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O-9 Phase 3 study to evaluate the efficacy and safety of naldemedine for the treatment of opioid-induced constipation (OIC) in cancer patients
  1. Takaaki Yokota1,
  2. Nobuyuki Katakami2,
  3. Toshiyuki Harada3,
  4. Yukio Tada1,
  5. Masaru Narabayashi4 and
  6. Narikazu Boku5
  1. 1Shionogi and Co., Ltd., Osaka, Japan
  2. 2Institute of Biomedical Research and Innovation, Kobe, Japan
  3. 3JCHO Hokkaido Hospital, Sapporo, Japan
  4. 4Cancer Institute Hospital of JFCR, Tokyo, Japan
  5. 5National Cancer Centre Hospital, Tokyo, Japan


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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