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.

Conflict of interest statement

Conflict of interest statement: KS and PG are employees and stockholders of Synergy Pharmaceuticals Inc. At the time of the study and of manuscript preparation, LB and BK were employees and stockholders of Synergy Pharmaceuticals Inc. MD states no potential conflict of interest.

Figures

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 ***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.