The Clinical Carbetocin Myocardium Trial
Phase: PHASE4
Conditions: Pregnancy
Sponsor: Oslo University Hospital

 
 
 
 
 
 
The Clinical Carbetocin Myocardium Trial 
 
 
 
Protocol Identification Number:   CarbetocinHeart2014 
EudraCT Number:   2014-000507-27 
 
 
SPONSOR: 
Kristin Sem Thagaard 
Address Division of Emergencies and Critical 
Care, Oslo University Hospital, Box 4950 
Nydalen, 0424 Oslo, Norway 
Tel : +4723070000 
E-mail: E-mail: kristin.sem.thagaard@ous-hf.no 
 
PRINCIPAL INVESTIGATOR: 
Leiv Arne Rosseland, Professor DMSc MD 
Address Division of Emergencies and Critical 
Care, Oslo University Hospital, Box 4950 
Nydalen, 0424 Oslo, Norway 
Tel : +4723070000 
E-Mail: l.a.rosseland@medisin.uio.no  
 
 
 
PROTOCOL VERSION NO. 9  -  06-02-2020 
Included amendment 2  (if applicable) 

 
CarbetocinHeart2014  VERSION NO.9  - 06-02-2020 
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CONTACT DETAILS  
Sponsor: 
Kristin Sem Thagaard, MD 
Address Division of Emergencies and Critical Care, Oslo 
University Hospital, Box 4950 Nydalen, 0424 Oslo, Norway 
Tel : +4723070000 
E-Mail: kristin.sem.thagaard@ous-hf.no 
Coordinating Investigator: 
Leiv Arne Rosseland, Professor DMSc MD 
Address Division of Emergencies and Critical Care, Oslo 
University Hospital, Box 4950 Nydalen, 0424 Oslo, Norway 
Tel : +4723070000 
E-Mail: l.a.rosseland@medisin.uio.no 
Principal investigator: 
Leiv Arne Rosseland, Professor DMSc MD 
Address Division of Emergencies and Critical Care, Oslo 
University Hospital, Box 4950 Nydalen, 0424 Oslo, Norway 
Tel : +4723070000 
E-Mail: l.a.rosseland@medisin.uio.no 
 
 
 
 
Participating Departments: 
Department of Cardiology, OUH, Department of Cardiology, 
Vestre Viken Trust, Drammen, Department of Obstetrics and 
Gynecology, OUH, Department of Clinical Biochemistry, OUH, 
Department of Clinical Biochemistry, Vestre Viken Trust, 
Drammen, Department of Biostatistics and Epidemiology, OUH, 
Department of Clinical Research Support, OUH, Department of 
Pain Medicine, Division of Emergencies and Critical Care, OUH.
 
  
 
 
 
 
 
 
 

 
CarbetocinHeart2014  VERSION NO.9  - 06-02-2020 
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SPONSOR SIGNATURE PAGE 
 
Title 
The Clinical Carbetocin Myocardium Trial 
 
Protocol ID no: 
CarbetocinHeart2014  
EudraCT no: 
2014-000507-27 
 
Sponsor signatory approval 
 
I hereby declare that I will conduct the study in compliance with the Protocol, ICH GCP and the 
applicable regulatory requirements: 
 
Kristin Sem Thagaard (sponsor) 
Head of Department of Emergencies and Critical Care 
 
 
Sponsor signature 
 
Date 
 
 
PI signatory approval 
 
I hereby declare that I will conduct the study in compliance with the Protocol, ICH GCP and the 
applicable regulatory requirements: 
 
Leiv Arne Rosseland, 
Professor DMSc MD 
 
 
PI signature 
 
Date 

 
CarbetocinHeart2014  VERSION NO.9  - 06-02-2020 
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PROTOCOL SYNOPSIS 
 
The Clinical Carbetocin Myocardium Trial 
 
Investigational  
Medicinal Product:        
Carbetocin (Pabal®) inj + Oxytocin (Syntocinon®) inj 
Centers: 
Oslo University Hospital 
Study Period: 
 
Estimated date of first patient enrolled: 01-10-2014 
Anticipated recruitment period: 2 years 
Estimated date of last patient completed: 31-12-2016 
Treatment Duration: 
1 minute 
Follow-up: 
48 h 
Endpoints: 
Primary endpoint: plasma Troponin I concentrations 
 
Secondary endpoint: Troponin T, ProBNP, other relevant myocardial markers, blood 
loss, uterine tone, adverse events rate, pain, and ECG changes. 
 
 
Study Design: 
Parallel group, blinded, randomized comparison with oxytocin 
Main Inclusion Criteria:    
Healthy pregnant women for elective caesarean section age 18 to 50 years 
 
Sample Size: 
40 patients 
Efficacy Criteria: 
Blood loss 
Safety Criteria: 
Plasma concentration of myocardial biomarkers. Adverse events.  

 
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TABLE OF CONTENTS 
CONTACT DETAILS .......................................................................................................................................................... 2 
SPONSOR SIGNATURE PAGE ......................................................................................................................................... 3 
PROTOCOL SYNOPSIS .................................................................................................................................................... 4 
TABLE OF CONTENTS ..................................................................................................................................................... 5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................................................................ 7 
1 
INTRODUCTION ........................................................................................................................................................ 8 
1.1 
Background –Treatment ....................................................................................................................................... 8 
1.2 
Background - Therapeutic Information ................................................................................................................. 8 
1.3 
Pre-Clinical & Clinical Experience with Carbetocin (IMP) ..................................................................................... 8 
1.4 
Rationale for the Study ......................................................................................................................................... 8 
2 
STUDY OBJECTIVES ................................................................................................................................................ 8 
2.1 
Primary Endpoint .................................................................................................................................................. 9 
2.2 
Secondary Endpoints ........................................................................................................................................... 9 
3 
STUDY POPULATION ............................................................................................................................................... 9 
3.1 
Selection of Study Population ............................................................................................................................... 9 
3.2 
Number of Patients ............................................................................................................................................... 9 
3.3 
Inclusion Criteria ................................................................................................................................................... 9 
3.4 
Exclusion Criteria .................................................................................................................................................. 9 
4 
OVERALL STUDY DESIGN ..................................................................................................................................... 10 
5 
INVESTIGATIONAL MEDICINAL PRODUCT ......................................................................................................... 10 
5.1 
Dosage and Drug Administration ........................................................................................................................ 10 
5.2 
Duration of Therapy ............................................................................................................................................ 10 
5.3 
Premedication and Monitoring (if applicable) ...................................................................................................... 10 
5.4 
Schedule Modifications ....................................................................................................................................... 10 
5.5 
Concomitant Medication ..................................................................................................................................... 10 
5.6 
Subject Compliance ............................................................................................................................................ 11 
5.7 
Drug Storage and Accountability ........................................................................................................................ 11 
5.8 
Drug Labelling .................................................................................................................................................... 11 
o 
In Norwegian: FORSØKSMEDISIN I.V INJEKSJON ............................................................................. 11 
6 
STUDY PROCEDURES ........................................................................................................................................... 12 
6.1 
Flow Chart .......................................................................................................................................................... 12 
6.2 
By Visit ............................................................................................................................................................... 14 
6.2.1 
Before Treatment Starts ............................................................................................................................... 14 
6.2.2 
During Treatment ......................................................................................................................................... 14 
6.3 
Criteria for Patient Discontinuation ..................................................................................................................... 14 
6.4 
Procedures for Discontinuation .......................................................................................................................... 15 
6.4.1 
Patient Discontinuation ................................................................................................................................. 15 

 
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6.4.2 
Trial Discontinuation ..................................................................................................................................... 15 
6.5 
Laboratory Tests ................................................................................................................................................. 15 
7 
EFFICACY ASSESSMENTS .................................................................................................................................... 15 
7.1 
Assessment of Efficacy ...................................................................................................................................... 15 
    7.2  Biobank……………………………………………………………………………………………………………………..15 
8 
SAFETY ASSESSMENTS ....................................................................................................................................... 16 
8.1 
Definitions ........................................................................................................................................................... 16 
8.1.1 
Adverse Event (AE) ...................................................................................................................................... 16 
8.1.2 
Serious Adverse Event (SAE) ...................................................................................................................... 16 
8.1.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ...................................................................... 17 
8.2 
Expected Adverse Events .................................................................................................................................. 17 
8.3 
Time Period and Frequency of Dectecting AE and SAE .................................................................................... 17 
8.4 
Recording of Adverse Events ............................................................................................................................. 17 
8.5 
Reporting Procedure .......................................................................................................................................... 18 
8.5.1 
AEs and SAEs .............................................................................................................................................. 18 
8.5.2 
SUSARs ....................................................................................................................................................... 19 
8.5.3 
Annual Safety Report ................................................................................................................................... 19 
8.5.4 
Clinical Study Report .................................................................................................................................... 19 
8.6 
Procedures in Case of Emergency ..................................................................................................................... 19 
9 
RECORDING OF DATA AND SOURCE VERIFICATION ....................................................................................... 19 
9.1 
Case Report Forms (CRFs) ................................................................................................................................ 19 
9.2 
Source Data........................................................................................................................................................ 19 
9.3 
Source Data Verification ..................................................................................................................................... 20 
9.4 
Storage of Study Documentation ........................................................................................................................ 20 
10 STATISTICAL CONSIDERATIONS ......................................................................................................................... 21 
10.1 Determination of Sample Size ............................................................................................................................ 21 
10.2 Randomisation ................................................................................................... Feil! Bokmerke er ikke definert. 
10.3 Statistical Analysis .............................................................................................................................................. 21 
11 STUDY MANAGEMENT .......................................................................................................................................... 22 
11.1 Investigator Delegation Procedure ..................................................................................................................... 22 
11.2 Study Amendments ............................................................................................................................................ 22 
11.3 Audit and Inspections ......................................................................................................................................... 22 
12 ETHICAL AND REGULATORY REQUIREMENTS ................................................................................................. 22 
12.1 Ethics Committee Approval ................................................................................................................................ 22 
12.2 Other Regulatory Approvals ............................................................................................................................... 22 
12.3 Informed Consent ............................................................................................................................................... 23 
12.4 Subject Identification .......................................................................................................................................... 23 
13 TRIAL SPONSORSHIP AND FINANCING .............................................................................................................. 23 

