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

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ClinicalTrials.gov Identifier: NCT03788837
Recruitment Status : Not yet recruiting
First Posted : December 28, 2018
Last Update Posted : March 13, 2019
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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.

Condition or disease Intervention/treatment Phase
Septic Shock Hyperdynamic Drug: Ilomedin Drug: NaCl Phase 3

Detailed Description:

In the 23 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 236 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: " Ilomedin for Treatment of Septic Shock With Persistent Microperfusion Defects ", a Double-blind, Randomized Controlled Trial:The I-MICRO Trial
Estimated Study Start Date : April 17, 2019
Estimated Primary Completion Date : April 15, 2021
Estimated Study Completion Date : April 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Shock

Arm Intervention/treatment
Experimental: intravenous Ilomedin
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
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.
Other Name: 50 microgrammes /0,5 ml vials

Placebo Comparator: Intravenous Placebo
Treatment with intravenous NaCl 0.9% therapy with incremental infusion rate every 30 minutes for 48h
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
Other Name: (Saline 0.9%)




Primary Outcome Measures :
  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. [ Time Frame: 7 days after randomisation ]

    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 :
  1. Mean SOFA score during the first 7 days after randomization [ Time Frame: 7 days after randomization ]
    SOFA and Delta SOFA calculation will be performed by the Intensivist.

  2. Number of survival days outside ICU in the 28 days post randomization [ Time Frame: Between ICU discharge and day 28 ]
    It will be calculated by the number of days between ICU discharge and day 28 in survivors of ICU stay.

  3. Number of ventilation-free survival days in the 28 days post randomization [ Time Frame: Between randomization and day 28. ]
    It will be calculated as the number of survival days without mechanical ventilation

  4. Number of renal replacement therapy-free survival days in the 28 days post randomization - [ Time Frame: Between randomization and day 28. ]
    It will be calculated as the number of survival days without renal replacement therapy

  5. Number of vasopressor-free survival days in the 28 days post randomization [ Time Frame: Between randomization and day 28. ]
    It will be calculated as the number of survival days without vasopressor therapy

  6. Molting score at day 1 after randomization. [ Time Frame: 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

    1. - Coin sized mottling area on the knee.
    2. - To the superior area of the knee cap.
    3. - Mottling up to the middle thigh
    4. - Mottling up to the fold of the groin
    5. - Severe mottling that extends beyond the the groin.



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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03788837


Contacts
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Contact: François DEPRET, MD (1) 42 49 95 70 ext 00 33 francois.depret@aphp.fr
Contact: Matthieu LEGRAND, MD,PhD (1) 42 49 95 70 ext 00 33 matthieu.m.legrand@gmail.com

Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: François DEPRET, MD APHP-Hôpital saint Louis
Study Director: Matthieu LEGRAND, MD,PhD APHP-Hôpital saint Louis

Publications:

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03788837     History of Changes
Other Study ID Numbers: P170924J
First Posted: December 28, 2018    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Microcirculatory defects
hemodynamic macroparameters
mottling
Septic shock
SOFA score
Additional relevant MeSH terms:
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Shock, Septic
Shock
Pathologic Processes
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation