Prevent Postpartum Hemorrhage in Women With Von Willebrand Disease: The VWD-WOMAN Trial

Prospective, Randomized Trial Comparing Recombinant Von Willebrand Factor (rVWF) Plus Tranexamic Acid vs. rVWF Alone to Reduce Postpartum Hemorrhage in Women With Von Willebrand Disease: The VWD-WOMAN Trial

This is a single-center randomized phase III clinical trial, the VWD-Woman Trial, in which 20 pregnant subjects with von Willebrand disease (VWD), defined as VWF ristocetin co-factor activity (VWF:RCo) <0.50 IU/ml (historic) and previous history of bleeding are enrolled. Subjects will include women with VWD age 18 years and older, excluding those who have a bleeding disorder other than VWD. Once enrolled, subjects who meet all of the inclusion and none of the exclusion criteria will be randomized to recombinant Von Willebrand factor (rVWF, Vonvendi ®) with Tranexamic Acid (TA, Cyclokapron®); or recombinant Von Willebrand factor (rVWF, Vonvendi®) alone to prevent postpartum hemorrhage after vaginal or caesarean delivery. The primary endpoint is quantitative blood loss (QBL) by a labor suite nurse at delivery. Secondary endpoints include safety assessment for postpartum lochial blood loss by Pictorial Blood Assessment Chart (PBAC), transfusion, blood products, thromboembolic events, and hysterectomy within 21 days; and mechanism of PPH reduction by VWF assays (VWF:RCo, VWF:Ag, VIII:C), fibrinogen, and d-dimer. Blood draws are at 5 time points, including at 36 weeks' gestation (screening), on admission for childbirth, and at 1 day, 2 days, and 21 days after delivery. The VWD-Woman Trial is considered greater than minimal risk as study drugs are given at delivery and special coagulation studies are obtained.

Study Overview

• Status: Completed
• Conditions: Postpartum Hemorrhage; Von Willebrand Diseases
• Intervention / Treatment: Drug: Recombinant Von Willebrand factor; Drug: Tranexamic Acid Injection [Cyklokapron]

Detailed Description

The purpose of this 8-week single center, randomized, open-label phase III trial to compare recombinant von Willebrand factor (rVWF, Vonvendi®)) plus tranexamic acid (TA, Cyclokapron®) vs. rVWF alone to prevent postpartum hemorrhage (PPH) in women with Von Willebrand disease (VWD). VWD is an inherited bleeding disorder that occurs in 1% of the population. It is caused by deficient or defective von Willebrand factor (VWF). Treatment at delivery is with VWF concentrate, based on U.S. and European guidelines, and as DDAVP, a non-VWF protein, is contraindicated as it may cause hyponatremia (low salt) and seizures due to fluid replacement at delivery. Yet, blood loss is 1.5-fold greater in VWD than non-VWD controls. The investigators believe this is due to physiologic (protective) fibrinolysis (clot breakdown) in the first 3 hours after delivery, which may protect controls from excess clotting after delivery, but which may increase bleeding in subjects with VWD. PPH a significant cause of maternal morbidity and mortality in women. PPH is defined as >1000 ml within the first 24 hours of vaginal or cesarean delivery. PPH peaks in the first 2-3 hours postpartum, a time during which there is early activation of the fibrinolytic system, with a 2-fold increase TPA (tissue plasminogen activator). So while uterine atony is the major cause of PPH, accounting for 63% of PPH cases, but in 37% of cases, uterotonic agents fail.

TA is an anti-fibrinolytic therapy (prevents clot breakdown) which reduces bleeding and prevents clot breakdown in surgery, trauma, and in controls at delivery, if it is given within 3 hours of delivery. In the WOMAN trial, a large trial of over 10,000 women without bleeding disorders, TA was safe and effective in reducing PPH when given intravenously (in a vein) within 3 hours of vaginal or cesarean delivery. As TA is approved by the US. Food and Drug Administration (FDA) to treat and prevent bleeding in VWD, the investigators propose to study rVWF plus TA vs. VWF alone to reduce PPH in subjects with VWD. This is a pilot study to determine if recruitment, randomization, and study drug administration can be performed successfully, and shows preliminary safety and efficacy in subjects with VWD. rVWF (Vonvendi®) will be administered by intravenous infusion before delivery and on day 1 and day 2 postpartum. Tranexamic acid (Cyclokapron®) will be administered by intravenous infusion within 3 hours postpartum. Randomization will be at delivery to either rVWF at delivery and on day 1 and day 2 postpartum, plus TA within three hours postpartum; or rVWF alone at delivery and on day 1 and day 2 postpartum.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Hemophilia Center of Western PA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Pregnant females >= 18 years of age
2. Confirmed VWD, as defined by VWF:RCo < 0.50 IU/dL and previous history of bleeding
3. Willingness to have blood drawn
4. Willing to be randomized to one of two treatments at delivery and for 2 days postpartum.
5. Willing to keep a diary for 3 weeks of postpartum bleeding by pictorial assessment chart (PBAC) and any blood products, transfusion, or medications taken.
6. Willing to return at 21 days for final blood draw and review of diary.

