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

Phase 4

Completed

• Conditions: Endothelial Dysfunction; Aortic Aneurysm, Thoracic
• Interventions: Biological: Fresh frozen plasma; Drug: OctaplasLG®

• Registration Number: NCT02253082
• Lead Sponsor: Rigshospitalet, Denmark

Brief Summary

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

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 Timeline

• Study First Submitted: 2014-09-25
• Study First Submitted QC: 2014-09-26
• Study First Posted: 2014-10-01
• Study Start: 2014-11
• Primary Completion: 2016-09
• Status Verified: 2016-12
• Study Completion: 2016-12
• Last Update Submitted: 2016-12-19
• Last Update Posted: 2016-12-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 44

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Standard fresh frozen plasma	Fresh frozen plasma	replacement to bleeding
OctaplasLG®	OctaplasLG®	replacement to bleeding

Primary Outcome Measures

Name	Time	Method
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

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

Trial Locations

Locations (1)

Rigshospitalet, Copenhagen University Hospital; 🇩🇰 Copenhagen, Denmark