A study comparing three medicines used for the active management of the third stage of labour (to help deliver the placenta after your baby has been born)
| ISRCTN | ISRCTN10232550 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN10232550 |
| EudraCT/CTIS number | 2014-001948-37 |
| ClinicalTrials.gov number | NCT02216383 |
| Secondary identifying numbers | 17677 |
- Submission date
- 19/02/2018
- Registration date
- 06/03/2018
- Last edited
- 28/05/2020
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Pregnancy and Childbirth
Plain English summary of protocol
Background and study aims
Excessive bleeding after giving birth is a major complication of pregnancy globally. Bleeding after delivery is known as postpartum haemorrhage (PPH). PPH can result from a failure of the uterus (womb) to contract properly following birth. In the UK PPH occurs in 10% of births and additional treatments are needed to control the bleeding. This can include surgical removal of the womb, blood transfusion and prolonged hospital stay. Research has shown that women who experience PPH are less likely to want another child and 60% of those who have another pregnancy experience anxiety.
The current method of preventing PPH involves using a uterotonic drug to help the womb contract following delivery. The use of a uterotonic drug along with cutting of the umbilical cord and delivery of the placenta by controlled traction of the cord is known as Active Management of the Third Stage of Labour (AMTSL). AMTSL reduces the risk of PPH by 66%. Two thirds of pregnant women who experience PPH have no risk factors, so AMTSL is currently offered to all pregnant women. In the UK Syntometrine and Syntocinon are the two most commonly uterotonic drugs used in AMTSL. Both of these drugs mimic the natural hormone in the body that causes the uterus to contract. Syntometrine contains ergometrine which makes its affects last longer. However, this medication is associated with nausea, vomiting, and high blood pressure, and in some rare cases it has been linked to stroke which has been fatal. Syntometrine is known to be better at preventing moderate blood loss but not severe blood loss. Currently international guidelines recommend Syntocinon as the medicine of choice for AMTSL. At Southmead Hospital in Bristol a telephone survey of all consultant-lead maternity units in the UK was conducted to find out whether the guidelines for AMTSL were being followed. It was found that 71.4% of consultant-lead units still use Syntometrine as their first choice of uterotonic instead of Syntocinon as recommended. Many units reported that they had changed to Syntocinon following the publication of the guidelines but changed back to Syntometrine as they were concerned that their PPH rates had increased with Syntocinon. There is therefore a concern that women are being given a medicine (Syntometrine) that can cause potentially dangerous high blood pressure, and is contrary to national recommendations. A newer uterotonic called Carbetocin is offered for management of the third stage of labour after birth by caesarean section. This medication is not licenced for use in vaginal births. Studies have shown that Carbetocin is more effective at preventing bleeding following birth than Syntometrine. It also has fewer side effects than Syntometrine. Studies comparing Carbetocin and Syntocinon have shown that there is no significant difference in the risk of women bleeding heavily. Furthermore, Carbetocin reduces the need to have additional medication to aid the contraction of the womb. To date there have been no studies directly comparing Syntometrine, Syntocinon and Carbetocin for management of AMTSL in vaginal births. The aim of this study is to compare the effectiveness, side effects and cost of Syntocinon, Syntometrine and Carbetocin in AMTSL in vaginal births.
Who can participate?
Women aged 18 and over with a single pregnancy who are planning to have a vaginal birth
What does the study involve?
Participants are randomly allocated to receive a single dose of either Syntocinon, Syntometrine or Carbetocin, given as an injection into the leg muscle after the vaginal birth of their baby and after the cord has been clamped. All participants are followed up until day 14 after giving birth. The proportion of women requiring additional uterotonic drugs to treat or prevent PPH is measured, along with incidence of PPH, blood transfusion, side effects, health-related quality of life, and cost.
What are the possible benefits and risks of participating?
Carbetocin may cause less nausea, vomiting and high blood pressure than Syntometrine, and Syntocinon causes less of these side effects than Syntometrine. Women who are allocated to either Carbetocin or Syntocinon may have a better overall birth experience because having fewer side effects may allow them to bond with their baby during the first few hours after birth. Not all participants will benefit from taking part in the study but their participation might be helpful to the NHS and to women giving birth in the future. All three drugs are currently used in routine care therefore no serious side effects are expected.
Where is the study run from?
