A study protocol for the cardiac effects of a single dose of either oxytocin 2.5 IU or carbetocin 100 µg after caesarean delivery: a prospective randomized controlled multi-centre trial in Norway

Ethics approval and consent to participate

The project has approval from the Regional Committee for Medical and Health Research Ethics (REC 2014/1210), The Norwegian Medicines Agency and the Institutional Data Protection officer at Oslo University Hospital. Signed informed consent form and expected cooperation of the participants for treatment and follow-up will be obtained and documented according to the International Council of Harmonisation-Good Clinical Practice (ICH GCP), and national/local regulations.

Study setting

Women will be recruited from the general population at the three birth clinics at Oslo University Hospital (two clinics) and Akershus University Hospital in Norway.

Eligibility criteria

All participants will have a normal singleton pregnancy at gestational age of 36 weeks or more, and will be able to read and understand Norwegian. Women with common comorbid diagnoses (diabetes, hypothyreosis, hypertension, etc) and pregnancy after in vitro fertilization will also be eligible for enrolment. Women will be excluded from enrolment if they have any of the following: placenta praevia or invasive placenta; pre-eclampsia; a bleeding disorder, such as von Willebrand disease type I; current treatment with low-molecular-weight heparin or other anticoagulation medication (not including aspirin); any known intolerance to either of the study drugs; prolonged QT-time or other serious cardiac disease; liver or kidney failure; epilepsy; or any medical reason why, in the opinion of the investigator, the patient should not participate. ECG was not part of the screening criteria.

Recruitment

A total of 240 healthy pregnant women aged between 18 and 50 years will be included in our trial. Signed informed consent form and expected cooperation of the participants for treatment and follow-up will be obtained and documented according to the International Council of Harmonisation-Good Clinical Practice (ICH GCP), and national/local regulations. All data pertaining each enrolled participant will be entered into the electronic clinical report file (eCRF; Viedoc^®, Uppsala, Sweden).

Screening

Potentially eligible participants will be screened for inclusion after their last consultation before their scheduled delivery by the principal investigator from each study site. Oral and written information about the trial will be provided to each woman at least 24 hours before delivery and written informed consent obtained before randomization. Consent, participation and redraw of consent will be documented in electronic patient record. All screened women, including those who do not give consent to participate in the study, will be registered by number. Screened women who are not enrolled due to exclusion criteria or non-fulfilment of inclusion criteria will be registered by number and the reason for not participating in the study will be recorded.

Randomization and blinding

Participants will be randomized 1:1 to receive either oxytocin 2.5 IU or carbetocin 100 μg after caesarean delivery. The patients will be randomized according to a computer-generated list of random numbers, with permutated blocks of different sizes unknown to the researchers. Each eligible woman who has given consent to participate in the study will be assigned a randomization number in consecutive order. The randomization number is linked to the randomization list as an integral part of Viedoc – the eCRF solution. Test assessing the blinding for each responsible investigator will be performed.

Although the standard procedure according to its label is to administer 1 mL of carbetocin (100 μg/mL),⁷ to maintain treatment masking, both study drugs will be diluted to 5 mL using normal saline by a trained member of staff otherwise uninvolved with the trial, and labelled with the trial identification and randomization number according with ICH GCP and local regulations.

Study drug dosage and administration

A single dose of either oxytocin 2.5 IU (Syntocinon^®, Swedish Orphan Biovitrum, Stockholm, Sweden) or carbetocin 100 μg (Pabal^®, Ferring Pharmaceuticals, St-Prex, Switzerland) will be administered by the investigator (a trained anaesthetist) as a one-minute IV injection immediately after delivery of the baby’s head and shoulders. IV oxytocin 2.5 IU is standard dose used prophylactically at our institutions. Both oxytocin and carbetocin are used prophylactically after delivery to prevent uterine atony and excessive blood loss. The dosing of the study drugs is in line with the recommended dosing regimens which stipulate oxytocin up to 3 IU and carbetocin up to 100 μg should be administered over a time period of more than 30 seconds.²

Prespecified analyses

Primary endpoint

The primary endpoint is the difference between the oxytocin 2.5 IU and carbetocin 100 μg treatment groups in change from baseline in high-sensitive troponin I plasma concentrations 6–10 hours after study drug administration. Details of laboratory testing are provided below.

