Carbetocin Monotherapy Versus Carbetocin Plus Oxytocin Infusion in Elective Cesarean Delivery: A Non-Inferiority Trial

Официальное название

Comparative Efficacy of Carbetocin Monotherapy Versus Carbetocin With Supplemental Oxytocin Infusion in Maintaining Uterine Tone and Preventing Blood Loss in Elective Cesarean Delivery: A Randomized, Double-Blind, Non-Inferiority Controlled Trial

Обзор

Background: Carbetocin is an established single-dose uterotonic agent for postpartum hemorrhage prophylaxis at elective cesarean delivery. Despite its proven efficacy, many clinicians routinely add a supplemental oxytocin infusion following carbetocin administration without evidence-based justification. Concurrent oxytocin receptor stimulation may be redundant, counterproductive through receptor desensitization, or incrementally beneficial - a mechanistic uncertainty that remains unresolved in the published literature. Objectives: To determine whether carbetocin monotherapy (100 micrograms IV bolus plus placebo infusion) is non-inferior to carbetocin plus supplemental oxytocin infusion (10 IU over 4 hours) in preventing the need for additional uterotonic agents within 24 hours of elective cesarean delivery. Study Design: Prospective, randomized, double-blind, placebo-controlled, non-inferiority trial with an integrated pilot phase. Phase 1 (Pilot, n=60) establishes local feasibility and event rate. Phase 2 (Full trial, n=332) provides the definitive non-inferiority analysis. Participants: Women aged 18-45 years undergoing elective cesarean delivery under spinal anesthesia at Qassim University Medical City, singleton pregnancy at or beyond 37 weeks, ASA physical status II, preoperative hemoglobin 9 g/dL or more. Interventions: Group C (Monotherapy): Carbetocin 100 micrograms IV bolus plus placebo saline infusion 500 mL over 4 hours. Group C+O (Combination): Carbetocin 100 micrograms IV bolus plus oxytocin 10 IU in 500 mL saline over 4 hours. Primary Outcome: Proportion of patients requiring at least one additional uterotonic agent within 24 hours of delivery. Secondary Outcomes: Quantitative intraoperative blood loss by gravimetric measurement; total 24-hour blood loss; actual blood loss by Gross formula; hemoglobin and hematocrit changes; uterine tone scores by verbal numerical rating scale (0-10) at 2, 5, and 10 minutes; incidence of postpartum hemorrhage; blood transfusion requirement; hemodynamic profiles; adverse effects. Sample Size: 332 patients (166 per group), non-inferiority margin 10 percentage points, one-sided alpha 0.025, 80% power, estimated baseline event rate 10%, with 15% dropout allowance.

Подробное описание

PHARMACOLOGICAL RATIONALE:

Carbetocin exerts its uterotonic effect through sustained occupancy of myometrial oxytocin receptors (OTRs). Continuous stimulation of OTRs triggers homologous receptor desensitization, progressively reducing myometrial responsiveness. The addition of an oxytocin infusion following carbetocin raises three competing hypotheses: (1) incremental benefit from residual unoccupied receptors; (2) receptor counterproductivity through accelerated downregulation; or (3) pharmacological redundancy. No published RCT has resolved this uncertainty.

TRIAL DESIGN:

The trial uses a non-inferiority design because the combination regimen is already practiced without evidence. Demonstrating non-inferiority of monotherapy would provide the first evidence to safely simplify uterotonic regimens, reduce drug costs, nursing workload, and unnecessary receptor stimulation.

BLOOD LOSS MEASUREMENT:

Intraoperative blood loss measured by gravimetric quantification: \[Weight soaked materials minus Weight dry materials\] divided by 1.05, plus suction canister volume, minus irrigation volume, minus amniotic fluid volume. Secondary measurement uses the Gross formula: ABL = EBV x (Hb preoperative minus Hb postoperative) divided by Hb preoperative, where EBV = body weight (kg) x 85 mL/kg.

UTERINE TONE ASSESSMENT:

Assessed using the 11-point Verbal Numerical Rating Scale (VNRS 0-10) with predefined anchor definitions, by the blinded operating obstetrician via bimanual palpation at 2, 5, and 10 minutes following carbetocin bolus. Pre-study inter-rater calibration session with intraclass correlation coefficient target of 0.80 or more.

