Vasculopathic Injury and Plasma as Endothelial Rescue in Septic Shock (SHOCK) Trial

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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This is a single center, randomized (1:1, active : standard of care), controlled, open-label, investigator-initiated pilot phase IIa trial in patients with septic shock investigating the efficacy and safety of administrating OctaplasLG® as compared to crystalloids, such as Ringer-Acetate (standard of care) in a total of 40 patients. 40 patients will be enrolled: Patients in the active treatment group (n = 20 patients) will receive OctaplasLG® as volume support according to trial algorithm. Patients in the standard of care group (n = 20 patients) will receive crystalloids, such as Ringer-Acetate, as volume support according to trial algorithm. All patients will be treated according to the standard ICU care.

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-Acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult intensive care patients (age ≥ 18 years) AND Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection AND Quick SOFA (qSOFA) with two or more of Respiratory rate ≥ 22/min Altered mentation (Glasgow Coma Scale score < 15) Systolic blood pressure ≤ 100mmHg AND Septic shock, defined as a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain MAP ≥65 mm Hg and having a serum lactate level >2 mmol/L despite adequate volume resuscitation AND Requiring infusion of noradrenalin 0.10 mcg/kg/min or more to maintain blood pressure AND Respiratory failure requiring intubation and mechanical ventilation 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 an interventional trial OR Known IgA deficiency with documented antibodies against IgA 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 |
| --- | --- |
| Active Comparator: OctaplasLG<br>OctaplasLG® is an industrial donor plasma product pooled from 630 -1520 single donor units. It possesses unique features when compared to standard FFP, such as having a standardized concentration of natural pro- and anti-coagulation factors, a standardized volume as well as being pathogen-free.12 Most importantly, the manufacturing method of OctaplasLG® removes immune complexes and cells in several steps of microfiltration. The manufacturing process also inactivates viral, bacterial and prion pathogen by immune neutralization, solvent-detergent treatment and a prion specific ligand affinity chromatography step. | Drug: OctaplasLG<br>* OctaplasLG is given as an infusion when resuscitation fluids are required.<br>* Other names: Octaplas;|
| Placebo Comparator: Ringer-Acetate<br>standard of care resuscitation fluid Ringer-acetate is a mixture of electrolytes in water to a slightly hypotonic solution. | Drug: Ringer-Acetate<br>* Ringer-acetate is given as an infusion when resuscitation fluids are required.<br>* Other names: Ringer's Acetate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microscan at 24 hours | Change in microvascular perfusion from baseline to 24 hours after inclusion as evaluated by sidestream darkfield (SDF; MicroVision Medical, Amsterdam, The Netherlands) imaging technique. | 24 hours after baseline | 
| Biomarkers at 24 hours | Change in biomarkers indicative of endothelial activation and damage (sE-selectin, syndecan-1, thrombomodulin, VEGFR1, VEGF, nucleosomes) from baseline to 24 hours after inclusion. | 24 hours after baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24 hour mortality | Difference in 24 hours mortality between patients receiving active treatment (OctaplasLG®) and standard of care (crystalloids such as Ringer-Acetate). | 24 hours after inclusion | 
| 7 day mortality | Difference in 7 day mortality between patients receiving active treatment (OctaplasLG®) and standard of care (crystalloids such as Ringer-Acetate). | 7 days after inclusion | 
| 30 day mortality | Difference in 30 day mortality between patients receiving active treatment (OctaplasLG®) and standard of care (crystalloids such as Ringer-Acetate). | 30 days after inclusion | 
| 90 day mortality | Difference in 90 day mortality between patients receiving active treatment (OctaplasLG®) and standard of care (crystalloids such as Ringer-Acetate). | 90 days after inclusion | 
| Length of stay in the ICU | The number of days in the ICU after inclusion | Days, assessed at 30-days and 90-days | 
| Days on vasopressors | The number of days on vasopressors after inclusion | Days, assessed at 30-days and 90-days | 
| Days on ventilator | The number of days on vasopressors after inclusion | Days, assessed at 30-days and 90-days | 
| Transfusion requirements | Bleeding requiring > 2 RBC / day | For the first 7 days after inclusion | 
| Serious Adverse Reactions at 72 hours | Severe adverse reactions, defined as symptomatic thromboembolism and TACO/TRALI | For the first 72 hours after inclusion | 
| Serious Adverse Reactions at day 30 | Severe adverse reactions, defined as symptomatic thromboembolism and TACO/TRALI | At day 30 after inclusion | 
| Oxygenation | As evaluated by the PaO2/FiO2-ratio during the ICU stay | At 24 hours, 48 hours, 72 hours and at day 7 after baseline | 
| RIFLE criteria: Risk, Injury, and Failure, Loss and End-stage kidney disease | Acute Kidney Injury according to RIFLE criteria | For the first 7 days in the ICU | 
| Renal Replacement Therapy | recording whether the patient is receiving dialysis or not | For the first 7 days after inclusion |