Comparing the Dose-response Profiles of Uterotonics After Initial Carbetocin Administration - an Ex-vivo Study in Desensitized Human Myometrium

NCT ID: NCT06285409

Last Updated: 2025-02-26

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-04-04
• Study Completion Date: 2025-12-31

Brief Summary

This study will investigate the effects of drugs called "uterotonics" that help with the contraction of the uterus after a baby is born. This uterine contraction is very important to stop the bleeding after delivery. An uncontracted uterine state is called "uterine atony", which can lead to an excessive amount of post-delivery bleeding. Carbetocin is an uterotonic drug that works well to prevent post-delivery bleeding. In some cases, carbetocin is not enough to contract the uterus, and ongoing bleeding continues. When that happens, there are other uterotonic medications that can be used. In this study, we aim to find which uterotonic drug, amongst those available (oxytocin, carbetocin, ergometrine or carboprost), is more effective to lower the risk of post-delivery bleeding once carbetocin has already been administered.

This study will be done by using a very small sample of uterine tissue, taken from the incision site, following delivery by cesarean section. The sample is taken to the laboratory and will be exposed to carbetocin followed by other uterotonic drugs. The information obtained from this study will help modify the treatment for uterine atony and post-delivery bleeding to lower the risk further.

Detailed Description

Postpartum hemorrhage (PPH) remains to be one of the leading causes of maternal morbidity and mortality. It has been noted that an increasing number of PPH is attributed to the increased incidence of uterine atony. Carbetocin is the first line therapy for prevention and treatment of uterine atony. Carbetocin is currently used as a single dose treatment without an option of redosing. It has been proven that exposure to oxytocin during labour results in a decrease in myometrial contractions, previous studies shows that the current dose of carbetocin (100 µcg) is insufficient for optimal uterine contraction in failure to progress caesarean section.

According to current guidelines for medical management of PPH, the first line therapy for post CD uterotonic agent in Canada is carbetocin. It is a reliable and safe agent; however, it is a "one shot" option for treatment due to its longer half-life (40 minutes). The clinicians are reluctant to re-dose carbetocin after an initial failure to achieve adequate uterine tone with the assumption that the oxytocin receptors would likely be saturated with the agonist. It is unknown whether re-dosing with oxytocics (carbetocin or oxytocin) would help augment myometrial contractions, thereby lowering post-partum bleeding and improving patient outcomes. It is also unknown if prior carbetocin administration would affect myometrial contractility induced by other second line uterotonics such as ergometrine or carboprost.

This study is essential to answer the clinical question of the efficacy of re-dosing with either oxytocics or second line agents uterotonics following the first prophylactic dose of carbetocin in women with previously desensitized myometrium. This will help us better understand the comparative myometrial contractility response for a range of uterotonics.

The primary hypothesis of this study is that treating a second dose of oxytocics(carbetocin/oxytocin) in oxytocin pre-treated myometrium, after the first standard bolus of 100 µcg carbetocin will cause enhanced myometrial contraction compared to control.

The second hypothesis is that the efficacy of second line agents (ergometrine or carboprost) would not be as effective, i.e. they are likely to be less effective than oxytocics.

Conditions

Postpartum Hemorrhage

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Carbetocin

Dose-response testing with increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-5 M to 10-5 M

Group Type: ACTIVE_COMPARATOR

Carbetocin

Intervention Type: DRUG

Carbetocin first bolus 10-8 M (equivalent to 100 mcg) will be added to the muscle bath to create ex-vivo environment similar to Cesarean delivery, and after 20 minutes the baths will be washed three time with physiological salt solution (PSS).

Oxytocin

Intervention Type: DRUG

Oxytocin 10-5M will be added to all strips for 2 hours to induce desensitization.

Carbetocin

Intervention Type: DRUG

Increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-5 M to 10-5 M

Oxytocin

Dose-response testing with increasing concentrations of oxytocin from 10-10 M to 10-5 M.

Group Type: ACTIVE_COMPARATOR

Carbetocin

Intervention Type: DRUG

Carbetocin first bolus 10-8 M (equivalent to 100 mcg) will be added to the muscle bath to create ex-vivo environment similar to Cesarean delivery, and after 20 minutes the baths will be washed three time with physiological salt solution (PSS).

Oxytocin

Intervention Type: DRUG

Oxytocin 10-5M will be added to all strips for 2 hours to induce desensitization.