 
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14 PUBLICATION POLICY ........................................................................................................................................... 23 
REFERENCES .................................................................................................................................................................. 23 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or special term 
Explanation 
AE 
Adverse Event  
CRF 
Case Report Form (electronic/paper) 
CSA 
Clinical Study Agreement 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Event 
DAE 
Discontinuation due to Adverse Event 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECG 
Electro Cardiography 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
MV 
MetaVision 
RCT 
Randomized Clinical Trial 
SAE 
Serious Adverse Event   
SD 
Stable Disease 
SDV  
Source Data Verification  
SOP  
Standard Operating Procedure  
 
 
.... 
.... 
.... 
.... 
.... 
.... 
.... 
.... 

 
CarbetocinHeart2014  VERSION NO.9  - 06-02-2020 
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1 
INTRODUCTION 
1.1 
Background –Treatment 
Caesarean delivery is a commonly performed surgical procedure. Uterus contraction after delivery of the baby is 
necessary to avoid excessive bleeding. 
1.2 
Background - Therapeutic Information 
Adequate uterus contraction after delivery of the baby is necessary to avoid excessive bleeding. Prophylactic 
administration of an oxytocin receptor agonist is first line practice. Intravenous injection of oxytocin has been the 
standard procedure but serious cardiovascular adverse events have been reported. By lowering the dose or administer 
the drug as a 5 minutes infusion may increase safety. Carbetocin, a synthetic oxytocin receptor agonist, has significantly 
longer half life and may reduce blood loss compared with oxytocin. The hemodynamic vasodilatory effects are 
comparable to oxytocin(1), but potential differences in adverse effects on myocardium are not well described yet.  
1.3 
Pre-Clinical & Clinical Experience with Carbetocin (IMP) and Oxytocin  
Carbetocin has been in clinical use in EU for some years and the efficacy is documented in several RCTs. In the 
proposed study, carbetocin will be used within the conditions of the marketing authorization. Oxytocin is the first line 
treatment and prophylaxis in Norway and most countries in the world. According to recently published goidelines fraom 
EU drug authorities (EMA) oxytocin should be given as a slow (5 minte) infusion in order to avoid hypotension. This has 
so far not been implemented in Norway. The pre-clinical and clinical experience of the two drugs are summarized in the 
Summaries of Product Characteristics. 
1.4 
Rationale for the Study 
Pregnancy and delivery is a natural process, but for many women this period is stressful and not without risks of 
morbidity, and even mortality. Circulatory adverse events leading to death has been reported after intravenous injection 
of oxytocin.(2) Some studies indicate that oxytocin may lead to dose dependent ischemic ECG changes(3;4), 
prolongation of QT time and liberation of biomarkers of myocardial cell death.(3) Previously we have demonstrated 
comparable vasodilatory effects of oxytocin and carbetocin.(1) There is no clinical study comparing the specific 
myocardial effects of oxytocin with carbetocin. It may have great impact on the choice of standard medication if the 
cardiotoxicity of carbetocin is lower compared with oxytocin. The study of potential cardiotoxicity has to be performed in 
healthy women. Knowing that millions of laboring women have had uneventful injections of oxytocin and carbetocin after 
delivery, there is probably no reason to fear long lasting negative effects of either drug. If there are differences in 
cardiotoxicity, this new information should be taken into consideration when planning delivery in pregnant women with 
heart disease. 
2 
STUDY OBJECTIVES 
The aims of this study are to compare 0h (before C-section), 4h, 12h, 24h, and 48h plasma concentrations of Troponin I 
(high sensitive methods), Troponin T, proBNP, CK, and other relevant myocardial markers in elective healthy C-section 
patients randomized to oxytocin 2.5 U or carbetocin 100 µg, 1 minute injection immediately after delivery. 

 
CarbetocinHeart2014  VERSION NO.9  - 06-02-2020 
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2.1 
Primary Endpoint  
Primary outcome measure is difference in the interaction of time*group in plasma concentration of Troponin I. Plasma 
concentrations will be collected before C-section, 4h, 12h, and 24h after test drug administration. If indicated by increase 
in some of the specific myocardial biomarkers (troponin T, CK, etc), which will be analyzed consecutively, an additional 
sample at 48h will be included. 
2.2 
Secondary Endpoints 
 
Other myocardial biomarkers 
 
Uterus tone evaluated repeatedly  
 
Blood loss (estimated calculated blood loss) 
 
Postoperative pain and side effects. 
 
BP, heart rate and ECG changes  
3 
STUDY POPULATION 
3.1 
Selection of Study Population 
3.2 
Number of Patients 
40 patients will be included in this trial. Based on analysis in this pilot trial, statistical power analysis and group size 
estimation will be performed in order to start a larger confirmatory study. This protocol will serve as protocol for the larger 
follow up study including up to 400 patients. Some endpoints may be omitted in this large randomized controlled trial.  
3.3 
Inclusion Criteria 
1. Healthy pregnant women age 18 to 50  
2. Singleton pregnancy at gestational age 36 weeks or more  
3. Able to read and understand Norwegian.  
4. Patients will be recruited from the general population at the birth clinic at Oslo University Hospital. Signed informed 
consent form (ICF) and expected cooperation of the patients for the treatment and follow up will be obtained 
and documented according to ICH GCP, and national/local regulations. 
3.4 
Exclusion Criteria 
1. Patients with placenta pathology such as praevia, acreta, pre-eclampsia 
2. Patients with bleeding disorders including vonWillebrand disease type I.  
3. Known intolerance to one of the two drugs.  
4. Patients with prolonged QT-time or other serious cardiac diseases.  
5. Liver or kidney failure.  
6. Epilepsy.  

 
CarbetocinHeart2014  VERSION NO.9  - 06-02-2020 
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7. Any medical reason why, in the opinion of the investigator, the patient should not participate. 
 
4 
Overall STUDY Design 
The study is a parallel, randomized, blinded phase 4 study (safety)   
Study Period 
 
Estimated date of first patient enrolled: 01-10-2014 
Anticipated recruitment period: 2 years 
Estimated date of last patient completed: 31-12-2016 
Treatment Duration: 
1 minute 
Follow-up: 
48h 
5 
INVESTIGATIONAL MEDICINAL PRODUCT  
5.1 
Dosage and Drug Administration  
Carbetocin (Pabal, Ferring Medical, Copenhagen, DK) 100 µg/ml, 1 ml diluted in normal saline to 5 ml will be injected 
slowly intravenously (1 minute duration). Control intervention is oxytocin (Syntocinon, Swedish Orphan Biovitrum, 
Stockholm, Sweden) 5 U/ml, 0.5 ml diluted in normal saline to 5 ml will be injected slowly intravenously (1 minute 
duration). 
5.2 
Duration of Therapy 
The IMPs will be injected slowly (1 minute). The patients will be followed 48h.  
 
5.3 
Premedication and Monitoring (if applicable) 
Preoperative blood sample will be analyzed for baseline values of interest regarding the study outcome measures 
(Troponin I (high sensitive methods) and other myocardial biomarkers). There will be no premedication. 
5.4 
Schedule Modifications 
N.a. 
5.5 
Concomitant Medication 
 
In case of uterus atony, patients will be treated with oxytocin 1 U every 2 minute up to maximum 5 U. Misoprostol 200 µg 
rectally will be given if need of a second drug mechanism. Any additional treatment of uterus, medical or surgical, will be 
decided by the attending obstetrician and anesthesiologist according to departmental procedures. Spinal anesthesia will 
be given according to study procedure (isobaric Bupivacaine 5 mg/ml 2 ml + fentanyl 50µg/ml 0.4 ml), hypotension 
prophylaxis (phenylephrine 0.1 mg/ml 0.25 µg/kg followed by infusion rate 0.25 µg/kg/min) and intravenous volume 
(normal saline 10 ml/kg starting concomitantly with spinal anesthesia ( see 6.2.2 for details). Pain treatment protocol 
includes oral paracetamol 1 g and ibuprofen 400 mg 4 times pr day and IV morphine administered according to 

