Effect of Naldemedine on Frequency of Spontaneous Bowel Movements and Associated Symptoms

Abstract

Introduction: Opioid-induced constipation (OIC) is a well-known side effect of opioid therapy. Naldemedine (NAL) is a peripherally-acting μ-opioid receptor antagonist approved for the treatment of OIC in patients with chronic non-cancer pain. Methods: Two randomized, double-blind placebo (PBO) controlled 12-week studies (NCT01965158 and NCT01993940), assessed the effect over time of NAL 0.2 mg once daily vs PBO in the frequency of spontaneous bowel movements (SBMs), complete SBMs (CSBMs, defined as SBMs with a perception of complete evacuation), SBMs without straining, and SBMs with a Bristol Stool Scale (BSS) Score of 3 or 4 in adult (age 18-80 years) subjects with chronic non-cancer pain and OIC. Subjects were required to not be on laxatives at screening or to agree to discontinue laxatives upon signing informed consent. The mean changes in the frequency per week from baseline to each week was compared between NAL and PBO, with a mixed-effects model repeated measures which opioid dose strata and study as a covariate and treatment group, time, time-by-treatment group interaction as fixed effects. Safety was assessed based on the incidence of adverse events (AEs). Results: In the two studies pooled, 1095 subjects were randomized 1:1 to NAL (N=549) or PBO (N=546) for 12 weeks. In all four endpoints, NAL was associated with a significantly (P≤0.0001) greater improvement from baseline at each week relative to PBO, starting at Week 1 and up to Week 12 (Figure). The overall incidence of AEs was generally similar between groups. Treatment with NAL was associated with a greater incidence of gastrointestinal AEs (abdominal pain, diarrhea, nausea) compared with PBO (Table).Figure: Change from Baseline* to Each Week (LS Mean ± SE) in Assessed Endpoints.Table: Table. Overall Summary of Treatment Emergent Adverse Events (Safety Population)Conclusion: Treatment with NAL over 12 weeks compared with placebo improved the frequency of bowel movements as well as the signs and symptoms of OIC frequently reported with bowel movements including perception of incomplete evacuation, need for straining, and hard stools,. NAL was generally well tolerated.