Secondary outcomes

Uterine tone will be assessed at 2.5 minutes and five minutes after study drug administration, using a numerical rating scale 0–10, where 0 = no tonus and 10 = maximum tonus, and 7 = clinically satisfactory tonus, and ≤6 correlates well with the need for rescue treatment.¹³ The obstetricians performing the caesarean delivery will be presented with the scale prior to starting the procedure. The scale has good interrater agreement.¹⁶ Blood loss will be estimated by volume during the surgical procedure as well as calculating estimated blood loss based on haematocrit percentage within 24 hours after delivery, height and weight prior to caesarean delivery.¹⁷

Postoperative pain during the first 48 hours after delivery will be assessed in a sub-study of 80 women at one centre to further investigate any differences in postpartum/post-operation pain for the two study drugs. For these women, pain intensity (numerical rating scale 0–10) and opioid consumption (time and dose) will be recorded. In addition to the standard pain-relief treatment, these patients will have a patient-controlled intravenous morphine pump.

Direct and indirect healthcare costs will be assessed. Direct costs will include administered study drugs and any rescue treatment of uterine atony required, as well as costs to treat blood loss, and side effects of the therapeutic interventions. Indirect costs include the number of hours staff spend with patients in theatre and in post-anaesthesia care unit.

Vital signs monitoring

Vital signs and baseline blood tests (haemoglobin and sodium concentrations) of participating women will be recorded prior to administration of anaesthesia. Throughout each caesarean delivery, there will be continuous monitoring of vital signs, including echocardiogram, blood pressure and heart rate.

Routine assessments of neonatal status will be recorded (Apgar 1 and 5 minutes, umbilical vein and artery acid-base status).

Safety assessments

The participants will be informed about the expected adverse events (AEs) prior to study enrolment and instructed to score grade of AEs at 0–2, >2–5 and >5–10 minutes after the start of study drug administration, when the majority of AEs are expected to occur. Each participant will be instructed to inform the investigator immediately if they manifest any signs or symptoms they perceive as AEs the following 48 hours (duration of the trial). Unexpected serious adverse events will be reported, also after this period, until discharge from the hospital. All AEs will be recorded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE).

Suspected unexpected serious adverse reactions that result in death, are immediately life-threatening, require hospitalisation, result in persistent or significant disability or incapacity, will be reported immediately to the health authorities. Other suspected serious unexpected adverse reactions will be reported in an unblinded manner to the health authorities as soon as possible but within a maximum of 15 days of first knowledge by the Sponsor (Oslo University Hospital). In order to keep the Investigator and other persons generating data to the study blinded to treatment group, the unblinding and the reporting will be performed by the clinical trial unit at Oslo University Hospital, who is also responsible for monitoring the trial and randomization.

Expected adverse events

Expected AEs are feeling of warmth, chest pain, shortness of breath, palpitations, flushing, headache, nasal congestion, xerostomia, and metallic taste. Both drugs in the study will lead to vasodilatation with a decrease in blood pressure and an increase in heart rate. The causal relationship of each AE to the study medication will be assessed by the investigators as either unrelated, unlikely to be related, possibly or probably related or definitely related.

Concomitant medication

Rescue medication

In case of uterus atony, patients will be treated with rescue oxytocin 1 IU every 2 minutes up to maximum 5 IU in additional to the administration of the study drug (oxytocin 2.5 IU or carbetocin 100 μg). If there is still need for additional uterotonic treatment, this will be provided according to departmental procedures, and may include administration of prolonged oxytocin infusion, methylergometrine, prostinphenem, misoprostol or surgical or mechanical intervention as required. Time of rescue medication administration and dose will be recorded. Any additional treatment required, whether medical or surgical, will be decided by the attending obstetrician and anaesthesiologist according to local guidelines.

Anaesthesia and pain medication

Spinal anaesthesia will be given according to study procedure (2 mL bupivacaine [5 mg/mL] + 0.4 mL fentanyl [50 μg/mL]), hypotension prophylaxis (0.5 μg/kg IV phenylephrine [0.1 mg/mL] followed by infusion rate 0.25 μg/kg/min) and IV volume (isotonic saline) 10 mL/kg starting concomitantly with spinal anaesthesia. Spinal induced hypotension (systolic arterial pressure <90 mmHg) will be treated with an extra IV bolus of phenylephrine if the heart rate is above 60 beats/min or with IV ephedrine 5–10 mg if 60 beats/min or below. Analgesic medication will be administered as required by the participants and will include oral paracetamol 1 g and oral ibuprofen 400–600 mg four times per day. Patients may be given one IV bolus ketorolac trometamol 30 mg and IV bolus or oral oxycodon administered according to local guidelines and as required by the participants.

All medication interventions, including drug dose and time of administration will be recorded.

