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

4. června 2026 aktualizováno: Mohamed Ahmed Tolba, Mansoura University

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

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.

Přehled studie

Postavení

Zatím nenabíráme

Podmínky

Intervence / Léčba

Detailní popis

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.

Typ studie

Intervenční

Zápis (Odhadovaný)

332

Fáze

  • Fáze 4

Kontakty a umístění

Tato část poskytuje kontaktní údaje pro ty, kteří studii provádějí, a informace o tom, kde se tato studie provádí.

Studijní kontakt

Studijní záloha kontaktů

Studijní místa

  • Saudská arábie
    • Al-Qassim Region
      • Buraidah, Al-Qassim Region, Saudská arábie, 51452
        • Qassim University Medical City
        • Kontakt:
        • Kontakt:
        • Vrchní vyšetřovatel:
          • Omar Saleh Al Misnid, MD

Kritéria účasti

Výzkumníci hledají lidi, kteří odpovídají určitému popisu, kterému se říká kritéria způsobilosti. Některé příklady těchto kritérií jsou celkový zdravotní stav osoby nebo předchozí léčba.

Kritéria způsobilosti

Věk způsobilý ke studiu

  • Dospělý

Přijímá zdravé dobrovolníky

Ne

Popis

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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

Studijní plán

Tato část poskytuje podrobnosti o studijním plánu, včetně toho, jak je studie navržena a co studie měří.

Jak je studie koncipována?

Detaily designu

  • Primární účel: Léčba
  • Přidělení: Randomizované
  • Intervenční model: Paralelní přiřazení
  • Maskování: Trojnásobný

Zbraně a zásahy

Skupina účastníků / Arm
Intervence / Léčba
Aktivní komparátor: Group C - Carbetocin Monotherapy
Carbetocin 100 micrograms IV bolus over 1 minute immediately after cord clamping, followed by placebo infusion (500 mL 0.9% sodium chloride at 83 mL/hour over 4 hours). The infusion bag is visually identical to the active arm.
Lék: Carbetocin
Carbetocin 100 micrograms (1 mL) IV bolus administered over 1 minute immediately after umbilical cord clamping. Identical administration in both arms.
Ostatní jména:
  • Duratocin
  • Pabal
Lék: 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.
Ostatní jména:
  • Normal Saline Placebo
Experimentální: Group C+O - Carbetocin Plus Oxytocin
Carbetocin 100 micrograms IV bolus over 1 minute immediately after cord clamping, followed by active infusion (oxytocin 10 IU in 500 mL 0.9% sodium chloride at 83 mL/hour over 4 hours).
Lék: Carbetocin
Carbetocin 100 micrograms (1 mL) IV bolus administered over 1 minute immediately after umbilical cord clamping. Identical administration in both arms.
Ostatní jména:
  • Duratocin
  • Pabal
Lék: 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.
Ostatní jména:
  • Syntocinon

Co je měření studie?

Primární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Additional Uterotonic Requirement Within 24 Hours
Časové okno: Within 24 hours of delivery
Proportion of patients requiring at least one additional rescue uterotonic agent at any timepoint within 24 hours of delivery, based on clinical assessment of inadequate uterine tone or uterine atony by the attending obstetrician or anesthesiologist.
Within 24 hours of delivery

