SWIFT - SWIss Factor XIII Trial in PPH

Official title

Early Factor XIII Replacement in Postpartum Hemorrhage: Multi-center, Randomized, Controlled, Investigator-initiated Trial

Overview

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

Interventions

• Drug Fibrogammin
  Fibrogammin is administered according to the Summary of product characteristics (SmPC) after measured blood loss exceeds 700 ml and bleeding is ongoing

Primary outcome measures

• Blood Loss during post partum hemorrhage [Time frame: Day 1 (within 24 hours after delivery)]

Secondary outcome measures (7)

• Outcome of postpartum hemorrhage [Time frame: Time point of assessment will be 48 hours (range 36 to 60) postpartum, if not stated otherwise]
• Changes in hematological standard value: hemoglobin [Time frame: shortly before delivery and 48 hours (range 36 to 60 hours) after delivery]
• Changes in hematological standard value: leucocyte count [Time frame: shortly before delivery and 48 hours (range 36 to 60 hours) after delivery]
• Changes in hematological standard value; thrombocyte count [Time frame: shortly before delivery and 48 hours (range 36 to 60 hours) after delivery]
• Hospital costs [Time frame: from admission to hospital until hospital discharge, up to 9 weeks]
• Breastfeeding [Time frame: 6 - 9 weeks after delivery]
• Patient survey (in a subgroup of patients only) [Time frame: discharge from hospital, estimated 3 - 5 days after delivery]

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),

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Switzerland · 9 centers

• University Hospital Geneva — Geneva
• Cantonal Hospital Winterthur — Winterthur
• Spital Zollikerberg — Zollikerberg
• University Hospital of Zurich — Zurich
• Cantonal Hospital Baden — Baden
• University Hospital Basel — Basel
• Inselspital-University Hospital Bern — Bern
• University Hospital Lausanne — Lausanne
• … and 1 more center

Publications

• 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. PMID 25103301
• 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. PMID 27733286
• 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. PMID 25289730
• 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/ PMID 23586122
• 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. PMID 19194150
• 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. PMID 15502066
• 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. PMID 32176833
• Jacobs JW, Abels EA, Adkins BD, Booth GS, Costa V, Raza S, Simon M, Woo JS, Wheeler AP. Factor XIII Supplementation in Postpartum Hemorrhage: From Biological Rationale to Clinical Implementation. Am J Hematol. 2026 Apr;101(4):794-806. doi: 10.1002/ajh.70181. Epub 2025 Dec 31. PMID 41472522

Identifiers

NCT: NCT06481995 · BASEC 2024 - 00374

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