Randomized phase 3 and extension studies: Efficacy and impacts on quality of life of naldemedine in subjects with opioid-induced constipation and cancer

Abstract

Background

The efficacy and safety of naldemedine (a peripherally-acting µ-opioid receptor antagonist) for opioid-induced constipation (OIC) in subjects with cancer was demonstrated in the primary report of a phase 3, double-blind study (COMPOSE-4) and its open-label extension (COMPOSE-5). The primary endpoint, the proportion of spontaneous bowel movement (SBM) responders, was met. Here, we report results from secondary endpoints including quality of life (QOL) assessments from these studies.

Patients and methods

In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned 1:1 to receive once-daily oral naldemedine 0.2 mg (n=97) or placebo (n=96) for 2 weeks, and those who continued on to COMPOSE-5 received naldemedine for 12 weeks (n=131). Secondary assessments in COMPOSE-4 included the proportion of complete SBM (CSBM) responders, SBM or CSBM responders by week, and subjects with ≥1 SBM or CSBM within 24 hours post-initial dose. Changes from baseline in the frequency of SBMs or CSBMs per week were assessed at Week 1 and Week 2. Time to the first SBM or CSBM post-initial dose was also evaluated. In both studies, QOL impact was evaluated by Patient Assessment of Constipation-Symptoms (PAC-SYM) and PAC-QOL questionnaires.

Results

Naldemedine improved bowel function for all secondary efficacy assessments vs placebo (all P≤0.0002). The timely onset of naldemedine activity vs placebo was evidenced by median time to the first SBM (4.7 vs 26.6 hours) and CSBM (24.0 vs 218.5 hours) post-initial dose (all P<0.0001). In COMPOSE-4, significant differences between groups were observed with the PAC-SYM stool domain (P=0.045) and PAC-QOL dissatisfaction domain (P=0.015). In COMPOSE-5, naldemedine significantly improved overall and individual domain scores of PAC-SYM and PAC-QOL from baseline (all P≤0.03).

Conclusions

Naldemedine provided effective and timely symptomatic relief from OIC and improved the QOL of subjects with OIC and cancer.

Trial registration ID

www.ClinicalTrials.jp: JAPIC-CTI-132340 (COMPOSE-4) and JAPIC-CTI-132342 (COMPOSE-5).