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

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ClinicalTrials.gov Identifier: NCT04344860
Recruitment Status : Recruiting
First Posted : April 14, 2020
Last Update Posted : August 4, 2021
Sponsor:
Information provided by (Responsible Party):
Margaret Ragni, University of Pittsburgh

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Von Willebrand Diseases Postpartum Hemorrhage Drug: Recombinant Von Willebrand factor Drug: Tranexamic Acid Injection [Cyklokapron] Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, Controlled Trial
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: 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
Actual Study Start Date : June 4, 2021
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bleeding

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 Name: 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 Name: 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 Name: rVWF, Vonvendi




Primary Outcome Measures :
  1. Volume of quantitative blood loss at delivery [ Time Frame: 1 day ]
    Blood loss at delivery by standard QBL.


Secondary Outcome Measures :
  1. Volume of lochia blood loss [ Time Frame: 21 days ]
    Blood loss postpartum by pictorial bleeding assessment chart (PBAC).

  2. Number of blood products used [ Time Frame: 21 days ]
    Blood product use by patient diary

  3. Concentration of von Willebrand factor [ Time Frame: 21 days ]
    Von Willebrand factor assay (VWF:RCo, VWF:Ag, FVIII:C)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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, aspirin or NSAIDs.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04344860


Contacts
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Contact: Margaret V Ragni, MD, MPH 412-209-7288 ragni@pitt.edu
Contact: Dana Ivanco 412-209-7425 des2@pitt.edu

Locations
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United States, Pennsylvania
Hemophilia Center of Western PA Recruiting
Pittsburgh, Pennsylvania, United States, 15213-4306
Contact: Margaret V. Ragni, MD, MPH    412-209-7288    ragni@dom.pitt.edu   
Contact: Dana Ivanco    412-209-7425    des2@pitt.edu   
Principal Investigator: Margaret V. Ragni, MD, MPH         
Magee Womens Hospital Not yet recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Stephen Caritis, MD    412-641-1000    carisn@mwri.magee.edu   
Sponsors and Collaborators
Margaret Ragni
Investigators
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Principal Investigator: Margaret V Ragni, MD, MPH University of Pittsburgh
Publications:
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Responsible Party: Margaret Ragni, Professor, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT04344860    
Other Study ID Numbers: STUDY20030186
First Posted: April 14, 2020    Key Record Dates
Last Update Posted: August 4, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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).
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Within 12 months of trial completion.
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.

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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
Additional relevant MeSH terms:
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Postpartum Hemorrhage
Von Willebrand Diseases
Hemorrhage
Pathologic Processes
Obstetric Labor Complications
Pregnancy Complications
Puerperal Disorders
Uterine Hemorrhage
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Blood Platelet Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Tranexamic Acid
Antifibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Hemostatics
Coagulants