Vasculopathic Injury and Plasma as Endothelial Rescue - OCTAplas Trial (EudraCT no. 2014-000452-28) (VIPER-OCTA)

Effects of OctaplasLG® on Endothelial Integrity in Patients Undergoing Emergency Surgery for Thoracic Aortic Dissections - a Randomized, Controlled, Single-blinded Investigator-initiated Pilot Trial

Effects of OctaplasLG® on endothelial integrity in patients undergoing emergency surgery for thoracic aortic dissections - a randomized, controlled, single-blinded investigator-initiated pilot trial

Study Overview

• Status: Completed
• Conditions: Endothelial Dysfunction; Aortic Aneurysm, Thoracic
• Intervention / Treatment: Drug: OctaplasLG®; Biological: Fresh frozen plasma

Detailed Description

Trial Name: VIPER-OCTA trial - Vasculopathic Injury and Plasma as Endothelial Rescue - OCTAplas trial

Background

• Patients operated for thoracic aortic dissections in deep hypothermic circulatory arrest are prone to develop postoperative renal failure secondary to severe endothelial dysfunction and capillary leakage, and currently no therapy addressing this complication has proven successful
• Data from animal models of shock and massively bleeding patients indicate that plasma may be beneficial for re-establishing endothelial integrity
• Patients operated for thoracic aortic dissections generally develop requirement for massive transfusion during surgery
• Current guidelines, however, recommend against plasma transfusion to patients not needing coagulation factor replacement due to the inherent risk of transfusion complications
• OctaplasLG® is an immune complex-free and cell-free, pathogen inactivated standardized plasma product that has been shown not to be related to the transfusion complications seen secondary to standard fresh frozen plasma (FFP), thus, OctaplasLG® may be a beneficial, alternative resuscitation fluid in patients with severe endothelial dysfunction/damage
• The purpose is to bridge the knowledge gap regarding the effect of OctaplasLG® on endothelial integrity and safety

Design Single-centre randomised, single-blinded, controlled, investigator-initiated pilot trial of 42 patients undergoing emergency surgery for thoracic aortic dissections randomized to administration of OctaplasLG®, as compared to standard FFP, as coagulation factor replacement related to bleeding, when need for coagulation factor replacement is deemed necessary by the clinician according to local protocol.

Inclusion criteria

• Patient eligible for emergency surgery on cardiopulmonary bypass pump for a thoracic aortic dissections AND
• Age > 18 years AND
• Consent obtainable from patient or by proxy (independent physicians and/or next of kin)

Exclusion criteria

• Documented refusal of blood transfusion OR
• FFP transfusion before randomization OR
• Aortic dissection due to trauma OR
• Treatment with GPIIb/IIIa inhibitors < 24h from screening OR
• Withdrawal from active therapy OR
• Expected to die < 24h OR
• Previously within 30 days included in a randomized trial, if known at the time of enrolment.
• Known immunoglobulin A (IgA) deficiency with documented antibodies against IgA
• Known hypersensitivity to OctaplasLG®: the active substance, any of the excipients (Sodium citrate dihydrate, Sodium dihydrogenphosphate dihydrate or Glycine) or residues from the manufacturing process (Tri (N-Butyl) Phosphate (TNBP) and Octoxynol (Triton X-100))
• Known severe deficiencies of protein S
• Pregnancy (non-pregnancy confirmed by patient being postmenopausal or having a negative serum-hCG).

Randomization Blood Bank staff will perform 24 hour on-site randomisation by envelope-opening to allow for immediate allocation to either receiving OctaplasLG® (intervention) or standard FFP (control) as coagulation factor replacement.

Outcome measures

Primary outcome measure:

• Plasma levels of endothelial markers (Syndecan-1, soluble thrombomodulin (sTM), sE-selectin, sVE-cadherin) at 24 hours after arrival in ICU for postoperative care, as compared to baseline

Secondary outcome measures:

• Plasma levels of endothelial markers (Syndecan-1, sTM, sE-selectin, sVE-cadherin) at 48 hours postoperatively, as compared to baseline
• Acute Kidney Injury (AKI) according to RIFLE Criteria in the first 7 postoperative days, see appendix 1
• Renal replacement therapy
• Sepsis-Related Organ Failure Assessment (SOFA), worst score during ICU stay, see appendix 2
• 30-day and 90-day mortality
• P-CRP, IL-6, P-Catecholamines at 24 hours and 48 hours
• Length of stay in ICU and hospital
• Severe adverse reactions

