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.