SUMMIT-07: a randomized trial of NKTR-181, a new molecular entity, full mu-opioid receptor agonist for chronic low-back pain

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

Abstract

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.

Conflict of interest statement

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

Figures

Figure 1.
Figure 1.
SUMMIT-07 study design. This enriched-enrollment, randomized-withdrawal study included a screening period, an open-label titration period, and a double-blind, placebo-controlled, treatment period lasting 12 weeks.
Figure 2.
Figure 2.
Patient disposition.
Figure 3.
Figure 3.
Primary and secondary efficacy outcomes in SUMMIT-07 (intent-to-treat population). (A) shows the mean weekly pain scores from screening through week 12 of the randomized treatment period, and (B) shows the cumulative distribution of change in pain score at week 12 (**P = 0.01, ***P < 0.001 vs placebo, respectively). Patients discontinued before 12 weeks were counted as nonresponders. NRS, numerical rating scale.

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