Tertiary outcome measures

• TRALI
• TACO

Trial size The calculation is based in part by data collected in a quality control investigation of the effect of OctaplasLG® vs. FFP. The power calculation is based on the finding of a significantly higher relative level of sTM in the FFP compared to the OctaplasLG® group (p=0.025). The relative values of sTM post-CPB: FFP group: mean 3.35 (SD 2.12); OctaplasLG® group: mean 1.70 (SD 0.49); SD across the entire group of patients: 1.574. To detect the above difference with a power of 0.90 (1-β) and alpha of 0.05 requires n=21 patients in each group. The investigators have chosen to include 42 patients, 21 evaluable patients in each randomization group in case of attrition, in the present trial.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, DK-2100
    • Rigshospitalet, Copenhagen University Hospital

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:

• Patient eligible for emergency surgery on cardiopulmonary bypass pump for a thoracic aortic dissections AND
• Age > 18 years AND
• Consent obtainable from patient or by proxy (independent physicians and/or next of kin)

Exclusion Criteria:

• Documented refusal of blood transfusion OR
• FFP transfusion before randomization OR
• Aortic dissection due to trauma OR
• Treatment with GPIIb/IIIa inhibitors < 24h from screening OR
• Withdrawal from active therapy OR
• Expected to die < 24h OR
• Previously within 30 days included in a randomized trial, if known at the time of enrolment
• Known IgA deficiency with documented antibodies against IgA
• Known hypersensitivity to OctaplasLG®: the active substance, any of the excipients (Sodium citrate dihydrate, Sodium dihydrogenphosphate dihydrate or Glycine) or residues from the manufacturing process (Tri (N-Butyl) Phosphate (TNBP) and Octoxynol (Triton X-100))
• Known severe deficiencies of protein S
• Pregnancy (non-pregnancy confirmed by patient being postmenopausal or having a negative serum-hCG)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: OctaplasLG®; replacement to bleeding	Drug: OctaplasLG®; OctaplasLG® is an industrial donor plasma product pooled from approximately 400 single donor units. It possess' unique features when compared to standard FFP, such as having standardized concentrations of natural pro- and anti-coagulation factors, standardized volume and as being pathogen free. Very importantly, the manufacturing method of OctaplasLG® removes immune complexes and cells in several steps of microfiltration in addition to viral, bacterial and prion pathogen inactivation.; Other Names: Octaplas
Placebo Comparator: Standard fresh frozen plasma; replacement to bleeding	Biological: Fresh frozen plasma; Standard FFP from the Blood Bank; Other Names: FFP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Plasma levels of endothelial markers (Syndecan-1, sTM, sE-selectin, sVE-cadherin)	At 24 hours after arrival in ICU for postoperative care, as compared to baseline

Secondary Outcome Measures

Outcome Measure	Time Frame
Plasma levels of endothelial markers (Syndecan-1, soluble thrombomodulin (sTM), sE-selectin, sVE-cadherin)	At 48 hours postoperatively, as compared to baseline
Acute Kidney Injury (AKI) according to RIFLE Criteria	In the first 7 postoperative days
Renal replacement therapy	In the first 7 postoperative days
Sepsis-Related Organ Failure Assessment (SOFA)	Worst score In the first 7 postoperative days
Mortality	30-day and 90-day
P-Creactive protein (CRP), Interleukin-6 (IL-6), P-Catecholamines	At 24 hours and 48 hours
Length of stay in ICU and hospital	Days, assessed at 30-days and 90-days
Severe adverse reactions	In the first 30 postoperative days

Other Outcome Measures

Outcome Measure	Time Frame
Transfusion associated acute lung injury (TRALI)	In the first 30 postoperative days
Transfusion associated circulatory overload (TACO)	In the first 30 postoperative days

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Octapharma
• Investigators: Principal Investigator: Jakob Stensballe, MD, PhD, Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Stensballe J, Ulrich AG, Nilsson JC, Henriksen HH, Olsen PS, Ostrowski SR, Johansson PI. Resuscitation of Endotheliopathy and Bleeding in Thoracic Aortic Dissections: The VIPER-OCTA Randomized Clinical Pilot Trial. Anesth Analg. 2018 Oct;127(4):920-927. doi: 10.1213/ANE.0000000000003545.

Study record dates

Study Major Dates

• Study Start: November 1, 2014
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: September 25, 2014
• First Submitted That Met QC Criteria: September 26, 2014
• First Posted (Estimate): October 1, 2014

Study Record Updates

• Last Update Posted (Estimate): December 20, 2016
• Last Update Submitted That Met QC Criteria: December 19, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Aortic Diseases; Aneurysm; Aortic Aneurysm; Aortic Aneurysm, Thoracic
• Other Study ID Numbers: VIPER-OCTA; H-3-2014-018 (Other Identifier: Regional Health Research Ethics Committee)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No