Sekundární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Intraoperative Blood Loss - Gravimetric Method
Časové okno: Intraoperative - from cord clamping to skin closure
Quantitative intraoperative blood loss measured by gravimetric method: weight of soaked materials minus dry materials divided by 1.05, plus suction volume, minus irrigation and amniotic fluid volumes.
Intraoperative - from cord clamping to skin closure
Total 24-Hour Blood Loss
Časové okno: 0 to 24 hours after delivery
Cumulative blood loss combining gravimetric intraoperative measurement and weighed postoperative lochia pads at 2 and 24 hours.
0 to 24 hours after delivery
Actual Blood Loss - Gross Formula
Časové okno: Preoperative baseline to 24 hours postoperatively
Calculated using estimated blood volume multiplied by the ratio of preoperative to postoperative hemoglobin change: ABL = EBV x (Hb preoperative minus Hb postoperative) divided by Hb preoperative, where EBV = body weight in kg x 85 mL/kg.
Preoperative baseline to 24 hours postoperatively
Hemoglobin Change
Časové okno: Preoperative baseline to 24 hours postoperatively
Change in venous hemoglobin concentration from preoperative baseline to 24 hours postoperatively, measured by automated complete blood count analyzer.
Preoperative baseline to 24 hours postoperatively
Hematocrit Change
Časové okno: Preoperative baseline to 24 hours postoperatively
Change in hematocrit from preoperative baseline to 24 hours postoperatively, measured by automated complete blood count analyzer.
Preoperative baseline to 24 hours postoperatively
Uterine Tone Score - Verbal Numerical Rating Scale
Časové okno: At 2, 5, and 10 minutes after carbetocin bolus
Uterine tone assessed by blinded obstetrician using 11-point Verbal Numerical Rating Scale (0 = completely atonic, 10 = maximally contracted) via bimanual palpation at three timepoints.
At 2, 5, and 10 minutes after carbetocin bolus
Postpartum Hemorrhage Incidence
Časové okno: Within 24 hours of delivery
Proportion of patients with total blood loss of 1000 mL or more within 24 hours of delivery, measured by gravimetric quantification.
Within 24 hours of delivery
Blood Transfusion Requirement
Časové okno: Within 24 hours of delivery
Proportion of patients receiving packed red blood cell transfusion and total units of packed red blood cells transfused.
Within 24 hours of delivery
Systolic Blood Pressure
Časové okno: Every 2.5 minutes intraoperatively and every 15 minutes for 4 hours postoperatively
Systolic blood pressure measured by non-invasive blood pressure cuff monitoring intraoperatively and in the postanesthesia care unit.
Every 2.5 minutes intraoperatively and every 15 minutes for 4 hours postoperatively
Heart Rate
Časové okno: Continuous intraoperatively and every 15 minutes for 4 hours postoperatively
Heart rate measured by continuous 5-lead electrocardiogram monitoring intraoperatively and in the postanesthesia care unit.
Continuous intraoperatively and every 15 minutes for 4 hours postoperatively
Adverse Effects Incidence
Časové okno: Within 24 hours of delivery
Incidence and severity of drug-related adverse effects including nausea, vomiting, facial flushing, headache, chest tightness, tachycardia, hypotension, and oliguria, documented by standardized checklist.
Within 24 hours of delivery

Spolupracovníci a vyšetřovatelé

Zde najdete lidi a organizace zapojené do této studie.

Sponzor

Mansoura University

Vyšetřovatelé

  • Vrchní vyšetřovatel: Mohamed A Tolba, MD, Qassim University Medical City

Termíny studijních záznamů

Tato data sledují průběh záznamů studie a předkládání souhrnných výsledků na ClinicalTrials.gov. Záznamy ze studií a hlášené výsledky jsou před zveřejněním na veřejné webové stránce přezkoumány Národní lékařskou knihovnou (NLM), aby se ujistily, že splňují specifické standardy kontroly kvality.

Hlavní termíny studia

Začátek studia (Odhadovaný)

1. srpna 2026

Primární dokončení (Odhadovaný)

1. dubna 2028

Dokončení studie (Odhadovaný)

1. srpna 2028

Termíny zápisu do studia

První předloženo

4. června 2026

První předloženo, které splnilo kritéria kontroly kvality

4. června 2026

První zveřejněno (Aktuální)

9. června 2026

Aktualizace studijních záznamů

Poslední zveřejněná aktualizace (Aktuální)

9. června 2026

Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality

4. června 2026

Naposledy ověřeno

1. června 2026

Více informací

Termíny související s touto studií

Klíčová slova

Další relevantní podmínky MeSH

Další identifikační čísla studie

  • CARBOXY-RCT-001
  • QU-IRB-26-23-4 (Jiný identifikátor: Qassim University Institutional Review Board)

Plán pro data jednotlivých účastníků (IPD)

Plánujete sdílet data jednotlivých účastníků (IPD)?

ANO

Popis plánu IPD

De-identified individual participant data for the primary and all secondary outcome measures will be made available upon reasonable request to the principal investigator following publication of the primary results manuscript. Requests will be reviewed and approved based on scientific merit and ethical appropriateness. Requestors will be required to sign a data access agreement.

Časový rámec sdílení IPD

Beginning 6 months after publication of the primary results manuscript and available for 5 years thereafter

Kritéria přístupu pro sdílení IPD

Researchers with a methodologically sound proposal directed to the corresponding author. A signed data access agreement is required.

Typ podpůrných informací pro sdílení IPD

  • PROTOKOL STUDY
  • MÍZA
  • ICF
  • ANALYTIC_CODE

Informace o lécích a zařízeních, studijní dokumenty

Studuje lékový produkt regulovaný americkým FDA

Ne

Studuje produkt zařízení regulovaný americkým úřadem FDA

Ne

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