ArticlesA phase 2, double-blind, randomized, placebo-controlled, dose-escalation study to evaluate the efficacy, safety, and tolerability of naloxegol in patients with opioid-induced constipationWebster, Lynna,*; Dhar, Sunitab,1; Eldon, Michaelc; Masuoka, Lorianned,1; Lappalainen, Jaakkoe; Sostek, Marke Author Information aCRI Lifetree Research, Salt Lake City, UT, USA bGenentech Inc., San Francisco, CA, USA cNektar Therapeutics, San Francisco, CA, USA dOakland, CA, USA eAstraZeneca Pharmaceuticals, Wilmington, DE, USA * Corresponding author. Address: CRI Lifetree Research, 3838 South 700 East, Suite 202, Salt Lake City, UT 84106, USA. Tel.: +1 801 892 5140; fax: +1 801 261 3341. E-mail addresses:[email protected], [email protected] 1 These authors are former employees of Nektar Therapeutics, San Francisco, CA, USA. Article history: Received 21 December 2012 Received in revised form 4 April 2013 Accepted 9 April 2013 Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Pain 154(9):p 1542-1550, September 2013. | DOI: 10.1016/j.pain.2013.04.024 Buy Metrics Abstract Summary Oral naloxegol was well tolerated and increased the frequency of spontaneous bowel movements in patients with opioid-induced constipation without compromising analgesia or inducing opioid withdrawal. Naloxegol (previously known as NKTR-118) is a peripherally acting μ-opioid receptor antagonist engineered using polymer conjugate technology in development as an oral, once-daily agent for the treatment of opioid-induced constipation (OIC). Eligible patients with OIC (n = 207), defined as <3 spontaneous bowel movements (SBMs) per week with accompanying symptoms, on a stable opioid regimen of 30–1000 mg/day morphine equivalents for ≥2 weeks were randomized to receive 4 weeks of double-blind placebo or naloxegol (5, 25, or 50 mg) once daily in sequential cohorts after a 1-week placebo run-in. The primary end point, median change from baseline in SBMs per week after week 1 of drug administration, was statistically significant for the 25- and 50-mg naloxegol cohorts vs placebo (2.9 vs 1.0 [P = 0.0020] and 3.3 vs 0.5 [P = 0.0001], respectively). The increase in SBMs vs placebo was maintained over 4 weeks for naloxegol 25 mg (3.0 vs 0.8 [P = 0.0022]) and 50 mg (3.5 vs 1.0 [P < 0.0001]). Naloxegol was generally well tolerated across all dosages. The most frequent adverse events (AEs) were abdominal pain, diarrhea, and nausea. Most AEs at 5 and 25 mg/day were mild and transient. Similar AEs occurred with increased frequency and severity in the 50-mg cohort. There was no evidence of a statistically significant increase from baseline in pain, opioid use for the 25- and 50-mg cohorts, or centrally mediated opioid withdrawal signs and/or symptoms with naloxegol. These data demonstrate that once-daily oral naloxegol improves the frequency of SBMs compared with placebo and is generally well tolerated in this population of patients with OIC. © 2013 Lippincott Williams & Wilkins, Inc.