Clinical trial NCT03788837: ILOPROST in Septic Shock With Persistent Microperfusion Defects (I-MICRO)
Official title: " ILOPROST for Treatment of Septic Shock With Persistent Microperfusion Defects ", a Double-blind, Randomized Controlled Trial:The I-MICRO Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Septic Shock Hyperdynamic
Keywords: Microcirculatory defects
hemodynamic macroparameters
mottling
Septic shock
SOFA score
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2018-12-28
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: In the 32 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 Iloprost (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) therapy at a dose of 0.5ng/kg/min with increments of 0.5 ng/kg/min every 30 minutes according to body weight with a maximum posology of 1,5 ng/kg/min 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.

Eligibility criteria: 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 \< 10000 /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
* persons of a protective measure

Primary outcomes:
measure: 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.
timeFrame: 7 days after randomisation
Secondary outcomes:
measure: Mean SOFA score during the first 7 days after randomization
timeFrame: 7 days after randomization
measure: Number of survival days outside ICU in the 28 days post randomization
timeFrame: Between ICU discharge and day 28
measure: Number of ventilation-free survival days in the 28 days post randomization
timeFrame: Between randomization and day 28.
measure: Number of renal replacement therapy-free survival days in the 28 days post randomization -
timeFrame: Between randomization and day 28.
measure: Number of vasopressor-free survival days in the 28 days post randomization
timeFrame: Between randomization and day 28.
measure: Molting score at day 1 after randomization.
timeFrame: At day 1 after randomization
measure: Conservation of plasma for future biological measurements
timeFrame: within 10 years after the end of the study.
measure: Microcirculation
timeFrame: At the baseline, and between day 2 and day 7
measure: mortality
timeFrame: At day 28
Other outcomes:
Locations:
city: Paris
country: France
facility: Departement of Anesthesiology, Critical Care and Burn Unit; Saint-Louis hospital
Study officials:
affiliation: APHP-Hôpital saint Louis
name: François DEPRET, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: APHP-Hôpital saint Louis
name: Matthieu LEGRAND, MD,PhD
role: STUDY_DIRECTOR
References:
citation: De Backer D, Donadello K. Assessment of microperfusion in sepsis. Minerva Anestesiol. 2015 May;81(5):533-40. Epub 2014 Jun 19.
citation: Ait-Oufella H, Lemoinne S, Boelle PY, Galbois A, Baudel JL, Lemant J, Joffre J, Margetis D, Guidet B, Maury E, Offenstadt G. Mottling score predicts survival in septic shock. Intensive Care Med. 2011 May;37(5):801-7. doi: 10.1007/s00134-011-2163-y. Epub 2011 Mar 4.
citation: Muller B, Schmidtke M. Microvascular effects of iloprost in the hamster cheek pouch. Adv Prostaglandin Thromboxane Leukot Res. 1987;17A:455-8.
citation: Johannes T, Ince C, Klingel K, Unertl KE, Mik EG. Iloprost preserves renal oxygenation and restores kidney function in endotoxemia-related acute renal failure in the rat. Crit Care Med. 2009 Apr;37(4):1423-32. doi: 10.1097/CCM.0b013e31819b5f4e.
citation: Hoeper MM, Gall H, Seyfarth HJ, Halank M, Ghofrani HA, Winkler J, Golpon H, Olsson KM, Nickel N, Opitz C, Ewert R. Long-term outcome with intravenous iloprost in pulmonary arterial hypertension. Eur Respir J. 2009 Jul;34(1):132-7. doi: 10.1183/09031936.00130408. Epub 2009 Feb 27.
citation: Lara B, Enberg L, Ortega M, Leon P, Kripper C, Aguilera P, Kattan E, Castro R, Bakker J, Hernandez G. Capillary refill time during fluid resuscitation in patients with sepsis-related hyperlactatemia at the emergency department is related to mortality. PLoS One. 2017 Nov 27;12(11):e0188548. doi: 10.1371/journal.pone.0188548. eCollection 2017.
citation: Depret F, Sitbon A, Soussi S, De Tymowski C, Blet A, Fratani A, Legrand M. Intravenous iloprost to recruit the microcirculation in septic shock patients? Intensive Care Med. 2018 Jan;44(1):121-122. doi: 10.1007/s00134-017-4935-5. Epub 2017 Sep 18. No abstract available.
citation: Legrand M, Oufella HA, De Backer D, Duranteau J, Leone M, Levy B, Rossignol P, Vicaut E, Depret F; I-MICRO trial investigators. The I-MICRO trial, Ilomedin for treatment of septic shock with persistent microperfusion defects: a double-blind, randomized controlled trial-study protocol for a randomized controlled trial. Trials. 2020 Jul 1;21(1):601. doi: 10.1186/s13063-020-04549-y.