Exclusion Criteria:

1. Any bleeding disorder other than VWD; or past thrombotic disease of other bleeding disorders.
2. Previous thrombosis, cardiac disease, congestive failure, arrhythmia, hypertension, MI, or stroke.
3. Platelet count < 100,000/ ul.
4. Past allergic reaction to VWF or tranexamic acid.
5. Surgery within the past 8 weeks.
6. Inability to comply with study protocol requirements.
7. Concomitant use of antiplatelet drugs, anticoagulants, or NSAIDs. Aspirin will be allowed for preeclampsia prevention.
8. Treatment with DDAVP, cryoprecipitate, whole blood, plasma or plasma derivatives containing substantial quantities of VWF within 5 days of study.
9. History of renal disease.
10. Inability to comply with study requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: rVWF plus TA; Subjects randomized to this arm will receive recombinant von Willebrand factor 80 IU/kg IV within 5-10 minutes of delivery (or epidural anesthesia) plus Tranexamic Acid 1 gm IV within 3 hours of delivery; and recombinant Von Willebrand factor 80 IU/kg on day 1 and day 2 postpartum.	Drug: Recombinant Von Willebrand factor; Recombinant Von Willebrand factor(Vonvendi) is an intravenous therapy that replaces missing VWF to restore hemostasis and reduce bleeding with surgery or delivery.; Other Names: rVWF, Vonvendi; Drug: Tranexamic Acid Injection [Cyklokapron]; Tranexamic acid (Cyclokapron) is an intravenous anti-fibrinolytic therapy that prevents clot breakdown and reduces bleeding with surgery or delivery.; Other Names: TA, Cyclokapron
Active Comparator: rVWF alone; Subjects randomized to this arm will receive recombinant von Willebrand factor 80 IU/kg IV within 5-10 minutes of delivery (or epidural anesthesia); and recombinant Von Willebrand factor 80 IU/kg on day 1 and day 2 postpartum.	Drug: Recombinant Von Willebrand factor; Recombinant Von Willebrand factor(Vonvendi) is an intravenous therapy that replaces missing VWF to restore hemostasis and reduce bleeding with surgery or delivery.; Other Names: rVWF, Vonvendi

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Volume of Quantitative Blood Loss at Delivery	Blood loss at delivery by standard QBL measured for 6 hours postpartum by the labor and delivery nursing staff.	6hrs

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Loss Postpartum by Pictorial Bleeding Assessment Chart (PBAC)	Blood loss postpartum by pictorial bleeding assessment chart (PBAC). Participants record the degree of saturation of sanitary products and the presence of clots. Total PBAC scores range from 0 to >500, with higher scores indicating heavier menstrual bleeding. A score ≥100 is conventionally consistent with heavy bleeding. Each sanitary product is assigned a score reflecting the amount of blood loss: Pads: 1 (point) for lightly stained, 5 for moderately soiled, 20 for fully soaked Tampons: 1 for lightly stained, 5 for moderately soiled, 10 for fully soaked Clots: 1 point for small (<1 cm), 5 for large (>1 cm) Daily scores are summed to produce a total cycle PBAC score. Subscale items (pads and clots) were summed to obtain a total PBAC score.	21 days
Number of Blood Products Used	Number of transfused blood products determined by electronic medical record review and patient diary.	21 days
Concentration of Von Willebrand Factor	Plasma levels of von Willebrand Factor antigen (VWF:Ag) and activity (VWF:RCo) measured during the peripartum period. Higher concentrations indicate greater clotting factor activity.	21 days

Collaborators and Investigators

• Sponsor: Nicoletta C Machin
• Investigators: Principal Investigator: Nicoletta Machin, DO, University of Pittsburgh

Publications and helpful links

General Publications

• Ragni MV, Machin N, James AH, Seaman CD, Malec LM, Kessler CM, Konkle BA, Kouides PA, Neff AT, Philipp CS, Brooks MM. Feasibility of the Von Willebrand disease PREVENT trial. Thromb Res. 2017 Aug;156:8-13. doi: 10.1016/j.thromres.2017.05.022. Epub 2017 May 25.
• Ragni MV. Blood volume-based von Willebrand factor to prevent postpartum hemorrhage in von Willebrand disease. Blood Adv. 2017 Apr 25;1(11):703-706. doi: 10.1182/bloodadvances.2017005090. eCollection 2017 Apr 25.
• Ragni MV. Case-based discussion on the implications of exogenous estrogens in hemostasis and thrombosis: the hematologist's view. Hematology Am Soc Hematol Educ Program. 2019 Dec 6;2019(1):152-157. doi: 10.1182/hematology.2019000022.

Study record dates

Study Major Dates

• Study Start (Actual): June 4, 2021
• Primary Completion (Actual): August 28, 2024
• Study Completion (Actual): September 1, 2024

Study Registration Dates

• First Submitted: April 9, 2020
• First Submitted That Met QC Criteria: April 9, 2020
• First Posted (Actual): April 14, 2020

Study Record Updates

• Last Update Posted (Estimated): October 31, 2025
• Last Update Submitted That Met QC Criteria: October 16, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Genetic Diseases, Inborn; Obstetric Labor Complications; Pregnancy Complications; Hemorrhage; Hematologic Diseases; Blood Coagulation Disorders; Hemorrhagic Disorders; Blood Platelet Disorders; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Puerperal Disorders; Uterine Hemorrhage; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Postpartum Hemorrhage; von Willebrand Diseases; Organic Chemicals; Carboxylic Acids; Acids, Carbocyclic; Cyclohexanecarboxylic Acids; Tranexamic Acid
• Other Study ID Numbers: STUDY20030186

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The IPD to be shared include individual bleeding data (EBL, PBAC); hemostasis agents (blood product usage, transfusion, other medications); and VWF assays (VWF:RCo, VWF:Ag, FVIII:C) and coagulation assays (fibrinogen, d-dimer).
• IPD Sharing Time Frame: Within 12 months of trial completion.
• IPD Sharing Access Criteria: Qualified investigators will have access to data and biospecimens, consistent with data sharing policies and applicable laws, and upon receipt of a Research Materials Distribution Agreement, data will be transferred by secure transfer through the GSPH portal website.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No