Carbetocin Myocardium Trial 2014 Part 2
Condition: Pregnancy Complications
MeSH terms: Pregnancy Complications
Study type: Interventional
Phase: Phase 4

Summary: 
      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: 
      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
    

Intervention name(s): Oxytocin; Carbetocin
Intervention type(s): Drug; Drug
Intervention description(s): Oxytocin 2.5 U i.v.; Carbetocin 100 µg i.v.
Intervention MeSH terms: Oxytocin; Carbetocin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: The study is a parallel, randomized, blinded phase 4 study (safety)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: cesarean delivery; blood loss; troponin