title: A Phase 2b, Randomized, Double-Blind Placebo-Controlled Study to Evaluate the Efficacy and Safety of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Noncancer Pain.
abstract: OBJECTIVE
  This study evaluated the efficacy and safety of oral naldemedine 0.1 mg, 0.2 mg, or 0.4 mg once daily in patients who had opioid-induced constipation (OIC) and maintained a stable laxative regimen.
  
  
  METHODS
  This four-week, phase 2b, randomized, double-blind placebo-controlled trial (clinicaltrials.gov identifier NCT01443403) enrolled patients on long-term opioid therapy for chronic noncancer pain with OIC. The primary efficacy end point was change in weekly spontaneous bowel movement (SBM) frequency from baseline to the last two weeks of treatment. Secondary end points included the proportion of SBM responders (patients with ≥3 SBMs/week and an increase of ≥1 SBM/week from baseline over the last 2 weeks of treatment). Safety parameters assessed included adverse events, effects on analgesia, and opioid withdrawal symptoms.
  
  
  RESULTS
  Overall, 244 patients were randomized 1:1:1:1 to naldemedine 0.1 mg, 0.2 mg, 0.4 mg, or placebo. Baseline patient characteristics were comparable. Weekly SBM frequency was significantly higher with naldemedine 0.2 mg (3.37, P = 0.0014) and 0.4 mg (3.64, P = 0.0003), but not with 0.1 mg (1.98, P = 0.3504), vs placebo (1.42). The proportion of SBM responders was significantly higher with naldemedine 0.2 mg (71.2%, P = 0.0005) and 0.4 mg (66.7%, P = 0.003), but not with 0.1 mg (52.5%, P = 0.1461), vs placebo (39.3%). Treatment-emergent adverse events were generally mild to moderate in severity; incidences increased with naldemedine dose. No clinically meaningful changes in other safety parameters were observed.
  
  
  CONCLUSIONS
  Naldemedine 0.2 mg once daily is the optimal dose for future confirmatory trials in OIC.
authors.affiliation: PRA Health Sciences, Early Development Services, Salt Lake City, Utah.
authors.forename: Lynn R
authors.initials: LR
authors.lastname: Webster
authors.affiliation: Shionogi, Inc., Clinical Development, Florham Park, New Jersey, USA.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Shionogi, Inc., Clinical Development, Florham Park, New Jersey, USA.
authors.forename: Juan Camilo
authors.initials: JC
authors.lastname: Arjona Ferreira
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects; D059350:Chronic Pain / Q000188:drug therapy*; D003248:Constipation / Q000139:chemically induced* / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009292:Narcotic Antagonists / Q000008:administration & dosage*
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; C000620491:naldemedine; D009271:Naltrexone
keywords: Chronic Noncancer Pain; Naldemedine; Opioid-Induced Constipation; Peripherally Acting μ-Opioid Receptor Antagonist