1. Southmead Hospital, North Bristol NHS Trust (UK)
2. St Michael's Hospital, University Hospitals NHS Foundation Trust (UK)
3. Royal United Hospital Bath NHS Trust (UK)
4. Gloucestershire Hospitals NHS Foundation Trust (UK)
5. Nottingham University Hospitals NHS Trust of City Hospital (UK)
6. The Great Western Hospital NHS Foundation Trust (UK)
When is the study starting and how long is it expected to run for?
February 2014 to August 2019
Who is funding the study?
Ferring Pharmaceuticals
Who is the main contact?
Michelle Mayer
Contact information
Scientific
The Chilterns
Southmead Hospital
North Bristol NHS Trust
Bristol
BS10 5NB
United Kingdom
Study information
| Study design | Randomised; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN10232550_PIS_V5_05Mar18.pdf |
| Scientific title | Intramuscular oxytocics: a multi-centre randomised comparison study of intramuscular carbetocin, syntocinon and syntometrine for the third stage of labour following vaginal birth |
| Study acronym | IMox |
| Study objectives | A quarter of all global pregnancy-related deaths occur due to excessive bleeding after childbirth, or “post partum haemorrhage” (PPH). Active Management of the Third Stage of Labour (AMTSL) after vaginal birth, which includes use of a preventative uterotonic drug, reduces the risk of PPH by 66%. Syntometrine is most commonly used for this purpose in the UK. Syntocinon is the drug which national guidelines recommend first-line. This is because Syntocinon is less likely to cause nausea , vomiting and transient high blood pressure, and is just as effective as Syntometrine at preventing PPH >1000ml. However, Syntometrine is more effective at preventing PPH of 500-1000ml. This is why maternity units still choose to use it, despite the nausea and vomiting experienced by ~25% of patients. Carbetocin, a newer uterotonic drug already used during caesarean section, is more expensive but potentially more effective. Previous studies suggest that patients receiving Carbetocin may need fewer additional drugs to treat and prevent PPH than those receiving Syntocinon. Compared with Syntometrine, patients receiving Carbetocin lose less blood and experience fewer side effects. No studies have directly compared these three drugs. The aim of the study is to compare carbetocin, syntometrine and syntocinon when administered intramuscularly after vaginal birth to prevent primary postpartum haemorrhage, in order to directly compare the: 1. Clinical effectiveness of each drug 2. Maternal side effects experienced with the use of each drug 3. Overall cost of each intervention |
| Ethics approval(s) | NRES Committee South Central - Oxford B, 28/10/2014, ref: 14/SC/1312 |
| Health condition(s) or problem(s) studied | Specialty: Reproductive health and childbirth, Primary sub-specialty: Reproductive and Sexual Medicine; UKCRC code/ Disease: Reproductive Health and Childbirth/ Complications of labour and delivery |
| Intervention | Patients are randomised to receive Carbetocin, Syntometrine or Syntocinon during the third stage of labour. The intervention is a single dose of intramuscular injection of the randomly allocated study drug (10iU Syntocinon, 500μg/5iU Syntometrine or 100μg Carbetocin) given after vaginal birth of the baby, once the cord has been clamped. Study participants are followed up until day 14 postnatal. Standard intrapartum care will be adopted leading up to, and after, this single-dosed intervention. The primary outcome measure will be the proportion of women requiring additional uterotonic drugs to treat or prevent PPH. Secondary outcomes will include incidence of PPH, blood transfusion, maternal side effects, health-related quality of life, and cost. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Carbetocin, Syntometrine, Syntocinon |
| Primary outcome measure | Requirement for additional uterotonic drugs. This is defined as the administration, following the administration of Imox IMP and prior to discharge from Delivery Suite (and not more than 24 hours after delivery), of any of the following: Syntocinon (IM/IV), Syntometrine (IM), Carboprost (IM), Carbetocin (IM/IV), Misoprostol (PO/PV/PR). This information is taken from the participant’s medical notes or the maternal database where the information is recorded routinely. |
