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

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

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

Study Overview

• Status: Terminated
• Conditions: Septic Shock
• Intervention / Treatment: Drug: OctaplasLG®; Drug: Ringer-acetat

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2400
    • Intensive Care Unit Bispebjerg 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:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: FACTORIAL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Control; Ringer-acetat	Drug: OctaplasLG®; 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.; Other Names: OctaplasLG
ACTIVE_COMPARATOR: Intervention; OctaplasLG®	Drug: Ringer-acetat; Crystalloid used as standard of care.; Other Names: Ringer

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
SOFA score	Maximal change in SOFA score	7 days
AKI	Acute Kidney Injury (AKI) according to RIFLE Criteria	7 days
CRRT	Renal replacement therapy as deemed necessary by the attending physician	7 days
TEG	Thrombelastography maximum amplitude (clot strength) in TEG and TEG Functional Fibrinogen (FF)	72 hours
DIC	Disseminated intravascular coagulation score (DIC)	7 days

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Octapharma
• Investigators: Study Director: Per I Johansson, MD, University of Copenhagen, Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2016
• Primary Completion (ACTUAL): November 8, 2016
• Study Completion (ACTUAL): November 8, 2016

Study Registration Dates

• First Submitted: August 11, 2016
• First Submitted That Met QC Criteria: August 22, 2016
• First Posted (ESTIMATE): August 23, 2016

Study Record Updates

• Last Update Posted (ACTUAL): January 9, 2018
• Last Update Submitted That Met QC Criteria: January 7, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock
• Other Study ID Numbers: Viper Sepsis

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: All data from the study will be made public in a peer review journal after last inclusion. But no individual participant data (IPD) will be public.