NKTR-181, a new molecular entity, full mu-opioid receptor agonist with an inherently slow rate of CNS entry, was designed to provide analgesia while reducing abuse potential. The objective of this phase 3, enriched-enrollment, randomized-withdrawal trial was to evaluate 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 non-opioid 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-181 100–400 mg every 12 hours or placebo for 12-weeks. The primary outcome measure was the 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 AEs 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 AEs.
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aDepartment of Neurosurgery, Translational Pain Research Program, University of Rochester School of Medicine and Dentistry, Rochester, NY
bPain Management Center, Englewood Hospital and Medical Center, Englewood, NJ
cCarolinas Pain Institute and The Center for Clinical Research, Winston-Salem, NC
dDepartment of Neurology, Albany Medical Center, Albany, NY
eCPMC Research Institute, San Francisco, CA
fClinical Investigation Specialists Inc, Kenosha, WI
gArizona Research Center, Phoenix, AZ
hTufts University School of Medicine, Boston, MA
iNektar Therapeutics, San Francisco, CA
jGold Coast Research, LLC, Plantation, FL
Correspondence to: John Markman, Department of Neurosurgery, Translational Pain Research Program, University of Rochester School of Medicine and Dentistry, 2180 S. Clinton Ave., Rochester, NY 14618. Phone: (585) 276-3616. Fax: (585) 473-1691. Email: email@example.com