O-9 Phase 3 study to evaluate the efficacy and safety of naldemedine for the treatment of opioid-induced constipation (OIC) in cancer patients

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Abstract

Background

While opioid analgesics play a central role in managing cancer pain, opioid-induced constipation (OIC) is one of the most common side effects. Naldemedine is a peripherally-acting µ-opioid receptor antagonist being developed to treat OIC.

Methods

Studies consisted of a 2 week randomised double-blind placebo-controlled treatment period (DBT) followed by a 12 week open-label extension (EXT). In DBT, cancer patients with OIC, defined as ≤5 spontaneous bowel movements (SBMs) 14 day before randomization, were randomised 1:1 to oral naldemedine 0.2 mg QD or placebo. Patients who completed DBT could receive naldemedine in EXT. The primary endpoint of DBT was SBM responder rate (percentage of patients with ≥3 SBMs/week and an increase from baseline of ≥1 SBM/week) in the naldemedine group compared with placebo. The primary objective of EXT was to assess long-term safety.

Results

A total of 193 patients were randomised in DBT, and 131 patients were enrolled in EXT. In DBT, significantly higher SBM responder rate was observed in naldemedine compared with placebo (71.1% vs 34.4%, respectively; p<0.0001). Naldemedine improved change from baseline in the frequency of SBMs (5.16 vs 1.54, p<0.0001), SBMs with a feeling of complete evacuation (2.76 vs 0.71, p<0.0001) and SBMs without straining (3.85 vs 1.17, p=0.0005) per week. Incidences of adverse event (AE) reported during treatment period in DBT were 44.3% and 26.0% in naldemedine and placebo, respectively. Diarrhoea was the only AE observed in ≥5% of patients in either group (19.6% vs 7.3%). No clinically meaningful changes in opioid withdrawal scores and pain intensity were observed in both groups. In EXT, 107 patients completed a 12 week treatment with naldemedine 0.2 mg QD, and the safety profile was similar to that in DBT.

Conclusions

Naldemedine improved the symptoms of OIC and was generally well tolerated.

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