In two identical randomized, placebo-controlled industry-funded trials, 2,189 patients with irritable bowel syndrome and constipation (IBS-C) were assigned to receive placebo or 3 or 6 mg of plecanatide for 12 weeks. A total of 1,879 patients completed the studies. In both trials, patients who received the study drug were more likely to be overall responders, defined as reporting at least 30% reduction from baseline in worst abdominal pain plus an increase of at least one complete spontaneous bowel movement (CSBM) weekly from baseline in the same week for at least 6 of 12 treatment weeks. Patients taking the study drug were also more likely to report sustained efficacy and improved stool frequency/consistency, straining, and abdominal symptoms than those taking placebo, and associated side effects were minimal.
The study reporting the two trials' results was published March 15 in the American Journal of Gastroenterology. The following commentary by Sander Veldhuyzen van Zanten, MD, MSc, MPH, PhD, appeared in the ACP Journal Club section of the July 17 Annals of Internal Medicine.
Over the past 20 years, the quality of treatment trials in IBS has markedly improved, in part due to efforts of the Rome Foundation of Functional Gastrointestinal Disorders, regulatory agencies, and the pharmaceutical industry. The trials by Brenner and colleagues investigate a new compound, plecanatide, which causes secretion of fluid into the intestinal tract to reduce constipation and associated symptoms. The 2 trials showed that oral plecanatide, 3 or 6 mg once daily, was superior to placebo, with improvement in the combined primary outcome (abdominal pain and number of CSBMs). Secondary outcomes, including stool frequency and consistency and associated symptoms, also showed improvement with plecanatide. The onset of action was fast, starting within 1 to 2 weeks. Within 2 weeks of stopping active treatment, symptoms and stool frequency did not differ between plecanatide and placebo, supporting the efficacy of the active drug but also suggesting that maintenance therapy will be required to sustain beneficial effects.
Although observed improvements were statistically significant, the overall severity of symptoms at trial inclusion was mild to moderate. Patients required a minimum mean abdominal pain score ≥3 for inclusion, with a 30% improvement on the 11-point scale deemed clinically meaningful. Similarly, the mean improvement of 1.2 to 1.4 CSBMs/wk is small. Whether this amount of improvement will be important for patients for whom the drug is considered is a matter of clinical judgment. The safety profile of the drug was excellent. The 2 trials found similar results for efficacy with the 3-mg and 6-mg doses. Based on these results and a previous phase 2 study, which found that 3 mg was better than 9 mg for weekly CSBMs, 3 mg seems to be the optimal dose.
Several other drugs have shown efficacy in IBS-C and constipation. Future head-to-head trials are needed to establish the comparative effectiveness of different drugs.