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

NCT03788837 | Completed Phase 3 DMC

• 1 other identifier: P170924J
• Study Type: interventional
• Target: 240
• Locations: 1 country
• Sites: 1

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.

Conditions

Septic Shock Hyperdynamic

Keywords

Microcirculatory defects; hemodynamic macroparameters; mottling; Septic shock; SOFA score

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• Mean SOFA score during the first 7 days after randomization

  7 days after randomization

• Number of survival days outside ICU in the 28 days post randomization

  Between ICU discharge and day 28

• Number of ventilation-free survival days in the 28 days post randomization

  Between randomization and day 28.

• Number of renal replacement therapy-free survival days in the 28 days post randomization -

  Between randomization and day 28.

• Number of vasopressor-free survival days in the 28 days post randomization

  Between randomization and day 28.

Study Arms (2)

intravenous ILOPROST

EXPERIMENTAL

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

Drug: ILOPROST

Intravenous Placebo

PLACEBO COMPARATOR

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

Drug: NaCl

Interventions

ILOPROST 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.

Also known as: 50 microgrammes /0,5 ml vials

intravenous ILOPROST

NaCl DRUG

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

Also known as: (Saline 0.9%)

Intravenous Placebo

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients over 18 years of age
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

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

Paris, 75010, France

Location

Related Publications (9)

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

  PMID: 24941897 BACKGROUND

• 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.

  PMID: 21373821 BACKGROUND

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

  PMID: 2444080 BACKGROUND

• 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.

  PMID: 19318827 BACKGROUND

• 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.

  PMID: 19251782 BACKGROUND

• 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.

  PMID: 29176794 BACKGROUND

• 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.

  PMID: 28921126 BACKGROUND

• 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.

  PMID: 40387381 DERIVED

• 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.

  PMID: 32611377 DERIVED

MeSH Terms

Conditions

Shock, Septic

Interventions

Iloprost; Sodium Chloride

Condition Hierarchy (Ancestors)

Sepsis; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Prostaglandins, Synthetic; Prostaglandins; Eicosanoids; Fatty Acids, Unsaturated; Fatty Acids; Lipids; Autacoids; Inflammation Mediators; Biological Factors; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• François DEPRET, MD

  APHP-Hôpital saint Louis

  PRINCIPAL INVESTIGATOR

• Matthieu LEGRAND, MD,PhD

  APHP-Hôpital saint Louis

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 20, 2018
• First Posted: December 28, 2018
• Study Start: July 3, 2019
• Primary Completion: January 5, 2024
• Study Completion: January 18, 2024
• Last Updated: July 3, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)