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

Primary Purpose

Septic Shock Hyperdynamic

Status

Recruiting

Phase

Phase 3

Locations

France

Study Type

Interventional

Intervention

Ilomedin

NaCl

About this trial

This is an interventional treatment trial for Septic Shock Hyperdynamic focused on measuring Microcirculatory defects, hemodynamic macroparameters, mottling, Septic shock, SOFA score

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

intravenous Ilomedin

Intravenous Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Mean SOFA score during the first 7 days after randomization

SOFA and Delta SOFA calculation will be performed by the Intensivist.

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.

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

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

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

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.

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.

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

mortality

Full Information

NCT ID

NCT03788837

First Posted

November 20, 2018

Last Updated

September 12, 2022

Sponsor

Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT03788837

Brief Title

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

Acronym

I-MICRO

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Recruiting

Study Start Date

July 3, 2019 (Actual)

Primary Completion Date

August 3, 2023 (Anticipated)

Study Completion Date

September 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Septic Shock Hyperdynamic

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

236 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

intravenous Ilomedin

Arm Type

Experimental

Arm Description

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

Arm Title

Intravenous Placebo

Arm Type

Placebo Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Ilomedin

Other Intervention Name(s)

50 microgrammes /0,5 ml vials

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

NaCl

Other Intervention Name(s)

(Saline 0.9%)

Intervention Description

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 Measure Information:

Title

Description

Time Frame

7 days after randomisation

Secondary Outcome Measure Information:

Title

Mean SOFA score during the first 7 days after randomization

Description

SOFA and Delta SOFA calculation will be performed by the Intensivist.

Time Frame

7 days after randomization

Title

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

Description

It will be calculated by the number of days between ICU discharge and day 28 in survivors of ICU stay.

Time Frame

Between ICU discharge and day 28

Title

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

Description

It will be calculated as the number of survival days without mechanical ventilation

Time Frame

Between randomization and day 28.

Title

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

Description

It will be calculated as the number of survival days without renal replacement therapy

Time Frame

Between randomization and day 28.

Title

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

Description

It will be calculated as the number of survival days without vasopressor therapy

Time Frame

Between randomization and day 28.

Title

Molting score at day 1 after randomization.

Description

Time Frame

At day 1 after randomization

Title

Conservation of plasma for future biological measurements

Description

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.

Time Frame

within 10 years after the end of the study.

Title

Microcirculation

Description

Time Frame

At the baseline, and between day 2 and day 7

Title

mortality

Time Frame

At day 28

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

99 Years

Accepts Healthy Volunteers

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 < 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

François DEPRET, MD

Phone

(1) 42 49 95 70

Ext

00 33

francois.depret@aphp.fr

First Name & Middle Initial & Last Name or Official Title & Degree

Matthieu LEGRAND, MD,PhD

Phone

(1) 42 49 95 70

Ext

00 33

matthieu.m.legrand@gmail.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

François DEPRET, MD

Organizational Affiliation

APHP-Hôpital saint Louis

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Matthieu LEGRAND, MD,PhD

Organizational Affiliation

APHP-Hôpital saint Louis

Official's Role

Study Director

Facility Information:

Facility Name

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

City

Paris

ZIP/Postal Code

75010

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

François DEPRET, MD, PhD

Phone

01 42 49 95 70

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

24941897

Citation

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

Results Reference

background

PubMed Identifier

21373821

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.

Results Reference

background

PubMed Identifier

2444080

Citation

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

Results Reference

background

PubMed Identifier

19318827

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.

Results Reference

background

PubMed Identifier

19251782

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.

Results Reference

background

PubMed Identifier

29176794

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.

Results Reference

background

PubMed Identifier

28921126

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.

Results Reference

background

PubMed Identifier

32611377

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.

Results Reference

derived

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

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