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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Cesarean Section; Postpartum Hemorrhage; Blood Loss, Surgical; Uterine Atony
• Intervention / Treatment: Drug: Carbetocin; Drug: Placebo Saline Infusion; Drug: Oxytocin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 332
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Mohamed A Tolba, MD; Phone Number: 966507439018; Email: m_atolba1234@mans.edu.eg
• Study Contact Backup: Name: Omar S Al Misnid, MD9; Phone Number: 966561205555; Email: OMisnid@qumc.edu.sa

Study Locations

• Saudi Arabia
  • Al-Qassim Region
    • Buraidah, Al-Qassim Region, Saudi Arabia, 51452
      • Qassim University Medical City
      • Contact: Mohamed A Tolba, MD; Phone Number: 966507439018; Email: m_atolba1234@mans.edu.eg
      • Contact: Omar S Al Misnid, MD; Phone Number: 966561205555; Email: OMisnid@qumc.edu.sa
      • Principal Investigator: Omar Saleh Al Misnid, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: Carbetocin; Carbetocin 100 micrograms (1 mL) IV bolus administered over 1 minute immediately after umbilical cord clamping. Identical administration in both arms.; Other Names: Duratocin; Pabal; Drug: 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.; Other Names: Normal Saline Placebo
Experimental: 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).	Drug: Carbetocin; Carbetocin 100 micrograms (1 mL) IV bolus administered over 1 minute immediately after umbilical cord clamping. Identical administration in both arms.; Other Names: Duratocin; Pabal; Drug: 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.; Other Names: Syntocinon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Additional Uterotonic Requirement Within 24 Hours	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intraoperative Blood Loss - Gravimetric Method	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	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	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	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	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	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	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	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	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	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	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

Collaborators and Investigators

• Sponsor: Mansoura University
• Investigators: Principal Investigator: Mohamed A Tolba, MD, Qassim University Medical City

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: June 4, 2026
• First Submitted That Met QC Criteria: June 4, 2026
• First Posted (Actual): June 9, 2026

Study Record Updates

• Last Update Posted (Actual): June 9, 2026
• Last Update Submitted That Met QC Criteria: June 4, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Oxytocin; Spinal Anesthesia; Carbetocin; Obstetric Anesthesia; Uterotonic; Non-Inferiority Trial; Uterine Tone; Elective Cesarean Delivery; Gravimetric Blood Loss
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Obstetric Labor Complications; Pregnancy Complications; Hemorrhage; Puerperal Disorders; Uterine Hemorrhage; Intraoperative Complications; Dystocia; Pathological Conditions, Signs and Symptoms; Postpartum Hemorrhage; Blood Loss, Surgical; Uterine Inertia; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins; Pituitary Hormones, Posterior; Pituitary Hormones; Oxytocin; carbetocin
• Other Study ID Numbers: CARBOXY-RCT-001; QU-IRB-26-23-4 (Other Identifier: Qassim University Institutional Review Board)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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 Sharing Time Frame: Beginning 6 months after publication of the primary results manuscript and available for 5 years thereafter
• IPD Sharing Access Criteria: Researchers with a methodologically sound proposal directed to the corresponding author. A signed data access agreement is required.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No