Criteria for patient discontinuation

Patients may be discontinued from study treatment and assessments at any time. Specific reasons for discontinuing a patient for this study are as follows: (1) Voluntary discontinuation by the patient who is at any time free to discontinue her participation in the study, without prejudice to further treatment; (2) Severe non-compliance to protocol as judged by the principal investigator; (3) Incorrect enrolment i.e., the patient does not meet the required inclusion/exclusion criteria for the study. Patients who withdraw or are withdrawn from the study, will stop further treatment. Reasons for discontinuation will be documented.

Laboratory tests

Blood samples from participating women will be collected at baseline (prior to caesarean delivery) and between six and 10 hours after study drug administration. Haemoglobin and sodium concentrations will be assessed using the point-of-care blood gas analyser(s) (ABL 800 Analyzer^®, Radiometer, Copenhagen, Denmark). Blood plasma samples, stored in a certified research biobank freezer (–70 °C), will be analysed centrally for troponin I concentration as one batch at the Vestre Viken Trust, Drammen Hospital, Norway, once the last participant has completed the study. Plasma Troponin I concentrations for each participant will be measured using high-sensitive detection with a chemiluminiscent microparticle immunoassay (Alinity i^®, Abbott, Illinois, U.S.A.). Normal values of troponin I in a female population (age 18 to 50 years) should be <15 ng/L, with the cut-off corresponding to the 99 percentile of a healthy reference population.^18–20 Recently, high-sensitivity circulating Troponin T <14 ng/L was deemed sufficient for ruling out myocardial ischaemia among 196 pregnant women and after delivery, and that elevated levels mandated further attention on cardiac symptoms.²¹

Data collection and monitoring

Every investigator responsible for entering data into the eCRF will be provided with a unique identity and password, thereby creating an electronic signature of the investigator attesting the accuracy of the data on each eCRF. If any assessments are omitted, the reason for such omissions will be noted on the eCRFs. Corrections, with the reason for the corrections if applicable, will be dated and signed by the investigator in the eCRF. Electronic files, including the data from CRF entered into an electronic database software will be stored at the research server at Oslo University Hospital. This data storage is administered by the Data Inspectorate’s local representative. The patient identification and the code list will be kept by the principal investigator in a locked office, ensuring confidentiality. Investigators involved with data analysis will have access to the study data base. Patient files will be kept for the maximum period of time permitted by each hospital.

The Clinical Study Monitor, independent from the investigators, will visit each investigator regularly to will check and collect completed CRFs, discuss the progress of the study and monitor drug usage according to ICH GCP guidelines. The monitoring will also include source data verification (data audit). A data monitoring committee will not be used as the data collection is expected to be straightforward. Authorized representatives of a regulatory authority and Ethics Committee may visit the centre to perform inspections, including source data verification.

Power and sample size considerations

The sample size required for our current study was calculated using data from a pilot study of 40 patients, in which the largest difference in plasma troponin I concentration was found at 10 hours, with a mean ± standard deviation change from baseline of 0.41 ± 0.79 ng/L in the carbetocin group versus 1.78 ± 4.48 in the oxytocin group. The sample size calculation was thus based on 80% power to detect a between-group difference in change from baseline to 10 hours of 1.37, to be analysed using a two-sample T-test with adjustments for unequal variances. With a significance level of 5%, our study will need to include 178 patients (89 in each treatment group) in this confirmatory trial. To adjust for loss of information from missing values and patient dropouts, 240 women will be enrolled. The drop-out rate after enrolment is expected to be low as the duration of the study is short.

Analysis plan

The primary endpoint and all other continuous endpoints that include baseline and ≥1 follow-up measurement(s) will be analysed with linear regression models, with the follow-up measurement defined as the dependent variable and treatment group and baseline measurement defined as independent variables. Based on the fitted models, we will estimate treatment group differences in changes from baseline with 95% confidence intervals (CIs), together with a p-value for the null hypothesis of no treatment group difference. We expect at least some degree of skewness in the primary and some of the secondary endpoints, and maybe in the residuals from the linear regression models. The amount of skewness will be assessed with histograms and descriptive statistics, such as mean, median, variance, and the skewness index. In cases where the distribution of the residuals deviates markedly from the normal distribution, or when the endpoints themselves are too skewed to use means as measures of central tendency, we will use median regression models instead of linear regression models, thus analysing between-group differences in median changes from baseline instead of mean changes from baseline. Standard errors and CIs in the median regression models will be obtained via bootstrapping with 100 replications.

