APOLLO-2: A Randomized, Placebo and Active-Controlled Phase III Study Investigating Oliceridine (TRV130), a G Protein-Biased Ligand at the μ-Opioid Receptor, for Management of Moderate to Severe Acute Pain Following Abdominoplasty

Abstract

Objectives: The clinical utility of conventional IV opioids is limited by the occurrence of opioid-related adverse events. Oliceridine is a novel G protein-biased μ-opioid receptor agonist designed to provide analgesia with an improved safety and tolerability profile. This phase III, double-blind, randomized trial (APOLLO-2 [NCT02820324]) evaluated the efficacy and safety of oliceridine for acute pain following abdominoplasty.

Methods: Patients received a loading dose of either placebo, oliceridine (1.5 mg), or morphine (4 mg), followed by demand doses via patient-controlled analgesia (0.1, 0.35, or 0.5 mg oliceridine; 1 mg morphine; or placebo) with a 6-minute lockout interval. The primary endpoint was the proportion of treatment responders over 24 hours for oliceridine regimens compared to placebo. Secondary outcomes included a predefined composite measure of respiratory safety burden (RSB, representing the cumulative duration of respiratory safety events) and the proportion of treatment responders vs. morphine.

Results: A total of 401 patients were treated with study medication. Effective analgesia was observed for all oliceridine regimens, with responder rates of 61.0%, 76.3%, and 70.0% for the 0.1-, 0.35-, and 0.5-mg regimens, respectively, compared with 45.7% for placebo (all P < 0.05) and 78.3% for morphine. Oliceridine 0.35- and 0.5-mg demand dose regimens were equi-analgesic to morphine using a noninferiority analysis. RSB showed a dose-dependent increase across oliceridine regimens (mean hours [standard deviation], 0.1 mg: 0.43 [1.56]; 0.35 mg: 1.48 [3.83]; 0.5 mg: 1.59 [4.26]; all comparisons not significant at P > 0.05 vs. placebo: 0.60 [2.82]). The RSB measure for morphine was 1.72 (3.86) (P < 0.05 vs. placebo). Gastrointestinal adverse events increased in a dose-dependent manner across oliceridine demand dose regimens (0.1 mg: 49.4%; 0.35 mg: 65.8%; 0.5 mg: 78.8%; vs. placebo: 47.0%; and morphine: 79.3%). In comparison to morphine, the proportion of patients experiencing nausea or vomiting was lower with the 2 equi-analgesic dose regimens of 0.35 and 0.5 mg oliceridine.

Conclusions: Oliceridine is a safe and effective IV analgesic for the relief of moderate to severe acute postoperative pain in patients undergoing abdominoplasty. Since the low-dose regimen of 0.1 mg oliceridine was superior to placebo but not as effective as the morphine regimen, safety comparisons to morphine are relevant only to the 2 equi-analgesic dose groups of 0.35 and 0.5 mg, which showed a favorable safety and tolerability profile regarding respiratory and gastrointestinal adverse effects compared to morphine. These findings support that oliceridine may provide a new treatment option for patients with moderate to severe acute pain where an IV opioid is warranted.

Keywords: abdominoplasty; analgesia; clinical trial; patient controlled; postoperative.

Conflict of interest statement

Mark Demitrack is a full‐time employees of Trevena Inc. and owns stock in Trevena Inc. David G. Soergel, Franck Skobieranda, Monica Salamea and David A. Burt were full‐time employees, and stockholders, of Trevena Inc. at the time the research was conducted and the manuscript was fully written. Neil Singla is the founder and CEO of Lotus Clinical Research LLC, an analgesic CRO and research site; in this capacity he has served as a consultant and provided clinical trial services for Trevena Inc. Eugene R. Viscusi has served as a consultant to Trevena Inc.

© 2019 The Authors. Pain Practice published by Wiley Periodicals, Inc. on behalf of World Institute of Pain.

Figures

Figure 1

Patient disposition. All percentages are based on the number of patients randomized. Efficacy and safety analyses were conducted on all randomized patients who received ≥1 dose of study medication. Efficacy analyses were based on the randomized treatment assignment, while safety analyses were based on the actual treatment received. This explains the minor discrepancies seen between the number of patients analyzed for efficacy and safety in some treatment regimens. IPP, immediate postoperative period.

Figure 2

A, Cumulative use of rescue pain medication. B, First perceptible and first meaningful pain relief. In (A), the cumulative percentage of patients using rescue pain medication in each regimen is shown at predefined time points throughout the 24‐hour treatment period. Patients could receive open‐label rescue pain medication (oral etodolac 200 mg every 6 hours PRN) if they reported a score ≥ 4 on the pain NRS. In (B), the median time to first perceptible and first meaningful pain relief is presented, as reported by patients using the two‐stopwatch method. *P < 0.05 compared to morphine. CI, confidence interval; NRS, numeric rating scale; PRN, as needed.

Figure 3

A, Primary treatment response analysis of oliceridine compared with placebo (treatment responders at 24 hours). B, Treatment responders over the full treatment period. This primary endpoint analysis compared the percentage of treatment responders in each oliceridine regimen with the percentage of responders in the placebo regimen at 24 hours post loading dose. Responders were those who reached a ≥30% improvement in time‐weighted sum of pain intensity difference (SPID‐24) from baseline, whilst (1) not received rescue pain medication, (2) not discontinuing study medication early, and (3) without reaching dosing limits. *P < 0.05 vs. placebo (Hochberg adjusted). CI, confidence interval.

Figure 4

The key prespecified secondary endpoint of cumulative respiratory safety burden. During the randomized treatment period, patients were monitored on a protocol‐defined schedule by either a certified registered nurse anesthetist or an anesthesiologist, blinded to study medication assignment. The monitoring professional intervened when clinically indicated and determined the onset and resolution of each respiratory safety event. Respiratory safety burden was defined as the expected cumulative duration of respiratory safety events in a particular treatment group and was calculated as the mathematical product of the prevalence of respiratory safety events and the mean conditional duration (ie, mean duration in affected patients) of such events (see Table 3). *P < 0.05 compared to morphine (unadjusted). Mean respiratory safety burden from the model‐based estimate was 7, 5, 19, 25, and 32 minutes for the placebo, oliceridine 0.1, 0.35, and 0.5 mg, and morphine groups, respectively. SD, standard deviation.

Figure 5

Clinical interventions. A, The proportion of patients in each regimen who experienced any dosing interruption of study medication during the study is presented. Exploratory analyses showed that the odds ratio of an interruption compared to morphine was 0.09 (P < 0.0001) for placebo, 0.15 (P = 0.0002) for oliceridine 0.1 mg, 0.57 (P = 0.13) for oliceridine 0.35 mg, and 0.64 (P = 0.23) for oliceridine 0.5 mg regimens. B, The proportion of patients in each regimen who required supplemental oxygen therapy is presented. Exploratory analyses showed that the odds ratio of an interruption compared to morphine was 0.15 (P = 0.0002) for placebo, 0.18 (P = 0.0005) for oliceridine 0.1 mg, 0.54 (P = 0.11) for oliceridine 0.35 mg, and 0.65 (P = 0.25) for oliceridine 0.5 mg regimens. *P < 0.05 odds ratio vs. morphine.

Figure 6

(A) The proportion of responders over the first 60 minutes of treatment and (B) time to 1‐point improvement in NRS score. A, Treatment response during this period can largely be attributed to study drug (loading dose at Time 0 and demand doses starting at 10 minutes) since supplemental study medication doses were prohibited and rescue pain medication was discouraged during this time. *P < 0.05 compared to morphine. B, NRS pain scores were reported at baseline (up to 10 minutes before loading dose [Time 0]); at 5, 10, 15, 30, and 45 minutes; and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, and 24 hours post‐loading dose. *P < 0.05 vs. morphine. CI, confidence interval; NRS, numeric rating scale.

Figure 7

Rescue antiemetic use. This analysis examined post‐treatment rescue antiemetic use. Patients could receive rescue antiemetic medication if they were actively vomiting, or if they requested an antiemetic and reported moderate to severe nausea on a 4‐point scale (none, mild, moderate, severe). Prophylactic antiemetics were not permitted perioperatively or during the randomized treatment period. *P < 0.05 for odds ratio for rescue antiemetic use vs. morphine.