Naldemedine vs. Placebo for Opioid-Induced Constipation

Title: Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): two multicentre, phase 3, double-blind, randomised, parallel-group trials

Hale, M. et al.


What You Need to Know:

Analysis of two phase 3 studies, COMPOSE-1 and COMPOSE-2, demonstrated that naldemedine, a µ-opioid receptor antagonist that acts peripherally, not only has a higher responder rate compared to placebo, but is also generally well tolerated in patients with chronic non-cancer pain and opioid-induced constipation.

Trial Design:

  • Two double-blind, placebo-controlled, multicenter, phase 3 studies evaluated the safety and efficacy of naldemedine in the treatment of opioid-induced constipation in adult, chronic non-cancer pain patients
  • Eligible patients included those with a stable opioid regimen of ≥30mg morphine equivalent daily and no history of laxative use for at least 1 month prior to screening
  • Patients were randomized (1:1) to receive 0.2mg oral naldemedine or placebo daily for 12 weeks
  • Primary endpoint: proportion of responders (defined as a patient with “at least three spontaneous bowel movements (SBMs) per week with an increase from baseline of at least one SBM per week for at least 9 weeks of the 12-week treatment period including at least three of the last 4 weeks”
  • Efficacy analysis conducted in the intention-to-treat population; safety analysis included all patients who received ≥1 dose of study medication

Key Outcomes:

  • Proportion of responders in COMPOSE-1: 47.6% of naldemedine patients (130/273) vs 34.6% of placebo patients (94/272) (difference: 13.0%; 95% CI: 4.8, 21.3; P=0.002)
  • Proportion of responders in COMPOSE-2: 52.5% of naldemedine patients (145/276) vs 33.6% of placebo patients (145/276) (difference: 18.9%; 95% CI: 10.8, 27.0; P<0.0001)
  • Incidence of adverse events in COMPOSE-1: 49% in the naldemedine group (132/271) vs 45% in the placebo group (123/272)
  • Incidence of adverse events in COMPOSE-2: 50% in the naldemedine group (136/271) vs 48% in the placebo group (132/274)
  • Treatment-related adverse events: reported by 22% and 20% of naldemedine-treated patients vs 17% and 11% of placebo patients, in COMPOSE-1 and COMPOSE-2, respectively
  • Gastrointestinal disorders: experienced by 15% and 16% of naldemedine-treated patients in COMPOSE-1 and COMPOSE-2, respectively, vs 7% of placebo patients in both trials