A Summary of Safety, Efficacy, and Dose Ranging in Phase 2 Clinical Studies of Meloxicam IV
Stewart McCallum, MD1; Randall Mack1; Sue Hobson1; Alex Freyer, PharmD1; Wei Du, PhD2
1Recro Pharma, Inc., Malvern, PA, USA; 2Clinical 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). 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 adult subject populations in four Phase 2 clinical studies. Meloxicam IV dose levels in clinical studies ranged from 5 to 60 mg in subject populations including dental extraction, abdominal hysterectomy, laparoscopic abdominal surgeries, and bunionectomy.
The cumulative objective of the meloxicam IV Phase 2 program was to evaluate the safety and efficacy of multiple dose levels, in order to identify the most appropriate dose(s) for advancement into Phase 3 studies.
Specific enrollment criteria varied between studies, but general criteria were similar across studies
•Healthy adult male and females subjects
•Planned to undergo designated surgical procedure (dental extraction, hysterectomy, abdominal surgery, or bunionectomy)
•Experiencing moderate to severe pain following surgical procedure
•Other painful condition or medication that might interfere with pain assessments
•Known bleeding disorder or taking agents affecting coagulation.
•Specific details of study design varied, but general subject flow was similar across studies with subjects undergoing a screening visit, an inpatient visit including study procedure and treatment, and follow-up visit(s) after discharge
•During the inpatient phase, subjects underwent the study specific procedure, after which those who achieved moderate to severe pain were randomized to treatment and received one or more study doses while undergoing pre- and post-dose efficacy and safety assessments.
Key demographics in each study were as follows:
•Study 02 consisted primarily of young (mean age 19.5-20.4 years), white, females.
•Study 04 included only female subjects, primarily white, with mean ages ranging from 46.9-48.0 years.
•Study 05 consisted primarily of white males with mean ages ranging from 38.5-44.6 years.
•Study 14 consisted primarily of black or African American females with a mean age of 47.2 years.
Individual efficacy measures and methods varied between studies.
Across studies, the primary efficacy endpoint was the summed pain intensity difference (SPID) from first dose through 24 or 48 hours. Secondary endpoints included SPID at other intervals, and measures of pain relief and rescue analgesia use.
•All evaluated doses of meloxicam IV (5-60 mg) produced significant reductions in SPID compared with placebo.
•Meloxicam IV 30 and 60 mg demonstrated significant improvement in SPID vs. active control in Study 02 and 04.
•An apparent dose related increase in SPID effect was seen with meloxicam IV up to the 30 mg dose level, the 60 mg dose level produced a grater result in Study 02, but not in Study 04 or Study 14.
•Significant improvement in SPID results were observed at all other evaluated intervals, beginning as early as SPID1 in Study 04, SPID2 in Study 02 and SPID6 in Study 14 (p<0.05)
Rescue Analgesia Use
•Opioid rescue analgesia was available in all studies for inadequately controlled pain.
•In Study 02 and 04, increasing doses of meloxicam IV generally resulted in a decreasing percentage of subjects utilizing rescue analgesia.
•In Study 04, the time to first rescue analgesia use was also observed to increase with increasing meloxicam IV dose levels.
•In Study 14 a significantly longer time to first rescue was observed in the 60 mg meloxicam IV group compared to placebo, no significant difference was observed at the 30 mg dose level; there was not a significant difference in the percentage of subjects utilizing rescue, and the time to first rescue
Adverse Events (AEs)
•Dosing with meloxicam IV was generally well tolerated across dose levels and study populations.
•Adverse events were generally similar between treatment groups, and no dose related increases in the incidence or severity of events was observed.
Administration of meloxicam IV was well tolerated across dose levels with a low incidence of injection site events.
•Investigator assessments of surgical wound healing were performed in Study 04, 05, and 14
•Wound healing was assessed as being normal or per investigator expectation in the majority of subjects; there was a low incidence of wound healing related AEs that was similar across treatment groups.
•Evaluation of meloxicam IV in Phase 2 clinical studies demonstrated a wide range of well tolerated doses (5-60 mg).
•Study results generally supported a dose related increase in analgesic effect; however, significant differences between 30 and 60 mg dose levels were not consistently observed.
•In review of the Phase 2 data in totality, the meloxicam IV 30 mg dose level administered once daily was selected for advancement to Phase 3 evaluation.
•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.