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Efficacy of Canrenone as add-on Treatment in Moderate to Severe ARDS in COVID-19 (MINECRAFT)

Primary Purpose

COVID-19 Acute Respiratory Distress Syndrome

Status
Not yet recruiting
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Potassium Canrenoate
Sponsored by
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID-19 Acute Respiratory Distress Syndrome focused on measuring COVID-19, potassium canrenoate

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age 18 - 80 y.o. Since over eighties are very fragile patients, a lot of confounding unpredictable events may interfere with the trial analyses; thus, these patients will be excluded from this exploratory proof-of-concept trial;
  • COVID-19 diagnosis through swab within 14 days from the beginning of symptoms
  • Hospitalization for moderate to severe ARDS (as determined by PaO2/FiO2 ≤300 mmHg at admission)
  • Serum concentration of potassium ≤4.5 mEq/L
  • Consent to participate

Exclusion Criteria:

  • Invasive mechanical ventilation
  • I.v. hydratation with Darrow's solution or half-strength Darrow's solution underway
  • Acute cardiovascular event (acute myocardial infarction, acute ischaemic stroke)
  • Current malignant disease
  • Creatinine >1.8 mg/dL (for women) and >2.0 mg/dL (for men) or glomerular filtration rate <50 mL/mm
  • Systolic blood pressure <110 mmHg and/or diastolic blood pressure <60 mmHg
  • Known or suspected hypersensitivity to canrenone
  • Hyponatremia
  • Anuria
  • Familial history of porphyria
  • Pregnancy and breastfeeding
  • known or suspected hypersensitivity to canrenone
  • Inclusion in any other pharmacological clinical trials

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    No Intervention

    Experimental

    Arm Label

    Reference group

    Experimental Group

    Arm Description

    Patients randomized to the Reference Group will receive the standard-of-care treatments, according to institutional procedures in force: Dexamethasone i.v. 6 mg die for consecutive 5 days Methylprednisolone i.v. 40 mg bid for consecutive 10 days Low-molecular-weight-heparin i.v. at standardized dose of 70 UI/kg twice Remdesivir i.v. 200 mg in bolus (1st day) then 100 mg die for 4 days; remdesivir will be used only in patients supported with low-flow nasal cannula oxygen or Venturi mask Antibiotic therapy: azithromycin: 500 mg/die per os for 5 days ceftriaxone: 2 g i.v. die for 8 days

    Patients randomized in the Experimental Group will receive canrenone as add-on therapy to standard-of-care treatments. Different starting doses of i.v. canrenone will be administrated in a single or double infusion per day, for 7 days, according to the serum concentration of potassium at randomization

    Outcomes

    Primary Outcome Measures

    in-hospital death
    patients discharged to a long-term care facility will be classified as "discharged alive"

    Secondary Outcome Measures

    Need of invasive mechanical ventilation throughout hospitalization
    Researchers will record if mechanical ventilation has been required during hospitalization (YES) or not (NO)
    Duration of hospitalization for alive patients
    from randomization to discharge
    Drug intolerance
    measured as number of AR and SAR
    Number of hypotensive events
    defined as systolic blood pressure constantly <90 mmHg and diastolic blood pressure constantly <60 mmHg)
    Number of hyperkaliemias events
    defined as [K+]hematic >5.1 mEq/L
    Number of renal failures
    defined as eGFR <30 ml/min
    Change in Sequential Organ Failure Assessment (SOFA) score from randomization to 7 days after randomization
    A score from 0 (better outcome) to 4 (worst outcome) for six different systems (respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems) will be assessed and recorded in CRF
    Change in inflammatory status
    CRP levels, IL-6, Ddimer and Ferritin
    Change in respiratory parameters
    Heart Rate, Blood Pressure (mmHg), PaO2/FiO2 (mmHg), alveolar-arterial gradient (mmHg)
    Changes in features of pulmonary interstitial disease measured by chest X-Ray
    Changes in [K+]hematic, renin, AngII, Ang1-7, Ang1-9, aldosterone and structurally related steroids
    [K+]hematic will be expressed as mEq/L Plasmatic Renin Activity will be expressed as µUI/mL Hematic Concentration of AngII, Ang1-7, Ang1-9, aldosterone and structurally related steroids will be expressed as ng/mL
    Correlation between levels of [K+]hematic, renin, AngII, Ang1-7, Ang1-9, aldosterone and structurally related steroids, at basal level (randomization) and clinical outcomes (in-hospital death, need of invasive mechanical ventilation, SOFA score)
    [K+]hematic will be expressed as mEq/L Plasmatic Renin Activity will be expressed as µUI/mL Hematic Concentration of AngII, Ang1-7, Ang1-9, aldosterone and structurally related steroids will be expressed as ng/mL

