Carbetocin Myocardium Trial 2014 Part 2

Study Overview
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Brief Summary
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Carbetocin has been in clinical use in EU for some years and the efficacy is documented in several RCTs. Circulatory adverse events leading to death has been reported after intravenous injection of oxytocin. Some studies indicate that oxytocin may lead to dose dependent ischemic ECG changes, prolongation of QT time and liberation of biomarkers of myocardial cell death. Previously the investigators have demonstrated comparable vasodilatory effects of oxytocin and carbetocin. 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.

Detailed Description
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Background -Treatment Caesarean delivery is a commonly performed surgical procedure. Uterus contraction after delivery of the baby is necessary to avoid excessive bleeding. 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. 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, but potential differences in adverse effects on myocardium are not well described yet. 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 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. 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. Some studies indicate that oxytocin may lead to dose dependent ischemic ECG changes, prolongation of QT time and liberation of biomarkers of myocardial cell death. Previously the investigators have demonstrated comparable vasodilatory effects of oxytocin and carbetocin. 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. STUDY OBJECTIVES The aims of this study are to compare 0h (before C-section) plasma concentrations of Troponin I (high sensitive methods) with a second measurement of plasma concentration of Troponin I drawn within an interval of 6 to 10 hours after administration of study drug, in elective healthy C-section patients randomized to oxytocin 2.5 U or carbetocin 100 µg, 1 minute injection immediately after delivery. Primary Endpoint Primary outcome measure is the difference in plasma concentration of Troponin I from baseline (0h) to the second measurement 6-10 hours after test drug administration, according to treatment allocation. Plasma concentrations will be collected before C-section, and at an interval of 6-10 h after test drug administration. 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

Official Title
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The Clinical Carbetocin Myocardium Trial Part 2

Conditions
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Pregnancy Complications

Intervention / Treatment
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* Drug: Oxytocin
* Drug: Carbetocin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy pregnant women age 18 to 50 Singleton pregnancy at gestational age 36 weeks or more Able to read and understand Norwegian. Patients will be recruited from the general population at the birth clinic at Oslo University Hospital or the birth clinic of Akershus 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. Exclusion Criteria: Patients with placenta pathology such as praevia, accreta, pre-eclampsia Patients with bleeding disorders including vonWillebrand disease type I. Known intolerance to one of the two drugs. Patients with prolonged QT-time or other serious cardiac diseases. Liver or kidney failure. Epilepsy. Any medical reason why, in the opinion of the investigator, the patient should not participate.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is a parallel, randomized, blinded phase 4 study (safety)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oxytocin<br>Oxytocin 2.5 U i.v. | Drug: Oxytocin<br>* Oxytocin 2.5 U i.v.<br>|
| Experimental: Carbetocin<br>Carbetocin 100 µg i.v. | Drug: Carbetocin<br>* Carbetocin 100 µg i.v.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration Troponin I | Group difference in Troponin I | 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Hct difference | Blood loss estimated by hematocrit | 8 hours | 
| Plasma concentraion NTproBNP | Group difference NTproBNP | 8 hours | 
| Uterine tone grade | Peroperative assessment of uterine tone grade 0-10 where 0 is no tonus, 10 is maximal tonus | 10 min | 
| Patient reported pain intensity (Numeric rating scale) | Group difference in postoperative pain (NRS 0-10 where 0 is no pain, 10 is Maximum pain intensity | 8 hours | 
| Side effects, patients reported palpitations | Peroperative side palpitations | 10 min | 
| Plasma concentration CK | Group difference in CK | 8 hours | 
| Plasma concentration Troponin T | Group difference in Troponin T | 8 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cesarean delivery, blood loss, troponin