Intramuscular Oxytocics: A Randomised Control Trial (IMox)

Intramuscular Oxytocics: A Randomised Control Trial of Intramuscular Carbetocin, Syntocinon and Syntometrine for the Third Stage of Labour Following Vaginal Birth

A quarter of all pregnancy and child-birth related deaths are due to excessive bleeding after the birth, "post-partum haemorrhage" (PPH). In the UK, PPH affects approx 10% of new mothers. PPH can be frightening for women and cause them to need additional treatments prolonging their hospital stay.

Commonly PPH is caused by an inadequately contracted womb after childbirth. Giving the mother an injection of "uterotonic" medicine following the birth of their baby can prevent this. It reduces the risk of PPH by 66%.

In the UK, the two medicines most commonly used are Syntocinon and Syntometrine. Syntometrine is longer acting, but a published review of trials concluded that Syntometrine is no better at preventing severe blood loss. Syntometrine is associated with more side effects including nausea, vomiting, and high blood pressure, and has been linked with rare, but fatal, cases of stroke. All guidelines therefore recommend Syntocinon for preventing PPH.Following a telephone survey of all maternity units in the UK, 71.4% of units still routinely use Syntometrine.

Carbetocin is a newer medicine, already widely used after caesarean section, but not yet after vaginal birth. Other studies have shown that Carbetocin is slightly better at preventing bleeding after birth when compared to Syntometrine, has fewer side effects than Syntometrine, and that it may be just as good as Syntocinon at preventing PPH. No studies have directly compared all three medicines or compared their overall cost; information vital to the NHS.

Investigators propose a trial of 5712 women over 13 months, in four maternity units to compare the effectiveness, side effects and cost of Syntocinon, Syntometrine and Carbetocin, for women having a vaginal birth.

Women will be randomly allocated to receive one of these drugs. Women and staff will not know which drug they receive. Staff will collect data such as the number of extra drugs and treatments needed and the volume of blood lost. Women will be asked to complete a side effects questionnaire. Investigators will perform an analysis of cost effectiveness once all results are available.

Aim: To directly compare the effectiveness, side effects and cost of Syntocinon, Syntometrine and Carbetocin given intramuscularly to prevent PPH in the 3rd stage of labour.

Study Overview

• Status: Completed
• Conditions: Post Partum Haemorrhage
• Intervention / Treatment: Drug: Carbetocin; Drug: Syntocinon; Drug: Syntometrine

Detailed Description

BACKGROUND Around a quarter of all global pregnancy and child-birth related deaths are due to excessive bleeding after the birth of the baby and placenta, or "post-partum haemorrhage" (PPH). In the UK, PPH affects approximately 10% of new mothers. PPH can be extremely frightening for women and can cause them to need additional treatments including blood transfusion and removal of the womb as well as prolonging their hospital stay.

The most common cause of PPH is an inadequately contracted womb after childbirth. Giving the mother an injection of "uterotonic" medicine following the birth of their baby can prevent this. It reduces the risk of PPH by 66% and this should routinely be offered to all labouring women.

In the UK, the two medicines most commonly used for this purpose are Syntocinon and Syntometrine. Both mimic natural hormones. Syntometrine is longer acting, but a published review of trials comparing these two medicines concluded that Syntometrine is no better at preventing severe blood loss. Syntometrine is associated with more side effects including nausea, vomiting, and high blood pressure, and has been linked with rare, but fatal, cases of stroke. All guidelines therefore recommend Syntocinon for preventing PPH.

Our group conducted a telephone survey of all maternity units in the UK, and found that 71.4% of units still routinely use Syntometrine. Investigators estimate that 40,000-70,000 women per year are experiencing distressing nausea and vomiting in the emotionally important first few hours following childbirth. These women are also receiving a medicine with the potential to cause dangerous high blood pressure.

Carbetocin is a newer medicine, already widely used after caesarean section, but not yet after vaginal birth. Other studies have shown that Carbetocin is slightly better at preventing bleeding after birth when compared to Syntometrine, that it has fewer side effects than Syntometrine, and that it may be just as good as Syntocinon at preventing PPH. No studies have directly compared all three medicines or compared their overall cost; information vital to the NHS.

METHOD Investigators propose a trial of 5712 women over 13 months, in four maternity units in the South-West to compare the effectiveness, side effects and cost of Syntocinon, Syntometrine and Carbetocin, for women having a vaginal birth.

Women will be randomly allocated to receive one of these drugs. Women and staff will not know which drug they receive, so as not to influence the results collected. Staff will collect data such as the number of extra drugs and treatments needed and the volume of blood lost. Women will be asked to complete a side effects questionnaire. Investigators will perform an analysis of cost effectiveness once all results are available.

AIMS To directly compare the effectiveness, side effects and cost of Syntocinon, Syntometrine and Carbetocin given intramuscularly to prevent PPH in the 3rd stage of labour.

