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Thursday, September 18, 2014

Naloxegol Shows Efficacy Against Multiple Symptoms of Opioid-Induced Constipation in Phase III Trials
 
San Diego—

Naloxegol, an oral, peripherally acting <03BC>-opioid receptor antagonist, appears safe and effective in relieving opioid-induced constipation (OIC).
OIC occurs in 40% to 60% of individuals taking opioids, and is a unique form of constipation, said William D. Chey, MD, who presented the findings of two identical, randomized controlled, Phase III trials of naloxegol at the 2013 annual meeting of the American College of Gastroenterology. It can become so problematic that some patients choose to forgo their pain medicine, leading to a significant negative effect on their quality of life.
“The study objectives were to evaluate the safety and efficacy of naloxegol in two doses versus placebo in patients taking opioids for noncancer pain,” said Dr. Chey, professor of medicine at the University of Michigan Health System in Ann Arbor.
The primary outcome of the two trials—KODIAC-04 and KODIAC-05—was greater than three spontaneous bowel movements (SBMs) per week, with an increase of more than one SBM per week over baseline for at least nine of the 12 randomization weeks, and for at least three of the four final weeks.
“In addition to this was the requirement of demonstrating symptom improvement for at least one of the following: straining, stool consistency and number of days with a complete spontaneous bowel movement,” Dr. Chey said. “We tend to focus on stool frequency, but like constipation in general, OIC is associated with alterations in a variety of other symptoms, including straining, hard stools and a sense of incomplete evacuation.”
The study population comprised patients aged 18 to 85 years with OIC who had been taking between 30 and 1,000 mg of oral morphine for noncancer pain for at least four weeks before the study period. About 65% of these patients had failed to respond to treatment with one or more laxatives before enrollment in the study.
During a two-week screening period, patients were required to have active symptoms of OIC, defined as fewer than three SBMs per week and at least one symptom of hard lumpy stools; straining; or a sensation of incomplete evacuation more than 25% of the time. This was followed by a two-week confirmation period during which patients had to experience the symptoms previously described, documented by electronic diary, to qualify for the trial.
Roughly 700 patients completed the qualification and were enrolled in the two trials. The patients, who were similar in terms of demographics and constipation-related symptoms, were randomized to receive 12 weeks of treatment with naloxegol at one of two doses, 12.5 or 25 mg, or placebo. The differences between the groups in each of the two studies were analyzed by the Cochran-Mantel-Haenszel comprehensive test stratified by response to laxatives at baseline. About 80% of the patients completed the trial.
In both trials, the higher dose of the drug resulted in improvement in the primary end point compared with placebo, even after symptoms beyond stool frequency were incorporated into the response. Additionally, in both trials, the higher dose was associated with statistically significant therapeutic gains of 10% to 15% in other symptoms of OIC (e.g., straining) compared with placebo. In the KODIAC-04 trial, the lower dose was associated with a statistically significant benefit over placebo in terms of meeting the primary end point; this was not seen in the KODIAC-05 trial.
Serious adverse events (AEs) and AEs were rare and were observed equally at both dose levels of naloxegol. The more commonly reported AEs, abdominal pain and diarrhea, were dose-dependent. Discontinuation of treatment occurred more often in the 25-mg group.

“To conclude, naloxegol was efficacious over 12 weeks of treatment for noncancer pain patients with OIC; efficacy was demonstrated with the 25-mg dose in both of these large, randomized Phase III studies,” Dr. Chey said.
The results presented by Dr. Chey and his colleagues are especially important “because they indicate not only that naloxegol has the potential to increase bowel movement frequency in OIC, but also to improve the associated symptoms that patients find so distressing,” said Brooks D. Cash, MD, professor of medicine at the University of South Alabama, in Mobile.
—Monica J. Smith

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