Opioid-Induced Constipation (OIC) is a common side effect of opioid analgesic therapy. Naldemedine (NAL), an orally available peripherally-acting μ-opioid receptor antagonist (PAMORA), has been shown to improve OIC without affecting analgesic effect of opioids across several clinical studies. However, the predictive factors determining the response to OIC treatment have not been elucidated. We conducted a subgroup analysis with the pooled data to explore the predictive factors in patient population for the efficacy and safety of NAL.
Data were pooled from 2 randomized, double-blinded, placebo (PBO)-controlled studies of NAL 0.2mg QD (Ph2b and Ph3) for cancer patients (JapicCTI-132340, JapicCTI-111510). Subgroup analysis (age, BMI, gender, opioid type or dosage, concomitant laxatives, with or without anti-cancer therapy, with or without possible disruption of blood brain barrier (BBB)) of spontaneous bowel movement (SBM) responder rate (percentage of patients with ≥ 3 SBMs/week and an increase from baseline of ≥ 1 SBM/week) was conducted. Overall safety and the incidence of diarrhea were evaluated. The pain intensity numerical rating scale (NRS) and clinical opiate withdrawal scale (COWS) were also analyzed in the population with or without possible BBB disruption.
SBM responder rate was 73.5% (114 of 155 patients) for the NAL group and 35.5% (54 of 152 patients) for the PBO group for all subjects. The difference between the groups was 38.0% and was statistically significant (P < 0.0001). In the subgroup analysis, the difference of proportion between NAL vs PBO for each efficacy and safety endpoint was consistent across all subgroups (The all point estimates were greater than zero). Although the difference of the incidence of diarrhea between the groups was relatively larger in the possible disruption of BBB group, there was no difference between with or without possible BBB disruption for NRS and COWS.
Overall, this analysis of subgroups supported that the benefits of NAL were observed regardless of background factor, and its safety profile in various subgroups was consistent with that observed in the overall population.
Clinical trial identification
Legal entity responsible for the study
Shionogi & Co., Ltd.
Shionogi & Co., Ltd.
T. Yokota: Employee and stock owner: Shionogi & Co., Ltd. Y. Tada, H. Sato, M. Okamoto: Employee: Shionogi & Co., Ltd. I. Osaka: Honoraria: Shionogi & Co., Ltd. All other authors have declared no conflicts of interest.