A Phase 3, Placebo-Controlled Study of Meloxicam IV Following Major Surgery: Safety and Opioid Use in the Overall Population
Sergio D. Bergese, MD1, Stephen F. Richardson, MD2, Randall J. Mack3, Stewart McCallum, MD3, Alexis Gomez3, Alex Freyer, PharmD3, Wei Du, PhD4
1The Ohio State University, Wexner Medical Center, Columbus, OH, USA; 2Jean Brown Research, Salt Lake City, UT, USA; 3Recro Pharma, Inc., Malvern, PA, USA; 4Clinical Statistics Consulting, Blue Bell, PA, USA.
Intravenous (IV) meloxicam (Meloxicam IV) is a novel formulation of NanoCrystal Colloidal Dispersion® meloxicam, being developed for the management of moderate to severe pain. Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) of the enolic acid class that possesses analgesic, anti-inflammatory, and antipyretic activities, which are believed to be related to the inhibition of cyclooxygenase (COX) and subsequent reduction in prostaglandin biosynthesis (Mobic 2016; Turck 1997; Del Tacca 2002). Oral meloxicam has a slow onset of action, largely due to poor solubility, and is not approved for the treatment of acute pain. The use of proprietary NanoCrystal technology has been shown to provide a rapid onset of action of meloxicam, thus rendering it suitable for the treatment of acute pain via the IV route, as an alternative to, or reducing the requirements for, opioid analgesics.
Meloxicam IV has been evaluated across a range of dose levels and patient populations during Phase 2 clinical studies, as well as completing Phase 3 efficacy studies in hard and soft tissue surgical populations. The Phase 3 program included a large, multi-center, placebo-controlled, safety study that enrolled subjects undergoing major surgeries who received study drug once daily for up to 7 days, which is reported here.
The primary objective of this study was to evaluate the safety and tolerability of meloxicam IV as evaluated with physical examination, vital signs, clinical laboratory tests, ECGs, wound evaluation, postoperative opioid consumption, and incidence of Adverse Events (AEs) and Serious AEs (SAEs).
This study was conducted under an FDA IND, IRB approval was obtained prior to study conduct, and all subjects provided written informed consent.
Selected inclusion criteria:
•Males and females aged 18 to 80 years.
•Planning to undergo major elective surgery with a postoperative inpatient course expected to exceed 24 hours.
Selected exclusion criteria:
•Active or recent gastrointestinal (GI) bleeding or peptic ulcer disease.
•Known bleeding disorder or taking agents affecting coagulation.
•Admission to the ICU following surgery
•Exclusionary surgical procedures included: cranial surgery, open heart procedures, coronary artery bypass graft, organ transplant, or any other surgical procedure in which NSAIDs were contraindicated.
•Moderate to severe renal or hepatic dysfunction.
The study sought to enroll a cohort of subjects of advanced age (age >65 years) with mild renal impairment (GFR 60-89 mL/min/1.73 m2).
•Multi-center, randomized, double-blind, placebo-controlled study.
•Participation consisted of a screening visit, a surgery and inpatient treatment/evaluation visit, and 2 follow-up visits, 7 days (in clinic) and 28 days (telephone contact) after the last study dose.
•Subjects were randomized 3:1 to meloxicam IV 30 mg or placebo, and dosed with study drug within 6 hours following the end of surgery.
•Study doses were administered every 24 hours for a maximum of 7 study doses.
•Subjects received peri- and postoperative analgesia per institution standards; additional NSAIDs were not allowed.
•Subjects received anticoagulation therapy per institution standards.
•722 subjects randomized (ITT population) with 721 subjects receiving ≥ 1 dose of study drug.
•The majority of subjects received 2 or 3 study doses during their participation in the study; 89.6% in meloxicam IV 30 mg group, 90.7% in placebo group.
•Doses of meloxicam IV 30 mg were well tolerated during the study, with most subjects receiving 2 or 3 study doses.
•The incidence and severity of AEs were generally similar between groups.
•No trends for changes in wound healing assessments, clinical laboratory testing, vital signs, or ECGs were observed.
•Statistically significant reductions in postoperative opioid use were observed with meloxicam IV compared to placebo.
SAEs were all reported as single incidence events in individual subjects with exception of post procedural pulmonary embolism in 3 (0.6%) meloxicam IV treated subjects, small intestinal obstruction in 2 (0.4%) meloxicam IV subjects, and acute kidney injury in 2 (0.4%) meloxicam IV subjects. These events of post procedural pulmonary embolism, small intestinal obstruction, and acute kidney injury observed in meloxicam IV treated subjects were all assessed as being moderate in intensity except one severe event (1 event of post procedural pulmonary embolism). All SAEs were assessed by the investigator as being not related to study treatment.
Wound Healing Assessment
•Surgical wounds were assessed for investigator satisfaction with healing on a 0-10 scale (0=completely unsatisfied; 10=completely satisfied), along with assessing characteristics of erythema, drainage, edema, induration, and hematoma.
•Overall satisfaction assessments were similar between meloxicam IV 30 mg and placebo at each assessment
The incidence of clinically significant wound assessment parameters was low and generally similar between treatments
Postoperative Opioid Use
•Opioid consumption was reduced in the meloxicam IV 30 mg group compared with placebo, with statistically significant (p<0.05) reductions in opioid use observed for meloxicam IV 30 mg compared with placebo over multiple intervals.]
•AEs were mild or moderate in intensity, and similar in incidence between treatment groups.
•There was a low incidence of SAEs, with events reported more frequently in the placebo group overall.
•Wound healing assessments were similar between treatment groups.
•A statistically significant reduction in total opioid use was observed at various intervals during treatment in the meloxicam IV group compared with placebo.
•This study supports the safety and tolerability of meloxicam IV 30 mg administered once daily as an IV bolus for up to 7 days following major surgery
•Del Tacca M, Colucci R, Fornai M, Blandizzi C. Efficacy and tolerability of meloxicam, a COX‑2 preferential nonsteroidal anti-inflammatory drug. Clin Drug Invest. 2002;22(12):799-818.
•Mobic [package insert] Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2016.
•Turck D, Busch U, Heinzel G, Narjes H. Clinical pharmacokinetics of meloxicam. Arzneim-Forsch/Drug Res. 1997;47(1):253-258.