The study design and the results of the randomized, double-blind, placebo- and morphine-controlled studies following either orthopedic surgery (hard-tissue model—bunionectomy) or plastic surgery (soft-tissue model—abdominoplasty) were previously described [16, 17] (See Electronic Supplementary Material Fig. 1: Study designs of the phase 3 pivotal trials). Both studies were conducted in compliance with the protocol and regulatory requirements consistent with the International Council on Harmonization Good Clinical Practice Guidelines and the ethical principles of the Declaration of Helsinki. The study was approved by an Institutional Review Board at each investigational site, and patients provided written informed consent before participation. Advarra Inc. (Columbia, MD, USA) provided a centralized institutional review board approval for all sites.
Although similar in design, these two studies differed in their use of anesthetics (regional anesthesia with popliteal sciatic nerve block in the bunionectomy study and general anesthesia with the use of fentanyl and propofol in the abdominoplasty study), time from surgery to the first dose of study medication, temporal courses of pain after discontinuation of anesthesia (within 9 h after discontinuation of regional anesthesia in the bunionectomy study, and within 4 h after surgery and at least 20 min after the last dose of fentanyl in the abdominoplasty study), qualifying numerical rating scale (NRS) pain intensity scores, and duration of the randomized treatment period (48 h for the bunionectomy study and 24 h for the abdominoplasty study).
In both studies, patients aged 18–75 years, with a body mass index ≤ 35 kg/m2 and body weight ≥ 40 kg, who underwent primary surgery of either bunionectomy (orthopedic surgery) or abdominoplasty (plastic surgery) and experienced moderate-to-severe pain as measured by the NRS (≥ 4 for the bunionectomy study and ≥ 5 for the abdominoplasty study) were enrolled. Patients were randomized to receive IV demand dose regimens of either placebo, oliceridine 0.1 mg, oliceridine 0.35 mg, oliceridine 0.5 mg, or morphine 1 mg. For each regimen, a clinician administered a fixed IV loading dose (oliceridine 1.5 mg, morphine 4 mg, or volume-matched placebo) followed by demand doses administered via a PCA device and blinded supplemental doses. PCA doses were allowed from 10 min after the loading dose and limited by a 6-min lockout interval. Blinded clinician-administered IV supplemental doses (oliceridine 0.75 mg and morphine 2 mg) were permitted as often as hourly as needed (PRN). The dosing limit for all groups was three PCA syringes or six clinician-administered supplemental PRN doses within the first 12 h (60 mg for the oliceridine group). Patients reaching this dosing limit were discontinued, managed with conventional therapies, and allowed to remain in the study as non-responders.
In both studies, RSB experienced by patients in each treatment group, calculated as the mathematical product of the incidence of a defined set of observed RSEs multiplied by the mean expected cumulative duration of these events (RSB; in hours), was a prespecified endpoint and findings have been previously reported [16, 17].
Both studies also reported overall safety and tolerability assessed via the occurrence of treatment-emergent AEs that were spontaneously reported during the randomized treatment and 7-day follow-up period, coded using MedDRA, version 19.0. For this exploratory analysis, the spontaneously reported MedDRA events, in particular, events that occurred in ≥ 10% of patients in any treatment group of oliceridine or morphine, was utilized. Patients receiving placebo were excluded from the analysis. The ORAEs (MedDRA-coded events) of nausea, vomiting, sedation, dizziness, pruritus, and hypoxia, with at least one treatment-emergent AE, was used as the composite safety endpoint. The AEs of oliceridine and morphine, adjusted for therapeutic effectiveness (analgesia as measured by SPID is held constant across treatment groups) were compared by logistic regression.
In the logistic regression model, the presence of at least one treatment-emergent AE as mentioned above (the composite safety endpoint) was defined as “Yes”; and absence of the AE was designated as “No.” Analgesia was determined utilizing the SPID-48 (SPID from baseline over 48 h) for the bunionectomy (hard-tissue surgery) and SPID-24 (SPID from baseline over 24 h) for the abdominoplasty (soft-tissue surgery) studies. For patients who received rescue analgesics (etodolac 200 mg every 6 h [q6h] as needed), the pre-rescue pain score was used instead of the pain scores measured after rescue medication usage for 6 h. This imputation was utilized in the calculation of the SPID score.
The logistic regression model included the effects of treatment, baseline pain score, and SPID-48/SPID-24. This analysis was done for both individual studies as well as on the pooled data. Interaction terms were included to explore the consistency of the effect across treatment groups. For the individual studies, the composite safety endpoint was the dependent variable, with treatment, baseline pain score, SPID-48 or SPID-24, and the interaction terms of treatment by baseline pain score, treatment by SPID-48/SPID-24, and baseline pain score by SPID-48/SPID-24 as explanatory variables. For the pooled data, the logistic regression model included the same dependent variable (composite safety endpoint) and all of the explanatory variables as for the individual studies, with the addition of study indicator interactions into the model. Additional interaction terms utilizing the study indicator were added to explore the consistency of the effect across the two studies. For ease of interpretation, treatment groups were dichotomized since patients could achieve the same amount of oliceridine despite the demand dose regimen. In the model, oliceridine demand dose regimens of 0.1, 0.35, and 0.5 mg were pooled and set as “zero” and morphine treatment regimen was set to “one.” A backward elimination methodology was utilized across all analyses using the p ≤ 0.15 criteria for determining the final model.
For the individual studies, we also evaluated the effects of treatment when adjusted for equal levels of analgesia on the AEs of nausea, vomiting, sedation, dizziness, pruritus, and hypoxia.