1466P - Treatment of opioid-induced constipation with naldemedine in patients with cancer: onset of action in a randomized phase 3 trial

Abstract

Opioid analgesics are widely administered to treat patients with cancer pain; however, many patients suffer from opioid-induced constipation (OIC) as a side effect. Naldemedine (NAL), a peripherally-acting &mgr;-opioid receptor antagonist (PAMORA), is being developed for the treatment of patients with OIC. The aim of this analysis was to assess the onset of action of NAL in the context of primary efficacy and safety results previously reported. The study was a double-blind, randomized, placebo-controlled phase 3 trial in Japan. Cancer patients with OIC, defined as having ≤ 5 spontaneous bowel movements (SBMs) during the 2-week qualification period, were evenly assigned to either oral NAL 0.2 mg QD or placebo (PBO). The primary efficacy endpoint was SBM responder rate (percentage of patients with ≥ 3 SBMs/week and an increase from baseline of ≥ 1 SBM/week) during the 2-week treatment period. To assess the onset of action, 1) time to the first SBM, 2) proportion of patients with at least 1 SBM at several time points after initial dose and 3) change in frequency of SBMs/week from baseline to first week were evaluated. A total of 193 patients were randomized (NAL: 97, PBO: 96). The SBM responder rate of NAL was significantly larger than that of PBO (71.1% vs 34.4%, respectively; P < 0.0001). Besides, the time to onset of action of NAL was shorter than that of PBO with a shorter median time to the first SBM after the initial dose (NAL: 4.67, PBO: 26.58 hrs). The differences between the two groups in the proportion of patients with at least one SBM were statistically significant at all assessed time points (up to 4 hrs: 48.5% vs 7.3%, 8 hrs: 60.8% vs 14.6%, 12 hrs: 71.1% vs 25.0%, 24 hrs: 77.3% vs 47.9%, P < 0.0001 for all). The change in the frequency of SBMs per week from baseline to the first week with NAL was significantly greater than that with PBO (5.70 vs 1.73, P < 0.0001). The overall incidences of adverse events reported during the treatment period were 44.3% and 26.0% for NAL and PBO, respectively. Only diarrhea was reported for ≥ 5% of patients (19.6% vs 7.3%). However, the most cases were reported as mild and recovered. Treatment with NAL led to timely improvement of OIC in patients with cancer and was generally well tolerated.