• Study Type: Interventional
• Enrollment (Actual): 5798
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham, United Kingdom
    • Nottingham University Hospitals NHS Trust
  • Swindon, United Kingdom, SN3 6BB
    • Great Western Hospital
  • Avon
    • Bristol, Avon, United Kingdom, BS10 5NB
      • North Bristol NHS Trust
  • Gloucestershire
    • Gloucester, Gloucestershire, United Kingdom, GL1 3NN
      • Gloucestershire Hospitals NHS Trust
  • Somerset
    • Bath, Somerset, United Kingdom, BA1 3NG
      • Royal United Hospital NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• ≥18 years of age at time of delivery
• Singleton pregnancy
• Vaginal birth (spontaneous and instrumental)
• >24 weeks gestation

Exclusion Criteria:

• Significant APH (>50ml) or suspected or proven placenta abruption
• Maternal coagulation disorder
• Intrauterine fetal death
• Patients who would decline blood products if required
• Known or suspected hypertensive disorders, including pre-eclampsia, pregnancy induced hypertension, essential hypertension (even if blood pressure well controlled)
• Hypertension in labour, or patients who have not had their blood pressure checked in labour
• Patients with peripheral, hepatic or cardiac disease
• Patients with an allergy or hypersensitivity to any of the active ingredients in Carbetocin, Syntometrine or Syntocinon
• Epilepsy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Carbetocin; One dose of 100 micrograms intramuscular Carbetocin given for active management of the third stage of labour, immediately after the birth of the baby	Drug: Carbetocin; The intervention is the administration of one dose of study drug to the recruited patient at the time of delivery. Carbetocin, listed here, is one of the of the three study drugs.; Other Names: Pabal
Active Comparator: Syntocinon; One dose of 10 International Units intramuscular Syntocinon given for active management of the third stage of labour, immediately after the birth of the baby	Drug: Syntocinon; The intervention is the administration of one dose of study drug to the recruited patient at the time of delivery. Syntocinon, listed here, is one of the of the three study drugs.; Other Names: Oxytocin
Active Comparator: Syntometrine; One dose of 500micrograms/5 International Units intramuscular Syntometrine given for active management of the third stage of labour, immediately after the birth of the baby	Drug: Syntometrine; The intervention is the administration of one dose of study drug to the recruited patient at the time of delivery. Syntometrine, listed here, is one of the of the three study drugs.; Other Names: Syntometrine 500 micrograms/5 IU Solution for Injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Requirement for additional uterotonic drugs within 24 hours of birth	Proportion of patients requiring additional uterotonic drugs after administration of study drug	From administration of prophylactic uterotonic agent to discharge from labour ward, within an expected average of 6 hours.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimated volume of blood loss at delivery	Estimated volume of blood loss at delivery	Within 24 hours of delivery
Transfusion of blood products (type and number of units given)	Number of units of blood transfused, or volume of own blood returned to patient if intraoperative cell salvage used	From delivery until transfer from Labour Ward, within an expected average of 6 hours.
Manual removal of placenta in theatre	The requirement for the placenta to be removed in theatre	From delivery until transfer from Labour Ward
Requirement for surgical intervention to manage PPH	As a result of significant PPH a surgical intervention was required to manage the PPH	From delivery until transfer from Labour Ward, within an expected average of 2 days
Maternal hypertension	Hypertension	First two postnatal hours following administration of study drug
Maternal hypotension	BP <90/60	In first two postnatal hours
Maternally-reported health-related quality of life	health-related quality of life reported by mother	24 hours after delivery and 14 days after delivery
Abdominal pain in the first two postnatal hours, recorded in Case Report Form (CRF) by midwife	Patient reported secondary outcome	First 2 post natal hours
Post-partum vomiting	Patient reported secondary outcome	First 2 post natal hours
Need for anti-emetic	Patient reported secondary outcome By definition, labour starts when the patient is at least 3-4cm dilated with regular, painful contractions.	First 2 post natal hours
Headache	Patient reported secondary outcome	First two post natal hours
Maternal experience of side effects	Captured using maternal side effects questionnaire	In first two post natal hours

Collaborators and Investigators

• Sponsor: North Bristol NHS Trust
• Collaborators: Ferring Pharmaceuticals; University of Bristol; University Hospitals Bristol and Weston NHS Foundation Trust; Gloucestershire Hospitals NHS Foundation Trust; University of the West of England; Royal United Hospital Bath NHS Trust
• Investigators: Study Director: Tim Draycott, BMBS, North Bristol NHS Trust/University of Bristol; Study Chair: Helen van der Nelson, BMBS, North Bristol NHS Trust/University of Bristol

Publications and helpful links

General Publications

• van der Nelson H, O'Brien S, Lenguerrand E, Marques E, Alvarez M, Mayer M, Burnard S, Siassakos D, Draycott T. Intramuscular oxytocin versus oxytocin/ergometrine versus carbetocin for prevention of primary postpartum haemorrhage after vaginal birth: study protocol for a randomised controlled trial (the IMox study). Trials. 2019 Jan 3;20(1):4. doi: 10.1186/s13063-018-3109-2.

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (Actual): August 31, 2018
• Study Completion (Actual): October 30, 2018

Study Registration Dates

• First Submitted: July 25, 2014
• First Submitted That Met QC Criteria: August 12, 2014
• First Posted (Estimate): August 15, 2014

Study Record Updates

• Last Update Posted (Actual): November 14, 2018
• Last Update Submitted That Met QC Criteria: November 9, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Labour; Syntocinon; Post partum haemorrhage; Carbetocin; Active Management of Third Stage of Labour; Syntometrine; Birth experience
• Additional Relevant MeSH Terms: Pathologic Processes; Pregnancy Complications; Obstetric Labor Complications; Puerperal Disorders; Uterine Hemorrhage; Hemorrhage; Postpartum Hemorrhage; Physiological Effects of Drugs; Reproductive Control Agents; Oxytocics; Oxytocin; Carbetocin; Ergonovine; Syntometrine
• Other Study ID Numbers: 3344; 2014-001948-37 (EudraCT Number)