Randomized clinical trial: efficacy and safety of plecanatide in the treatment of chronic idiopathic constipation

Abstract

Background: Plecanatide, with the exception of a single amino acid replacement, is identical to human uroguanylin and is approved in the United States for adults with chronic idiopathic constipation (CIC). This double-blind, placebo-controlled, phase III study evaluated the efficacy and safety of plecanatide versus placebo in CIC.

Methods: Adults meeting modified Rome III CIC criteria were randomized to plecanatide 3 mg (n = 443), 6 mg (n = 449), or placebo (n = 445). Patients recorded bowel movement (BM) characteristics [including spontaneous BMs (SBMs) and complete SBMs (CSBMs)] and rated CIC symptoms in daily electronic diaries. The primary endpoint was the percentage of durable overall CSBM responders (weekly responders for ⩾9 of 12 treatment weeks, including ⩾3 of the last 4 weeks). Weekly responders had ⩾3 CSBMs/week and an increase of ⩾1 CSBM from baseline for the same week.

Results: A significantly greater percentage of durable overall CSBM responders resulted with each plecanatide dose compared with placebo (3 mg = 20.1%; 6 mg = 20.0%; placebo = 12.8%; p = 0.004 each dose). Over the 12 weeks, plecanatide significantly improved stool consistency and stool frequency. Significant increases in mean weekly SBMs and CSBMs began in week 1 and were maintained through week 12 in plecanatide-treated patients. Adverse events were mostly mild/moderate, with diarrhea being the most common (3 mg = 3.2%; 6 mg = 4.5%; placebo = 1.3%).

Conclusions: Plecanatide resulted in a significantly greater percentage of durable overall CSBM responders and improved stool frequency and secondary endpoints. Plecanatide was well tolerated; the most common AE, diarrhea, occurred in a small number of patients.[ClinicalTrials.gov identifier: NCT02122471].

Keywords: complete spontaneous bowel movement; durable overall CSBM responder; guanylate cyclase-C; uroguanylin.

Figure 1.

Patient disposition.

Figure 2.

(a) Percentage of patients in the intent-to-treat population who were durable overall complete spontaneous bowel movement responders, which was the primary efficacy endpoint. **p < 0.01 versus placebo. Error bars represent 95% confidence intervals.Durable overall CSBM responders were defined as patients who fulfilled both ⩾3 CSBMs per week and an increase of ⩾1 CSBM from baseline in the same week for ⩾9 of the 12 treatment weeks, including ⩾3 of the last 4 weeks of treatment. (b) Percentage of patients who were weekly complete spontaneous bowel movement responders. ^***p < 0.001, ^**p < 0.01, ^*p < 0.05, ^†p = 0.05 (3 mg) versus placebo. Error bars represent standard error. CSBM, complete spontaneous bowel movement.

Figure 3.

(a) Change in weekly complete spontaneous bowel movement frequency from baseline. ^***p < 0.001, ^**p < 0.01, ^*p < 0.05 versus placebo. Error bars indicated standard error. (b) Change in spontaneous bowel movement weekly frequency from baseline. ^***p < 0.001, ^**p < 0.01, ^*p < 0.05, ^†p = 0.051 (3 mg) versus placebo. CSBM, complete spontaneous bowel movement; SBM, spontaneous bowel movement. Error bars indicate standard error.

Figure 4.

Change in weekly stool consistency from baseline, which was measured using the Bristol Stool Form Scale (BSFS). ^***p < 0.001, ^*p < 0.05 versus placebo. Error bars indicate standard error.

Figure 5.

(a) Percentage of patients with a complete spontaneous bowel movement within 24 h after the first dose of study medication. ^***p < 0.001 versus placebo. Error bars indicate 95% confidence intervals. (b) Percentage of patients with a spontaneous bowel movement within 24 h after the first dose of study medication. ^***p < 0.001, ^*p < 0.05 versus placebo. Error bars indicate 95% confidence intervals. CSBM, complete spontaneous bowel movement; SBM, spontaneous bowel movement.