Clinical trial NCT06481995: SWIFT - SWIss Factor XIII Trial in PPH
Official title: Early Factor XIII Replacement in Postpartum Hemorrhage: Multi-center, Randomized, Controlled, Investigator-initiated Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Postpartum Hemorrhage
Coagulation Disorder
Coagulation Factor Deficiency
Hemorrhage
Postpartum Complication
Keywords: Postpartum hemorrhage
coagulation factor XIII
Lead sponsor: University of Zurich
Sponsor class: OTHER
Collaborators: name: Swiss National Science Foundation, Switzerland
First posted: 2024-07-01
Enrollment: 988
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: multi- center, randomized, controlled
Primary purpose: TREATMENT

Brief summary: The goal of this trial is to determine if postpartum blood loss can be reduced by replenishing coagulation factor XIII (FXIII) at an early stage of postpartum hemorrhage (PPH).

Summary of current body of evidence:

* Morbidity and mortality due to PPH is rising.
* Current guidelines focus on replenishment of fibrinogen as an initial step in the treatment of PPH-related coagulopathy, despite non-conclusive evidence in all prospective trials.
* Trials from other specialties demonstrate a significant impact of FXIII on perioperative bleeding complications; a previous study at the University Hospital Zurich showed that pre-partum factor XIII activity had a strong association to postpartum blood loss.

Therefore, this nationwide, multi-center, randomized, controlled trial in multiple perinatal centers across Switzerland will be conducted. The goal is to determine if postpartum blood loss and PPH-related complications can be reduced by replenishing FXIII.

All participating women receive, according to the national guideline, 1g tranexamic acid (TXA) i.v. in case of PPH (measured blood loss \[MBL\] ≥ 500 mL) during the pre-study phase. Randomization takes place if bleeding continues and exceeds 700mL. The intervention group then receives FXIII (Fibrogammin®) according to approved dosage in addition to obstetric standard of care treatment for causes of PPH; the control group receives only standard of care treatment.

Detailed description: Postpartum hemorrhage (PPH) is a main reason for maternal mortality and morbidity. PPH, defined by the WHO as blood loss of 500 mL or more within 24 hours after delivery, causes about 30% of maternal deaths worldwide. The internationally observed trend towards increased PPH-related morbidity and mortality is disturbing and demands new strategies in the prevention and treatment of PPH.

Although the most frequent causes for severe PPH are believed to be uterine atony or retained placenta, virtually all cases of severe PPH lead to a disorder of the coagulation system which itself aggravates bleeding.

At the moment, most guidelines on coagulation management during PPH and expert opinions focus on the replenishment of coagulation factor I (fibrinogen) although three out of three randomized controlled trials with early or pre-emptive administration of fibrinogen during PPH were negative.

Based on earlier research, it was hypothesized that coagulation factor XIII (FXIII) might play a significant role in women with increased postpartum blood loss, because of its role in the establishment of blood clot stability and fibrinolytic resistance. This hypothesis was tested in a prospective diagnostic study involving 1300 parturient women at the University Hospital Zurich and showed that pre-partum factor XIII activity had a strong association to postpartum blood loss.

Therefore, this nationwide, multi-center, open-label, randomized controlled trial in major perinatal centers across Switzerland will be conducted. The goal is to determine if postpartum blood loss and PPH-related complications can be reduced by substitution of FXIII at an early stage of PPH.

Irrespective of the answer to the question whether FXIII is effective in the treatment of PPH, this trial will contribute to enhancing the comprehension of coagulopathy in the context of PPH

Eligibility criteria: Inclusion Criteria:

* planned vaginal delivery
* singleton vital pregnancy
* gestational age at delivery \>= 30+0 weeks
* maternal weight at admission for delivery \<100 kg

Exclusion Criteria:

* Antithrombotic therapy in pregnancy (therapeutic dosage) until admission for delivery (LMWH, UFH)
* diagnosis of preeclampsia (ISSHP classification , eclampsia or HELLP syndrome),
* known history of deep vein thrombosis or pulmonary embolism,
* known diagnosis of bleeding disorder or thrombophilia,
* known thrombocytopenia during second half of pregnancy with thrombocytes \< 100 G/L,
* known anemia during second half of pregnancy with Hb\<80 g/L,
* known sickle cell disease,
* known malignant tumor(s),
* participation in another study with investigational drug within the 30 days preceding and during the present study,
* inability to follow the procedures of the study, e.g. due to language problems,
* known or suspected non-compliance, drug or alcohol abuse.

