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

NCT ID: NCT03788837

Last Updated: 2024-07-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 240 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-07-03
• Study Completion Date: 2024-01-18

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.

Conditions

Septic Shock Hyperdynamic

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

intravenous ILOPROST

a first dose of ILOPROST of 0.5ng/kg/ min with increments every 30 minutes up to a maximum of 1,5 ng/kg/min for 48h

Group Type: EXPERIMENTAL

ILOPROST

Intervention Type: DRUG

The patient will receive treatment with intravenous ILOPROST 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.

Intravenous Placebo

Treatment with intravenous NaCl 0.9% therapy with incremental infusion rate every 30 minutes for 48h

Group Type: PLACEBO_COMPARATOR

NaCl

Intervention Type: DRUG

The patient will receive treatment with intravenous NaCl 0.9% (placebo-double blinded) with increments of infusion rate every 30 minutes for 48h

Interventions

ILOPROST

The patient will receive treatment with intravenous ILOPROST 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.

Intervention Type: DRUG

NaCl

The patient will receive treatment with intravenous NaCl 0.9% (placebo-double blinded) with increments of infusion rate every 30 minutes for 48h

Intervention Type: DRUG

Other Intervention Names

50 microgrammes /0,5 ml vials; (Saline 0.9%)

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

François DEPRET, MD

Role: PRINCIPAL_INVESTIGATOR

APHP-Hôpital saint Louis

Matthieu LEGRAND, MD,PhD

Role: STUDY_DIRECTOR

APHP-Hôpital saint Louis

Locations

Departement of Anesthesiology, Critical Care and Burn Unit; Saint-Louis hospital

Paris, , France

Countries

France

References

De Backer D, Donadello K. Assessment of microperfusion in sepsis. Minerva Anestesiol. 2015 May;81(5):533-40. Epub 2014 Jun 19.

Reference Type: BACKGROUND

PMID: 24941897 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21373821 (View on PubMed)

Muller B, Schmidtke M. Microvascular effects of iloprost in the hamster cheek pouch. Adv Prostaglandin Thromboxane Leukot Res. 1987;17A:455-8.

Reference Type: BACKGROUND

PMID: 2444080 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19318827 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19251782 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 29176794 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28921126 (View on PubMed)

Legrand M, Jullien E, Kimmoun A, Geri G, Ait-Oufella H, Abrard S, Gaugain S, Bounes F, Guerci P, Pottecher J, Jamme M, Poncelin de Raucourt Y, Barraud D, Constantin JM, Juguet W, Lasocki S, Sonneville R, Audibert J, Plantefeve G, Ellrodt O, Fedou AL, Leone M, Lefebvre L, Auvet A, Chen D, Vicaut E, Depret F; I-MICRO Trial Investigators. Iloprost for the Treatment of Severe Septic Shock with Persistent Hypoperfusion: A Double-Blind, Randomized Controlled Trial. Am J Respir Crit Care Med. 2025 Jul;211(7):1211-1219. doi: 10.1164/rccm.202410-1924OC.

Reference Type: DERIVED

PMID: 40387381 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32611377 (View on PubMed)

Other Identifiers

P170924J

Identifier Type: -

Identifier Source: org_study_id