A Phase IV Randomized Trial of Maxigesic® Versus Standard Analgesia After Radical Gastrectomy

Официальное название

A Phase IV, Multicenter, Double-blind, Randomized Controlled Trial to Evaluate the Superiority of Maxigesic® Over Standard Analgesia in Patients Undergoing Radical Gastrectomy

Обзор

Background: Radical gastrectomy causes moderate-to-severe pain during the first 48 hours after surgery. Opioids are effective but carry adverse effects and risks of prolonged use, so ERAS-based care recommends multimodal analgesia. Acetaminophen is the most commonly used non-opioid analgesic in gastrectomy patients; adding ibuprofen as a fixed-dose combination has shown improved analgesia and opioid-sparing effects compared with acetaminophen alone in other surgical populations, but direct evidence in gastrectomy patients is limited. Objective: To evaluate whether scheduled administration of an acetaminophen-ibuprofen fixed-dose combination (Maxigesic® IV) is superior to acetaminophen alone for pain relief after radical gastrectomy, with exploratory assessment of cost-effectiveness and of differences in analgesic efficacy according to genetic polymorphisms. Hypothesis: When given on an identical scheduled regimen, the acetaminophen-ibuprofen fixed-dose combination produces significantly lower pain scores (NRS) over the first 48 postoperative hours than acetaminophen alone (superiority). Study plan: This is a phase IV, multicenter, double-blind, randomized controlled trial in which 160 gastric cancer patients scheduled for minimally invasive radical gastrectomy (80 per arm) are randomized 1:1 with stratification by institution. In both arms, the assigned drug is given as a 15-minute intravenous infusion every 6 hours, starting 30 minutes before the end of surgery through 48 hours postoperatively. The primary endpoint is the between-group difference in the time-weighted average (TWA) of repeatedly measured resting and active NRS over 48 hours, analyzed using a mixed model for repeated measures (MMRM); secondary endpoints include opioid consumption (MME), the Quality of Recovery score (QoR-15K), the incidence of chronic postsurgical pain (CPSP), and in-hospital costs.

Подробное описание

This is a phase IV, multicenter, double-blind, randomized controlled trial conducted at four Yonsei University-affiliated hospitals in the Republic of Korea (Severance, Gangnam Severance, Wonju Severance, and Yongin Severance Hospitals). A total of 160 patients with gastric cancer scheduled for minimally invasive (laparoscopic or robotic) radical gastrectomy are randomized 1:1 to the experimental arm (acetaminophen-ibuprofen fixed-dose combination, Maxigesic IV) or the active comparator arm (acetaminophen alone, Newaminophen Premix). Randomization uses a stratified block design with the participating institution as the stratification factor, and allocation is concealed through a web-based system using a sequence generated by an independent statistician.

To maintain double blinding, study drugs are prepared by an unblinded research pharmacist in a separate area and dispensed in containers masked with opaque labels, so that participants, care providers, and outcome assessors remain unaware of the allocation.

In both arms, the assigned study drug is administered as a 15-minute intravenous infusion every 6 hours, beginning 30 minutes before the end of surgery and continuing through 48 hours after surgery (9 doses in total), with the total daily acetaminophen dose not exceeding 4 g. For breakthrough pain, a standardized stepwise rescue protocol (tramadol followed by pethidine) is applied without altering the scheduled study-drug regimen, and fever requiring an antipyretic is managed with ibuprofen. The two arms are identical except for the addition of ibuprofen in the experimental arm.

Pain intensity is assessed using the 11-point Numerical Rating Scale at rest and on movement at predefined time points over the first 72 hours after surgery. Additional assessments include opioid consumption (morphine milligram equivalents), the Korean Quality of Recovery score (QoR-15K), in-hospital costs, and chronic postsurgical pain at 3 months measured with the Brief Pain Inventory-Korean (BPI-K). Safety is evaluated by postoperative complications (Clavien-Dindo classification), adverse drug reactions, and liver enzyme elevation.