Exclusion criteria prior randomization

* Maternal fever ≥39.0°C
* unplanned cesarean delivery is performed,
* Measured Blood Loss remains \< 700 mL after administration of 1g tranexamic acid .
* Postpartum hemorrhage due to occult bleeding (intra-abdominal, retroperitoneal, parametric),

Primary outcomes:
measure: Blood Loss during post partum hemorrhage
timeFrame: Day 1 (within 24 hours after delivery)
Secondary outcomes:
measure: Outcome of postpartum hemorrhage
timeFrame: Time point of assessment will be 48 hours (range 36 to 60) postpartum, if not stated otherwise
measure: Changes in hematological standard value: hemoglobin
timeFrame: shortly before delivery and 48 hours (range 36 to 60 hours) after delivery
measure: Changes in hematological standard value: leucocyte count
timeFrame: shortly before delivery and 48 hours (range 36 to 60 hours) after delivery
measure: Changes in hematological standard value; thrombocyte count
timeFrame: shortly before delivery and 48 hours (range 36 to 60 hours) after delivery
measure: Hospital costs
timeFrame: from admission to hospital until hospital discharge, up to 9 weeks
measure: Breastfeeding
timeFrame: 6 - 9 weeks after delivery
measure: Patient survey (in a subgroup of patients only)
timeFrame: discharge from hospital, estimated 3 - 5 days after delivery
Other outcomes:
measure: Thromboembolic events
timeFrame: 6 - 9 weeks after delivery (visit 4)
Locations:
city: Winterthur
country: Switzerland
facility: Cantonal Hospital Winterthur
state: Zurich
city: Zollikerberg
country: Switzerland
facility: Spital Zollikerberg
state: Zurich
city: Baden
country: Switzerland
facility: Cantonal Hospital Baden
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Bern
country: Switzerland
facility: Inselspital-University Hospital Bern
city: Genève
country: Switzerland
facility: University Hospital Geneva
city: Lausanne
country: Switzerland
facility: University Hospital Lausanne
city: Saint Gallen
country: Switzerland
facility: Cantonal Hospital St. Gallen
city: Zurich
country: Switzerland
facility: University Hospital of Zurich
Study officials:
affiliation: University of Zurich
name: Christian Haslinger, Prof. Dr.
role: STUDY_CHAIR
affiliation: University Hospital, Geneva
name: Begoña Martinez de Tejada, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Lausanne Hospitals
name: David Baud, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Basel, Switzerland
name: Beatrice Mosimann, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Cantonal Hospital St. Gallen
name: Tina Fischer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kantonsspital Baden
name: Leonhard Schäffer, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Spital Zollikerberg
name: Michael Winter, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Inselspital-University Hospital Bern
name: Jarmila Zdanowicz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cantonal Hospital Winterthur
name: Leila Sultan-Beyer, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Say L, Chou D, Gemmill A, Tuncalp O, Moller AB, Daniels J, Gulmezoglu AM, Temmerman M, Alkema L. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014 Jun;2(6):e323-33. doi: 10.1016/S2214-109X(14)70227-X. Epub 2014 May 5.
citation: GBD 2015 Maternal Mortality Collaborators. Global, regional, and national levels of maternal mortality, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016 Oct 8;388(10053):1775-1812. doi: 10.1016/S0140-6736(16)31470-2.
citation: Weeks A. The prevention and treatment of postpartum haemorrhage: what do we know, and where do we go to next? BJOG. 2015 Jan;122(2):202-10. doi: 10.1111/1471-0528.13098. Epub 2014 Oct 7.
citation: WHO Recommendations for the Prevention and Treatment of Postpartum Haemorrhage. Geneva: World Health Organization; 2012. Available from http://www.ncbi.nlm.nih.gov/books/NBK131942/
citation: Haslinger C, Korte W, Hothorn T, Brun R, Greenberg C, Zimmermann R. The impact of prepartum factor XIII activity on postpartum blood loss. J Thromb Haemost. 2020 Jun;18(6):1310-1319. doi: 10.1111/jth.14795. Epub 2020 Apr 16.
citation: Korte WC, Szadkowski C, Gahler A, Gabi K, Kownacki E, Eder M, Degiacomi P, Zoller N, Devay J, Lange J, Schnider T. Factor XIII substitution in surgical cancer patients at high risk for intraoperative bleeding. Anesthesiology. 2009 Feb;110(2):239-45. doi: 10.1097/ALN.0b013e318194b21e.
citation: Wettstein P, Haeberli A, Stutz M, Rohner M, Corbetta C, Gabi K, Schnider T, Korte W. Decreased factor XIII availability for thrombin and early loss of clot firmness in patients with unexplained intraoperative bleeding. Anesth Analg. 2004 Nov;99(5):1564-1569. doi: 10.1213/01.ANE.0000134800.46276.21.