Ilomedin in Septic Shock With Persistent Microperfusion Defects (I-MICRO)

Study Overview
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Brief Summary
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Septic shock remains a major cause of death in critically ill patients. Alterations in microcirculation have long been proposed as a key pathophysiological factor of organ dysfunction and death in septic shock patients. Persistence of mottling, prolonged skin recoloration time and cyanosis of the extremities are the easily and frequently observed manifestations of these microcirculatory disorders. Ilomedin is a prostaglandin analog with a potent vasodilatory effect together with anti-thrombotic properties (inhibition of platelet aggregation) preferentially at the microcirculatory level. An increase in cardiac output with increased arterial oxygen delivery has been observed in clinical and preclinical studies with no episodes of hypotension. Improvement in mesenteric perfusion has moreover been observed in experimental sepsis using Ilomedin. Our group has furthermore reported that administration of Ilomedin in patients with refractory septic shock (peripheral hypoperfusion) resulted in a rapid and sustained improvement in peripheral perfusion. Altogether, Ilomedin may prevent or improve recovery of organ dysfunction in septic shock patients through recruitment of the microcirculation and, thereby, ultimately improve outcome.

Detailed Description
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In the 25 participating centers: patients with septic shock and persistent peripheral hypoperfusion despite hemodynamic optimization (skin mottling and/or finger skin recoloration time > 3sec, and/or knee skin recoloration time > 4sec), after 6 to 24 hours of norepinephrine onset will be eligible for randomization. Patients fulfilling the eligibility criteria will be included and randomized by the intensivist in two groups: *Experimental group: The patient will receive treatment with intravenous Ilomedin (blinded) therapy at a dose of 0.5 ng/kg/min with increments of 0.5 ng/kg/min every 30 minutes up to a maximum posology of 1.5ng/kg/min for 48h. Placebo group: The patient will receive treatment with intravenous NaCl 0.9% (placebo-double blinded) with increments of infusion rate every 30 minutes for 48h. Primary outcome will be Delta Sequential Organ Failure Assessment (SOFA) score between infusion onset and day 7. *within the 12 first hours after randomization : blood samples : 15 ml of blood will be collected at the same time as the sample routinely collected, within the 12 first hours after randomization in ICU, when the patients are perfused. The blood will be drawn and worked as follows: 2 x EDTA tubes of 5 ml : After centrifugation each tube will be directly divided into 4 aliquots of 500 µL (8 aliquots per patient) 1 x aprotinine tube of 5 ml : After centrifugation, it will be directly divided into 4 aliquots of 500 µL The aliquots previously will be stored locally, and will be transported to the Centre de Ressources Biologiques (CRB) of the Lariboisière Hospital.

Official Title
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 Ilomedin for Treatment of Septic Shock With Persistent Microperfusion Defects , a Double-blind, Randomized Controlled Trial:The I-MICRO Trial

Conditions
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Septic Shock Hyperdynamic

Intervention / Treatment
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* Drug: Ilomedin
* Drug: NaCl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients over 18 years of age Signed informed consent or inclusion under the emergency provisions of the law (Article L1122 -1-3 of the PHC / modified by Order n°2016-800 of June 16 2016 - art. 2). Patients with septic shock defined by the third international definition: suspected or proven infection, and organ dysfunction defined by an acute change in total SOFA score >or=2 and persistent hypotension requiring vasopressor treatment to maintain mean arterial pressure > 65 mmHg despite standard of care hemodynamic optimization and serum lactate level > 2 mmol/L despite standard of care hemodynamic optimization and persistence of peripheral hypoperfusion (skin mottling and/or finger skin recoloration time > 3sec, and/or knee skin recoloration time > 4sec) despite standard of care hemodynamic optimization Within 6 to 24 hours after norepinephrine onset Exclusion Criteria: Refusal to participate in the study Pregnancy, breastfeeding Hypersensitivity to Ilomedin or to any of the excipients. Conditions where the hemorrhagic risk may be increased due to the effects of Ilomedin on platelets (i.e., evolving hemorrhage, trauma, intracranial hemorrhage, active gastric ulcer). Platelet count < 30000 /mm3 unstable angina. severe cardiac rhythm disorders since Norepinephrine onset severe hypoxemia (PaO2/FiO2 <100) myocardial infarction in the last 6 months lack of Social Insurance persons deprived of liberty

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: intravenous Ilomedin<br>a first dose of Ilomedin of 0.5ng/kg/ min with increments every 30 minutes up to a maximum of 1,5 ng/kg/min for 48h | Drug: Ilomedin<br>* The patient will receive treatment with intravenous Ilomedin therapy at a dose of 0.5ng/kg/min with increments of 0.5 ng/kg/min every 30 minutes up to a maximum posology of 1,5 ng/kg/min for 48h.<br>* Other names: 50 microgrammes /0,5 ml vials;|
| Placebo Comparator: Intravenous Placebo<br>Treatment with intravenous NaCl 0.9% therapy with incremental infusion rate every 30 minutes for 48h | Drug: NaCl<br>* The patient will receive treatment with intravenous NaCl 0.9% (placebo-double blinded) with increments of infusion rate every 30 minutes for 48h<br>* Other names: (Saline 0.9%);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delta (Sequential Organ Failure Assessment (SOFA)) score between infusion onset and day 7. SOFA score assesses organ failure (respiratory, hemodynamics, liver, coagulation, neurological and kidney) in ICU patients. | SOFA and Delta SOFA calculation will be performed by the Intensivist. Patients deceased before day 7 will be attributed a maximum SOFA score. SOFA score range from 0 (no organ failure) to a maximum of 24 (worst SOFA score). | 7 days after randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean SOFA score during the first 7 days after randomization | SOFA and Delta SOFA calculation will be performed by the Intensivist. | 7 days after randomization | 
| Number of survival days outside ICU in the 28 days post randomization | It will be calculated by the number of days between ICU discharge and day 28 in survivors of ICU stay. | Between ICU discharge and day 28 | 
| Number of ventilation-free survival days in the 28 days post randomization | It will be calculated as the number of survival days without mechanical ventilation | Between randomization and day 28. | 
| Number of renal replacement therapy-free survival days in the 28 days post randomization - | It will be calculated as the number of survival days without renal replacement therapy | Between randomization and day 28. | 
| Number of vasopressor-free survival days in the 28 days post randomization | It will be calculated as the number of survival days without vasopressor therapy | Between randomization and day 28. | 
| Molting score at day 1 after randomization. | In order to identifying and quantifying microcirculatory dysfunction in septic shock. A picture of patient's knees will be taken. Molting score range from 0 to a maximum of 5 : 0. - No mottling - Coin sized mottling area on the knee. - To the superior area of the knee cap. - Mottling up to the middle thigh - Mottling up to the fold of the groin - Severe mottling that extends beyond the the groin. | At day 1 after randomization | 
| Conservation of plasma for future biological measurements | 15 ml of blood will be collected at the same time as the sample routinely collected, within the 12 first hours after randomization, when the patients are perfused. | within 10 years after the end of the study. | 
| Microcirculation | Monitoring of microcirculation using non-invasive monitoring devices including: photoplethysmography,cutaneous Doppler coupled with iontophoresis, near-infrared spectroscopy, videomicroscopy, tissular PCO2, urethral photoplethysmography, perfusion index using phtoplethysmography | At the baseline, and between day 2 and day 7 | 
| mortality |  | At day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Microcirculatory defects, hemodynamic macroparameters, mottling, Septic shock, SOFA score