Celecoxib‐tramadol co‐crystal in patients with moderate‐to‐severe pain following bunionectomy with osteotomy: A phase 3, randomized, double‐blind, factorial, active‐ and placebo‐controlled trial

BACKGROUND: Celecoxib‐tramadol co‐crystal (CTC) is a first‐in‐class analgesic co‐crystal of celecoxib and racemic tramadol with an improved pharmacologic profile, conferred by the co‐crystal structure, compared with its active constituents administered alone/concomitantly. AIM: We evaluated CTC in moderate‐to‐severe acute postoperative pain. MATERIALS AND METHODS: This randomized, double‐blind, factorial, active‐ and placebo‐controlled phase 3 trial (NCT03108482) was conducted at 6 US clinical research centers. Adults with moderate‐to‐severe acute pain following bunionectomy with osteotomy were randomized to oral CTC (200 mg [112 mg celecoxib/88 mg rac‐tramadol hydrochloride] every 12 h), tramadol (50 mg every 6 h), celecoxib (100 mg every 12 h), or placebo for 48 h. Patients, investigators, and personnel were blinded to assignment. The primary endpoint was the 0–48 h sum of pain intensity differences (SPID0–48) in all randomized patients. Pain intensity was assessed on a 0–10 numerical rating scale (NRS). Safety was analyzed in patients who received study medication. Funded by ESTEVE Pharmaceuticals. RESULTS: In 2017 (March to November), 1323 patients were screened and 637 randomized to CTC (n = 184), tramadol (n = 183), celecoxib (n = 181), or placebo (n = 89). Mean baseline NRS was 6.7 in all active groups. CTC had a significantly greater effect on SPID0–48 (least‐squares mean: −139.1 [95% confidence interval: −151.8, −126.5]) than tramadol (−109.1 [−121.7, −96.4]; p < 0.001), celecoxib (−103.7 [−116.4, −91.0]; p < 0.001), or placebo (−74.6 [−92.5, −56.6]; p < 0.001). Total treatment‐emergent adverse events (TEAEs) were 358 for CTC and 394 for tramadol. Drug‐related TEAEs occurred in 37.7% patients in the CTC group, compared with 48.6% in the tramadol group. There were no serious TEAEs/deaths. CONCLUSION: CTC provided greater analgesia than comparable daily doses of tramadol and celecoxib, with similar tolerability to tramadol. CTC is approved in the United States.