, said Dr. Espay.

Results were presented at the Movement Disorders Society 15th International Congress of Parkinson's Disease and Movement Disorders. The study was funded by Abbott.

Bypasses Stomach

The study included 192 patients (mean age, 64.1 years) with advanced Parkinson's disease (PD) who had severe motor fluctuations despite optimized treatment with available medications and who were proven to be levodopa-carbidopa responders. The patients underwent a surgical procedure to implant an intrajejunal percutaneous endoscopic gastrostomy (PEG-J) tube in the abdomen. The tube connects to a pump that is controlled by the patient. Patients received the treatment for 16 hours per day and kept diaries to track symptoms, off and on times, and dyskinesias.

An advantage of the therapy is that it goes directly to the jejunum, bypassing the stomach, and therefore avoiding "erratic" absorption, said Dr. Espay. As well, the intestinal gel delivers the medication in a continuous fashion instead of in periodic surges, he said. "This means that the dopamine is stimulating receptors in the brain in a constant or tonic fashion, meaning without the peaks and the valleys."

This interim analysis included all patients who had had their PEG-J tube inserted at least 12 weeks before the cutoff data of July 30, 2010.

Results showed that at 12 weeks, off time was reduced by a mean of 3.9 hours per day, on times with troublesome dyskinesias were reduced 0.7 hour per day, and on times without dyskinesia plus on time with nontroublesome dyskinesias were increased 4.6 hours per day.

Patients were "thrilled" with these "dramatic" results, said Dr. Espay. And so were the researchers. "There is nothing that has brought us more joy by seeing patients that were literally not doing much of anything by virtue of their disability."

One patient in the study was able to return to college, another could return to his law practice, and another, a doctor, who was forced to cut his hours because of his illness, was able to go back full-time. "There are very few therapies that I can think of that will bring patients back into sort of full force than this one," said Dr. Espay.

Surgical Insertion Complications

However, the therapy is not without complications — adverse events occurred in 168 patients (87.5%). The most common adverse events were abdominal pain (30.7%), complications of device insertion (21.4%), and procedural pain (17.7%). The most severe complications from surgery were peritonitis (3.6%) and pneumoperitoneum (5.7%). Fourteen patients (7.3%) withdrew because of an adverse event.

Most complications were related to the surgery and occurred during the first 2 or 3 months, said Dr. Espay. He added that he and his colleagues are trying to find ways of inserting the tube that are less prone to complications.

Additional adverse events included constipation (13.5%), nausea (13.5%), excessive granulation tissue (13.5%), fall (10.9%), dyskinesia (10.9%), insomnia (10.9%), postoperative wound infection (10.4%), and anxiety (10.4%).

Patients in the study did not find the external pump restrictive. Men could attach it to their belt, and women found creative ways to hide it by making purse-like holders, said Dr. Espay. "They would have to literally pull their shirt up for you to know that they have a pump; it's not something you’d notice walking down the street."

The study, an ongoing 54-week efficacy and safety trial sponsored by Abbott, is being carried out at 35 locations in the United States, Germany, and New Zealand. Dr. Espay expects to have the study published by the summer of 2012. Another study, a 3-month double-dummy, double-blind trial of the gel, should be completed by this fall, with submission for publication early in 2012.

The gel is currently approved for use in 38 countries but is not yet available in the United States.

Results "Impressive" But Questions Remain

Asked for a comment, Leonard A. Verhagen, MD, PhD, associate professor of neurological science in the Movement Disorder Section and medical director of the Movement Disorder Surgery Program, Rush University Medical Center, Chicago, Illinois, said the study results are expected but nonetheless impressive.

Because the intestinal gel appears to eliminate a substantial amount of the off time while diminishing dyskinesia severity, it has the potential to become a welcome treatment option in advanced PD, he said.

"We have known for decades that continuous intestinal administration of levodopa is a successful strategy, but we did not have the ability to do this in a practical fashion," Dr. Verhagen told Medscape Medical News. "The innovation of the product tested in the study is that the gel formulation allows for a much higher levodopa concentration and therefore requires much smaller volumes to be infused."

There are, however, some "unknowns" still to be clarified, he said. "For instance, the frequency of tube-related side effects (infection, clogging up, displacement) needs to be determined but appears high. Similarly, the frequency of side effects related to the PEG-J procedure needs to be established in this patient group," he noted.

"In addition, there have been case reports of neuropathies emerging during intestinal gel infusion. The frequency and cause of these potential side effects remain to be clarified, and the current cohorts under study will likely provide some answers."

As well, Dr. Verhagen questioned how many patients will embrace this therapy because it involves visible, external equipment that requires frequent maintenance and may be costly.

In addition to costs, the "downside" to the therapy is potential gastrointestinal complications, said Kapil D. Sethi, MD, professor of neurology and director of the Movement Disorders Program, Medical College of Georgia, Augusta, in an email. "In the hands of a well trained and motivated team, including a movement disorders specialist and a gastroenterologist, [levodopa-carbidopa intestinal gel] is a highly effective treatment for off periods in advanced PD."

Dr. Espay is supported by the KL2 Research Scholars mentored career development award through the National Institutes of Health Institutional Clinical and Translational Science Award (RR026315-02). He has received grant support from Medtronic, CleveMed, Davis Phinney Foundation, and Michael J Fox Foundation; personal compensation as a consultant for Solvay/Abbott; and honoraria from Novartis, the American Academy of Neurology, and the Movement Disorders Society. Dr. Sethi’s site participated in the study.

Movement Disorders Society (MDS) 15th International Congress of Parkinson's Disease and Movement Disorders: Abstract 375. Presented June 7, 2011.