Von Willebrand Factor Concentrate During ECMO Support

Study Overview
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Brief Summary
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During treatments with extracorporeal circuits such as extracorporeal membrane oxygenation (ECMO) degradation of high molecular weight (HMW) of von Willebrand factor (vWF) multimers occur leading to an acquired von Willebrand disease. This disease is associated with increased bleeding and requirement for the transfusion with allogenic blood products especially packed red blood cells (PRBCs). A continuous treatment with von Willebrand factor concentrate (vWFC) may restore the multimers and bleeding can be avoided. Therefore a randomized, double-blind, prospective, controlled, two-arm clinical trial was designed, comparing patients receiving vWFC versus placebo.

Detailed Description
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Increased shear stress during mechanical circulatory support (MCS) by extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VAD) can provoke premature degradation of high molecular weight (HMW) of von Willebrand factor (vWF) multimers. In patients with intractable cardiac and/or respiratory failure requiring emergency ECMO support, the investigators recently demonstrated an essential decrease in high molecular weight (HMW) vWF multimer bands 24 and 48 hours after initiation of ECMO compared to baseline. Blood loss and transfusion requirement during and shortly after ECMO support may be strengthened by loss of HMW vWF multimers. Administration of vWF concentrates may support restoration of primary hemostasis in patients during ECMO support. Consequently the need for packed red blood cells (PRBCs) during ECMO support may be reduced thus positively influencing morbidity and mortality of ECMO patients. The investigators hypothesize, that treatment with vWF concentrate reduces the need for PRBCs during ECMO support. Therefore the primary aim of this clinical trial is to find out if the need of PRBCs differs in the group receiving a von Willebrand factor concentrate (vWFC), or the placebo group (saline). This clinical trial is planned as a randomized, double-blind, prospective, controlled, two-arm, two-center study. Patients with intractable cardiac and/or respiratory failure requiring emergency ECMO support undergoing surgery (Department of Anaesthesiology and Intensive Care Medicine) or treated at the General and Surgical Intensive Care Unit (ACI), Traumatologic Intensive Care Unit (TICU), Cardiologic Intensive Care Unit (CCU) or the ICU of the Department of Visceral, Transplant and Thoracic Surgery at the Hospital Innsbruck (Tirol Kliniken GmbH), Austria will be enrolled in the study when meeting the inclusion- and exclusion criteria. If a patient meets the inclusion criteria and is recruited for the study, the patient will be randomized either to the group receiving vWFC or placebo S. Before the implementation of the ECMO the Baseline investigations need to be conducted. As soon as they are completed the ECMO cannula can be inserted. The administration of the Investigational Medicinal Product (IMP) will be start within 24h after ECMO installation. Directly before IMP-start blood samples (Visit 2) will be drawn. After 24h (Visit 3), 60h (Visit 4) and on day 5 (Visit 5) of the start of the study medication visits will be conducted, whereas on day 5 (Visit 5) no special laboratory (measurement of HMW vWF) will be analyzed. If ECMO can be terminated, a visit (Visit 6) directly before the stop of the ECMO will be conducted. 36 h after the termination of the ECMO Visit 7 (termination) will be performed. If the ECMO is needed longer than 7 days, the administration of the IMP will be stopped on day 7 and a visit after 36 hours of IMP-stop will be done for safety reasons but without special laboratory. After 30 days an interview will be performed with the treating physician.

Official Title
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A Double-blind, Placebo-controlled Pilot Trial to Investigate the Administration of Von Willebrand Factor Concentrate (Willfact®, LFB France) in Adult Patients During Extracorporeal Membrane Oxygenation

Conditions
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Acquired Von Willebrand Disease

Intervention / Treatment
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* Drug: Von Willebrand Factor
* Drug: Saline Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with the need of veno-arterial or veno-venous ECMO for a minimum of 48 hours Age ≥ 18 years Exclusion Criteria: Patient with known thromboembolic event in the last 30 days Inevitable lethal course Severe Liver failure: Quick < 30 % Pregnancy Patient with known refusal of a participation in this clinical trial Active participation in another clinical trial Any condition, including the presence of laboratory abnormalities, which would place the subject at unacceptable risk if he/she were to participate in the study or confound the ability to interpret data from the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group W (von Willebrand factor concentrate)<br>The patient receives von Willebrand factor concentrate (vWFC) as a bolus of 25 IU/kg followed by a continuous infusion of 50 IU/kg/24h until the weaning from ECMO is completed or if ECMO is needed longer than 7 days, the administration of the Investigational Medicinal Product (IMP) will be stopped on the 7th day. | Drug: Von Willebrand Factor<br>* Bolus and continuous infusion of the Investigational Medicinal Product (IMP) during extracorporeal membrane oxygenation (ECMO)<br>|
| Placebo Comparator: Group S (standard therapy with saline solution)<br>The patient receives the standard therapy plus an additional volume of saline solution equivalent to the amount of von Willebrand factor concentrate (vWFC) the patient would receive in Group W to keep the blind. The volume is given according to the VWFC-solution (0.25 ml/kg BW) what would be resulting from the patient's weight followed by a continuous saline infusion (0.50 ml/kg BW) until the weaning from ECMO is completed or if ECMO is needed longer than 7 days, the Investigational Medicinal Product (IMP) administration is stopped on the 7th day. | Drug: Saline Solution<br>* Bolus and continuous infusion of the Investigational Medicinal Product (IMP) during extracorporeal membrane oxygenation (ECMO)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transfusion requirement of PRBC | Difference in the number of red blood cells concentrates between the treatment arms per day | Between start of IMP (Visit 2) until 24 hours after IMP-start (Visit 3) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transfusion requirements of other allogenic blood products | Difference in the number of other high risk allogenic transfusion products (fresh frozen plasma and platelet concentrate) between the treatment arms per day | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | 
| Requirements of coagulation factor concentrates | Amount of coagulation factor concentrates given during ECMO support between the treatment arms per day | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | 
| Number of vWF-HMW multimer bands | Number of vWF multimer bands measured via SDS-agarose gel electrophoresis between the treatment arms | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | 
| Assessment of thromboelastometry | Difference in thromboelastometry between the treatment arms | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | 
| Changes in thrombocytes | Difference in platelet number | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | 
| Renal function | Difference in the daily urine output | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | 
| Number of participants with bleeding events | Number of patients with bleeding events assessed by a bleeding score based on Mazzeffi et al 2013 | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | 
| Assessment vWF-HMW function | vWF function (vWF:Ag, vWF:RCo, and F:VIII) via photooptical measurement between the treatment arms | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | 
| Assessment of activated partial thromboplastin time (aPTT) assay | aPTT assay [seconds] between the treatment arms | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | 
| Changes in red blood cell number | Differences in red blood cell number and hemoglobin between the treatment arms | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | 
| Number of participants with thromboembolic events | Number of participants with thromboembolic events as assessed via duplex ultrasonic investigation of the cervical vessels (Carotis und Vertebralis) and major leg veins | 36 hours after IMP-Stop | 
| Assessment of Prothrombin time (PT) assay | PT assay [%] between the treatment arms | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | 
| Assessment of activated clotting time (ACT) | ACT assay [seconds] between the treatment arms | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) |