| Secondary outcome measures | Current secondary outcome measures as of 27/06/2018: Secondary clinical outcomes 1. Number and type of additional uterotonic drugs required within 24 hours of delivery 2. Estimated weighed blood loss following delivery until 24 hours after delivery 3. Transfusion of blood products (type and number of units given) 4. Volume of own blood returned to participant (if cell salvage used) 5. Use of prophylactic oxytocin infusion to reduce the risk of haemorrhage before a diagnosis of PPH was made 6. Manual removal of placenta in theatre 7. Requirement for surgical intervention to manage PPH (examination under anaesthetic in theatre/intrauterine balloon tamponade/uterine compression sutures/hysterectomy) 8. Maternal hypertension in first two postnatal hours following administration of study drug, defined as either: 8.1. Postpartum systolic BP >140 mmHg on any occasion in first two postnatal hours 8.2. Postpartum diastolic BP >90 mmHg on any occasion in first two postnatal hours 9. Maternal hypotension (BP <90/60) in first two postnatal hours 10. Maternally-reported health-related quality of life, measured using EQ-5D-5L questionnaire at day 1 and day 14 postpartum Patient reported secondary outcomes: 1. Abdominal pain in the first two postnatal hours, recorded in Case Report Form (CRF) by midwife 2. Postpartum vomiting in first two postnatal hours 3. Need for antiemetic in first two postnatal hours 4. Headache in the first two postnatal hours, recorded in CRF by midwife Previous secondary outcome measures: 1. Blood transfusion requirement is measured as the need to have a blood transfusion (including number of units given) following delivery (within 24 hours), at day 1 postnatal and at any point from day 1 to day 14 postnatal 2. Volume of own blood returned to participant (if Cell Salvage used) (ml). Method is this a yes or no documented in the notes. If yes, volume returned within 24 hours of birth 3. Requirement for any other blood products including fresh frozen plasma, cryoprecipitate, Factor VII (number of units of each given) Method is this a yes or no documented in the notes. If yes, number of units within 24 hours of birth 4. Estimated blood loss at delivery (including estimated total blood loss (ml or L) until transfer from Delivery Suite i.e. if there is excessively heavy lochia within 24 hours of birth (ml) 5. Use of prophylactic Syntocinon infusion to reduce the risk of hemorrhage before a diagnosis of PPH; was prophylactic Syntocinon infusion given immediately after birth, yes or no 6. Whether or not a Syntocinon infusion was used to either augment or induce labour. Was Syntocinon infusion given during labour? Yes or no 7. Whether terbutaline 0.25 mg was given subcutaneously to reduce uterine hypercontractility during the 2nd stage of labour. Yes or no 8. Duration of third stage of labour (mins) 9. Need for manual removal of placenta in theatre – yes or no, within 24 hours following birth 10. Need for examination under anaesthetic in theatre - yes or no, within 24 hours following birth 11. Use of interuterine balloon tamponade/uterine compression sutures/hysterectomy to control PPH, yes or no, within 24 hours following birth 12. Maternal hypertension in first two postnatal hours, following administration of study drug. Blood pressure readings taken at 1 hour and 2 hours following drug administration 13. Postpartum systolic BP >140 mmHg on any occasion in first two postnatal hours (and maximum systolic BP in first two postnatal hours). Blood pressure readings taken at 1 hour and 2 hours following drug administration 14. Postpartum diastolic BP >90 mmHg on any occasion in first two postnatal hours (and maximum diastolic BP in first two postnatal hours). Blood pressure readings taken at 1 hour and 2 hours following drug administration 15. Maternal hypotension (BP <90/60) in first two postnatal hours. Blood pressure readings taken at 1 hour and 2 hours following drug administration 16. Intrapartum vomiting – yes or no for vomiting during labour 17. Post-partum vomiting in first two postnatal hours - yes or no for vomiting during two hours postnatal 18. Need for antiemetics in first two postnatal hours - yes or no for for antimetics given during two hours postnatal 19. Time from delivery to discharge from Delivery Suite (either to postnatal ward or home) (mins) 20. Time spent in recovery (mins) 21. Maternal side effects including hypertension, nausea and vomiting, headache, abdominal pain and dizziness will be captured using a maternal questionnaire at 2 hours postnatal. Participants are asked to score their experiences as either none, mild, moderate, severe or severe 22. Health-related quality of life, measured using EQ5D- 5L questionnaire antenatally from 20 weeks gestation, at 1 day postnatal, and day 14 postnatal 23. Cost per patient – length of hospital stay following birth and cost of additional uterotonics |
