PMID- 38183526 OWN - NLM STAT- MEDLINE DCOM- 20240222 LR - 20240223 IS - 1865-8652 (Electronic) IS - 0741-238X (Print) IS - 0741-238X (Linking) VI - 41 IP - 3 DP - 2024 Mar TI - Co-crystal of Tramadol-Celecoxib Versus Tramadol or Placebo for Acute Moderate-to-Severe Pain After Oral Surgery: Randomized, Double-Blind, Phase 3 Trial (STARDOM1). PG - 1025-1045 LID - 10.1007/s12325-023-02744-2 [doi] AB - INTRODUCTION: Co-crystal of tramadol-celecoxib (CTC) is the first analgesic co-crystal for acute pain. This completed phase 3 multicenter, double-blind trial assessed the efficacy and safety/tolerability of CTC in comparison with that of tramadol in the setting of moderate-to-severe pain up to 72 h after elective third molar extraction requiring bone removal. METHODS: Adults (n = 726) were assigned randomly to five groups (2:2:2:2:1): orally administered twice-daily CTC 100 mg (44 mg rac-tramadol hydrochloride/56 mg celecoxib; n = 164), 150 mg (66/84 mg; n = 160) or 200 mg (88/112 mg; n = 160); tramadol 100 mg four times daily (n = 159); or placebo four times daily (n = 83). Participants in CTC groups also received twice-daily placebo. The full analysis set included all participants who underwent randomization. The primary endpoint was the sum of pain intensity differences over 0 to 4 h (SPID(0-4); visual analog scale). Key secondary endpoints included 4-h 50% responder and rescue medication use rates. Safety endpoints included adverse events (AEs), laboratory measures, and Opioid-Related Symptom Distress Scale (OR-SDS) score. RESULTS: All CTC doses were superior to placebo (P < 0.001) for primary and key secondary endpoints. All were superior to tramadol for SPID(0-4) (analysis of covariance least squares mean differences [95% confidence interval]: - 37.1 [- 56.5, - 17.6], - 40.2 [- 59.7, - 20.6], and - 41.7 [- 61.2, - 22.2] for 100, 150, and 200 mg CTC, respectively; P < 0.001) and 4-h 50% responder rate. Four-hour 50% responder rates were 32.9% (CTC 100 mg), 33.8% (CTC 150 mg), 40.6% (CTC 200 mg), 20.1% (tramadol), and 7.2% (placebo). Rescue medication use was lower in the 100-mg (P = 0.013) and 200-mg (P = 0.003) CTC groups versus tramadol group. AE incidence and OR-SDS scores were highest for tramadol alone. CONCLUSIONS: CTC demonstrated superior pain relief compared with tramadol or placebo, as well as an improved benefit/risk profile versus tramadol. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02982161; EudraCT number, 2016-000592-24. CI - (c) 2024. The Author(s). FAU - Langford, Richard AU - Langford R AD - The London Clinic, London, W1G 6BW, UK. richard.langford@me.com. FAU - Pogatzki-Zahn, Esther M AU - Pogatzki-Zahn EM AD - University Hospital Munster, Munster, Germany. FAU - Morte, Adelaida AU - Morte A AD - ESTEVE Pharmaceuticals, Barcelona, Spain. FAU - Sust, Mariano AU - Sust M AD - ESTEVE Pharmaceuticals, Barcelona, Spain. FAU - Cebrecos, Jesus AU - Cebrecos J AD - ESTEVE Pharmaceuticals, Barcelona, Spain. FAU - Vaque, Anna AU - Vaque A AD - ESTEVE Pharmaceuticals, Barcelona, Spain. FAU - Ortiz, Esther AU - Ortiz E AD - ESTEVE Pharmaceuticals, Barcelona, Spain. FAU - Fettiplace, James AU - Fettiplace J AD - Mundipharma Research Limited, Cambridge, UK. FAU - Adeyemi, Shola AU - Adeyemi S AD - Mundipharma Research Limited, Cambridge, UK. FAU - Lopez-Cedrun, Jose Luis AU - Lopez-Cedrun JL AD - Complexo Hospitalario Universitario de A Coruna, A Coruna, Spain. FAU - Bescos, Socorro AU - Bescos S AD - Hospital Universitari Vall d'Hebron, Barcelona, Spain. FAU - Gascon, Neus AU - Gascon N AD - ESTEVE Pharmaceuticals, Barcelona, Spain. FAU - Plata-Salaman, Carlos AU - Plata-Salaman C AD - ESTEVE Pharmaceuticals, Barcelona, Spain. LA - eng SI - ClinicalTrials.gov/NCT02982161 PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial DEP - 20240106 PL - United States TA - Adv Ther JT - Advances in therapy JID - 8611864 RN - 39J1LGJ30J (Tramadol) RN - JCX84Q7J1L (Celecoxib) RN - 0 (Analgesics, Opioid) MH - Adult MH - Humans MH - *Tramadol/adverse effects MH - Celecoxib/therapeutic use/adverse effects MH - *Acute Pain/drug therapy MH - Analgesics, Opioid/adverse effects MH - Tooth Extraction/adverse effects MH - Double-Blind Method MH - Pain, Postoperative/drug therapy PMC - PMC10879371 OTO - NOTNLM OT - Acute pain OT - CTC OT - Celecoxib OT - Co-crystal OT - Efficacy OT - SPID0-4 OT - Tramadol COIS- Richard Langford has received fees from Pfizer, Eli Lilly, Compass, GSK, Avenue Therapeutics, MedinCell, Heron, Camurus, BioQ Pharma, Mundipharma, Grunenthal GmbH, Grunenthal Ltd and Syntetica for consultancy and speaker activities, and travel support from ESTEVE. Esther M. Pogatzki-Zahn received financial support for research activities, advisory board activities and lecture fees from Grunenthal, Medtronic, Mundipharma, and Novartis; she also receives scientific support from the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), the Federal Joint Committee (G-BA) and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 777500. This Joint Undertaking receives support from the European Union's Horizon 2020 Research and Innovation program and the European Federation of Pharmaceutical Industries and Associations. All money went to the institutions (WWU/UHM) where Esther M. Pogatzki-Zahn is employed. Adelaida Morte, Mariano Sust, Jesus Cebrecos, Anna Vaque, Esther Ortiz, and Neus Gascon are employees of ESTEVE Pharmaceuticals. Socorro Bescos's institution was paid commercial fees from Mundipharma Research GmbH & Co. KG for work on the study. Carlos Plata-Salaman was an employee of ESTEVE Pharmaceuticals and has pending or issued patents relevant to CTC. James Fettiplace and Shola Adeyemi were employees of Mundipharma Research Limited at the time of study. Jose Luis Lopez-Cedrun has nothing to disclose. EDAT- 2024/01/07 06:42 MHDA- 2024/02/22 06:43 PMCR- 2024/01/06 CRDT- 2024/01/06 11:09 PHST- 2023/10/16 00:00 [received] PHST- 2023/11/16 00:00 [accepted] PHST- 2024/02/22 06:43 [medline] PHST- 2024/01/07 06:42 [pubmed] PHST- 2024/01/06 11:09 [entrez] PHST- 2024/01/06 00:00 [pmc-release] AID - 10.1007/s12325-023-02744-2 [pii] AID - 2744 [pii] AID - 10.1007/s12325-023-02744-2 [doi] PST - ppublish SO - Adv Ther. 2024 Mar;41(3):1025-1045. doi: 10.1007/s12325-023-02744-2. Epub 2024 Jan 6.