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Clinical Trial
. 2023 Jan;23(1):8-22.
doi: 10.1111/papr.13136. Epub 2022 Jul 8.

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

Eugene R Viscusi  1 , Oscar de Leon-Casasola  2 , Jesús Cebrecos  3 , Adam Jacobs  4 , Adelaida Morte  3 , Esther Ortiz  3 , Mariano Sust  3 , Anna Vaqué  3 , Ira Gottlieb  5 , Stephen Daniels  6 , Joseph S Gimbel  7 , Derek Muse  8 , Peter Winkle  9 , Michael E Kuss  10 , Sebastián Videla  3 , Neus Gascón  3 , Carlos Plata-Salamán  3
Affiliations
Clinical Trial

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

Eugene R Viscusi et al. Pain Pract. 2023 Jan.

Erratum in

  • Corrigendum.
    Viscusi ER. Viscusi ER. Pain Pract. 2024 Sep;24(7):969-970. doi: 10.1111/papr.13376. Epub 2024 Apr 21. Pain Pract. 2024. PMID: 38644630 Free PMC article. No abstract available.

Abstract

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.

Keywords: acute pain; analgesia; celecoxib; co-crystal; efficacy; pain; postoperative; postoperative pain; safety; tramadol.

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Conflict of interest statement

This study was supported by ESTEVE Pharmaceuticals S.A. E.R. Viscusi reports consulting fees for ESTEVE Pharmaceuticals, Fresenius, Heron Therapeutics, Innocoll Pharmaceuticals, Merck, and Salix Pharmaceuticals. O. de Leon‐Casasola reports personal fees for advisory board membership for ESTEVE Pharmaceuticals during the conduct of the study, and for ESTEVE Pharmaceuticals, Stimgenix, and Medtronic outside the submitted work. J. Cebrecos, A. Morte, E. Ortiz, M. Sust, A. Vaqué, and N. Gascón are employees of ESTEVE Pharmaceuticals. A. Jacobs is an employee of Premier Research (Premier Research was paid commercial fees by ESTEVE Pharmaceuticals for work on the study). I. Gottlieb reports grants for ESTEVE Pharmaceuticals for participation as a principal investigator in the current study and personal fees for ESTEVE Pharmaceuticals for consulting projects. S. Daniels is an employee of Optimal Research (Optimal Research was paid commercial fees by ESTEVE Pharmaceuticals for work on the study). M.E. Kuss was an employee of Premier Research during the conduct of the study. S. Videla was an employee of ESTEVE Pharmaceuticals during the conduct of the study. C. Plata‐Salamán was an employee of ESTEVE Pharmaceuticals and has pending or issued patents relevant to CTC. The remaining authors have no conflicts of interest to declare.

Figures

FIGURE 1
FIGURE 1
Patient disposition. CTC, celecoxib‐tramadol co‐crystal; q6h, every 6 h; q12h, every 12 h
FIGURE 2
FIGURE 2
(A) Mean pain intensity (NRS score) over time. (B) Mean change from baseline in pain intensity (NRS score) over time. (C) Sum of pain intensity differences (SPID) by time point. Full analysis set; data are adjusted for rescue medication. Analyzed using analysis of covariance, adjusting for center and baseline pain intensity. Asterisk (*) denotes p < 0.05 versus CTC. CTC, celecoxib‐tramadol co‐crystal; NRS, numerical rating scale
FIGURE 3
FIGURE 3
Onset of analgesia (time to onset and proportion of patients). Full analysis set. Time to onset of analgesia was defined as the time to perceptible pain relief by stopwatch assessment, if confirmed by meaningful pain relief by stopwatch assessment within 8 h. CTC, celecoxib‐tramadol co‐crystal; NR, not reached
FIGURE 4
FIGURE 4
Use of oxycodone rescue medication (time to first use and proportion of patients). Odds ratio for oxycodone rescue medication use at 48 h for CTC versus tramadol: 0.581 (95% confidence interval: 0.378, 0.891; p = 0.01). Logistic regression adjusted for center and baseline pain. CTC, celecoxib‐tramadol co‐crystal; NR, not reached
See this image and copyright information in PMC

References

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