| Overall study start date | 07/02/2014 |
| Completion date | 30/09/2018 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Female |
| Target number of participants | Planned Sample Size: 5712; UK Sample Size: 5712 |
| Total final enrolment | 5717 |
| Key inclusion criteria | Current inclusion criteria as of 27/06/2018: 1. ≥18 years of age at time of delivery 2. Vaginal birth 3. Live, singleton pregnancy 4. >24 weeks gestation Previous inclusion criteria: 1. ≥18 years of age at time of baby’s birth 2. Planning to have a vaginal birth (spontaneous and instrumental) 3. Singleton pregnancy 4. Any gestational age |
| Key exclusion criteria | Current exclusion criteria as of 27/06/2018: 1. Significant antepartum haemorrhage (>50ml) or suspected or proven placenta abruption 2. Maternal coagulation disorder 3. Women who would decline blood products if required 4. Known or suspected hypertensive disorders 5. Peripheral, hepatic or cardiac disease 6. Epilepsy 7. Patients with an allergy or hypersensitivity to any of the active ingredients of the study drugs Previous exclusion criteria: 1. Significant antepartum haemorrhage (>50ml) or suspected or proven placenta abruption 2. Maternal coagulation disorder 3. Multiple pregnancy (twins or higher order) 4. Intrauterine fetal death 5. Patients who would decline blood products if required (i.e., Jehovah's Witnesses - clinicians may have a lower threshold for administering additional prophylactic uterotonic drugs to these patients) 6. Known or suspected hypertensive disorders, including pre-eclampsia, pregnancy induced hypertension, essential hypertension (even if blood pressure well controlled), and patients with hypertension in labour 7. Patients with peripheral, hepatic or cardiac disease 8. Patients with an allergy or hypersensitivity to any of the active ingredients in Carbetocin, Syntometrine or Syntocinon |
| Date of first enrolment | 13/02/2015 |
| Date of final enrolment | 31/07/2018 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Westbury-on-Trym
Bristol
BS10 5NB
United Kingdom
1st Floor PAW
Zone D (by D10)
RUH Combe Park
Bath
BA1 3NG
United Kingdom
1 College Lawn
Cheltenham
GL53 7AG
United Kingdom
Hucknall Road
Nottingham
NG5 1PB
United Kingdom
Marlborough Street
Bristol
BS1 3NU
United Kingdom
Swindon
SN3 6BB
United Kingdom
Sponsor information
Hospital/treatment centre
Southmead Hospital
Southmead Road
Westbury-On-Trym
Bristol
BS10 5NB
England
United Kingdom
"ROR" |
https://ror.org/036x6gt55 |
|---|
Funders
Funder type
Industry
Private sector organisation / For-profit companies (industry)
- Alternative name(s)
- Ferring
- Location
- Switzerland
Results and Publications
| Intention to publish date | 31/08/2019 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Stored in repository |
| Publication and dissemination plan | The protocol will be published in an open-access peer-reviewed journal. Planned publication of the results in a high-impact peer reviewed journal within 1 year of the last patient last visit. |
| IPD sharing plan | Anonymised participant-level data will be publicly available for free access within the University of Bristol Research Data Management Depository (https://data.bris.ac.uk/data/group/health-sciences ) for 5 years after the end of the study. The specific DOI will be made available in the publication of results. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version V5 | 05/03/2018 | 06/03/2018 | No | Yes |
| Protocol article | protocol | 03/01/2019 | Yes | No | |
| Basic results | 28/05/2020 | No | No | ||
| HRA research summary | 28/06/2023 | No | No |
Additional files
- ISRCTN10232550_PIS_V5_05Mar18.pdf
- Uploaded 06/03/2018
Editorial Notes
28/05/2020: The following changes were made to the trial record:
1. Added clinicaltrialsregister.eu link to basic results (scientific).
2. The total final enrollment was added.
25/06/2019: Internal review.
07/01/2019: Publication reference added.
27/06/2018: The following changes were made to the trial record:
1. The target number of participants was changed from 6285 to 5712.
2. The overall trial end date was changed from 31/08/2018 to 30/09/2018.
3. The secondary outcome measures and inclusion and exclusion criteria were updated.
15/05/2018: Contact updated.
03/04/2018: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/08/2018 to 31/07/2018.
2. The overall trial end date was changed from 31/08/2019 to 31/08/2018.