 
CarbetocinHeart2014  VERSION NO.9  - 06-02-2020 
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departmental procedure using a patient controlled analgesia pump (PCA). All interventions, including all administered 
medication will be registered with doses and timing. 
5.6 
Subject Compliance 
N.a. 
5.7 
Drug Storage and Accountability 
Drug preparation will be immediately before administration and prepared syringe will be destroyed if not used within 24h 
after preparation. All IMP use will be accounted for with registration of amount used, date given, batch, expiry date and 
the trial participant the IMP has been given to. Both oxytocin and carbetocin are in routine use in the department of 
anesthesiology and are easily accessible for the person responsible for preparation of study drug.   
5.8 
Drug Labeling 
The investigational medicinal product will have a label permanently affixed to the outside and will be labeled according 
with ICH GCP and local regulations (4.4.”Merking av utprøvingspreparatet “in FOR 2009-10-30-1321 Forskrift om klinisk 
utprøving av legemidler til mennesker and Veiledning til forskrift av 30. oktober 2009 om klinisk utprøving av legemidler 
til mennesker versjon 2.0./8.-sept-2011.)  
o (In Norwegian)  
Til klinisk utprøving 
CarbetocinHeart2014 Batch nr:______ 
Ansvarlig: Dr.Rosseland (Tlf 92204274) 
PAS. NR. |__|__|   Oslo Universitetssykehus 
Til iv injeksjon (60 sek) 
Carbetocin 100 µg eller Oxytocin 2,5 IE  
Oppbevares i kjøleskap (2°C-8°C),  
Holdbar 24 t til kl |__|__|:|__|__| 
Dato: ………… Signatur: ……… 
 

 
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6 
STUDY procedures 
6.1 
Flow Chart 
 
 
Delivery of the baby and injection of study drug 
0
4
12
24
48
Screening of patients on their last visit to 
outpatients 
clinic 
before 
planned 
cesarean section 
Informed and consented 
Excluded  
Randomized to carbetocin 
Randomized to oxytocin 
Baseline measurements and data collection  

 
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Table 1.  Trial flow chart  
 
Screening Period 
Treatment 
Period 
Treatment 
Period 
Treatment 
Period 
Treatment Period 
End of 
study 
Time 
Within 
14 days 
of 
treatme
nt 
Within 2 
h of 
treatment 
Time 0 
(before C-
section) 
 
Time after 
C-section – 
0 - 30 min 
Time 4h 
 
 
Time 12h 
 
 
Time 24h 
Time 48h 
Time 48h 
Informed consent 
X 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
Evaluation 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Demographics1) 
 
 
X 
 
 
 
 
 
 
Vital signs2) 
 
 
X 
X 
 
 
 
 
 
Blood samples3) 
 
 
X 
 
X 
X 
X 
X 
X 
IMP 
administration/dispensation 
 
 
X 
 
X 
 
 
 
 
Uterine tone 
 
 
 
2.5 and 5 
min 
 
 
 
 
 
Adverse event, pain intensity 
 
 
X 
X  
X 
X 
X 
X 
X 
Record of concomitant 
medication 
 
X 
 
X 
X 
X 
X 
X 
X 
 
1. 
Demographics including pre-pregnant weight, actual weight, height, age, gestational weeks, parity at baseline.  
2. Blood pressure, heart rate, ECG, at baseline and until 30 min.  
3. Hb, Na, TropT, TropI, CK, CK-MB, ProBNP, etc. Sample after 48h only if Troponin T > 20 ng/L at 4h. 

 
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6.2 
By Visit 
6.2.1 
Before Treatment Starts  
Potentially eligible participants will be screened by the principal investigator for inclusion at their last midwife 
consultation before their scheduled delivery. An additional screening of psychological distress and pain 
catastrophizing will be administered by self-report during the visit in order to assess a potential association with 
adverse events (post-surgical pain). Oral and written information will be given to each woman at least 24 h before 
her delivery and written informed consent obtained before randomization. Consent (ICF), participation and 
redrawal of consent will be documented in electronic patient journal (see 9.2). Name of trial, eligibility, date of 
signed consent and randomization number will be documented. Screened, but not consented patients will be 
registered by number. Screened but not included due to exclusion criteria or unfulfillment of inclusion criteria will 
be registered by number and reason for non-inclusion/exclusion.  
 
6.2.2 
During Treatment 
Vital signs, preoperative pain status, and baseline blood samples will be registered before anesthesia. With the 
woman in a right lateral position, spinal anesthesia will be induced in the L2–L3 vertebral interspace, and 
bupivacaine 10 mg + fentanyl 20 μg injected through a 27 or 25-gauge non-traumatic needle. Concomitantly, we 
start a rapid i.v. infusion of saline 0.9 mg/ml (37°C, 10 ml/kg), a phenylephrine bolus (0.25 μg/kg) followed by a 
phenylephrine infusion (0.25 μg⋅kg−1⋅min−1). During surgery, the patient will be supine with an operating wedge 
under her right hip (19° Tempur pillow; Trulife®, Dublin, Ireland). Hypotension (systolic arterial pressure <90 
mmHg) is treated with an extra i.v. bolus of phenylephrine if the heart rate is above 60 beats/min or with i.v. 
ephedrine 5–10 mg if 60 beats/min or below. The level of anesthesia will be tested by cold sensation 5 min after 
spinal anesthesia as well as by pinching with surgical tweezers before horizontal skin incision (pfannenstiel). The 
study drug will be injected slowly, over the course of 60 s, starting when the baby’s head and shoulders is 
delivered. Exteriorization of the uterus is performed routinely according to departmental policy. The patient will be 
asked if she experienced any of the listed side effects, and to grade the intensity of the side effects as mild, 
moderate, or severe. The duration of the side effects will also be recorded. Side effects, pain intensity and 
medications will be registered until 48h. Registration of side effects will be performed 1, 2, 3, 4, 5 and 10 minutes 
after study drug administration. The rest of the observation period side effects will be registered when reported by 
the patient. 
The obstetrician in charge of the Cesarean delivery assess uterine tone  2.5, and 5 min after 
administration of study drug, using a numeric rating scale that range from 0 to 10, where a score of 0 means “no 
effect”, 10 means “maximal uterus contraction”, and 7 indicates “clinically satisfactory contraction”. This uterine 
contraction scale was introduced to the obstetricians before a previously published RCT. Because visual 
assessment of blood loss during delivery is of limited value, we will calculate estimated blood loss using the 
formula for calculated estimated blood loss as published by Stafford(5), revised with weight in kg (last 
measurement prior to operation), height in cm.(1) 
Routine assessments of newborn status are registered (Apgar 1 and 5 minutes, umbilical vein and artery 
acid-base status).  
 
 
 
 
6.3 
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: 
1. Voluntary discontinuation by the patient who is at any time free to discontinue her participation in the study, 
without prejudice to further treatment. 

 
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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 
6.4 
Procedures for Discontinuation 
6.4.1 
Patient Discontinuation 
Patients who withdraw or are withdrawn from the study, will stop further treatment.   
Patients who withdraw or are withdrawn from the study before randomization, will be replaced. 
6.4.2 
Trial Discontinuation 
The whole trial may be discontinued at the discretion of the sponsor (Kristin Sem Thagaard) or PI (Leiv Arne 
Rosseland) in the event of any of the following: 
 
Occurrence of AEs unknown to date in respect of their nature, severity and duration 
 
Medical or ethical reasons affecting the continued performance of the trial 
 
Difficulties in the recruitment of patients 
The principal investigator will inform the relevant regulatory authorities of the termination of the trial along with the 
reasons for such action. If the study is terminated early on grounds of safety, the relevant authorities should be 
informed within 15 days. 
6.5 
Laboratory Tests 
The aims of this study are to compare 0h, 4h, 12h, and 24h plasma concentrations of Troponin I (high sensitive 
methods) and other myocardial biomarkers. Blood samples are collected by laboratory personnel who also store 
the plasma aliquots in the biobank freezer. The project will establish a research biobank at Oslo University 
Hospital. Some blood tests will be analyzed consecutively at Oslo University Hospital. Some biomarkers of 
specific scientific interest, such as Troponin I  will be analyzed at Vestre Viken Trust, Drammen Hospital when the 
last patient has been included and after 48h follow up.  
7 
Efficacy assessments 
7.1 
Assessment of Efficacy 
The primary outcome measure is the interaction of time and plasma concentrations of Troponin I. Group 
differences in this variable and other biomarkers (secondary outcomes) will be analyzed after the end of this pilot 
trial (N=40). Decisions will be made regarding primary outcome measure and group size in the final study based 
on these calculations. Maximum number of participants in the final study is 400. 
7.2 
Biobank 
Blood samples will be handled by staff at Department of Clinical Biochemistry, OUH, stored in the 
specific biobank according to the internal regulations and procedures at OUH. 
 

 
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8 
Safety assessments 
The investigator is responsible for the detection and documentation of events meeting the criteria and definition of 
an adverse event (AE) or serious adverse event (SAE). Each patient will be instructed to inform the investigator 
immediately should they manifest any signs or symptoms they perceive as adverse. 
The safety data are the outcome measures in the study (cardiovascular biomarkers, continuous monitoring of vital 
signs, ECG, blood pressure) and the registration of side effects and adverse events during the continuous 
bedside communication with the patient. Troponin I (high sensitive method) will be analyzed after entering all data 
on the last patient. Hence, these lab results can not lead to changes in the study, but may affect the procedure in 
the main study that follows this pilot study. Other biomarkers, such as troponin T, will be analyzed consecutively 
as routine laboratory tests. Patients with troponin T at 4h is above 20 ng/L will have a second ECG at 24h and 
additional blood tests at 48h as clinically indicated follow up.  
. 
8.1 
Definitions 
8.1.1 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product and which does 
not necessarily have a causal relationship with this treatment.  
An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether 
or not related to the medicinal (investigational) product.  
The term AE is used to include both serious and non-serious AEs. 
Expected side effects are defined in 8.2. The participating patients will be informed about the expected side 
effects prior to inclusion and instructed to score grade of side effects every minute during the initial 5 minutes 
after injection and after 10 minutes. It is expected that all adverse events are unlikely after 10 minutes but 
possible AE occurring after 10 minutes will be registered until end of trial (48h). The patients are asked to grade 
the degree of side effects as mild, moderate and severe. In case of grades 4 and 5, according to NCI Common 
Terminology Criteria for Adverse Events, this will be registered by the investigator.  
Patient follow up will be completed 48h after injection and this defines the AE period. Unexpected AE/SAE will be 
reported, also after this period, until discharge from the hospital.  
 
8.1.2 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose:  
 
 
Results in death 
 
Is immediately life-threatening 

 
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 
Requires in-patient hospitalization or prolongation of existing hospitalization  
 
Results in persistent or significant disability or incapacity 
 
Is an important medical event that may jeopardize the subject or may require medical intervention to 
prevent one of the outcomes listed above. 
 
8.1.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
Adverse Reaction: all untoward and unintended responses to an investigational medicinal product related to any 
dose administered; 
 
Unexpected Adverse Reaction: an adverse reaction, the nature or severity of which is not consistent with the 
applicable product information. 
 
Suspected Unexpected Serious Adverse Reaction: Unexpected Adverse Reaction that: 
 
 
Results in death 
 
Is immediately life-threatening 
 
Requires in-patient hospitalization or prolongation of existing hospitalization  
 
Results in persistent or significant disability or incapacity 
 
Is a congenital abnormality or birth defect 
 
Is an important medical event that may jeopardize the subject or may require medical intervention to 
prevent one of the outcomes listed above. 
8.2 
Expected Adverse Events 
Expected side effects are feeling of warmth, chest pain, shortness of breath, palpitations, flushing, headache, 
nasal congestion, xerostomia, and metallic taste or other events or reactions listed in the SmPCs of the 
investigational medicinal products. Both drugs in the study will lead to vasodilatation with decrease in blood 
pressure and increasing heart rate.  
8.3 
Time Period and Frequency of Detecting AE and SAE  
The standard time period for collecting and recording AE and SAEs will be 0 to 48h after study drug injection for 
each patient. Unexpected AE/SAE will be reported also after this period until discharge from the hospital. 
During the course of the study all AEs and SAEs will be proactively followed up for each patient; events will be 
followed up to resolution. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
8.4 
Recording of Adverse Events 
If the patient has experienced adverse event(s), the investigator will record the following information in the CRF: 

 
CarbetocinHeart2014  VERSION NO.9  - 06-02-2020 
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 
The nature of the event(s) will be described by the investigator in precise standard medical terminology (i.e. 
not necessarily the exact words used by the patient). 
 
The duration of the event will be described in terms of event onset time and event ended data. 
 
The intensity of the adverse event will be described according to Common Terminology Criteria for Adverse 
Events version 4.0 (CTCAE). 
 
The Causal relationship of the event to the study medication will be assessed as one of the following: 
Unrelated: 
There is not a temporal relationship to investigational product administration (too early, or late, or 
investigational product not taken), or there is a reasonable causal relationship between non-investigational 
product, concurrent disease, or circumstance and the AE. 
 
Unlikely:  
There is a temporal relationship to investigational product administration, but there is not a reasonable causal 
relationship between the investigational product and the AE. 
 
Possible:  
There is reasonable causal relationship between the investigational product and the AE. Dechallenge 
information is lacking or unclear. 
 
Probable:  
There is a reasonable causal relationship between the investigational product and the AE. The event 
responds to dechallenge. Rechallenge is not required. 
 
Definite:  
There is a reasonable causal relationship between the investigational product and the AE.  
 
Comment: Dechallange – rechallange of IMPs is not possible in this patient population. 
 
8.5 
Reporting Procedure 
8.5.1 
AEs and SAEs 
All adverse events and serious adverse events that should be reported as defined in section 8.1.1 will be 
recorded in the patient's CRF. 
Every SAE will be documented by the investigator on the SAE pages (see CRF page 4). The initial report shall 
promptly be followed by detailed, written reports if necessary. The initial and follow-up reports shall identify the 
trial subjects by unique code numbers assigned to the latter. The principal investigator will inform the sponsor 
(Kristin Sem Thagaard,  Division of Emergencies and Critical Care, Oslo University Hospital) within 24h. 
The principal investigator keeps detailed records of all SAEs and performs an evaluation with respect to 
seriousness, causality and expectedness. 

 
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8.5.2 
SUSARs 
SUSARs will be reported to the Competent Authority. The following procedure will be followed: 
The sponsor will ensure that all relevant information about suspected serious unexpected adverse reactions that 
are fatal or life-threatening is recorded and reported as soon as possible to the Competent Authority in any case 
no later than seven days after knowledge by the sponsor of such a case, and that relevant follow-up information 
is subsequently communicated within an additional eight days. 
All other suspected serious unexpected adverse reactions will be reported in an unblinded manner to the 
Competent Authority concerned as soon as possible but within a maximum of fifteen days of first knowledge by 
the sponsor. In order to keep the investigator and other persons generating data to the study blinded, the 
unblinding and the reporting will be performed by Department of Clinical Research Support. 
SUSARs will be reported using the CIOMS form since Oslo University Hospital is not connected to 
EudraVigilance.  
8.5.3 
Annual Safety Report 
Once a year throughout the clinical trial, the sponsor will provide the Competent Authority with an annual safety 
report. The format will comply with national requirements and follow guidelines published at www.norcrin.no. 
8.5.4 
Clinical Study Report 
The adverse events and serious adverse events occurring during the study will be discussed in the safety 
evaluation part of the Clinical Study Report. 
8.6 
Procedures in Case of Emergency 
Medical treatment of serious events will be according to international guidelines described in local procedures in 
Oslo University Hospital (E-håndbok). The PI and the sponsor will decide how to handle each serious patient 
event. Emergencies will be treated as usual, by the personnel specially trained in relevant medical emergencies. 
9 
The investigator recording of data and source verification  
9.1 
Case Report Forms (CRFs) 
Case report forms (CRF) will be provided for the recording of all data. Data will be recorded legibly onto the 
record forms, in blue/black ink. The signature of the investigator will attest the accuracy of the data on each CRF. 
If any assessments are omitted, the reason for such omissions will be noted on the CRFs. Corrections, with the 
reason for the corrections if applicable, should be made legibly, dated and initialed. Correction fluid is not allowed.   
9.2 
Source Data  
The medical records for each patient should contain information which is important for the patient’s safety and 
continued care and to fulfill the requirement that critical study data should be verifiable. To achieve this, the 
medical records (MetaVision electronic anesthesia version (MV), or DIPS) of each patient should clearly describe 
at least: 
 
That the patient is participating in the study, e.g. by including the enrollment number and the study code 
(CarbetocinHeart2014)(MV); 

 
CarbetocinHeart2014  VERSION NO.9  - 06-02-2020 
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 
Date when ICF was obtained from the patient and statement that patient received a copy of the signed and 
dated ICF (DIPS); 
 
Results of all assessments confirming a patient’s eligibility for the study (DIPS); 
 
Diseases/patient history (past and current; both the disease studied and others, as relevant) (DIPS); 
 
Treatments given, changes in treatments during the study and the time points for the changes (MV);  
 
Non-Serious Adverse Events and Serious Adverse Events (if any) including causality assessments (MV);  
 
Date of, and reason for, discontinuation from study treatment (DIPS);  
 
Date of, and reason for, withdrawal from study (DIPS); 
 
Additional information according to local regulations and practice (DIPS). 
 
Some blood analyses will be analyzed consecutively (troponin T. proBNP, Na, K, Ck, CK-MB etc) and these 
data will be entered into the database when made available. 
Some biochemical analyses (troponin I) will be performed in one batch when all patients are included and the 
follow up period is over (48h). A biobank consisting of blood samples marked by patient number (not initials or 
any person identification) will be established. This biobank will consist of aliquots of plasma, stored in a 
certified biobank freezer (-70 °C), and transported to department of clinical biochemistry, Vestre Viken Trust– 
Drammen Hospital for final analyses. 
 
Electronic files, including the data from CRF entered into an electronic database software (FileMaker PRO), will 
be stored at the research server at Oslo University Hospital. This data storage is administered by the Data 
Inspectorate’s local representative who also will handle the application for approval of data storage and ICF.  
9.3 
Source Data Verification 
The investigator will be visited on a regular basis by the Clinical Study Monitor, who will check and collect 
completed CRFs, discuss the progress of the study and monitor drug usage according to ICH GCP. The 
monitoring will also include source data verification (SDV). 
All data will be entered into a computer database at Oslo University Hospital for further handling. 
Sponsor’s representatives, Department of Clinical Research Support, and Norwegian Medicines Agency will be 
allowed access to source data for source data verification in which case a review of those parts of the hospital 
records relevant to the study may be required. 
9.4 
Storage of Study Documentation 
The patient identification and the code list will be kept by the PI in a locked office. Patient files will be kept for the 
maximum period of time permitted by each hospital. The study documentation (CRFs, Site File etc) will be 
retained and stored during the study and for 15 years after study closure. All information concerning the study will 
be stored in a safe place inaccessible to unauthorized personnel. 

 
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10 
Statistical considerations 
10.1 
Determination of Sample Size:  
Based on the primary endpoint of interest, Troponin I, group size in order to detect statistically significant 
differences between the two treatments will be calculated. This is the first clinical study comparing these outcome 
measures and calculation of statistical power and group size estimations is not possible. The stage one of the 
study will be a parallel group (1:1 group size) randomized, double blinded study. After all data from the 40 
patients have been collected and the database is locked, a blinded analysis based on these study data will be 
performed by a medical statistician (Are Hugo Pripp). He will get access to outcome measures and information 
about treatment allocation, but not the actual treatment. Unblinding will be performed when all analyses have 
been done 
10.2 
Randomization and blinding 
After inclusion patients will be randomized to one of two arms. The randomization will be performed immediately 
before study start. The person responsible for preparing the syringes will open one sealed envelop with 
information about treatment allocation. Randomization list and envelops will be made by a researcher not 
involved in the data collection using an electronic random number generator or a randomization software. The 
randomization responsible will decide block size and if variable block size will be used.  
Everybody will be blinded to treatment allocation with the exception of the person responsible for preparing the 
syringes and the person generating the randomization list. These persons will not be the same as the one 
responsible for analysis of the trial data. Department of Clinical Research Support will be responsible for sending 
SUSARs to the Competent Authority and will also have a randomization list available. Unblinding of one or more 
patients will be performed by this third party only. 
There will be two sets of sealed envelopes containing the treatment allocation for the different patients; one set is 
kept by the personnel responsible for preparation of study drug and the other is kept by the principal investigator 
for emergency unblinding of one single patient, as described under 8.6.  
Blinding of study drug will be secured by using standard 10-ml syringes marked with information as described 
under 5.8.   
 
10.3 
Statistical Analysis 
The statistical test will be ANCOVA, probably MIXED MODEL in SPSS, or similar, for repeated measurements 
with main outcome group differences in the interaction of time and treatment allocation. Ho hypothesis will be no 
difference between the treatments. Level of statistical significance will be α<0.05 and 1-β 0.8. These principles 
will be utilized in both stage one of the study and the main study. 
Primary efficacy variable is troponin I. Intention to treat analyses will be performed and group differences in side 
effects will be analyzed and presented regardless of rejection of the H0 hypothesis or not. All data will be entered 
and locked in the database, and treatment allocation information will not be revealed until complete dataset are 
obtained in the main study. 
All adverse events, whether spontaneously reported by the patients or observed by the investigator, will be 
described and categorized both by their nature and severity using the NCI Common Terminology Criteria for 
Adverse Events, Version 4.03. An attempt to relate the incidence and severity of adverse symptoms to certain 
patient characteristics will be made.   

 
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11 
STUDY MANAGEMENT 
11.1 
Investigator Delegation Procedure 
The principal investigator is responsible for making and updating a “delegation of tasks” listing all the involved co-
workers and their role in the project. He will ensure that appropriate training relevant to the study is given to all of 
these staff, and that any new information of relevance to the performance of this study is forwarded to the staff 
involved. 
11.2 
Study Amendments 
If it is necessary for the study protocol to be amended, the amendment and/or a new version of the study protocol 
(Amended Protocol) will be notified to and approved by the Norwegian Medicines Agency and the Ethics 
Committee according to EU and national regulations. 
11.3 
Audit and Inspections 
Authorized representatives of a regulatory authority and Ethics Committee may visit the centre to perform 
inspections, including source data verification. Likewise the representatives from monitor may visit the center to 
perform an audit. The purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (ICH GCP), and any 
applicable regulatory requirements. The principal investigator will ensure that the inspectors and auditors will be 
provided with access to source data/documents. 
12 
Ethical and regulatory requirements 
The study will be conducted in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and are consistent with ICH/Good Clinical Practice and applicable regulatory requirements. Registration 
of patient data will be carried out in accordance with national personal data laws. 
12.1 
Ethics Committee Approval 
The study protocol, including the patient information and ICF to be used, will be approved by the regional ethics 
committee before enrolment of any patients into the study. 
The investigator is responsible for informing the ethics committee of any serious and unexpected adverse events 
and/or major amendments to the protocol as per national requirements. 
12.2 
Other Regulatory Approvals 
The protocol will be submitted and approved by the applicable competent authorities before commencement of 
the study, including local representatives of Data Inspectorate, Norway (“Personvernansvarlig” at Oslo University 
Hospital) and Norwegian Medicines Agency. 
The protocol will also be registered in www.clinicaltrials.gov before inclusion of the first patient. 

 
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12.3 
Informed Consent 
The investigator will give the patients full and adequate verbal and written information about the nature, purpose, 
possible risk and benefit of the study. They will be informed as to the strict confidentiality of their patient data, but 
that their medical records may be reviewed for trial purposes by authorized individuals other than their treating 
physician.  
It will be emphasized that the participation is voluntary and that the patient is allowed to refuse further 
participation in the protocol whenever she wants. This will not prejudice the patient’s subsequent care. 
Documented informed consent will be obtained for all patients included in the study before they are registered in 
the study. This will be done in accordance with the national and local regulatory requirements. The investigator is 
responsible for obtaining signed informed consent (ICF).  
A copy of the patient ICF will be given to the patients. The signed and dated ICF will be filed in the Investigator 
File binder and also scanned to be part of the patient’s electronic medical record at the hospital. 
The information will be given to potential participants at least 24h prior to registration of consent followed by 
randomization. 
12.4 
Subject Identification 
The investigator will keep a list of all patients (who have received study treatment or undergone any study specific 
procedure) including patient numbers, full names and last known addresses.  
The patients will be identified in the CRFs by patient number and birth year.  
Number of patients screened, informed, and non-consenting patients will also be registered. 
13 
Trial sponsorship and financing 
The study is supported by an unrestricted grant by Inven2 funds from the manufacturer of carbetocin (Pabal), 
Ferring Medical, Copenhagen, DK. The funds are assigned M61631. Other expenses will be covered by Division 
of Emergencies and Critical Care or the University of Oslo. After End of study data will be shared with Ferring 
Medical. Data will be handled confidentially and the purpose is contact with Regulatory institutions, and not for 
further analyses or publication. 
14 
Publication policy 
All personnel who have contributed significantly with the planning and performance of the study (Vancouver 
convention 1988) may be included in the list of authors. Collaborators (+ main responsibility) in the project are: 
Tore Henriksen (Obstetrician, patient recruitment, data collection), Department of Obstetrics, OUS, Are Hugo 
Pripp (Statistical analyses), Division of Biostatistics, OUS, Ole Geir Solberg (Cardiology), Dep. Of Cardiology, 
OUS, Olav Klingenberg (Biomarker analyses), Dep. Of Medical Biochemistry, OUS, Bjørn Jørgensen 
(Cardiology), Dep. Of Cardiology, Drammen Hospital, and Jon Norseth (Biomarker analyses), Dep. Of Medical 
Biochemistry, Vestre Viken Trust, Drammen Hospital, Luis G. Romundstad (Randomization), Dep. Of 
Anesthesiology, Division of Critical Care, OUS, and Silje Reme (pain sub-study), Dep. Of Pain Medicine, Division 
of Critical Care, OUS. In addition a PhD candidate working in the project will be appointed.  
REFERENCES 
 

 
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REFERENCE LIST 
 
 (1)  ROSSELAND LA, HAUGE TH, GRINDHEIM G, STUBHAUG A, LANGESAETER E. CHANGES IN 
BLOOD PRESSURE AND CARDIAC OUTPUT DURING CESAREAN DELIVERY: THE EFFECTS OF 
OXYTOCIN AND CARBETOCIN COMPARED WITH PLACEBO. ANESTHESIOLOGY 2013 
SEP;119(3):541-51. 
 (2)  THOMAS TA, COOPER GM. MATERNAL DEATHS FROM ANAESTHESIA. AN EXTRACT FROM WHY 
MOTHERS DIE 1997-1999, THE CONFIDENTIAL ENQUIRIES INTO MATERNAL DEATHS IN THE 
UNITED KINGDOM. BR J ANAESTH 2002 SEP;89(3):499-508. 
 (3)  MORAN C, NI BM, GEARY M, CUNNINGHAM S, MCKENNA P, GARDINER J. MYOCARDIAL 
ISCHAEMIA IN NORMAL PATIENTS UNDERGOING ELECTIVE CAESAREAN SECTION: A 
PERIPARTUM ASSESSMENT. ANAESTHESIA 2001 NOV;56(11):1051-8. 
 (4)  JONSSON M, HANSON U, LIDELL C, NORDEN-LINDEBERG S. ST DEPRESSION AT CAESAREAN 
SECTION AND THE RELATION TO OXYTOCIN DOSE. A RANDOMISED CONTROLLED TRIAL. BJOG 
2010 JAN;117(1):76-83. 
 (5)  STAFFORD I, DILDY GA, CLARK SL, BELFORT MA. VISUALLY ESTIMATED AND CALCULATED 
BLOOD LOSS IN VAGINAL AND CESAREAN DELIVERY. AM J OBSTET GYNECOL 
2008;199(5):E511-E517. 
 
