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

4. juni 2026 opdateret af: 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.

Studieoversigt

Status

Ikke rekrutterer endnu

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

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.

Undersøgelsestype

Interventionel

Tilmelding (Anslået)

332

Fase

  • Fase 4

Kontakter og lokationer

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Studiekontakt

Undersøgelse Kontakt Backup

Studiesteder

  • Saudi Arabien
    • Al-Qassim Region
      • Buraidah, Al-Qassim Region, Saudi Arabien, 51452
        • Qassim University Medical City
        • Kontakt:
        • Kontakt:
        • Ledende efterforsker:
          • Omar Saleh Al Misnid, MD

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

  • Voksen

Tager imod sunde frivillige

Ingen

Beskrivelse

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

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Behandling
  • Tildeling: Randomiseret
  • Interventionel model: Parallel tildeling
  • Maskning: Tredobbelt

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Aktiv komparator: 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.
Medicin: Carbetocin
Carbetocin 100 micrograms (1 mL) IV bolus administered over 1 minute immediately after umbilical cord clamping. Identical administration in both arms.
Andre navne:
  • Duratocin
  • Pabal
Medicin: 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.
Andre navne:
  • Normal Saline Placebo
Eksperimentel: 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).
Medicin: Carbetocin
Carbetocin 100 micrograms (1 mL) IV bolus administered over 1 minute immediately after umbilical cord clamping. Identical administration in both arms.
Andre navne:
  • Duratocin
  • Pabal
Medicin: 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.
Andre navne:
  • Syntocinon

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Additional Uterotonic Requirement Within 24 Hours
Tidsramme: 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

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Intraoperative Blood Loss - Gravimetric Method
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

Mansoura University

Efterforskere

  • Ledende efterforsker: Mohamed A Tolba, MD, Qassim University Medical City

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart (Anslået)

1. august 2026

Primær færdiggørelse (Anslået)

1. april 2028

Studieafslutning (Anslået)

1. august 2028

Datoer for studieregistrering

Først indsendt

4. juni 2026

Først indsendt, der opfyldte QC-kriterier

4. juni 2026

Først opslået (Faktiske)

9. juni 2026

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

9. juni 2026

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

4. juni 2026

Sidst verificeret

1. juni 2026

Mere information

Begreber relateret til denne undersøgelse

Nøgleord

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

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

Plan for individuelle deltagerdata (IPD)

Planlægger du at dele individuelle deltagerdata (IPD)?

JA

IPD-planbeskrivelse

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.

IPD-delingstidsramme

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

IPD-delingsadgangskriterier

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

IPD-deling Understøttende informationstype

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE

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