Acid Suppression Therapy Does Not Affect the Efficacy of Plecanatide: A Patient-Level Pooled Analysis of Two Large Randomized Controlled Trials

Abstract

Introduction: Chronic Idiopathic Constipation (CIC) affects approximately 14% of the North American population. The most recently FDA-approved medication for the treatment of CIC is plecanatide, which is an analog of the endogenous GI peptide, uroguanylin. Like uroguanylin, it exhibits pH-sensitive activity and is most active in a slightly acidic environment. As many CIC patients may also be on concomitant acid suppressing medications such as proton pump inhibitors (PPIs) and histamine receptor antagonists (H2 blockers), it is important to determine whether plecanatide is efficacious if given with a concomitant acid suppressor. Methods: The efficacy and safety of plecanatide for the treatment of CIC has been established in two 12-week, double-blind, placebo-controlled trials. Enrolled patients met modified Rome III criteria for CIC. Patients were randomized 1:1 to plecanatide 3 mg or placebo (PBO). These phase 3 CIC studies permitted patients to enter the studies while on concomitant PPIs and/or H2 blockers if the dosing of the medication was not stopped or changed during the study. By combining data from the two phase 3 studies, there was a sufficiently large sample size to determine the efficacy of CIC patients being treated with plecanatide while on a concomitant acid suppressor. The primary endpoint for efficacy was the Efficacy Responder Rate, defined as a patient who had at least 3 complete spontaneous bowel movements (CSBMs) in a given week and an increase of at least 1 CSBM from baseline in the same week for at least 9 of the 12 treatment weeks and at least 3 of the last 4 weeks of the study. A post-hoc analysis was performed exploring the impact of concomitant acid suppressor use on efficacy parameters. Results: A total of 883 patients received plecanatide 3 mg across the two studies and 892 received PBO. Of these, approximately 10% also received concomitant treatment with acid suppressors (n=106 in the plecanatide group [96 on a PPI]; n=119 in the PBO group [102 on a PPI]). Significantly more patients who received plecanatide were Efficacy Responders as compared to PBO (23.6% plecanatide; 7.6% PBO [P=0.001]). Secondary endpoints were also significantly improved in the plecanatide group as compared to placebo (Table). Conclusion: In this subset analysis of two phase 3 trials, CIC patients treated with plecanatide, who were receiving a concomitant acid suppressing medication, demonstrated significant improvement in their constipation symptoms.444 Figure 1. Secondary Endpoint Outcome Measures