Fibrinogen Concentrate as Initial Treatment for Postpartum Haemorrhage: A Randomised Clinically Controlled Trial

Condition(s) targeted: Postpartum Haemorrhage

Intervention: Fibrinogen Concentrate (Drug); Isotonic Saline (Drug)

Phase: Phase 2/Phase 3

Status: Recruiting

Sponsored by: Copenhagen University Hospital at Herlev

Official(s) and/or principal investigator(s):
Anne J. Wikkelsoe, MD, Principal Investigator, Affiliation: Department of Anaesthesiology, University Hospital of Herlev, Denmark
Ann M. Møller, MD, DmSc, Study Chair, Affiliation: Department of Anaesthesiology, University Hospital of Herlev, Denmark
Jakob Stensballe, MD, PhD, Study Chair, Affiliation: Blood Bank of Danish Capital Region, Rigshospitalet
Jens Langhoff-Roos, MD, DmSc, Study Chair, Affiliation: Department of Obstetrics, Juliane Marie Centre, Rigshospitalet
Arash Afshari, MD, Study Chair, Affiliation: Department of Anaesthesiology, Juliane Marie Centre, Rigshospitalet, Denmark
Hellen McKinnon Edwards, M.D., Study Chair, Affiliation: Dep. of Anaesthesiology, Herlev

Overall contact:
Anne Juul Wikkelsoe, MD, Phone: +45 44883595, Email: wikkelso@gmail.com

Severe maternal bleeding is a serious complication of birth and causes 125. 000 deaths worldwide each year. The investigators aim to investigate if early treatment with fibrinogen concentrate versus saline can reduce the incidence of blood transfusion in women with postpartum haemorrhage.

A low level of fibrinogen has been associated with increased blood loss and transfusion requirements in different clinical settings including obstetrical bleeding. Early up-front treatment with fibrinogen may reduce incidence of transfusion by securing optimal haemostatic capacity in women with postpartum haemorrhage.

The investigators plan to enrol 245 patients on four hospitals in the Capital Region of Denmark during a two year period.

As safety measure the investigators plan to use TEG®/Functional Fibrinogen/Rapid-TEG as haemostatic monitoring of all participants during the trial: Baseline test is taken at inclusion before administration of fibrinogen concentrate/placebo. Further tests are taken immediately after intervention, 4 hours and 24 hours after. Baseline test is blinded to the

providers of treatment - the rest is clinically available.

Official title: Fibrinogen Concentrate as Initial Treatment for Postpartum Haemorrhage - A Randomised Clinically Controlled Trial

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Supportive Care

Primary outcome: Incidense of transfusion with allogenic blood products

Secondary outcome:

Severe Postpartum Haemorrhage (PPH)

Estimated blood loss

Total amount of blood transfused

The development of re-bleeding

Hemoglobin level below 3,6 mmol/L

Side-effects including thromboembolic complications

Detailed description: Experimental design Design: We plan to conduct a randomised double-blinded clinically controlled trial: The participants are assigned to either 1) placebo (100 ml of isotonic saline) i. v. or 2) the intervention drug: 2 g of fibrinogen concentrate (Haemocomplettan, CSL Behring) i. v. We intend to use a fixed dose for all patients randomized to the intervention group without prior measurement of the fibrinogen level. This strategy is primarily based on the clinical urgency since the treatment is required to be administered as early as possible.

Materials and duration of study Patients will be included during a two year period at the four largest hospitals in the Capital Region: Rigshospitalet, Hvidovre, Hillerød and Herlev if they fulfil the following eligibility criteria Plan of trial execution In order to secure the ethical aspect "Time for reflection" we will provide all pregnant women who appear in the centres during the trial period with written information on the trial during their midwife evaluation. Only 1,75% of these women are estimated to meet the inclusion criteria postpartum.

