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Von Willebrand Factor Concentrate During ECMO Support

Primary Purpose

Acquired Von Willebrand Disease

Status
Unknown status
Phase
Phase 2
Locations
Austria
Study Type
Interventional
Intervention
Von Willebrand Factor
Saline Solution
Sponsored by
Tirol Kiniken GmbH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acquired Von Willebrand Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

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

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Group W (von Willebrand factor concentrate)

Group S (standard therapy with saline solution)

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Transfusion requirement of PRBC
Difference in the number of red blood cells concentrates between the treatment arms per day

Secondary Outcome Measures

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
Requirements of coagulation factor concentrates
Amount of coagulation factor concentrates given during ECMO support between the treatment arms per day
Number of vWF-HMW multimer bands
Number of vWF multimer bands measured via SDS-agarose gel electrophoresis between the treatment arms
Assessment of thromboelastometry
Difference in thromboelastometry between the treatment arms
Changes in thrombocytes
Difference in platelet number
Renal function
Difference in the daily urine output
Number of participants with bleeding events
Number of patients with bleeding events assessed by a bleeding score based on Mazzeffi et al 2013
Assessment vWF-HMW function
vWF function (vWF:Ag, vWF:RCo, and F:VIII) via photooptical measurement between the treatment arms
Assessment of activated partial thromboplastin time (aPTT) assay
aPTT assay [seconds] between the treatment arms
Changes in red blood cell number
Differences in red blood cell number and hemoglobin between the treatment arms
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
Assessment of Prothrombin time (PT) assay
PT assay [%] between the treatment arms
Assessment of activated clotting time (ACT)
ACT assay [seconds] between the treatment arms

Full Information

First Posted
March 22, 2018
Last Updated
March 11, 2020
Sponsor
Tirol Kiniken GmbH
Collaborators
LFB BIOMEDICAMENTS
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1. Study Identification

Unique Protocol Identification Number
NCT03613584
Brief Title
Von Willebrand Factor Concentrate During ECMO Support
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Unknown status
Study Start Date
April 16, 2018 (Actual)
Primary Completion Date
March 10, 2021 (Anticipated)
Study Completion Date
March 10, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Tirol Kiniken GmbH
Collaborators
LFB BIOMEDICAMENTS

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acquired Von Willebrand Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Masking Description
The vWFC or placebo will be prepared by the local hospital pharmacy or independent nurses from another ward (on holidays and weekends). To keep the blinding for the treating physicians and the study team syringes and lines with light protection (orange color) will be used. So the color of the medication (colorless to slightly yellowish) cannot be distinguished.
Allocation
Randomized
Enrollment
68 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group W (von Willebrand factor concentrate)
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Group S (standard therapy with saline solution)
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Von Willebrand Factor
Intervention Description
Bolus and continuous infusion of the Investigational Medicinal Product (IMP) during extracorporeal membrane oxygenation (ECMO)
Intervention Type
Drug
Intervention Name(s)
Saline Solution
Intervention Description
Bolus and continuous infusion of the Investigational Medicinal Product (IMP) during extracorporeal membrane oxygenation (ECMO)
Primary Outcome Measure Information:
Title
Transfusion requirement of PRBC
Description
Difference in the number of red blood cells concentrates between the treatment arms per day
Time Frame
Between start of IMP (Visit 2) until 24 hours after IMP-start (Visit 3)
Secondary Outcome Measure Information:
Title
Transfusion requirements of other allogenic blood products
Description
Difference in the number of other high risk allogenic transfusion products (fresh frozen plasma and platelet concentrate) between the treatment arms per day
Time Frame
Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7)
Title
Requirements of coagulation factor concentrates
Description
Amount of coagulation factor concentrates given during ECMO support between the treatment arms per day
Time Frame
Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7)
Title
Number of vWF-HMW multimer bands
Description
Number of vWF multimer bands measured via SDS-agarose gel electrophoresis between the treatment arms
Time Frame
Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7)
Title
Assessment of thromboelastometry
Description
Difference in thromboelastometry between the treatment arms
Time Frame
Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7)
Title
Changes in thrombocytes
Description
Difference in platelet number
Time Frame
Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7)
Title
Renal function
Description
Difference in the daily urine output
Time Frame
Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7)
Title
Number of participants with bleeding events
Description
Number of patients with bleeding events assessed by a bleeding score based on Mazzeffi et al 2013
Time Frame
Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7)
Title
Assessment vWF-HMW function
Description
vWF function (vWF:Ag, vWF:RCo, and F:VIII) via photooptical measurement between the treatment arms
Time Frame
Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7)
Title
Assessment of activated partial thromboplastin time (aPTT) assay
Description
aPTT assay [seconds] between the treatment arms
Time Frame
Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7)
Title
Changes in red blood cell number
Description
Differences in red blood cell number and hemoglobin between the treatment arms
Time Frame
Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7)
Title
Number of participants with thromboembolic events
Description
Number of participants with thromboembolic events as assessed via duplex ultrasonic investigation of the cervical vessels (Carotis und Vertebralis) and major leg veins
Time Frame
36 hours after IMP-Stop
Title
Assessment of Prothrombin time (PT) assay
Description
PT assay [%] between the treatment arms
Time Frame
Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7)
Title
Assessment of activated clotting time (ACT)
Description
ACT assay [seconds] between the treatment arms
Time Frame
Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
Medical University Innsbruck / Department for Anesthesia and Intensive Care Medicine
City
Innsbruck
ZIP/Postal Code
6020
Country
Austria
Facility Name
Medical University Innsbruck / Department for General and Surgical Critical Care Medicine
City
Innsbruck
ZIP/Postal Code
6020
Country
Austria

12. IPD Sharing Statement

Citations:
PubMed Identifier
27321792
Citation
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.
Results Reference
background
PubMed Identifier
25565317
Citation
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.
Results Reference
background
PubMed Identifier
18922429
Citation
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.
Results Reference
background

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Von Willebrand Factor Concentrate During ECMO Support

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