A 12-week extension study to assess the safety and tolerability of naloxegol in patients with noncancer pain and opioid-induced constipation

Lynn Webster, MD; Raj Tummala, MD, MBA, MS; Ulysses Diva, PhD; Jaakko Lappalainen, MD, PhD

doi:10.5055/jom.2016.0360

Authors

Lynn Webster, MD
Raj Tummala, MD, MBA, MS
Ulysses Diva, PhD
Jaakko Lappalainen, MD, PhD

DOI:

https://doi.org/10.5055/jom.2016.0360

Keywords:

constipation, naloxegol, opioid-induced constipation, opioid receptor antagonist, safety, tolerability

Abstract

Objective: To compare the long-term safety and tolerability of naloxegol with placebo in patients with opioid-induced constipation (OIC) and noncancer pain.

Design: Twelve-week, multicenter, randomized, double-blind, parallel-group phase 3 extension study (KODIAC-07, NCT01395524).

Setting: Clinical investigation centers in the United States.

Patients: Adult outpatients (N = 302) with confirmed OIC who had completed a 12-week pivotal phase 3 study (KODIAC-04, NCT01309841).

Interventions: Daily oral administration of naloxegol (12.5 and 25 mg) or placebo.

Main Outcome Measures: Adverse events (AEs), including treatment-related AEs, serious AEs, and AEs of special interest; changes from baseline to week 12 in pain scores, daily opioid dose, and symptoms and quality-of-life measurements.

Results: No important new AEs occurred during this extension study compared with KODIAC-04. AEs occurred more frequently with naloxegol 25 mg (41.2 percent) versus naloxegol 12.5 mg (34.0 percent) and placebo (33.0 percent). Treatment-emergent AEs occurring in >5 percent of patients in either naloxegol group during the treatment period were arthralgia (25 mg; 5.2 percent) and diarrhea (12.5 mg; 5.3 percent); two reported AEs attributable to opioid withdrawal syndrome in naloxegol groups were deemed unrelated to study medication. None of the gastrointestinal serious AEs was adjudicated as bowel perforation; one patient (naloxegol 12.5 mg) had an event adjudicated as a major cardiovascular event and was unrelated to study medication. Pain scores and daily opioid dose were unchanged, and improvements in symptoms and quality-of-life observed in KODIAC-04 were maintained throughout the extension study.

Conclusion: Naloxegol was generally safe and well tolerated in this 12-week extension study in patients with noncancer pain and OIC.

Author Biographies

Lynn Webster, MD

Vice President of Scientific Affairs, PRA Health Sciences, Salt Lake City, Utah.

Raj Tummala, MD, MBA, MS

Director of Clinical Research, AstraZeneca Pharmaceuticals LP, Gaithersburg, Maryland.

Ulysses Diva, PhD

Principal Statistician, AstraZeneca Pharmaceuticals LP, Gaithersburg, Maryland; now with Ardea Biosciences, San Diego, California

Jaakko Lappalainen, MD, PhD

Senior Director of Clinical Research, AstraZeneca Pharmaceuticals LP, Wilmington, Delaware; now with Marinus Pharmaceuticals, Radnor, Pennsylvania.

References

Brock C, Olesen SS, Olesen AE, et al.: Opioid-induced bowel dysfunction: Pathophysiology and management. Drugs. 2012; 72(14): 1847-1865.

Camilleri M: Opioid-induced constipation: Challenges and therapeutic opportunities. Am J Gastroenterol. 2011; 106(5): 835-842.

Panchal SJ, Müller-Schwefe P, Wurzelmann JI: Opioid-induced bowel dysfunction: Prevalence, pathophysiology and burden. Int J Clin Pract. 2007; 61(7): 1181-1187.

Pappagallo M: Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg. 2001; 182(5A suppl): 11S-18S.

Diego L, Atayee R, Helmons P, et al.: Novel opioid antagonists for opioid-induced bowel dysfunction. Expert Opin Investig Drugs. 2011; 20(8): 1047-1056.

Thomas J: Opioid-induced bowel dysfunction. J Pain Symptom Manage. 2008; 35(1): 103-113.

Bell TJ, Panchal SJ, Miaskowski C, et al.: The prevalence, severity, and impact of opioid-induced bowel dysfunction: Results of a US and European Patient Survey (PROBE 1). Pain Med. 2009; 10(1): 35-42.

Eldon MA, Song D, Neumann TA, et al.: NKTR-118 (oral PEGnaloxol), a PEGylated derivative of naloxone: Demonstration of selective peripheral opioid antagonism after oral administration in preclinical models. Poster 28 presented at: 18th Annual Clinical Meeting of the American Academy of Pain Management; 27-30 September, 2007; Las Vegas, NV.

Faassen F, Vogel G, Spanings H, et al.: Caco-2 permeability, P-glycoprotein transport ratios and brain penetration of heterocyclic drugs. Int J Pharm. 2003; 263(1-2): 113-122.

Chey WD, Webster L, Sostek M, et al.: Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014; 370(25): 2387-2396.

Farrar JT, Young JP Jr. LaMoreaux L, et al.: Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001; 94(2): 149-158.

Culpepper-Morgan JA, Inturrisi CE, Portenoy RK, et al.: Treatment of opioid-induced constipation with oral naloxone: A pilot study. Clin Pharmacol Ther. 1992; 52(1): 90-95.

Himmelsbach CK: The morphine abstinence syndrome, its nature and treatment. Ann Intern Med. 1941; 15(5): 829-839.

Posner K, Brown GK, Stanley B, et al.: The Columbia-Suicide Severity Rating Scale: Initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011; 168(12): 1266-1277.

Frank L, Kleinman L, Farup C, et al.: Psychometric validation of a constipation symptom assessment questionnaire. Scand J Gastroenterol. 1999; 34(9): 870-877.

Marquis P, De La Loge C, Dubois D, et al.: Development and validation of the Patient Assessment of Constipation Quality of Life questionnaire. Scand J Gastroenterol. 2005; 40(5): 540-551.

Webster L, Chey WD, Tack J, et al.: Randomised clinical trial: The long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation. Aliment Pharmacol Ther. 2014; 40(7): 771-779.

Becker G, Blum HE: Novel opioid antagonists for opioid-induced bowel dysfunction and postoperative ileus. Lancet. 2009; 373(9670): 1198-1206.

Bream-Rouwenhorst HR, Cantrell MA: Alvimopan for postoperative ileus. Am J Health Syst Pharm. 2009; 66(14): 1267-1277.