 
 

1 
 
 
 
CMT2014 
Statistical Analysis Plan (SAP) 
Version: V1-5 
Author: Leiv Arne Rosseland, Maria Egeland Bøgh Bekkenes, Morten Wang Fagerland 
Date: 25-05-2021 
 

2 
 
APPROVAL PAGE 
 
 
 
Biostatistician Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital 
 
 
Signature: 
_________________________________ 
 
 
Morten Wang Fagerland, PhD MSc 
 
Date:   
_________________________________ 
 
 
 
 
Principal Investigator/Project Leader 
 
 
Signature: 
_________________________________ 
 
 
Leiv Arne Rosseland, MD PhD 
 
Date:  
_________________________________ 
 
 
 
 
 
 

3 
 
1.0 
INTRODUCTION 
 
Adequate uterus contraction after delivery of the baby is necessary to avoid excessive 
bleeding. Prophylactic administration of an oxytocin receptor agonist is first line practice. 
Intravenous injection of oxytocin has been the standard procedure, but serious 
cardiovascular adverse events have been reported. Lowering the dose or administering the 
drug as a 5-minute infusion may increase safety. 
Carbetocin, a synthetic oxytocin receptor agonist, has significantly longer half-life, and may 
reduce blood loss compared with oxytocin. The hemodynamic vasodilatory effects are 
comparable to oxytocin(1), but potential differences in adverse effects on myocardium are 
not well described yet.  
Carbetocin has been in clinical use in EU since 2007, and the efficacy is documented in 
several RCTs. In the proposed study, carbetocin will be used within then conditions of the 
marketing authorization. Oxytocin is the first line treatment and prophylaxis in Norway and 
most countries in the world.  
According to recently published guidelines from EU drug authorities (EMA), oxytocin should 
be given as a slow 5-minute infusion in order to avoid hypotension. This has so far not been 
implemented in Norway. The pre-clinical and clinical experience of the two drugs are 
summarized in the Summaries of Product Characteristics. 
 
Pregnancy and delivery is a natural process, but for many women this period is stressful and 
not without risks of morbidity, and even mortality. Circulatory adverse events leading to 
death have been reported after intravenous injection of oxytocin(2). Some studies indicate 
that oxytocin may lead to dose dependant ischemic ECG changes(3, 4), prolongation of QT 
time and liberation of biomarkers of myocardial cell death(3). 
Previously we have demonstrated comparable vasodilatory effects of oxytocin and 
carbetocin(1). There is no clinical study comparing the specific myocardial effects of oxytocin 
with carbetocin. It may have great impact on the choice of standard medication if the 
cardiotoxicity of carbetocin is lower compared with oxytocin. The study of potential 
cardiotoxicity has to be performed in healthy women. Knowing that millions of labouring 
women have had uneventful injections of oxytocin and carbetocin after delivery, there is 
probably no reason to fear long lasting negative effects of either drug. Improved knowledge 
about the effects of the two drugs on heart and circulation will aid treatment decisions 
especially for women with underlying heart disease or hypertensive complications of 
pregnancy, but even for healthy women undergoing caesarean delivery.  
 
The aim of the pilot study is to compare 0h (before C-section), 4h, 10h and 24h plasma 
concentrations of troponin I (highly sensitive methods), troponin T, NT-proBNP, CK-MB and 
other relevant myocardial markers and ECG changes in elective healthy C-section patients 
randomized to oxytocin 2.5 U or carbetocin 100 µg, by 1-minute injection immediately after 
delivery.      
 
Based on the results from the pilot trial, sample size calculation for the main trial (CMT2) will 
be performed to answer which of the drugs causes more release of high sensitive troponin I. 
 
Some clinical studies indicate that administering carbetocin will influence pain perception. 
One clinical study comparing carbetocin and oxytocin for prevention of PPH after caesarean 

4 
 
delivery, reported significantly reduced pain intensity in patients receiving carbetocin(5). A 
secondary analysis of postoperative opioid consumption in another clinical trial comparing 
hemodynamic effects of oxytocin and carbetocin, found a tendency of lower consumption of 
opioids in the carbetocin group, but the differences were not statistically significant(6).  
The CMT-pain trial, a substudy of the CMT trial, will be conducted to investigate group 
differences in reported pain intensity and opioid consumption. Information on the patients 
level of anxiety, depression and pain catastrophizing traits will be obtained prior to the 
operation. In addition, biobank material will be analysed for levels of inflammatory markers 
related to pain.  
 
 
2.0 
DATA SOURCE 
 
2.1  
Patients 
We will conduct a double blinded randomized controlled trial where healthy women 
undergoing C-section will receive either oxytocin or carbetocin immediately after delivery of 
the baby. Ratio between the groups will be 1:1.  
 
2.1.1  CMT pilot trial 
Forty patients will be recruited from the general population of the birth clinics of Oslo 
University Hospital (OUH). Based on blinded analysis in this pilot trial, statistical power 
analysis and group size estimation will be performed to prepare for a larger confirmatory 
main trial (CMT2). 
 
2.1.2 CMT2 trial 
240 patients will be included into the CMT2 trial from the general population of the birth 
clinics of OUH and Akershus University Hospital (AHUS).  
 
2.1.3 CMT pain trial 
This trial will include 40 patients from the pilot trial and the first 40 patients from the CMT2-
trial included at the birth clinic of OUH, Rikshospitalet.  
 
2.2  
Inclusion and exclusion criteria 
Inclusion criteria are healthy pregnant women aged 18 to 50, singleton pregnancy at 
gestational age 36 weeks or more, who are able to read and understand Norwegian.  
Patients with placenta pathology, bleeding disorders, organ failure, prolonged QT-time or 
other serious cardiac diseases, epilepsy or known intolerance to any of the two drugs will be 
excluded from entering the trial.  
 
2.3  
Follow-up and timing of measurements 
Patients will be followed for a period of 48 hours after the administration of study drug.  
In the pilot trial, blood samples will be drawn at 0h, before C-section (=baseline), and at 4h, 
10h and 24h after delivery (=test drug administration). The myocardial biomarkers including 
high sensitive troponin I, troponin T, CK, CK-MB and NT-proBNP will be measured at all time 
points. If indicated by increase in some of the specific biomarkers, which will be analysed 
consecutively, an additional sample at 48h will be included. 
 

5 
 
 
During the C-section the patients will be attached to a Holter-monitor that will allow us to 
read ECG changes that are triggered by administration of test drug. The first ten minutes 
immediately following administration of study medicine will be evaluated for ST-segment 
changes, duration of ST-segment changes, prolonged QT-time and occurrence of arrhythmia. 
Data on ECG changes will be analysed only in the pilot trial. 
 
In the CMT2 trial, blood samples of high sensitive troponin I and levels of sodium and 
hemoglobin will be measured at 0h and at an interval of 6-10h after study drug 
administration. 
 
Data on uterine contraction, routine assessments of newborn status, side effects of test 
drug, consumption of analgesics and reported level of postoperative pain, nausea and 
tiredness will be obtained. Prior to the C-section patients will be asked to fill in standardized 
self-reporting forms designed to determine level of anxiety, depression and pain 
catastrophizing traits.  
 
 
3.0 
STUDY OBJECTIVES 
 
3.1 
Primary objectives 
 
3.1.1  CMT pilot trial  
To measure the difference between oxytocin and carbetocin in changes over time in 
Troponin I release from baseline to 24h after test drug administration, and ECG changes 
from baseline to 10 minutes after test drug administration.   
 
3.1.2 CMT2 trial 
To measure the difference between oxytocin and carbetocin in changes over time in 
Troponin I release from baseline to an interval of 6-10h after test drug administration.   
 
3.1.3 CMT pain trial 
To measure the difference between oxytocin and carbetocin in changes over time in opioid 
consumption and reported pain intensity from baseline to 48h after test drug 
administration.   
 
3.2 
Secondary objectives 
Plasma levels of sodium, hemoglobin and myocardial biomarkers such as troponin T, CK, CK-
MB and NT-proBNP will be analysed for group differences in changes over time.  
 
A study biobank is established both for the CMT pilot trial and the CMT2 trial. 
 
To measure the difference between oxytocin and carbetocin in: uterine tone, blood loss, 
perioperative side effects, postoperative pain and side effects, consumption of analgesics, 
ECG changes, and time consumption from time of delivery till end of surgery. 
 

6 
 
To describe the relationship between the preoperative reported level of anxiety, depression 
and pain catastrophizing trait and opioid consumption and pain intensity during the first 48 
hours after caesarean delivery. 
 
3.3 
Explorative objectives 
We expect further analysis to be performed on the data set that may generate separate 
analysis and publications.  
 
3.4 
Study design 
The study is designed as a double-blinded randomized controlled trial including healthy 
singleton pregnant women undergoing Caesarean delivery. The participants will be 
randomized 1:1 to oxytocin 2.5 U or carbetocin 100µg, 1-minute injection immediately after 
delivery.  
 
