Efficacy and safety of co‐crystal of tramadol‐celecoxib (CTC) in acute moderate‐to‐severe pain after abdominal hysterectomy: A randomized, double‐blind, phase 3 trial (STARDOM2)

Abstract

Background: STARDOM2 is a randomized, double-blind, phase 3 trial evaluating the efficacy and safety of co-crystal of tramadol-celecoxib (CTC)-a firstin-class analgesic co-crystal comprising racemic tramadol hydrochloride and celecoxib in a supramolecular network that modifies their pharmacokinetic properties-for the management of acute postoperative pain (NCT03062644;EudraCT:2016-000593-38).Methods: Patients with moderate-to-severe pain following abdominal hysterectomy were randomized 2:2:2:2:2:1 to oral CTC 100 mg (rac-tramadol hydrochloride 44 mg/celecoxib 56 mg) twice daily (BID); CTC 150 mg (66/84 mg) BID; CTC 200 mg (88/112 mg) BID; immediate-release tramadol 100 mg four times daily (QID); celecoxib 100 mg BID; or placebo, for 5 days. The primary endpoint was the sum of pain intensity differences over 0-4 h (SPID 0-4 ). Key secondary endpoints were rescue medication use within 4 h, 50% response rate at 4 h, and safety/tolerability. Results: Of 1355 patients enrolled, 1138 were randomized (full analysis set) and 1136 treated (safety analysis set). In the prespecified gatekeeping analysis of SPID 0-4 , CTC 200 mg was not superior to tramadol but showed non-inferior efficacy (p < 0.001) that was sustained throughout the 120-h period, despite a 5-day cumulative tramadol administration of 880 mg with CTC 200 mg BID versus 2000 mg with tramadol 100 mg QID. Treatment-emergent adverse events (TEAEs) and severe TEAEs were less common with CTC 200 mg versus tramadol.Treatment-related TEAEs were 14.4% with CTC 200 mg and 23.6% with tramadol.Conclusions: Although the study did not meet its primary endpoint, CTC 200 mg showed a clinically relevant improvement in overall benefit/risk profile versus tramadol alone, with considerably lower cumulative opioid exposure.

Combination Drug Therapy for the Management of Chronic Neuropathic Pain

“…Phase I clinical studies confirmed that the co-crystal was associated with the expected improved pharmacokinetic profile relative to either of the individual formulations or their combination [150]. Subsequently, Phase II and III studies confirmed the significant improvement in the risk/benefit ratio observed with the co-crystal relative to either agent alone [151][152][153]. Seglentis ® is now approved for the treatment of acute pain in adults that is severe enough to require an opioid analgesic for which other treatments are inadequate [154].…”

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)

“…Although celecoxib monotherapy is not approved for use in acute pain in Europe, it is approved for this indication in other geographic regions. A recent phase 3 trial—of postoperative pain following abdominal hysterectomy—included both tramadol and celecoxib comparator arms and found CTC 200 mg to be noninferior, but not superior, to tramadol [ 29 ]. Another recent phase 3 trial of CTC 200 mg after bunionectomy with osteotomy [ 28 ] included a celecoxib comparator arm (100 mg BID) and demonstrated that CTC significantly improved efficacy over celecoxib, as well as over tramadol.…”

“…In a phase 3 trial of pain following bunionectomy with osteotomy, CTC was associated with greater pain relief than similar daily doses of tramadol or celecoxib, with comparable tolerability as tramadol [ 28 ]. CTC 200 mg was also found to be noninferior and to have an improved benefit/risk profile compared with tramadol in a phase 3 trial of pain following abdominal hysterectomy [ 29 ]. CTC was approved by the US Food and Drug Administration in 2021 [ 30 ], and received its first European regulatory approval (in Spain) in September 2023 [ 31 ].…”

Abdominal hysterectomy and postoperative quality of recovery: emphasis on pain relief

“…Інтенсивність болю після гістеректомії була нижчою в разі комбінованого використання трамадолу із целекоксибом, ніж трамадолу окремо [21]. Додавання налбуфіну як допоміжного препарату для інтратекального введення до бупівакаїну при проведенні нейроаксіальної анестезії покращувало якість і тривалість сенсорної блокади та подовжувало післяопераційну аналгезію.…”