APOLLO-1: 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 bunionectomy

Abstract

Purpose: Oliceridine is a novel G protein-biased µ-opioid receptor agonist designed to provide intravenous (IV) analgesia with a lower risk of opioid-related adverse events (ORAEs) than conventional opioids.

Patients and methods: APOLLO-1 (NCT02815709) was a phase III, double-blind, randomized trial in patients with moderate-to-severe pain following bunionectomy. 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). The primary endpoint compared the proportion of treatment responders through 48 hours for oliceridine regimens and placebo. Secondary outcomes included a composite measure of respiratory safety burden (RSB, representing the cumulative duration of respiratory safety events) and the proportion of treatment responders vs morphine.

Results: Effective analgesia was observed for all oliceridine regimens, with responder rates of 50%, 62%, and 65.8% in the 0.1 mg, 0.35 mg, and 0.5 mg regimens, respectively (all P<0.0001 vs placebo [15.2%]; 0.35 mg and 0.5 mg non-inferior to morphine). RSB showed a dose-dependent increase across oliceridine regimens (mean hours [SD]: 0.1 mg: 0.04 [0.33]; 0.35 mg: 0.28 [1.11]; 0.5 mg: 0.8 [3.33]; placebo: 0 [0]), but none were statistically different from morphine (1.1 [3.03]). Gastrointestinal adverse events also increased in a dose-dependent manner in oliceridine regimens (0.1 mg: 40.8%; 0.35 mg: 59.5%; 0.5 mg: 70.9%; placebo: 24.1%; morphine: 72.4%). The odds ratio for rescue antiemetic use was significantly lower for oliceridine regimens compared to morphine (P<0.05).

Conclusion: Oliceridine is a novel and effective IV analgesic providing rapid analgesia for the relief of moderate-to-severe acute postoperative pain compared to placebo. Additionally, it has a favorable safety and tolerability profile with regard to respiratory and gastrointestinal adverse effects compared to morphine, and may provide a new treatment option for patients with moderate-to-severe postoperative pain where an IV opioid is required.

Keywords: analgesia; clinical trial; orthopedic surgery; patient controlled; postoperative.

Figure 1

Patient disposition. Notes: All percentages based on the number of patients randomized. Efficacy and safety analyses include all randomized patients who received ≥1 dose of study medication. Abbreviation: IPP, immediate postoperative period.

Figure 2

(A) Primary treatment response analysis of oliceridine compared with placebo (treatment responders at 48 hours). Notes: This primary endpoint analysis compared the percentage of treatment responders in each oliceridine regimen with the percentage of responders in the placebo regimen at 48 hours post-loading dose. (B) Treatment responders over the full treatment period. Responders were those who reached a ≥30% improvement in time-weighted SPID-48 from baseline while not receiving rescue pain medication, discontinuing study medication early, or reaching dosing limits. *P<0.0001 vs placebo (Hochberg adjusted). Abbreviation: SPID, sum of pain intensity difference.

Figure 3

(A) The cumulative percentage of patients using rescue pain medication in each regimen is shown at predefined time points throughout the 48-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. (B) Time to first perceptible and first meaningful pain relief. Median time in hours is presented, as reported by patients using the two-stopwatch method. Placebo data were N/E for time to meaningful pain relief. Abbreviations: N/E, not evaluable; NRS, numeric rating scale; PRN, as needed.

Figure 4

(A) The proportion of responders over the first 60 minutes of treatment. Responses 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 for odds ratio vs morphine. (B) Time to 1-, 2-, and 3-point improvement in NRS score. NRS pain scores were reported at baseline (up to 10 minutes before loading dose [Time 0]), 5, 10, 15, 30, and 45 minutes, and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 32, 40, and 48 hours post-loading dose. Median data for the placebo group were not calculable for time to 2- and 3-point improvements due to small number of patients achieving this improvement. Responses in the oliceridine groups were not statistically different from morphine. Abbreviation: N/E, not evaluable; NRS, numeric rating scale.

Figure 5

The key prespecified secondary endpoint of cumulative respiratory safety burden. Notes: 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 (in hours) 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 (Table 3). Mean respiratory safety burden was 1, 1, 9, 15, and 33 minutes for the placebo, oliceridine 0.1 mg, 0.35 mg, 0.5 mg, and morphine groups, respectively (from the model-based estimate). There were no statistically significant differences for this composite outcome measure for any of the oliceridine treatment groups compared to morphine in the prespecified key secondary analysis with Hochberg adjustment. Abbreviation: SEM, standard error of the mean.

Figure 6

Clinical interventions. Notes: (A) The proportion of patients in each regimen who experienced any dosing interruption of study medication during the study. Exploratory analyses showed that the odds ratio of an interruption compared to morphine was 0.02 (P=0.0049) for placebo, 0.07 (P=0.0014) for oliceridine 0.1 mg, 0.29 (P=0.0169) for oliceridine 0.35 mg, and 0.56 (P=0.1968) for oliceridine 0.5 mg regimens. (B) The proportion of patients in each regimen who required supplemental oxygen therapy. Exploratory analyses showed that the odds ratio of requiring supplemental oxygen therapy compared to morphine was 0.02 (P=0.0076) for placebo, 0.08 (P=0.0030) for oliceridine 0.1 mg, 0.42 (P=0.0864) for oliceridine 0.35 mg, and 0.66 (P=0.3790) for oliceridine 0.5 mg regimens. *P<0.05 odds ratio vs morphine.

Figure 7

Post-treatment rescue antiemetic use. Notes: 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.