Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Mar 11:12:927-943.
doi: 10.2147/JPR.S171013. eCollection 2019.

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

Eugene R Viscusi  1 , Franck Skobieranda  2 , David G Soergel  2 , Emily Cook  2 , David A Burt  2 , Neil Singla  3
Affiliations

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

Eugene R Viscusi et al. J Pain Res. .

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.

PubMed Disclaimer

Conflict of interest statement

Disclosure David A Burt, Emily Cook, David G Soergel, and Franck Skobieranda were full-time employees and stockholders of Trevena Inc. at the time the research was conducted and manuscript was under preparation. Neil Singla is founder and CEO of Lotus Clinical Research, LLC, an analgesic Clinical Research Organization 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. The authors report no other conflicts of interest in this work.

Figures

Figure 1
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
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
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
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
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
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
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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. National Pharmaceutical Council (NPC) Pain: current understanding of assessment, management, and treatments. Reston, VA: NPC, Joint Commission on Accreditation of Health Care Organization; 2001.
    1. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11(2 Suppl):S105–S120. - PubMed
    1. Wheeler M, Oderda GM, Ashburn MA, Lipman AG. Adverse events associated with postoperative opioid analgesia: a systematic review. J Pain. 2002;3(3):159–180. - PubMed
    1. Swegle JM, Logemann C. Management of common opioid-induced adverse effects. Am Fam Physician. 2006;74(8):1347–1354. - PubMed
    1. Rogers E, Mehta S, Shengelia R, Reid MC. Four strategies for managing opioid-induced side effects in older adults. Clin Geriatr. 2013;21(4) - PMC - PubMed