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SUMMIT-07

a randomized trial of NKTR-181, a new molecular entity, full mu-opioid receptor agonist for chronic low-back pain

Markman, Johna,*; Gudin, Jeffreyb; Rauck, Richardc; Argoff, Charlesd; Rowbotham, Michaele; Agaiby, Evaf; Gimbel, Josephg; Katz, Nathanielh; Doberstein, Stephen K.i; Tagliaferri, Maryi; Lu, Lini; Siddhanti, Sureshi; Hale, Martinj

doi: 10.1097/j.pain.0000000000001517
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NKTR-181, a new molecular entity, mu-opioid receptor agonist with an inherently slow rate of central nervous system (CNS) entry, was designed to provide analgesia while reducing abuse potential. This phase 3, enriched-enrollment, randomized-withdrawal trial evaluated the analgesic efficacy, safety, and tolerability of NKTR-181 in patients with chronic low-back pain (CLBP). Adults with moderate-to-severe CLBP refractory to nonopioid analgesics achieving an analgesic NKTR-181 dosage (100-400 mg twice daily) during the open-label titration period were randomized to continued NKTR-181 treatment, double-blind, or switched to placebo. The study was conducted at 55 sites in the United States. Of 1189 patients exposed to NKTR-181 during the titration period, 610 were randomized to NKTR-181 100 to 400 mg every 12 hours or placebo for 12 weeks. The primary outcome measure was change in weekly pain score (scale, 0-10) at 12 weeks from randomization baseline. Secondary outcome measures included responder rates defined by ≥30% and ≥50% improvement in pain score from screening to 12 weeks. Among 610 randomized patients, the mean pain score decreased from 6.73 to 2.32 during open-label titration. After randomization, the least-squares mean change in pain score was +0.92 for NKTR-181 vs +1.46 for placebo (P = 0.002). The ≥30%-improvement responder rate of NKTR-181 vs placebo was 71.2% vs 57.1% (P < 0.001), and the ≥50%-improvement responder rate was 51.1% vs 37.9% (P = 0.001). NKTR-181 was well tolerated with a low incidence (<3%) of CNS-related adverse events during the randomized treatment phase. In patients with moderate-to-severe CLBP, NKTR-181 demonstrated significant analgesic efficacy and a favorable safety/tolerability profile, with a low incidence of CNS adverse events.

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NKTR-181 provides effective analgesia in patients with moderate-to-severe chronic low-back pain with low incidence of central nervous system side effects.

aDepartment of Neurosurgery, Translational Pain Research Program, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States

bPain Management and Palliative Care Center, Englewood Hospital and Medical Center, Englewood, NJ, United States

cCarolinas Pain Institute, The Center for Clinical Research, Winston-Salem, NC, United States

dDepartment of Neurology, Albany Medical Center, Albany, NY, United States

eSutter Health, CPMC Research Institute, San Francisco, CA, United States

fClinical Investigation Specialists Inc, Kenosha, WI, United States

gArizona Research Center, Phoenix, AZ, United States

hTufts University School of Medicine, Department of Anesthesia, Boston, MA, United States

iNektar Therapeutics, San Francisco, CA, United States

jGold Coast Research, LLC, Plantation, FL, United States

Corresponding author. Address: Department of Neurosurgery, Translational Pain Research Program, University of Rochester School of Medicine and Dentistry, 2180 S. Clinton Ave, Rochester, NY 14618, United States. Tel.: (585) 276-3616; fax: (585) 473-1691. E-mail address: john_markman@urmc.rochester.edu (J. Markman).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received September 28, 2018

Received in revised form January 04, 2019

Accepted January 30, 2019

© 2019 International Association for the Study of Pain