Oxytocin

Intervention Type: DRUG

Increasing concentrations of oxytocin from 10-10 M to 10-5 M

Ergometrine

Dose-response testing with increasing concentrations of ergometrine from 10-10 M to 10-5 M

Group Type: ACTIVE_COMPARATOR

Carbetocin

Intervention Type: DRUG

Carbetocin first bolus 10-8 M (equivalent to 100 mcg) will be added to the muscle bath to create ex-vivo environment similar to Cesarean delivery, and after 20 minutes the baths will be washed three time with physiological salt solution (PSS).

Oxytocin

Intervention Type: DRUG

Oxytocin 10-5M will be added to all strips for 2 hours to induce desensitization.

Ergonovine

Intervention Type: DRUG

Increasing concentrations of ergometrine from 10-10 M to 10-5 M

Carboprost

Dose-response testing with increasing concentrations of carboprost from 10-10 M to 10-5 M

Group Type: ACTIVE_COMPARATOR

Carbetocin

Intervention Type: DRUG

Carbetocin first bolus 10-8 M (equivalent to 100 mcg) will be added to the muscle bath to create ex-vivo environment similar to Cesarean delivery, and after 20 minutes the baths will be washed three time with physiological salt solution (PSS).

Oxytocin

Intervention Type: DRUG

Oxytocin 10-5M will be added to all strips for 2 hours to induce desensitization.

Carboprost

Intervention Type: DRUG

Increasing concentrations of carboprost from 10-10 M to 10-5 M

Control

No drug added to physiological salt solution (PSS).

Group Type: PLACEBO_COMPARATOR

Carbetocin

Intervention Type: DRUG

Carbetocin first bolus 10-8 M (equivalent to 100 mcg) will be added to the muscle bath to create ex-vivo environment similar to Cesarean delivery, and after 20 minutes the baths will be washed three time with physiological salt solution (PSS).

Oxytocin

Intervention Type: DRUG

Oxytocin 10-5M will be added to all strips for 2 hours to induce desensitization.

Interventions

Carbetocin

Carbetocin first bolus 10-8 M (equivalent to 100 mcg) will be added to the muscle bath to create ex-vivo environment similar to Cesarean delivery, and after 20 minutes the baths will be washed three time with physiological salt solution (PSS).

Intervention Type: DRUG

Oxytocin

Oxytocin 10-5M will be added to all strips for 2 hours to induce desensitization.

Intervention Type: DRUG

Carbetocin

Increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-5 M to 10-5 M

Intervention Type: DRUG

Oxytocin

Increasing concentrations of oxytocin from 10-10 M to 10-5 M

Intervention Type: DRUG

Ergonovine

Increasing concentrations of ergometrine from 10-10 M to 10-5 M

Intervention Type: DRUG

Carboprost

Increasing concentrations of carboprost from 10-10 M to 10-5 M

Intervention Type: DRUG

Other Intervention Names

Duratocin; Pitocin; Duratocin; Pitocin; Ergometrine; Hemabate

Eligibility Criteria

Inclusion Criteria

• Patients who give written consent to participate in this study
• Patients with gestational age 37-41 weeks
• Non-laboring patients, not exposed to exogenous oxytocin
• Patients requiring elective primary or first repeat CD
• Patients undergoing CD under spinal anesthesia

Exclusion Criteria

• Patient refusal
• Patients who require general anesthesia
• Patients in labour and those receiving oxytocin for induction of labour
• Emergency CD
• placenta accreta spectrum disorder
• Patients who have had previous uterine surgery or >1 previous CD
• Patients with any condition predisposing to uterine atony and PPH (BMI > 40 kg/m2,
• Patients on medications that could affect myometrial contractility, such as insulin, nifedipine, labetalol or magnesium sulphate.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Samuel Lunenfeld Research Institute, Mount Sinai Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mrinalini Balki, MD

Role: PRINCIPAL_INVESTIGATOR

MOUNT SINAI HOSPITAL

Locations

Mount Sinai Hospital

Toronto, Ontario, Canada

Site Status: RECRUITING

Countries

Canada

Central Contacts

Mrinalini Balki, MD

Role: CONTACT

mrinalini.balki@uhn.ca

416-586-4800 ext. 5270

Facility Contacts

Mrinalini Balki, MD

Role: primary

mrinalini.balki@uhn.ca

416-586-4800 ext. 5270

Wafa Bellan, MD

Role: backup

Ronald George, MD

Role: backup

Joseph Park, BSc

Role: backup

Anuradha Baishnob, BSc

Role: backup

Other Identifiers

24-02

Identifier Type: -

Identifier Source: org_study_id