Prucalopride Eased Chronic Constipation; More Data Sought
The selective 5-hydroxytryptamine receptor agonist prucalopride improved the rate of spontaneous, complete bowel movements in patients with severe chronic constipation, researchers reported.
Over 12 weeks of treatment in the phase III clinical trial, prucalopride also reduced the frequency and severity of abdominal and stool symptoms, and it significantly improved quality of life, compared with placebo, according to Dr. Michael Camilleri of the Mayo Clinic, Rochester, Minn., and his associates.
However, there is concern about potential cardiac risks with the drug, which is “similar in function to cisapride and tegaserod, two constipation-reducing drugs that were voluntarily removed from the market after warnings from the Food and Drug Administration about life-threatening cardiac side effects,” Dr. Arthur J. Moss of the University of Rochester (N.Y.) said in an editorial comment accompanying the report.
There are additional concerns about the 9-year delay in publishing the results.
The trial was designed by Johnson & Johnson in 1998 and conducted in 1998–1999, but the final analysis was done by a Belgian company, Movetis NV, in 2007, after Movetis purchased the drug.
“It is not known why clinical trials with prucalopride were temporarily suspended around 2001, or why it took so long to bring this study to publication,” Dr. Moss noted (N. Engl. J. Med. 2008;358:2402-3).
The study was conducted at 38 U.S. medical centers and involved 620 patients who had two or fewer spontaneous, complete bowel movements per week for a minimum of 6 months.
Patients had hard or very hard stools, a sensation of incomplete evacuation, or straining during defecation at least 25% of the time.
In all, 207 patients were randomly assigned to receive 2 mg of prucalopride, 204 patients received 4 mg of prucalopride, and 209 patients received placebo orally once a day for 3 months. The percentage of patients whose bowel function normalized to three or more spontaneous, complete bowel movements per week was 31% with the 2-mg dose, and 28% with the 4-mg dose of prucalopride, a difference that was not statistically significant.
The percentages were significantly greater than the 12% of subjects in the placebo group whose bowel function normalized, Dr. Camilleri and his associates said (N. Engl. J. Med. 2008;358:2344-54).
Similarly, the percentage of patients who reported an increase in the number of spontaneous, complete bowel movements per week was 47% with 2 mg prucalopride and 47% with 4 mg prucalopride, compared with 26% with placebo, the investigators reported.
Patients in both active-treatment groups also were able to decrease their use of “rescue” laxatives by approximately half during the study.
Quality of life improved in 45% of patients taking 2 mg prucalopride and in 49% of those taking 4 mg, compared with 24% of those patients taking placebo.
Adverse events occurred in 80% of patients taking 2 mg of prucalopride, in 78% of patients taking 4 mg, and in 71% of patients taking placebo. The most frequent adverse events were abdominal pain, headache, nausea, and diarrhea.
Adverse events led to treatment stoppage in 8.2% of patients on 2 mg of prucalopride, in 8% of patients on 4 mg, and in 2% of those on placebo. Three patients discontinued treatment because of adverse events that included cardiovascular events.
“Further assessment of the cardiovascular safety of prucalopride in other trials is required to ensure that rare adverse cardiovascular effects are ruled out,” the investigators said.
In his editorial comment, Dr. Moss concurred. “More complete clinical, electrophysiological, and pharmacokinetic data are required before this drug can be brought to market for the treatment of chronic constipation,” he said.
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