STANDARDIZED FLUID PROTOCOL:

All patients receive a standardized intravenous fluid protocol to eliminate hemodilution as a confounding variable: spinal coload Ringer's Lactate 500 mL; intraoperative maintenance 100 mL/hour; study infusion 500 mL over 4 hours identical in both groups; postoperative Ringer's Lactate 80 mL/hour for 8 hours. Total 24-hour fluid volume recorded as a statistical covariate.

STATISTICAL ANALYSIS:

Non-inferiority declared if the upper bound of the two-sided 95% confidence interval of the risk difference does not exceed +0.10. Both per-protocol and intention-to-treat analyses performed; concordance of both required per ICH E9(R1). IRB approval: Subcommittee of Health and Bioethics Research Ethics, Qassim University, Approval No. 26-23-4, dated June 02, 2026.

Вмешательства

• Препарат Carbetocin
  Carbetocin 100 micrograms (1 mL) IV bolus administered over 1 minute immediately after umbilical cord clamping. Identical administration in both arms.
• Препарат Oxytocin
  Oxytocin 10 IU added to 500 mL 0.9% sodium chloride, infused at 83 mL/hour over 4 hours, initiated within 2 minutes of carbetocin bolus. Administered in the combination arm only.
• Препарат Placebo Saline Infusion
  500 mL 0.9% sodium chloride infused at 83 mL/hour over 4 hours, initiated within 2 minutes of carbetocin bolus. Visually identical to the active oxytocin infusion. Administered in the monotherapy arm only.

Первичные конечные точки

• Additional Uterotonic Requirement Within 24 Hours [Срок оценки: Within 24 hours of delivery]

Вторичные конечные точки (11)

• Intraoperative Blood Loss - Gravimetric Method [Срок оценки: Intraoperative - from cord clamping to skin closure]
• Total 24-Hour Blood Loss [Срок оценки: 0 to 24 hours after delivery]
• Actual Blood Loss - Gross Formula [Срок оценки: Preoperative baseline to 24 hours postoperatively]
• Hemoglobin Change [Срок оценки: Preoperative baseline to 24 hours postoperatively]
• Hematocrit Change [Срок оценки: Preoperative baseline to 24 hours postoperatively]
• Uterine Tone Score - Verbal Numerical Rating Scale [Срок оценки: At 2, 5, and 10 minutes after carbetocin bolus]
• Postpartum Hemorrhage Incidence [Срок оценки: Within 24 hours of delivery]
• Blood Transfusion Requirement [Срок оценки: Within 24 hours of delivery]
• Systolic Blood Pressure [Срок оценки: Every 2.5 minutes intraoperatively and every 15 minutes for 4 hours postoperatively]
• Heart Rate [Срок оценки: Continuous intraoperatively and every 15 minutes for 4 hours postoperatively]
• Adverse Effects Incidence [Срок оценки: Within 24 hours of delivery]

Критерии участия

Критерии включения

• Adult women aged 18 to 45 years
• Scheduled for elective non-emergency cesarean delivery
• Spinal anesthesia planned and administered as the sole anesthetic technique
• Singleton pregnancy at gestational age of 37 completed weeks or more
• ASA physical status II
• Preoperative hemoglobin of 9 g/dL or more
• Able to provide written informed consent in Arabic or English

Критерии исключения

• Emergency or crash cesarean delivery
• Placenta previa, placenta accreta spectrum disorder, or other abnormal placentation
• Known uterine anomalies likely to impair contractility including fibroids greater than 5 cm, bicornuate or unicornuate uterus
• Grand multiparity defined as 5 or more previous deliveries
• Multiple gestation including twins or higher order
• Polyhydramnios defined as amniotic fluid index greater than 24 cm
• Prior oxytocin augmentation in current pregnancy for more than 6 hours
• Known hypersensitivity to carbetocin, oxytocin, or any formulation excipient
• Severe preeclampsia, eclampsia, or HELLP syndrome
• Cardiovascular disease including arrhythmia, valvular disease, cardiomyopathy, or ischemic heart disease
• Known coagulopathy or thrombocytopenia with platelets less than 100 x 10\^9/L
• Hepatic or renal impairment
• Body mass index greater than 40 kg/m2 at time of delivery
• Enrollment in another interventional clinical trial

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

Саудовская Аравия · 1 центр

• Qassim University Medical City — Buraidah

Идентификаторы

NCT: NCT07636421 · CARBOXY-RCT-001 · QU-IRB-26-23-4

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