A randomized, Phase IIb study investigating oliceridine (TRV130), a novel µ-receptor G-protein pathway selective (μ-GPS) modulator, for the management of moderate to severe acute pain following abdominoplasty

Abstract

Background

Oliceridine (TRV130), a novel μ-receptor G-protein pathway selective (μ-GPS) modulator, was designed to improve the therapeutic window of conventional opioids by activating G-protein signaling while causing low β-arrestin recruitment to the μ receptor. This randomized, double-blind, patient-controlled analgesia Phase IIb study was conducted to investigate the efficacy, safety, and tolerability of oliceridine compared with morphine and placebo in patients with moderate to severe pain following abdominoplasty (NCT02335294; oliceridine is an investigational agent not yet approved by the US Food and Drug Administration).

Methods

Patients were randomized to receive postoperative regimens of intravenous oliceridine (loading/patient-controlled demand doses [mg/mg]: 1.5/0.10 [regimen A]; 1.5/0.35 [regimen B]), morphine (4.0/1.0), or placebo with treatment initiated within 4 hours of surgery and continued as needed for 24 hours.

Results

Two hundred patients were treated (n=39, n=39, n=83, and n=39 in the oliceridine regimen A, oliceridine regimen B, morphine, and placebo groups, respectively). Patients were predominantly female (n=198 [99%]) and had a mean age of 38.2 years, weight of 71.2 kg, and baseline pain score of 7.7 (on 11-point numeric pain rating scale). Patients receiving the oliceridine regimens had reductions in average pain scores (model-based change in time-weighted average versus placebo over 24 hours) of 2.3 and 2.1 points, respectively (P=0.0001 and P=0.0005 versus placebo); patients receiving morphine had a similar reduction (2.1 points; P<0.0001 versus placebo). A lower prevalence of adverse events (AEs) related to nausea, vomiting, and respiratory function was observed with the oliceridine regimens than with morphine (P<0.05). Other AEs with oliceridine were generally dose-related and similar in nature to those observed with conventional opioids; no serious AEs were reported with oliceridine.

Conclusion

These results suggest that oliceridine may provide effective, rapid analgesia in patients with moderate to severe postoperative pain, with an acceptable safety/tolerability profile and potentially wider therapeutic window than morphine.

Keywords:

• TRV130
• acute pain
• analgesic
• opioid
• biased ligand

Supplementary materials

In stage I, 19 and 42 patients were treated with placebo and the morphine regimen, respectively. In stage II, 20 and 41 patients were treated with placebo and the morphine regimen, respectively. Analyses were performed to test whether there were statistically significant differences in efficacy (time-weighted average change in numeric pain rating scale over 24 hours from baseline) between stage I and stage II in each treatment group.

In comparisons over 0–4, 0–8, 0–12, and 0–24 hours, no statistically significant differences were seen in the placebo treatment groups between stage I and II (Figure S2A–D). Similarly, over 0–4, 0–8, 0–12, and 0–24 hours, the difference in the morphine treatment groups between stage I and II did not reach statistical significance (Figure S2A–D). Because of the similarity in efficacy demonstrated in each treatment group between stage I and II, the respective groups were combined for the primary efficacy and safety analyses to provide greater sample size and more robust evaluation versus oliceridine.

Figure S1 Patient disposition.

Figure S2 Least squares mean change from baseline in TWA NPRS from (A) 0–4 hours, (B) 0–8 hours, (C) 0–12 hours, and (D) 0–24 hours with placebo and morphine by study stage.

Note: Loading/patient-controlled demand doses (mg/mg): morphine, 4.0/1.0.

Abbreviations: TWA, time-weighted average; NPRS, numeric pain rating scale.

Acknowledgments

Medical writing support was provided by Kevin Wang of Xelay Acumen (San Mateo, CA, USA) and Donna McGuire of Engage Scientific Solutions (Philadelphia, PA, USA) and data analytical support by Cory Mekelburg of Xelay Acumen, which were funded by Trevena, Inc (King of Prussia, PA, USA).

The results of this study were presented at the American Society of Regional Anesthesia 41st Annual Regional Anesthesiology and Acute Pain Medicine Meeting (March 31 to April 2, 2016, New Orleans, LA, USA).

Author contributions

All the authors contributed to the conception or design of the study; contributed to the acquisition, analysis, or interpretation of the data; contributed to the drafting and revision of the manuscript for important intellectual content; agreed to be accountable for the work; and provided final approval of this version to be published.

Disclosure

This study was supported by Trevena, Inc (King of Prussia, PA, USA). Neil Singla is an employee of Lotus Clinical Research, LLC, contracted by the sponsor to conduct the study; Dr Singla has also received consulting fees from Trevena, Inc. Harold S Minkowitz has received investigator fees and consulting fees from Trevena, Inc, AcelRx, and The Medicines Company. Ruth Ann Subach was an employee of Trevena, Inc, during the conception/conduct of the study and owns Trevena, Inc, stock. David G Soergel, David A Burt, Monica Y Salamea, Michael J Fossler, and Franck Skobieranda are employees of the study’s sponsor, Trevena, Inc. The authors report no other conflicts of interest in this work.