Intensive haemostatic monitoring Haemostatic blood samples including thrombelastography (TEG®), functional fibrinogen-assay for TEG®, Rapid-TEG, fibrinogen-level, d-Dimer, INR (international normalized ratio), platelet count and Antithrombin III will be drawn 15 minutes after the intervention is given, 4 hours and 24 hours later. The samples taken after the intervention are fully available for evaluation by the clinicians responsible for the patient. The patient will be observed with blood pressure, pulseoximetry, ECG and possible side effects or re-bleeding will be evaluated.

Follow up The patients will remain hospitalized for a minimum of 24 hours. We will contact all participants by phone six weeks after the intervention. Upon discharge from the hospital, all included patients receive information-material addressing possible late side effects and a contact number.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Female.

Criteria:

Inclusion Criteria:

1. Informed consent from participant.

2. Women who develop PPH defined as bleeding from uterus and/or the birth canal within 24 hours postpartum.

3. Age ≥ 18 years.

4. If vaginal birth: indication of one of the following procedures at the operation theatre with anaesthetic assistance: a) Estimated blood loss ≥ 500 ml and indication of manual removal of placenta or b) Indication of manual exploration of the uterus due to continuous bleeding after the birth of placenta.

5. If birth by Caesarean section: A perioperative blood loss ≥ 1000 ml.

Exclusion Criteria:

1. Patients with known inherited deficiencies of coagulation.

2. Patients in anti-thrombotic treatment prepartum due to increased risk of thrombosis.

3. Patients with a pre-pregnancy weight <45 kg.

4. Patients who refuse to receive blood transfusion.

Anne Juul Wikkelsoe, MD, Phone: +45 44883595, Email: wikkelso@gmail.com

Juliane Marie Centre, Rigshospitalet, Copenhagen, Capital Region 2100, Denmark; Recruiting
Charlotte Albrechtsen, MD, Email: charlotte.krebs.albrechtsen@rh.regionh.dk
Heidi F Sharif, MD, Email: heidi.fosgrau.sharif@rh.regionh.dk
Charlotte Albrechtsen, MD, Principal Investigator
Kim Ekelund, MD, Sub-Investigator
Gabrielle Hanke, MD, Sub-Investigator
Erik S Secher, MD, Sub-Investigator
Marina Christensen, MD, Sub-Investigator
Benedicte Utke Ramsing, MD, Sub-Investigator
Peter Jensen-Gadegaard, MD, Sub-Investigator
Anna Engskov, MD, Sub-Investigator
Camilla Wulff, MD, Sub-Investigator
Marianne Berntsen, MD, Sub-Investigator
Kristian J Andersen, MD, Sub-Investigator

University Hospital of Herlev, Herlev, Capital Region 2730, Denmark; Recruiting
Anja Mitchell, MD, Email: aumi@heh.regionh.dk
Jens Svare, MD, Email: jesv@heh.regionh.dk
Anja Mitchell, MD, Sub-Investigator
Lone Fuhrmann, MD, PhD, Principal Investigator
Christian Viggo Nielsen, MD, Sub-Investigator
Michelé Lefort Sønderskov, MD, Sub-Investigator
Rasmus Winkel, MD, Sub-Investigator

University Hospital of Hilleroed, Hilleroed, Capital Region 3400, Denmark; Recruiting
Mette G Madsen, MD, Email: mgm@noh.regionh.dk
Birgit Boedker, MD, Email: bibod@noh.regionh.dk
Mette G Madsen, MD, Principal Investigator
Rasmus Berthelsen, MD, Sub-Investigator
Karen Elisabeth Linnet, MD, Sub-Investigator
Line Stendall, MD, Sub-Investigator

University Hospital of Hvidovre, Hvidovre, Capital Region 2650, Denmark; Recruiting
Ane Troelstrup, MD, Email: Ane.Troelstrup@hvh.regionh.dk
Jeannet Lauenborg, MD, Email: jeannet.lauenborg@hvh.regionh.dk
Ane Troelstrup, MD, Principal Investigator
Lars Moeller Pedersen, MD, Sub-Investigator
Mette Andersson, MD, Sub-Investigator

Trial website - information for potential patients entering the study during post delivery phase and information for staff at trial sites. (In danish only)

Starting date: May 2011
Last updated: December 11, 2012