Phase 3 Study of the Efficacy and Safety of Meloxicam IV in Subjects with Moderate to Severe Pain following Bunionectomy
Richard Pollak, DPM1; Ira J. Gottlieb, DPM2; Fardin Hakakian, DPM3; John Zimmerman, DPM4; Stewart McCallum, MD5; Randall Mack5; Alex Freyer, PharmD5; Wei Du, PhD6
1Endeavor Clinical Trials, San Antonio, TX, USA; 2Chesapeake Research Group, Pasadena, MD, USA; 3Lotus Clinical Research, Pasadena, CA, USA; 4Trovare Clinical Research, Bakersfield, CA, USA; 5Recro Pharma, Inc., Malvern, PA, USA; 6Clinical 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 IV has been evaluated across a range of dose levels and patient populations during Phase 2 clinical studies. The meloxicam IV Phase 3 program included 2 randomized, placebo-controlled efficacy studies in subjects with moderate to severe pain following hard and soft tissue surgeries, as well as a large placebo controlled safety study in subjects undergoing various major surgeries. The reported Phase 3 study was designed to evaluate the efficacy and safety of once daily dosing with meloxicam IV 30 mg in an adequate and well controlled trial in an established hard tissue surgical model of moderate to severe pain.
The primary objective of this study was to demonstrate the analgesic efficacy of meloxicam IV compared with placebo, using the summed pain intensity difference over the first 48 hours (SPID48) in subjects with moderate to severe pain following unilateral bunionectomy.
Secondary objectives of this study included:
•Evaluating the analgesic effects of meloxicam IV versus placebo at various time points using a series of secondary efficacy endpoints for pain intensity, pain relief, and use of rescue medication
•Determine the safety and tolerability of meloxicam IV as evaluated with physical examination, vital signs, clinical laboratory tests, ECGs, wound evaluation, 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:
•Healthy males and females aged 18 to 75 years.
•Underwent primary unilateral first metatarsal bunionectomy repair, without collateral procedures.
•Moderate to severe pain within 9 hours of popliteal block discontinuation on Postoperative Day 1, with a numeric pain rating scale (NPRS) score ≥ 4 out of 10.
Selected exclusion criteria:
•Active or recent gastrointestinal (GI) bleeding or peptic ulcer disease.
•Known bleeding disorder or taking agents affecting coagulation.
•Taking or had taken an opioid chronically (more than one month of routine use) for pain in the past year
•Major surgery within previous 3 months or another painful condition that could interfere with pain assessments
•Multi-center, randomized, double-blind, placebo controlled study at 4 US sites
•Participation consisted of a screening visit, surgery and inpatient evaluation, and 2 follow-up visits.
•Following bunionectomy, subjects were maintained using a popliteal block and other analgesics until Postoperative Day 1, when subjects were eligible to randomize to treatment
•Randomized 1:1 to meloxicam IV 30 mg or placebo
•Study doses were administered every 24 hours for up to 3 doses.
Efficacy and safety analyses were performed using the Intent-to-Treat (ITT) analysis set, which included all treated subjects. Analysis of covariance (ANCOVA) was used to assess the difference between treatment groups for SPID, including main effects of treatment and investigational site and a covariate of baseline pain intensity score.
•The study enrolled 201 subjects, all enrolled subjects were randomized and treated with study drug, and were included in the safety and efficacy analyses.
Primary Efficacy Endpoint - SPID48
•Statistically significant difference in SPID48 favoring meloxicam IV 30 mg over placebo (p=0.0034).
SPID At Other Intervals
•SPID assessed at other postdose intervals (SPID6, SPID12, SPID24, and SPID24-48) were statistically significant favoring meloxicam IV 30 mg over placebo at all intervals (p<0.05).
Rescue Analgesia Use
•Rescue analgesia (oxycodone 5 mg PO) was available for inadequately controlled pain during the treatment phase
•Time to first rescue use was significantly longer in meloxicam IV 30 mg subjects compared with placebo (p=0.0076).
•The number of subjects utilizing rescue was significantly lower for meloxicam IV 30 mg compared with placebo (p<0.001)
•The number of rescue doses per subject was significantly lower for meloxicam IV 30 mg compared with placebo (p<0.05).
•Doses of meloxicam IV 30 mg were well tolerated, with the majority of subjects receiving 3 study doses (73%).
•AEs of special interest (including hepatic, renal, cardiovascular, bleeding, wound healing, and injection site events) were infrequent, with a greater incidence overall in the placebo group.
•There was no apparent trend in clinically meaningful abnormal laboratory results between treatment groups.
•No trends for changes in vital signs or ECGs were observed.
Wound Healing Assessment
•Surgical wounds were assessed for investigator satisfaction rated using a 0-10 scale (0=completely unsatisfied; 10=completely satisfied), along with assessing various characteristics including erythema, drainage, edema, induration, and hematoma.
•Overall satisfaction assessments were similar between meloxicam IV 30 mg and placebo at Hour 48, 7 days post last study dose, and at 28 days post last study dose.
•Clinically significant wound assessment parameters were more common in the placebo group versus meloxicam IV 30 mg.
•Meloxicam IV 30 mg administered as an IV push once daily, was well tolerated with no SAEs, and a low incidence of AEs and infusion events.
•Dosing with meloxicam IV 30 mg was demonstrated to provide a significant reduction in pain, as evidenced by SPID48 results, and the reduction in opioid rescue use.
•Once daily dosing with meloxicam IV maintained analgesia over the 24-hour dosing interval
•The study supported the efficacy and safety of meloxicam IV 30 mg administered IV once daily in subjects with moderate to severe pain following bunionectomy surgery.