Von Willebrand Factor Concentrate During ECMO Support

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

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.

Study Overview

• Status: Unknown
• Conditions: Acquired Von Willebrand Disease
• Intervention / Treatment: Drug: Von Willebrand Factor; Drug: Saline Solution

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 68
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Medical University Innsbruck / Department for Anesthesia and Intensive Care Medicine
  • Innsbruck, Austria, 6020
    • Medical University Innsbruck / Department for General and Surgical Critical Care Medicine

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group W (von Willebrand factor concentrate); 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; Bolus and continuous infusion of the Investigational Medicinal Product (IMP) during extracorporeal membrane oxygenation (ECMO)
Placebo Comparator: Group S (standard therapy with saline solution); 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; Bolus and continuous infusion of the Investigational Medicinal Product (IMP) during extracorporeal membrane oxygenation (ECMO)

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Tirol Kiniken GmbH
• Collaborators: LFB BIOMEDICAMENTS

Publications and helpful links

General Publications

• Tauber H, Streif W, Fritz J, Ott H, Weigel G, Loacker L, Heinz A, Velik-Salchner C. Predicting Transfusion Requirements During Extracorporeal Membrane Oxygenation. J Cardiothorac Vasc Anesth. 2016 Jun;30(3):692-701. doi: 10.1053/j.jvca.2016.01.009. Epub 2016 Jan 11.
• Tauber H, Ott H, Streif W, Weigel G, Loacker L, Fritz J, Heinz A, Velik-Salchner C. Extracorporeal membrane oxygenation induces short-term loss of high-molecular-weight von Willebrand factor multimers. Anesth Analg. 2015 Apr;120(4):730-6. doi: 10.1213/ANE.0000000000000554.
• Velik-Salchner C, Eschertzhuber S, Streif W, Hangler H, Budde U, Fries D. Acquired von Willebrand syndrome in cardiac patients. J Cardiothorac Vasc Anesth. 2008 Oct;22(5):719-24. doi: 10.1053/j.jvca.2007.05.013. Epub 2007 Aug 3. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): April 16, 2018
• Primary Completion (Anticipated): March 10, 2021
• Study Completion (Anticipated): March 10, 2021

Study Registration Dates

• First Submitted: March 22, 2018
• First Submitted That Met QC Criteria: July 27, 2018
• First Posted (Actual): August 3, 2018

Study Record Updates

• Last Update Posted (Actual): March 12, 2020
• Last Update Submitted That Met QC Criteria: March 11, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Blood Platelet Disorders; Von Willebrand Diseases
• Other Study ID Numbers: ECMO-vWFC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No