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Carbetocin Myocardium Trial 2014 Part 2 (CMT2014/2)

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ClinicalTrials.gov Identifier: NCT03899961
Recruitment Status : Recruiting
First Posted : April 2, 2019
Last Update Posted : April 4, 2019
Sponsor:
Collaborator:
University Hospital, Akershus
Information provided by (Responsible Party):
Leiv Arne Rosseland, Oslo University Hospital

Brief 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.

Condition or disease Intervention/treatment Phase
Pregnancy Complications Drug: Oxytocin Drug: Carbetocin Phase 4

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
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)
Masking Description: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: The Clinical Carbetocin Myocardium Trial Part 2
Actual Study Start Date : April 2, 2019
Estimated Primary Completion Date : January 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Oxytocin

Arm Intervention/treatment
Active Comparator: Oxytocin
Oxytocin 2.5 U i.v.
Drug: Oxytocin
Oxytocin 2.5 U i.v.

Experimental: Carbetocin
Carbetocin 100 µg i.v.
Drug: Carbetocin
Carbetocin 100 µg i.v.




Primary Outcome Measures :
  1. Plasma concentration Troponin I [ Time Frame: 8 hours ]
    Group difference in Troponin I


Secondary Outcome Measures :
  1. Blood Hct difference [ Time Frame: 8 hours ]
    Blood loss estimated by hematocrit

  2. Plasma concentraion NTproBNP [ Time Frame: 8 hours ]
    Group difference NTproBNP

  3. Uterine tone grade [ Time Frame: 10 min ]
    Peroperative assessment of uterine tone grade 0-10 where 0 is no tonus, 10 is maximal tonus

  4. Patient reported pain intensity (Numeric rating scale) [ Time Frame: 8 hours ]
    Group difference in postoperative pain (NRS 0-10 where 0 is no pain, 10 is Maximum pain intensity

  5. Side effects, patients reported palpitations [ Time Frame: 10 min ]
    Peroperative side palpitations

  6. Plasma concentration CK [ Time Frame: 8 hours ]
    Group difference in CK

  7. Plasma concentration Troponin T [ Time Frame: 8 hours ]
    Group difference in Troponin T



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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 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:

  1. Patients with placenta pathology such as praevia, accreta, 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.
  7. Any medical reason why, in the opinion of the investigator, the patient should not participate.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03899961


Contacts
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Contact: Leiv Arne Rosseland, PhD MD 92204274 ext 47 l.a.rosseland@medisin.uio.no
Contact: Maria Bekkenes, MD 47379384 ext 47 maeg1@ous-hf.no

Locations
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Norway
Akershus University Hospital Recruiting
Lørenskog, Norway
Contact: Vegard Dahl, MD PhD    91674604    vegard.dahl@ahus.no   
Division of Anaesthesia and Intensive Care Medicine, Oslo University Hospital - Rikshospitalet Recruiting
Oslo, Norway, 0027
Contact: Leiv Arne Rosseland, MD PhD    23073700 ext 47    l.a.rosseland@medisin.uio.no   
Contact: Maria Bekkenes, MD    23073700 ext 47    maeg1@ous-hf.no   
Sponsors and Collaborators
Oslo University Hospital
University Hospital, Akershus

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Responsible Party: Leiv Arne Rosseland, Professor PhD MD, Oslo University Hospital
ClinicalTrials.gov Identifier: NCT03899961     History of Changes
Other Study ID Numbers: 2014/1210
First Posted: April 2, 2019    Key Record Dates
Last Update Posted: April 4, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Leiv Arne Rosseland, Oslo University Hospital:
cesarean delivery
blood loss
troponin

Additional relevant MeSH terms:
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Pregnancy Complications
Oxytocin
Carbetocin
Oxytocics
Reproductive Control Agents
Physiological Effects of Drugs