Vasculopathic Injury and Plasma as Endothelial Rescue in Septic Shock Trial. VIPER-Sepsis (EudraCT no. 2016-000707-81)

Study Overview
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Brief Summary
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Efficacy and safety of octaplasLG® administration vs. crystalloids (standard) in patients with septic shock - a randomized, controlled, open-label investigator-initiated pilot trial.

Detailed Description
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Recently a great interest in the role of the endothelium in the pathophysiology of sepsis has been introduced. The endothelium is coated by a thick endothelial glycocalyx protecting it from becoming activated and prevents capillary leakage. The glycocalyx binds approximately 1-1.5 litres of the plasma portion of the circulating blood and regulates the dynamic exchange between the intra -and extravascular space, therefore, functioning both as a barrier and as a mechano transducer. Damage to the glycocalyx is caused by major trauma, major surgery, or ischemia and reperfusion injury, and resulting in vascular leakage. Damage to the endothelium is further augmented by resuscitation of crystalloids and colloids as well as related to bleeding. Thawed fresh frozen plasma may cause a further inflammatory hit towards the glycocalyx and endothelium. The degradation of the glycocalyx increases endothelial permeability with edema formation entitled 'the endothelial leakage syndrome', and resulting in the development of hypotension, pulmonary complications, abdominal compartment syndrome, multi-organ failure and death. The current strategy for maintaining the intravascular volume in patients with acute critical illness focuses on the administration of crystalloids, such as Ringer-Acetate, and natural colloids. Crystalloids, especially, are known to extravasate and cause edema, which is associated with hypoperfusion and compromised vital organ function by the increased tissue pressure that limits oxygen delivery, and ultimately leading to the complications described above. Until recently, synthetic colloids were the preferred choice of fluids for these patients, but a Scandinavian study in patients with severe sepsis and septic shock (6S trial) demonstrated an increased mortality in patients receiving synthetic colloids, thereby, establishing the adverse effect of such a strategy. Consequently, new resuscitation fluids are needed, preferably not only to support the intravascular volume, but also to support and restore the endothelial integrity.

Official Title
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Efficacy and Safety of OctaplasLG Administration vs. Crystalloids (Standard) in Patients With Septic Shock - a Randomized, Controlled, Open-label Investigator-initiated Pilot Trial

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: OctaplasLG®
* Drug: Ringer-acetat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult intensive care patients AND Septic shock requiring infusion of vasopressor/inotropic agents to maintain blood pressure as defined in international guidelines AND Consent obtainable from patient or by proxy (independent physicians and/or next of kin) Exclusion Criteria: Documented refusal of blood transfusion OR Treatment with GPIIb/IIIa inhibitors < 24h from screening OR Withdrawal from active therapy OR Previously within 30 days included in a randomised trial, if known at the time of enrolment OR Known Immunoglobulin A deficiency with documented antibodies against Immunoglobulin A OR 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)) OR Known severe deficiencies of protein S OR Pregnancy (non-pregnancy confirmed by patient being postmenopausal or having a negative urine-hCG) OR Severe cirrhotic hepatic failure with expected need for treatment with terlipressin

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: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Ringer-acetat | Drug: OctaplasLG®<br>* OctaplasLG is an donor plasma product pooled from approximately 1000 single donor units. It possesses unique features when compared to standard fresh frozen plasma, such as having standardized concentrations of natural pro- and anti-coagulation factors, a standardized volume as well as being pathogen free. The manufacturing method of OctaplasLG removes immune complexes and cells in several steps of microfiltration in addition to viral, bacterial and prion pathogen inactivation by immune neutralization. OctaplasLG should reduce the inflammatory hit on the endothelium, including the glycocalyx, by having standardized levels of coagulation proteins, which can give more sustainable support to the endothelial regeneration as compared to standard fresh frozen plasma.<br>* Other names: OctaplasLG;|
| Active Comparator: Intervention<br>OctaplasLG® | Drug: Ringer-acetat<br>* Crystalloid used as standard of care.<br>* Other names: Ringer;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microvascular perfusion | Change in microvascular perfusion as evaluated by sidestream darkfield (SDF; MicroVision Medical, Amsterdam, The Netherlands) imaging technique. | 6 hours after inclusion | 
| Endothelial activation and damage | Change in biomarkers indicative of endothelial activation and damage (soluble E-selectin, syndecan-1, thrombomodulin, soluble VE-cadherin, nucleosomes) | 6 hours after inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Difference in mortality between patients receiving active treatment (OctaplasLG®) and standard of care (crystalloids) | From 6 hours until 90 days | 
| Length of stay in Intensive Care Unit | Length of stay in the Intensive Care Unit | through study completion, an average of 1 month | 
| Vasopressors | Days on vasopressors | through study completion, an average of 1 month | 
| Ventilator | Days on ventilator | through study completion, an average of 1 month | 
| Bleeding | Bleeding requiring > 2 RBC / day | 1 week | 
| SAR | Severe adverse reactions, defined as symptomatic thromboembolism | 30 days | 
| TACO | Transfusion associated circulatory overload | 30 days | 
| TRALI | Transfusion Related Acute Lung Injury | 30 days |