Long-term Safety and Tolerability of NKTR-181 in Patients with Moderate to Severe Chronic Low Back Pain or Chronic Noncancer Pain: A Phase 3 Multicenter, Open-Label, 52-Week Study (SUMMIT-08 LTS)

Jeffrey Gudin, Richard Rauck, Charles Argoff, Eva Agaiby, Joseph Gimbel, Nathaniel Katz, Stephen K Doberstein, Mary Tagliaferri, Margit Tagliaferri, Jeffrey Potts, James Wild, Lin Lu, Suresh Siddhanti, Martin Hale, John Markman, Jeffrey Gudin, Richard Rauck, Charles Argoff, Eva Agaiby, Joseph Gimbel, Nathaniel Katz, Stephen K Doberstein, Mary Tagliaferri, Margit Tagliaferri, Jeffrey Potts, James Wild, Lin Lu, Suresh Siddhanti, Martin Hale, John Markman

Abstract

Objective: To evaluate the long-term safety of NKTR-181, a novel mu-opioid receptor agonist that may have reduced human abuse potential, in patients with moderate to severe chronic low back pain (CLBP) or other chronic noncancer pain (CNP).

Design: Uncontrolled, multicenter, open-label, long-term study of NKTR-181 comprised of three periods: screening (≤21 days), treatment (52 weeks), and safety follow-up (∼14 days after the last dose of NKTR-181).

Setting: Multicenter, long-term clinical research study.

Methods: NKTR-181 administered at doses of 100-600 mg twice daily (BID) was evaluated in opioid-naïve and opioid-experienced patients. Patients were enrolled de novo or following completion of the randomized, placebo-controlled phase 3 efficacy study (SUMMIT-07). Safety assessments included adverse event documentation, measurements of opioid withdrawal, and clinical laboratory tests. Effectiveness was assessed using the modified Brief Pain Inventory Short Form (mBPI-SF).

Results: The study enrolled 638 patients. The most frequently reported treatment-emergent adverse events (TEAEs) were constipation (26%) and nausea (12%). Serious TEAEs, reported in 5% of patients, were deemed by investigators to be unrelated to NKTR-181. There were no deaths or reported cases of respiratory depression. A sustained reduction in mBPI-SF pain intensity and pain interference from baseline to study termination was observed throughout treatment. Only 2% of patients discontinued NKTR-181 due to lack of efficacy, and 11% discontinued due to treatment-related AEs. NKTR-181 doses of up to 600 mg BID were generally well tolerated, and patients experienced low rates of opioid-related adverse events.

Conclusions: The study results support the premise that NKTR-181 is a safe and effective option for patients with moderate to severe CLBP or CNP.

Keywords: Chronic Noncancer Pain; Chronic Pain; Long-term Safety; Low Back Pain; NKTR-181; Opioids; Oxycodegol; SUMMIT-08.

© 2019 American Academy of Pain Medicine.

Figures

Figure 1
Figure 1
Study schematic.
Figure 2
Figure 2
Disposition of patients.
Figure 3
Figure 3
Mean total Subjective Opiate Withdrawal Scale (SOWS) scores after last dose over time by subgroup (patients completing the study). SOWS total scores could range from 0 to 64.
Figure 4
Figure 4
A) Mean pain intensity and (B) mean pain interference over each visit, as measured by the modified Brief Pain Inventory Short Form.
Figure 5
Figure 5
Percentage of patients in the safety population with NKTR-181 dose adjustments (+/- 100 mg twice daily) during the 52-week treatment period. Only the first dose change after a stable dose was achieved in the first five weeks of treatment was used for classifying dose decrease or increase. For subjects with tolerability issues, the dose of NKTR-181 may have been adjusted downwards, as necessary, based on the investigator’s clinical judgment in stepwise 100-mg changes.

