Clinical trial NCT01359878: Fibrinogen Concentrate as Initial Treatment for Postpartum Haemorrhage: A Randomised Clinically Controlled Trial
Official title: Fibrinogen Concentrate as Initial Treatment for Postpartum Haemorrhage - A Randomised Clinically Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Postpartum Haemorrhage
Keywords: Postpartum haemorrhage
Postpartum bleeding
Postnatal bleeding
Fibrinogen concentrate
Transfusion
Haemostatis
Thrombelastography
Lead sponsor: Copenhagen University Hospital at Herlev
Sponsor class: OTHER
Collaborators: name: Rigshospitalet, Denmark
name: Copenhagen University Hospital, Hvidovre
name: Hillerod Hospital, Denmark
name: Blood Bank of the Danish capital region
name: Unit for monitoring of Good Clinical Practice Copenhagen University
name: Danish Council for Independent Research
name: Herlev Hospital
name: Laerdal Foundation
name: Aase and Ejnar Danielsens Foundation
name: The Foundation of 17.12.1981
name: Fonden til Lægevidenskabens Fremme
name: Hans og Nora Buchards Fond
name: Haemonetics Corporation
First posted: 2011-05-25
Enrollment: 249
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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.

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.

Eligibility 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.

Primary outcomes:
measure: Incidense of transfusion with allogenic blood products
timeFrame: During hospital stay or until 6 weeks postintervention
Secondary outcomes:
measure: Severe Postpartum Haemorrhage (PPH)
timeFrame: During hospital stay or until 6 weeks postintervention
measure: Estimated blood loss
timeFrame: During hospital stay During hospital stay or until 6 weeks postintervention
measure: Total amount of blood transfused
timeFrame: During hospital stay During hospital stay or until 6 weeks postintervention
measure: The development of re-bleeding
timeFrame: Untill follow-up 6 weeks postintervention
measure: Hemoglobin level below 3,6 mmol/L
timeFrame: During hospital stay or until 6 weeks postintervention
measure: Side-effects including thromboembolic complications
timeFrame: Untill 6 weeks postintervention
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Juliane Marie Centre, Rigshospitalet
state: Capital Region
city: Herlev
country: Denmark
facility: University Hospital of Herlev
state: Capital Region
city: Hilleroed
country: Denmark
facility: University Hospital of Hilleroed
state: Capital Region
city: Hvidovre
country: Denmark
facility: University Hospital of Hvidovre
state: Capital Region
Study officials:
affiliation: Department of Anaesthesiology, University Hospital of Herlev, Denmark
name: Anne J. Wikkelsoe, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Anaesthesiology, University Hospital of Herlev, Denmark
name: Ann M. Møller, MD, DmSc
role: STUDY_CHAIR
affiliation: Blood Bank of Danish Capital Region, Rigshospitalet
name: Jakob Stensballe, MD, PhD
role: STUDY_CHAIR
affiliation: Department of Obstetrics, Juliane Marie Centre, Rigshospitalet
name: Jens Langhoff-Roos, MD, DmSc
role: STUDY_CHAIR
affiliation: Department of Anaesthesiology, Juliane Marie Centre, Rigshospitalet, Denmark
name: Arash Afshari, MD
role: STUDY_CHAIR
affiliation: Dep. of Anaesthesiology, Herlev
name: Hellen McKinnon Edwards, M.D.
role: STUDY_CHAIR
References:
citation: Wikkelso AJ, Edwards HM, Afshari A, Stensballe J, Langhoff-Roos J, Albrechtsen C, Ekelund K, Hanke G, Secher EL, Sharif HF, Pedersen LM, Troelstrup A, Lauenborg J, Mitchell AU, Fuhrmann L, Svare J, Madsen MG, Bodker B, Moller AM; FIB-PPH trial group. Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial. Br J Anaesth. 2015 Apr;114(4):623-33. doi: 10.1093/bja/aeu444. Epub 2015 Jan 13.
citation: Wikkelsoe AJ, Afshari A, Stensballe J, Langhoff-Roos J, Albrechtsen C, Ekelund K, Hanke G, Sharif HF, Mitchell AU, Svare J, Troelstrup A, Pedersen LM, Lauenborg J, Madsen MG, Bodker B, Moller AM. The FIB-PPH trial: fibrinogen concentrate as initial treatment for postpartum haemorrhage: study protocol for a randomised controlled trial. Trials. 2012 Jul 17;13:110. doi: 10.1186/1745-6215-13-110.