Cardiac safety data following treatment in a phase 3, randomized, controlled trial of oral methylnaltrexone in chronic noncancer pain patients with opioid-induced constipation
Authors: Richard Rauck, MD, The Center for Clinical Research, Winston-Salem, NC
Neal E. Slatkin, MD, University of California Riverside, Riverside, CA; Salix Pharmaceuticals, Bridgewater, NJ
Nancy Stambler, DrPH, Progenics Pharmaceuticals, Inc., New York, NY
Robert J. Israel, MD, Salix Pharmaceuticals, Bridgewater, NJ
Introduction: In July 2016, oral methylnaltrexone, a selective peripheral µ-opioid receptor antagonist, was approved for opioid induced constipation (OIC) treatment in patients with chronic noncancer pain. This analysis reports cardiac safety from a randomized, controlled trial of oral methylnaltrexone for OIC treatment in patients with chronic noncancer pain.
Materials and Methods: This phase 3, double-blind, placebo-controlled trial included patients with chronic noncancer pain for ≥2 months, receiving ≥50 mg/d of oral morphine equivalents for ≥14 days, and experiencing OIC (confirmed during a 14-day screening period and defined by <3 rescue-free bowel movements [RFBMs] per week, on average, associated with ≥1 of the following: ≥25% of RFBMs categorized as type 1 or type 2 on the Bristol Stool Form Scale, straining during ≥25% of RFBMs, or ≥25% of RFBMs with a sensation of incomplete evacuation). Following local IRB approval and informed consent, patients received oral methylnaltrexone at 150 mg, 300 mg, or 450 mg or placebo once daily for the first 4 weeks, as randomly assigned; for the following 8 weeks, oral methylnaltrexone or placebo as needed. Double-blinding was maintained throughout all 12 weeks of the study.
Results: Overall, 803 patients received ≥1 dose of study medication (oral methylnaltrexone 150 mg, n=201; 300 mg, n=201; 450 mg, n=200; placebo, n=201). During the 4-week period of once-daily dosing, 8.5%, 9.0%, 12.5%, and 10.4% of patients discontinued treatment in the 150-mg, 300-mg, 450-mg, and placebo groups, respectively; of the 177, 181, 169, and 167 patients who remained in these 4 groups during the 8-week period of as-needed dosing, 9.6%, 13.8%, 12.4%, and 14.4% discontinued treatment, respectively. Demographic and baseline characteristics were similar among all groups. Cardiac disorders were reported as treatment-emergent adverse events (TEAEs) by 13 patients: 2 (1.0%) in the 150-mg group, 6 (3.0%) in the 300-mg group, 3 (1.5%) in the 450-mg group, and 2 (1.0%) in the placebo group. Three patients reported palpitations (150 mg, n=2; 300 mg, n=1), ventricular extrasystoles in 2 patients (300 mg, n=1; 450 mg, n=1), and the following in 1 patient each: angina pectoris (300 mg), arrhythmia (150 mg), atrial fibrillation (150 mg), atrial flutter (placebo), first-degree atrioventricular block (450 mg), bradycardia (300 mg), left bundle branch block (300 mg), right bundle branch block (300 mg), extrasystoles (300 mg), left atrial dilation (300 mg), sinus tachycardia (450 mg), and tachycardia (placebo). Overall, mean changes from baseline in electrocardiogram, QTcF, QTcB, and QTcL results were minimal. QTcF intervals increased by >30 ms in 2.5%, 3.5%, 3.5%, and 4.5% of patients in the 150-mg, 300-mg, 450-mg, and placebo groups, respectively, and by >60 ms in 0.5%, 1.0%, 1.5%, and 1.5% of patients in these groups. Minimal changes from baseline in heart rate, diastolic blood pressure, and systolic blood pressure were observed 1 hour after the first dose.
Discussion: In this study of once-daily oral methylnaltrexone for OIC in patients with chronic noncancer pain, few TEAEs related to cardiac safety were observed, and frequencies of cardiac disorders were similar between patients receiving oral methylnaltrexone and patients receiving placebo.