References

    1. Han B, Compton WM, Blanco C, et al. Prescription opioid use, misuse, and use disorders in U.S. adults: 2015 National Survey on Drug Use and Health. Ann Intern Med 2017;167(5):293–301.
    1. Vowles KE, McEntee ML, Julnes PS, et al. Rates of opioid misuse, abuse, and addiction in chronic pain: A systematic review and data synthesis. Pain 2015;156(4):569–76.
    1. Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid therapy for chronic pain: A systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med 2015;162(4):276–86.
    1. Middleton C, Harden J.. Acquired pharmaco-dynamic opioid tolerance: A concept analysis. J Adv Nurs 2014;70(2):272–81.
    1. Blendon RJ, Benson JM.. The public and the opioid-abuse epidemic. N Engl J Med 2018;378(5):407–11.
    1. Florence CS, Zhou C, Luo F, et al. The economic burden of prescription opioid overdose, abuse, and dependence in the United States, 2013. Med Care 2016;54(10):901–6.
    1. Litman RS, Pagan OH, Cicero TJ.. Abuse-deterrent opioid formulations. Anesthesiology 2018;128(5):1015–26.
    1. Adler JA, Mallick-Searle T.. An overview of abuse-deterrent opioids and recommendations for practical patient care. J Multidiscip Healthc 2018;11:323–32.
    1. Cicero TJ, Ellis MS.. Abuse-deterrent formulations and the prescription opioid abuse epidemic in the United States: Lessons learned from Oxycontin. JAMA Psychiatry 2015;72(5):424–30.
    1. Coplan PM, Kale H, Sandstrom L, et al. Changes in oxycodone and heroin exposures in the National Poison Data System after introduction of extended-release oxycodone with abuse-deterrent characteristics. Pharmacoepidemiol Drug Saf 2013;22(12):1274–82.
    1. Becker WC, Fiellin DA.. Abuse-deterrent opioid formulations-putting the potential benefits into perspective. N Engl J Med 2017;376(22):2103–5.
    1. Wakabayashi KT, Weiss MJ, Pickup KN, et al. Rats markedly escalate their intake and show a persistent susceptibility to reinstatement only when cocaine is injected rapidly. J Neurosci 2010;30(34):11346–55.
    1. Samaha AN, Mallet N, Ferguson SM, Gonon F, Robinson TE. The rate of cocaine administration alters gene regulation and behavioral plasticity: Implications for addiction. J Neurosci 2004;24(28):6362–70.
    1. Samaha AN, Yau WY, Yang P, Robinson TE. Rapid delivery of nicotine promotes behavioral sensitization and alters its neurobiological impact. Biol Psychiatry 2005;57(4):351–60.
    1. Marsch LA, Bickel WK, Badger GJ, et al. Effects of infusion rate of intravenously administered morphine on physiological, psychomotor, and self-reported measures in humans. J Pharmacol Exp Ther 2001;299(3):1056–65.
    1. Webster LR, Bath B, Medve RA, et al. Randomized, double-blind, placebo-controlled study of the abuse potential of different formulations of oral oxycodone. Pain Med 2012;13(6):790–801.
    1. Shram MJ, Sathyan G, Khanna S, et al. Evaluation of the abuse potential of extended release hydromorphone versus immediate release hydromorphone. J Clin Psychopharmacol 2010;30(1):25–33.
    1. Harris SC, Perrino PJ, Smith I, et al. Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users. J Clin Pharmacol 2014;54(4):468–77.
    1. Comer SD, Ashworth JB, Sullivan MA, Vosburg SK, Saccone PA, Foltin RW. Relationship between rate of infusion and reinforcing strength of oxycodone in humans. J Opioid Manag 2009;5(4):203–12.
    1. Miyazaki T, Choi IY, Rubas W, et al. NKTR-181: A novel mu-opioid analgesic with inherently low abuse potential. J Pharmacol Exp Ther 2017;363(1):104–13.
    1. Webster L, Henningfield J, Buchhalter AR, et al. Human abuse potential of the new opioid analgesic molecule NKTR-181 compared with oxycodone. Pain Med 2018;19(2):307–18.
    1. Markman J, Gudin J, Rauck R, et al. SUMMIT-07: A randomized trial of NKTR-181, a new molecular entity, for chronic low-back pain. Pain 2019;160(6):1374–82.
    1. Kroenke K, Strine TW, Spitzer RL, et al. The PHQ-8 as a measure of current depression in the general population. J Affect Disord 2009;114(1–3):163–73.
    1. Tompkins DA, Bigelow GE, Harrison JA, et al. Concurrent validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices against the Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument. Drug Alcohol Depend 2009;105(1–2):154–9.
    1. Wesson DR, Ling W.. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs 2003;35(2):253–9.
    1. Handelsman L, Cochrane KJ, Aronson MJ, et al. Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse 1987;13(3):293–308.
    1. Treister R, Trudeau JJ, Van Inwegen R, et al. Development and feasibility of the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS(R)). Am J Addict 2016;25(8):641–51.
    1. Lanier RK, Henningfield JE, Gudin J, et al. Assessment of potentially abuse-related events in two phase 3 studies of NKTR-181, a novel opioid analgesic, using the MADDERS(R) system (Misuse, Abuse, and Diversion Drug Event Reporting System). Curr Med Res Opin. 2019:1–10 (doi: 10.1080/03007995.2019.1594744).
    1. Mundt JC, Greist JH, Jefferson JW, et al. Prediction of suicidal behavior in clinical research by lifetime suicidal ideation and behavior ascertained by the electronic Columbia-Suicide Severity Rating Scale. J Clin Psychiatry 2013;74(09):887–93.
    1. 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):1266–77.
    1. Mundt JC, Greist JH, Gelenberg AJ, et al. Feasibility and validation of a computer-automated Columbia-suicide severity rating scale using interactive voice response technology. J Psychiatr Res 2010;44(16):1224–8.
    1. Mendoza T, Mayne T, Rublee D, et al. Reliability and validity of a modified Brief Pain Inventory short form in patients with osteoarthritis. Eur J Pain 2006;10(4):353–61.
    1. Coats TL, Borenstein DG, Nangia NK, et al. Effects of valdecoxib in the treatment of chronic low back pain: Results of a randomized, placebo-controlled trial. Clin Ther 2004;26(8):1249–60.
    1. Zheng Y, Kostenbader K, Barrett T, et al. Tolerability of biphasic-release hydrocodone bitartrate/acetaminophen tablets (MNK-155): A phase III, multicenter, open-label study in patients with osteoarthritis or chronic low back pain. Clin Ther 2015;37(6):1235–47.
    1. Enthoven WTM, Roelofs PD, Koes BW.. NSAIDs for chronic low back pain. JAMA 2017;317(22):2327–8.
    1. Chou R, Deyo R, Friedly J, et al. Nonpharmacologic therapies for low back pain: A systematic review for an American College of Physicians clinical practice guideline. Ann Intern Med 2017;166(7):493–505.
    1. Chou R, Deyo R, Friedly J, et al. Systemic pharmacologic therapies for low back pain: A systematic review for an American College of Physicians clinical practice guideline. Ann Intern Med 2017;166(7):480–92.
    1. Center for Drug Evaluation and Research. Abuse-Deterrent Opioids-Evaluation and Labeling Guidance for Industry. Silver Spring, MD: Food and Drug Administration, Center for Drug Evaluation and Research; 2015.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner