Efficacy and Safety of Naloxegol in Patients with Chronic Non-Cancer Pain Who Experience Opioid-Induced Constipation: A Pooled Analysis of Two Global, Randomized Controlled Studies

Abstract

Objective

This study evaluates the onset, magnitude, and consistency of improvement of opioid-induced constipation (OIC) symptoms with naloxegol treatment.

Methods

This was a pooled analysis of two Phase 3, double-blind, randomized, placebo-controlled studies (KODIAC-04/05, NCT01309841/NCT01323790) in patients with chronic non-cancer pain and OIC treated with naloxegol 25mg or 12.5mg daily. This analysis assessed improvements in response rates, frequency of spontaneous bowel movement (SBM) and complete SBMs (CSBM), OIC constipation symptoms (straining, stool consistency), time to first post-dose SBM and CSBM, and onset of adverse events over the 12-week period.

Subjects

The population of 1337 subjects had a mean age of 52 years and mean duration of opioid use of 3.6 years at baseline. Mean SBM frequency was 1.4/week.

Results

Naloxegol 25mg and 12.5mg demonstrated significantly higher response rates vs placebo (PBO) [41.9% (P < 0.001), 37.8% (P = 0.008), 29.4% respectively]. Rapid (within 1 week) and sustained (over 12 weeks) symptom improvement was significantly greater for naloxegol vs PBO (P < 0.05). Both doses showed statistically significant and clinically meaningful improvements in straining, stool consistency, number of SBMs and CSBMs/wk. Significantly shorter times to first post-dose SBM and CSBM were observed with naloxegol vs PBO (SBM HR: 25mg = 1.90, 12.5mg= 1.60; CSBM HR: 25mg = 1.42, 12.5mg = 1.36; P < 0.001 for each regimen). Adverse events occurred more frequently in the naloxegol 25mg group and were most frequently reported during the first week.

Conclusion

In patients with chronic non-cancer pain, naloxegol 25mg and 12.5mg demonstrated significantly higher response rates and rapid and sustained improvements in OIC symptoms compared with PBO.

Keywords:

• opioid-induced constipation
• naloxegol
• clinical trials

Acknowledgments

The authors acknowledge Phil Yeung (Medical Affairs 360, LLC.) for his contributions to the study concepts.

Disclosure

William Chey consulted for AbbVie, Biomerica, Comvita, Gemelli, Ironwood, Isothrive, QOL Medical, Nestle, Phathom Pharmaceuticals, Progenity, Quest, Redhill Biopharma, Salix, Urovant, and Vibrant and stock options in Coprata, Dieta, Gastro Girl, Kiwi Bioscience, Isothrive, and Modify Health. In addition, Dr William D Chey has a patent Rectal Expulsion Device issued. Darren Brenner is Consultant Advisor and/or Speaker for the following: Anji, Ardelyx, AbbVie, Salix, Ironwood, Takeda, Bayer, Alnylam, Arena, Gemelli Laborie, Vibrant, RedHill Biopharma Inc, and Mahana Therapeutics. Brooks Cash is a consultant: RedHill, Salix, Phathom, AbbVie, Takeda, Medtronic and a speaker for Salix, QOL, Anylam, AbbVie, Takeda. Martin Hale has no conflicts to report. Jeremy Adler is a speaker for Averitas, Redhill, California Academy of PAs and a Consultant for AppliedVR and AbbVie.

Mansi S. Jamindar and Carol B. Rockett are previous employees and stockholders of RedHill Biopharma Inc. and June S. Almenoff is a current employee and stockholder of RedHill Biopharma Inc. Enoch Bortey has no conflicts to report. Jeffrey Gudin is a consultant to Collegium, Hisamitsu, Redhill- Quest Diagnostics, Sanofi, and principal and on the Boards of Virpax and Optimus Health. No authors were compensated for work performed on this paper, except for RedHill Employees.

Additional information

Funding

Funding support for this research was provided by RedHill Biopharma Inc.