3.4.1 CMT pilot trial 
40 patients will be included from the birth clinics of OUH. 
 
3.4.2 CMT2 trial 
240 patients will be included from the birth clinics of OUH and AHUS. 
 
3.4.3 CMT pain trial 
40 patients from the pilot trial and the first 40 patients from the CMT2 trial included at OUH, 
Rikshospitalet will be included in the trial.  
 
 
4.0 
HYPOTHESIS AND DECISION RULES 
 
4.1 
Primary endpoint and statistical hypotheses 
The protocol is designed to investigate group changes over time in patients receiving 
carbetocin compared to oxytocin.  
 
The primary null hypothesis states that there is no difference between the treatment 
groups. The alternative hypothesis states that the changes over time differ between the 
treatment groups. 
 
4.1.1 CMT pilot trial 
The primary endpoint of interest is the treatment difference in changes over time in high-
sensitive troponin I levels, measured at baseline 4h, 10h, and 24h after drug administration.  
 
4.1.2 CMT2 trial 
The primary endpoint is the treatment difference in changes over time in high-sensitive 
troponin I levels, measured at baseline and at an interval of 6-10h after drug administration.  
 
4.1.3 CMT pain trial 
The primary endpoint is treatment difference in opioid consumption and reported pain 
intensity within the first 48h after test drug administration.  
 

7 
 
 
 
4.2 
Statistical decision rule 
The primary and all secondary outcomes will be analysed with two-sided tests and 
confidence intervals and a statistical significance level of 5%.  
 
 
5.0 
ANALYSIS SETS 
 
5.1 
Enrolled 
The enrolled set will include healthy singleton pregnant women undergoing Caesarean 
delivery at the birth clinics at OUH or AHUS, who have provided informed consent and have 
been included into the study data base.  
 
5.2 
Full analysis set 
The full analysis set will be defined as all enrolled patients randomly assigned to a treatment 
group having received the study drug.  
 
The patients are included in the study at an interval of 1-14 days prior to the set date of the 
planned C-section. Some of the patients will go into active labor prior to the planned date, 
and some of the planned C-sections will be shifted to an inconvenient time point for study 
completion due to competing acute activity at the maternity ward. These patients will be 
included in the study, but will end their study participation prior to receiving the study drug. 
The same is true for patients requiring general anaesthesia due to inadequate effect of 
spinal anaesthesia.   
A modified intention to treat analysis will be performed on all the patients included in the 
study having received the study drug. 
 
5.3 
Safety analysis set 
The safety analysis set will be equal to the full analysis set. 
 
5.4 
Per protocol analysis set 
The per protocol analysis set will include all randomised patients meeting the study eligibility 
criteria and with no major protocol deviations affecting the treatment efficacy.  
Major protocol deviations include entering into active labor prior to set date of planned C-
section, planned C-section shifted to an inconvenient time point for study completion due to 
competing acute activity at the maternity ward, and need for general anaesthesia due to 
inadequate effect of spinal anaesthesia.  
 
5.5  
Treatment misallocation 
If patients were randomized but not treated, the patients will appear on the study flowchart 
as randomized but not treated. This is the extent of how much the patient will be reported. 
 
5.6 
Protocol deviation  
The following sections describe any protocol deviations that relate to the statistical analyses 
and forms the requirements for exclusion from the PPS. 
 

8 
 
5.6.1 Deviations to inclusion and/or exclusion criteria 
Any patient who enters the study when the inclusion or exclusion criteria would have 
prevented entry, will be considered to have had a protocol deviation.  
 
5.6.2 Deviations assessed post-randomization 
Any patient who withdraw their consent during the observation period of 48 hours following 
administration of study medicine.  
Randomised patients that for any medical reason will be prevented from completing the 
study according to study protocol.  
 
 
6.0 
ASSESSMENT, DEFINITION AND DERIVED VARIABLES 
 
6.1 
Primary outcome: High sensitive troponin I 
Level of troponin I is measured at baseline (before administration of test drug) and at fixed 
time points following administration of test drug, and is a continuous variable measured in 
ng/L. 
 
6.1.1 CMT pilot trial 
Level of troponin I is measured at baseline and at 4, 10, 24 and if necessary 48 hours after 
study drug administration. 
 
6.1.2 CMT2 trial 
Level of troponin I is measured at baseline and at an interval of 6-10 hours after study drug 
administration. 
 
6.2 
Secondary outcomes 
 
6.2.1 Other myocardial biomarkers. 
The following myocardial biomarkers will be analysed at the same time points in the CMT 
pilot trial. 
 Troponin T, a continuous variable measured in ng/L. The lower detection level of 
troponin T is 5 ng/L.  
 CK, a continuous variable measured in U/L. 
 CK-MB, a continuous variable measured in µg/L. The lower detection level of CK-MB is 1 
µg/L. 
 NT-proBNP, a continuous variable measured in ng/L. The lower detection level of NT-
proBNP is 50 ng/L. 
 
All measurements of biomarkers below their detection limits will be randomly imputed from 
a uniform distribution with lower limit equal to 0 and upper limit equal to the detection 
limit. 
 
6.2.2 Other blood analyses 
The following analyses will be performed at the same time points as for analysis of troponin 
I, for the CMT pilot trial at 0, 4, 10 and 24 hours and for the CMT2 trial at 0 and 6-10 hours 
after study drug administration.  

9 
 
 Hemoglobin, a continuous variable measured in g/100ml. 
 Sodium (Na), a continuous variable measured in mmol/L 
 Biobank analyses, continuous variables measured in units according to the specific 
variable. 
 
6.2.3 Uterine tone 
Uterine tone will be evaluated by obstetrician in charge of the C-section at 2.5 and 5 minutes 
after test drug administration 
A numeric rating scale ranging from 0-10 is used (0 = no effect, 7 = clinically satisfactory 
contraction, 10 = maximal uterus contraction). The variable will be treated as continuous in 
the statistical analyses. 
 
In case of need for additional uterotonic agent(s) for adequate uterine tone, time to rescue 
medication will be reported as a continuous variable in minutes. 
 
6.2.4 Blood loss 
Blood loss will be estimated by the formula for calculated blood loss as published by 
Stafford, revised with weight in kg and height in cm(7). 
A continuous variable measured in mL. 
 
6.2.5 Perioperative side effects. 
During the first 10 minutes after administration of test drug, the patient will be asked to 
report any side effects. Severity of side effects will be registered in time gaps as follows 0-2 
min, 2-5 min and 5-10 min.  
Severity of side effects is an ordered categorical variable:  
 0 = no side effects at the given point  
 1 = mild side effects 
 2 = moderate side effects 
 3 = severe side effects.  
 
Treatment given to alleviate side effects (a binary variable) will be registered as 
 0 = no treatment administered 
 1 = treatment administered 
 
6.2.6  Postoperative pain and side effects  
Pain at rest, pain after coughing, nausea and tiredness will be registered at 4h, 10h, 24h and 
48 h after administration of test drug in the CMT pilot trial.. 
A numeric rating scale ranging from 0-10 is used (0 = no discomfort, 10 = maximal discomfort 
imaginable). The variables will be treated as continuous in the statistical analyses. 
 
6.2.7 Consumption of analgesics 
Postoperative pain treatment protocol includes oral paracetamol 1 g and ibuprofen 400 mg 
4 times daily and IV morphine administered by a patient controlled analgesia pump (PCA).   
In the CMT pain trial, overall postoperative morphine consumption in mg will be measured, 
as well as morphine consumption in the time periods 0-4h, 4-10h, 10-24h and 24-48h after 
test drug administration. 
A continuous variable measured in mg. 

10 
 
 
6.2.8 QOL forms detecting level of anxiety, depression and pain catastrophizing trait  
Prior to the operation the patients will be asked to fill inn QOL forms detecting level of 
anxiety, depression and pain catastrophizing trait. Only in the CMT pain trial. 
 
6.2.8.1 Modified three simple questions 
A numeric rating scale ranging from 0-100 is used to rate anxiety, anticipated level of pain, 
need for analgesics and coping with motherhood (0 = not at all, 100 = to an extreme degree).  
The variables will be treated as continuous in the statistical analyses.  
 
6.2.8.2 Pain Catastrophizing Scale (PCS) 
PCS consists of 13 questions scored as follows. 
 0 = not at all 
 1 = to a slight degree 
 2 = to a moderate degree 
 3 = to a great degree 
 4 = all the time 
 
The overall score is achieved by summarizing the scores of the 13 questions. Results from 
the PCS will range from 0-52. The variable will be treated as continuous in the statistical 
analyses.  
 
A PCS score of ≥ 30 is considered to be associated with clinical relevance. Reported level of 
PCS ≥ 30 will be reported as a binary variable (PCS < 30 = 0, and PCS ≥ 30 = 1). 
 
6.2.8.3 Hopkins Symtom CheckList (HSCL-25) 
HSCL-25 consists of 25 questions measuring level of anxiety and depression. Each question is 
scored as follows. 
 1 = Not at all 
 2 = A little bit 
 3 = Quite a bit 
 4 = Extremely 
 
The value for HSCL-25 is obtained by calculating the mean score of the 25 questions. The 
variable will be reported as a continuous variable.  
 
HSCL-25 of ≥ 1.75 is considered clinically relevant, and will be reported as a binary variable 
(HSCL-25 < 1.75 = 0, HSCL-25 ≥ 1.75 = 1). 
  
