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: email@example.com (J. Markman).
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Received September 28, 2018
Received in revised form January 04, 2019
Accepted January 30, 2019