As exploratory analyses, an economic evaluation and a pharmacogenomic analysis are performed. No biospecimen is collected in this study. The pharmacogenomic analysis is conducted only in the subset of participants who are also enrolled in the National Bio Big Data Project, a separate national genomic study; for these participants, whole-genome sequencing data generated by that project are used-under that project's own consent and governance framework-to explore whether genetic polymorphisms are associated with differences in analgesic efficacy.

The primary efficacy analysis is performed in the full analysis set, with the per-protocol set used for sensitivity analysis. The treatment effect on the primary outcome is evaluated as the between-group difference in the time-weighted average of NRS over 0-48 hours, estimated using a mixed model for repeated measures, with a covariate-adjusted linear mixed model as a supportive analysis. A Data Safety Monitoring Board reviews safety and data validity, and an interim analysis for safety and futility is conducted when 50% of the target participants have completed 72-hour follow-up. A two-sided significance level of 0.05 is applied.

Вмешательства

• Препарат Acetaminophen (Newaminophen Premix)
  As an active comparator, Newaminophen Premix 100 mL will be administered by 15-minute intravenous infusion every 6 hours during the first 48 hours after surgery.
• Препарат Maxigesic IV (acetaminophen/ibuprofen)
  Maxigesic 100 mL will be administered as a 15-minute intravenous infusion every 6 hours for the first 48 hours after surgery

Первичные конечные точки

• Postoperative pain intensity (NRS) [Срок оценки: At rest - 0 (immediately postoperatively), 2, 4, 6, 12, 18, 24, 30, 36, 42, and 48 hours after surgery; on movement - 6, 12, 18, 24, 30, 36, 42, and 48 hours after surgery]

Вторичные конечные точки (5)

• Total opioid consumption [Срок оценки: From the day of operation (day 0) to 72 hours after surgery]
• Change in Quality of Recovery (QoR-15K) [Срок оценки: Preoperative, 24 hours aftery surgery, 48 hours after surgery, 72 hours after surgery]
• Incidence of chronic postsurgical pain (CPSP) [Срок оценки: At 3 months after surgery (±14 days)]
• (exploratory analysis) In-hospital cost [Срок оценки: Through discharge, an average of 5 days]
• (exploratory analysis) Difference in analgesic efficacy according to genetic polymorphisms [Срок оценки: Genetic polymorphism assessed preoperatively. NRS scores measured through 72 hours after surgery.]

Критерии участия

Критерии включения

• Patients aged 20 to 80 years diagnosed with gastric cancer by endoscopic biopsy who are scheduled for minimally invasive radical gastrectomy (laparoscopic or robotic)
• Patients scheduled for distal, proximal, or total gastrectomy among minimally invasive procedures (wedge resection, pylorus-preserving gastrectomy, and segmental gastrectomy are not eligible)
• Patients with an ECOG performance status of 0 or 1 and an ASA classification of I-III
• Patients who have voluntarily agreed to participate after receiving a full explanation of the study's purpose and content, and who have signed the written informed consent form approved by the Institutional Review Board
• Patients residing in Korea who are able to complete follow-up for 3 months after surgery

Критерии исключения

• Patients with a reported history of hypersensitivity, allergy, or adverse reaction to NSAIDs, opioids, or acetaminophen
• Patients currently taking medications that may affect the study results, such as opioid or non-opioid analgesics, aspirin, warfarin or other anticoagulants, steroids, or high-dose hepatotoxic drugs
• Pregnant or breastfeeding patients
• Patients with a contraindication to NSAIDs or acetaminophen identified from medical history or preoperative evaluation-for example, active liver disease, heart failure, chronic kidney disease, thrombocytopenia, or a history of asthma (peptic ulcer disease is not an exclusion criterion)
• Patients unable to read or understand the informed consent form
• Patients weighing less than 45 kg
• Patients scheduled for transfer to the intensive care unit instead of a general ward after surgery (ICU preparation)
• Patients scheduled for emergency surgery

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT07687394 · 4-2026-0528

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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