Continuous endpoints measured at a single time point will be analysed with two-sample T tests and 95% CIs for the difference between means based on the t distribution, with adjustment for unequal variances. Median regression will be used for variables with highly skewed distributions.

Binary outcomes will be analysed with Fisher mid-P tests and Newcombe hybrid score confidence intervals for the difference between probabilities.²² Ordered categorical outcomes will be analysed with score tests for effect in a proportional odds model (the Wilcoxon-Mann-Whitney test).²²

All analyses will be performed on the modified intention-to-treat population, comprising all patients included in the trial who received the study drug. AEs and vital signs will be presented with descriptive statistics. In addition, the primary endpoint will also be analysed in a sub-population that will comprise all participants who receive their allocated study drug and who do not require rescue treatment for uterine atony. Further details of the statistical methods, including definitions of the intention-to-treat and per protocol populations, how to handle missing data, and sensitivity and exploratory analyses are available in the Statistical Analysis Plan (SAP) available on the trial registration page.

Data dissemination plan

The results of the study will be published in an open-access peer-reviewed journal and deposited at the trial registration page. Requests for data sharing/case pooling may be directed to the project Principal Investigator: Professor Rosseland on email: lrossela@ous-hf.no.

Study status

The trial is actively recruiting at all sites.

Strengths and limitations

The study design is robust, the sample size based on a priori power calculations with parameters estimated from recent, relevant pilot data, and the trial will be conducted in a representative sample of pregnant women at three Norwegian birth clinics. Our study is enrolling women from general obstetric practice, including those with comorbidities such as gestational diabetes and hypertension. There is no upper limit for body mass index for participating women, and with an upper age limit of 50 years, nearly all women with singleton pregnancies at the three clinics will be eligible for inclusion. Women aged between 18 and 50 years make up approximately 25% of the Norwegian population.³¹ Although this is not an international study, many other countries in Europe have similar obstetric practices.

In 2019, a core outcomes set was published for prevention of post-partum haemorrhage to aid better comparison of clinical trials ensuring a minimum of outcomes to be reported.³² Our protocol was approved prior to its publication. Nevertheless, our study will assess seven out of nine of the core outcomes (blood loss, shock, transfer to higher level of care, use of additional haemostatic interventions and adverse events). We will not assess breastfeeding or patient satisfaction with treatment, but will report pain and pain relief medication.

All caesarean deliveries will be performed with standardized anaesthesia and surgery, including the meticulous blood pressure control to reduce cardiac troponin I due to spinal anaesthesia–induced hypotension and/or tachycardia. Both intraoperative tachycardia and hypotension are associated with myocardial injury after noncardiac surgery,³³ thereby, we are limiting an important confounding factor that may complicate the interpretation of our results.

As all participating women have to be able to read and understand Norwegian in order to provide informed consent, this may limit generalizability to diverse ethnic background to some extent. We will provide detailed demographic and baseline characteristics of all participating women.

In the analyses of direct and indirect costs, any potential drug specific long-term cardiac adverse events rate will not be included. We expect differences in health care costs between oxytocin and carbetocin cost to be minor.

Interpretation

Women with an obstetric history of pregnancy induced hypertension, gestational diabetes mellitus, preterm birth, placental abruption, and stillbirth are at increased risk of future cardiovascular disease.^34,35 Women undergoing caesarean delivery should be assessed for cardiovascular risk. Any additional ischaemic myocardial risk from uterotonic agents administered postpartum need to be balanced with the benefit of reducing the risk of postpartum haemorrhage. We anticipate that data from our study will help future clinical management decisions around planning delivery in pregnant women, including those with heart disease. As far as we can tell, no other study has compared the myocardial effects of oxytocin and carbetocin when used as postpartum uterotonic agents after caesarean delivery. We currently know little about troponin release after vaginal delivery and the role of uterontonics on troponin release in this population, which would require further investigation.

Extended data

Zenodo: Supporting material for article ‘A study protocol for the cardiac effects of a single dose of either oxytocin 2.5 IU or carbetocin 100 μg after caesarean delivery: a prospective randomized controlled multi-centre trial in Norway’, https://doi.org/10.5281/zenodo.5217789.³⁶

This project contains the following extended data:

Reporting guidelines

Zenodo: SPIRIT and TIDieR checklists for ‘A study protocol for the cardiac effects of a single dose of either oxytocin 2.5 IU or carbetocin 100 μg after caesarean delivery: a prospective randomized controlled multi-centre trial in Norway’, https://doi.org/10.5281/zenodo.5519494.³⁶

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).