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A Phase 3, Placebo-Controlled Study of Meloxicam IV Following Major Surgery: Safety and Opioid Use in Subjects of Advanced Age with Impaired Renal Function
Session: MP-01b
Thurs, April 19, 8-9:45 am
Uris (Shubert Complex), 6th floor

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A Phase 3, Placebo-Controlled Study of Meloxicam IV Following Major Surgery: Safety and Opioid Use in Subjects of Advanced Age with Impaired Renal Function

Timothy I. Melson, MD1; David Boyer, MD2; Randall J. Mack3; Stewart McCallum, MD3; Alexis Gomez3; Alex Freyer, PharmD3; Wei Du, PhD4

1Shoals Medical Trials, Inc. Sheffield, AL, USA; 2Shoals Clinical Research Associates, Florence, AL, USA; 3Recro Pharma, Inc., Malvern, PA, USA; 4Clinical Statistics Consulting, Blue Bell, PA, USA.

 

INTRODUCTION

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 and Phase 3 clinical studies.  The Phase 3 program included a large, multi-center, placebo-controlled, safety study that enrolled subjects undergoing major surgeries.  This abstract reports the findings for subjects of advanced age (>65 years) with impaired renal function from this safety study, to evaluate the safety of meloxicam IV in a population with potential for increased risk of complications and toxicities associated with NSAID use.

 

OBJECTIVE

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).

 

METHODS

Subjects

Selected inclusion criteria:

•Males and females aged 18 to 80 years (overall); only subjects aged > 65 years were included in the presented study population.
•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.
•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 enrolled a cohort of subjects age >65 years with impaired renal function (GFR <89 mL/min/1.73 m2) which is the focus of this poster.

Study Design

•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.
 
 
RESULTS

Demographics

•119 subjects meeting age and renal function criteria were randomized and dosed; 721 subjects were randomized and dosed overall in the study.
•The majority of subjects received 2 or 3 study doses during their participation in the study; 78.4% in meloxicam IV 30 mg group, 93.5% in placebo group.
 

Safety

•Doses of meloxicam IV 30 mg were well tolerated during the study, with the majority of 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 in the meloxicam IV group compared with placebo.

Adverse Events

 •Low incidence of renal system related AEs

•SAEs were all reported as single incidence events in individual subjects with exception of post procedural pulmonary embolism in 2 (2.3%) meloxicam IV treated subjects; both events were assessed by the investigator as being moderate in intensity and 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.

 
 
CONCLUSIONS
•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 in subjects aged > 65 years with impaired renal function.
 
REFERENCES
•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.
 
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