A Randomized Phase III Clinical Trial of Plecanatide, a Uroguanylin Analog, in Patients With Chronic Idiopathic Constipation

Abstract

Objectives: This study assessed the efficacy and safety of plecanatide, a guanylate cyclase-C (GC-C) agonist and the first uroguanylin analog approved for the treatment of chronic idiopathic constipation (CIC).

Methods: This phase III, multicenter, double-blind, placebo-controlled study randomized 1,394 patients with CIC. Patients received either plecanatide (3 or 6 mg) or placebo, orally, once daily, for 12 weeks. The primary efficacy endpoint was the percentage of patients who were durable overall complete spontaneous bowel movement (CSBM) responders over the 12-week treatment period. Patients were instructed to record their daily bowel movements, stool consistency scores, and abdominal symptoms in an electronic diary. Treatment-emergent adverse events (AEs) were collected.

Results: Each dose of plecanatide resulted in a significantly greater percentage of durable overall CSBM responders (21.0%, 3 mg; 19.5%, 6 mg) as compared with placebo (10.2%; P<0.001 for both). Plecanatide (3 and 6 mg) also significantly increased mean weekly CSBM frequency from baseline (increase of 2.5 and 2.2/week, respectively) vs. placebo (1.2/week; P<0.001 for both) and mean weekly spontaneous bowel movement frequency (increase of 3.2 and 3.1/week, respectively) vs. placebo (1.3/week; P<0.001, for both) over the 12-week treatment period. Both plecanatide doses significantly improved all secondary and additional efficacy endpoints. The most common AE, diarrhea, occurred in 1.3% (placebo), 5.9% (3 mg) and 5.7% (6 mg) of patients.

Conclusions: Plecanatide significantly improved constipation and its related symptoms with a low rate of adverse events. These results suggest that plecanatide will be a useful treatment option in the management of CIC. ClinicalTrials.gov: NCT01982240.

Figure 1

Disposition of the study population.

Figure 2

(a) Percentage of patients in each treatment group assessed as a durable overall complete spontaneous bowel movement (CSBM) responder in the intention-to-treat (ITT) population, the primary efficacy endpoint. 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. Error bars represent 95% confidence intervals. (b) Weekly evolution of the percentage of CSBM responders in the ITT population. Values are LS means; bars represent 95% confidence intervals. *P=0.001, **P=0.003, ^†P=0.005, ^‡P=0.011 vs. placebo.

Figure 3

(a) Changes from baseline in weekly complete spontaneous bowel movement (CSBM) frequency. Values are least squares (LS) mean; bars represent s.e. *P<0.001 vs. placebo. (b) Changes from baseline in mean weekly spontaneous bowel movement (SBM) frequency. Values are LS mean; bars represent s.e. *P<0.001 vs. placebo. (c) Percentage of patients experiencing a CSBM or SBM within 24 h after the first dose of study medication. *P<0.001 vs. placebo.

Figure 4

(a) Changes from baseline in weekly stool consistency. Stool consistency was measured by the Bristol Stool Form Scale (BSFS). Values are least squares (LS) mean; bars represent s.e. *P<0.001 vs. placebo. (b) Weekly BSFS scores during the study. Values are LS mean.