6.2.9 ECG changes 
In the CMT pilot trial, the patients will be attached to a digital Holter monitor (Medilog AR4, 
Schiller) during the C-section to evaluate ECG changes during the first 10 minutes following 
administration of test drug.  
The following parameters will be registered: 
 Occurrence of ischemic episode (ST-segment depression of ≥ 0.1mV). Registered as a 
binary variable (no ischemic episode = 0, one/more ischemic episodes = 1) 
 Duration of ischemic episode. Continuous variable measured in seconds. 

11 
 
 Degree of ST-segment depression from baseline. Continuous variable measured in mV. 
 Beat to beat analysis of QT time corrected according to Framingham. Continuous 
variable measured in msec. 
 Occurrence of arrhythmia. Registered as a binary variable (no episodes of arrhythmia = 0, 
one/more episodes of arrhythmia = 1) 
 
6.2.8 Time consumption 
Time consumption from time of delivery until end of surgery and from time of delivery to 
time of discharge form postoperative ward unit. 
A continuous variable measured in minutes.  
 
6.3 
Summary of endpoints (TABLE) 
 
OUTCOME 
ENDPOINT 
TYPE 
Primary 
Troponin I level 
Continuous 
Other myocardial markers 
Troponin T level 
Continuous 
 
CK level 
Continuous 
 
CK-MB level 
Continuous 
 
NT-proBNP level 
Continuous 
Other blood analyses 
Hemoglobin level 
Continuous 
 
Sodium level 
Continuous 
 
Biobank analyses 
Continuous 
Uterine tone 
Uterine tone 
Continuous 
 
Time till rescue, min 
Continuous 
Blood loss 
Calculated blood loss, ml 
Continuous 
Perioperative side effects 
Severity of side effects 
Ordered categorical 
 
Treatment of side effects 
Binary 
Postoperative pain and side eff. 
Pain at rest 
Continuous 
 
Pain after coughing 
Continuous 
 
Nausea 
Continuous 
 
Tiredness 
Continuous 
Consumption of analgetics 
Morphine consumption, mg 
Continuous 
QOL forms 
Modified three simple questions 
Continuous 
 
PCS 
Continuous 
 
PCS ≥ 30 
Binary 
 
HSCL-25 
Continuous 
 
HSCL-25 ≥ 1.75 
Binary 
ECG changes 
Occurrence ischemic episode 
Binary 
 
Duration ischemic episode, sec 
Continuous 
 
ST-segment depression, mV 
Continuous 
 
Prolonged QTc interval 
Binary 
 
Beat to beat analyses QTc interval Continuous 
 
Occurrence of arrhythmia 
Binary 
Time consumption 
Time consumption, min 
Continuous 
 
 

12 
 
7.0 
STATISTICAL METHODOLOGY 
 
7.1 
Sample size determination 
 
7.1.1 CMT pilot trial 
The predefined main outcome variable in this double blinded randomized controlled study is 
group differences in changes over time in high sensitive troponin I levels. This is the first 
clinical study comparing these outcome measures and calculation of statistical power and 
group size estimations are not possible. After all data from 40 patients (1:1 group size) have 
been collected, a blinded analysis based on these study data will be performed by a medical 
statistician, who will get access to outcome measures and information about treatment 
allocation, but not the actual treatment. Unblinding will be performed when all analyses 
have been completed. 
 
7.1.2 CMT2 trial 
Based on preliminary results of the CMT pilot trial, 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 a mean change of 1.78±4.48 in the oxytocin 
group. The sample size calculation was 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%, we will need to 
include 178 patients (89 in each treatment group) in the CMT2 trial. To adjust for loss of 
information from missing values and patient drop outs, 240 women will be enrolled. The 
drop-out rate after enrolment is expected to be low as the duration of the study is short. 
 
7.2 
Randomization 
After inclusion, patients will be randomized to one of two study arms. The randomization 
will be performed immediately before study start. The person responsible for preparing the 
study drug will be unblinded and not otherwise involved in patient treatment. Research 
personnel involved in patient treatment, data collection and analysis will not receive 
information about actual treatment allocation until all data has been collected and analyses 
have been completed. Randomization will be performed by a researcher not involved in the 
data collection. The randomization responsible will decide block size and if variable block 
size will be used. 
 
7.3 
Blinding 
All study participants will be blinded to the treatment allocation with the exception of the 
person responsible for preparing the study drug and the person generating the 
randomization list. These persons will not be the same as the one responsible for analysis of 
the trial data. Blinding of study drug will be secured by using standard 5 ml syringes marked 
with date and randomization number according to study protocol. 
 
 
7.4 
Statistical methods 
 
7.4.1 Primary and secondary analyses 

13 
 
The primary analysis will be a modified intention to treat analysis of the primary outcome 
(highly sensitive troponin I) on the full analysis set. 
 
Secondary analyses will be: 
1. A per protocol analysis on the primary outcome (troponin I) on the per protocol analysis 
set 
2. Modified intention to treat analyses of all secondary outcomes on the full analysis set 
3. Sensitivity analyses to examine the impact of missing data (Section 7.4.5) 
 
7.4.2 Repeated-measures continuous outcomes 
The primary endpoint and all other continuous endpoints, including baseline and ≥1 follow-
up measurements, 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 also 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. 
 
7.4.3 Continuous outcomes measured at single time points 
Continuous outcome variables measured at single time points will be analysed with two-
sample t-tests (and 95% confidence intervals for the differences between means), with 
adjustment for unequal variances (the Welch U test). In situations where the distribution of 
the variable is difficult to assess or deemed to be highly skewed, median regression models 
will be used instead of t-tests to test and estimate differences in medians. 
 
7.4.4 Categorical outcomes 
Binary outcomes will be analysed with Fisher mid-P tests and Newcombe hybrid score 
confidence intervals for the difference between probabilities. 
 
Ordered categorical outcomes will be analysed with score tests for effect in a proportional 
odds model (the Wilcoxon-Mann-Whitney test). 
 
7.4.5 Handling of missing data 
Due to a short interval of observation in the CMT trial, only 48 hours after test drug 
administration, we expect a low level of missing data in this trial.  
For categorical outcomes and continuous outcomes measured at one or two timepoints, a 
complete case analysis will be the primary analysis. In addition, sensitivity analyses will be 

14 
 
performed for the primary outcome, where missing data will be imputed according to the 
following scenarios: 
 
1. Best-case outcome in the oxytocin group and worst-case outcome in the carbetocin 
group. 
2. Worst-case outcome in the oxytocin group and best-case outcome in the carbetocin 
group. 
 
Best case outcome = group mean + 2SD 
Worst case outcome = group mean - 2SD, levels below 0 are set to 0. 
 
3. Group-specific mean values 
 
Similar sensitivity analyses for missing data will be performed for other continuous and 
categorical secondary end points, if the proportion of missing outcome values is greater than 
10%. Best and worst case for categorical variables will be the lowest or highest possible 
score according to each variable. For the binary variable occurrence of arrhythmia, for 
instance, best case score = 0 (no episodes of arrhythmia)  and worst case score = 1 
(one/more episodes of arrhythmia). 
 
Continuous variables measured at more than two time points will be analysed with linear 
mixed models (Section 7.4.2), which automatically handle missing data under the missing at 
random assumption. 
 
7.4.6 Statistical software 
StataSE version 16 (StataCorp LLC, College Station, TX) will be used for all statistical analyses, 
except analyses of categorical outcomes, which will be done with MATLAB version R2019b 
(MathWorks, Inc.). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

15 
 
8.0 References 
 
1. 
Rosseland LA, Hauge TH, Grindheim G, Stubhaug A, Langesaeter E. Changes in blood 
pressure and cardiac output during cesarean delivery: the effects of oxytocin and carbetocin 
compared with placebo. Anesthesiology. 2013;119(3):541-51. 
2. 
Thomas TA, Cooper GM. Maternal deaths from anaesthesia. An extract from Why 
mothers die 1997-1999, the Confidential Enquiries into Maternal Deaths in the United 
Kingdom. Br J Anaesth. 2002;89(3):499-508. 
3. 
Moran C, Ni Bhuinneain M, Geary M, Cunningham S, McKenna P, Gardiner J. 
Myocardial ischaemia in normal patients undergoing elective Caesarean section: a 
peripartum assessment. Anaesthesia. 2001;56(11):1051-8. 
4. 
Jonsson M, Hanson U, Lidell C, Norden-Lindeberg S. ST depression at caesarean 
section and the relation to oxytocin dose. A randomised controlled trial. BJOG. 
2010;117(1):76-83. 
5. 
De Bonis M, Torricelli M, Leoni L, Berti P, Ciani V, Puzzutiello R, et al. Carbetocin 
versus oxytocin after caesarean section: similar efficacy but reduced pain perception in 
women with high risk of postpartum haemorrhage. J Matern Fetal Neonatal Med. 
2012;25(6):732-5. 
6. 
Gawecka E, Rosseland LA. A secondary analysis of a randomized placebo-controlled 
trial comparing the analgesic effects of oxytocin with carbetocin: postcesarean delivery 
morphine equivalents. Anesth Analg. 2014;119(4):1004. 
7. 
Stafford I, Dildy GA, Clark SL, Belfort MA. Visually estimated and calculated blood loss 
in vaginal and cesarean delivery. Am J Obstet Gynecol. 2008;199(5):519.e1-7.