    Full Information

    First Posted
    July 21, 2021
    Last Updated
    May 16, 2022
    Sponsor
    Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
    Collaborators
    University of Milan, IRCCS Azienda Ospedaliero-Universitaria di Bologna
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04977960
    Brief Title
    Efficacy of Canrenone as add-on Treatment in Moderate to Severe ARDS in COVID-19
    Acronym
    MINECRAFT
    Official Title
    MINECRAFT Study: MINEralcorticoid Receptor Antagonism With CanRenone As eFfective Treatment in Moderate to Severe ARDS in COVID-19, a Phase 2 Clinical Trial.
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    July 2021
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    September 2022 (Anticipated)
    Primary Completion Date
    May 2023 (Anticipated)
    Study Completion Date
    December 2023 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
    Collaborators
    University of Milan, IRCCS Azienda Ospedaliero-Universitaria di Bologna

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    The main aim of the study is to estimate the potential efficacy of i.v. canrenone as add-on therapy on maximal medical treatment versus maximal medical treatment alone in treating moderate-to-severe ARDS due to SARS-CoV-2.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    COVID-19 Acute Respiratory Distress Syndrome
    Keywords
    COVID-19, potassium canrenoate

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Model Description
    Open label, 1:1 randomized parallel arms, Simon's two stage design, single centre.
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    180 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Reference group
    Arm Type
    No Intervention
    Arm Description
    Patients randomized to the Reference Group will receive the standard-of-care treatments, according to institutional procedures in force: Dexamethasone i.v. 6 mg die for consecutive 5 days Methylprednisolone i.v. 40 mg bid for consecutive 10 days Low-molecular-weight-heparin i.v. at standardized dose of 70 UI/kg twice Remdesivir i.v. 200 mg in bolus (1st day) then 100 mg die for 4 days; remdesivir will be used only in patients supported with low-flow nasal cannula oxygen or Venturi mask Antibiotic therapy: azithromycin: 500 mg/die per os for 5 days ceftriaxone: 2 g i.v. die for 8 days
    Arm Title
    Experimental Group
    Arm Type
    Experimental
    Arm Description
    Patients randomized in the Experimental Group will receive canrenone as add-on therapy to standard-of-care treatments. Different starting doses of i.v. canrenone will be administrated in a single or double infusion per day, for 7 days, according to the serum concentration of potassium at randomization
    Intervention Type
    Drug
    Intervention Name(s)
    Potassium Canrenoate
    Other Intervention Name(s)
    Canrenone
    Intervention Description
    potassium canrenoate for 7 days in addition to maximal medical treatment
    Primary Outcome Measure Information:
    Title
    in-hospital death
    Description
    patients discharged to a long-term care facility will be classified as "discharged alive"
    Time Frame
    At the event (discharge or death)
    Secondary Outcome Measure Information:
    Title
    Need of invasive mechanical ventilation throughout hospitalization
    Description
    Researchers will record if mechanical ventilation has been required during hospitalization (YES) or not (NO)
    Time Frame
    at discharge or death
    Title
    Duration of hospitalization for alive patients
    Description
    from randomization to discharge
    Time Frame
    From date of randomization until the date discharge or in-hospital death from any cause, whichever came first, assessed up to 48 months
    Title
    Drug intolerance
    Description
    measured as number of AR and SAR
    Time Frame
    From the date of randomization until three days after the end of IMP administration (10 days after randomization)
    Title
    Number of hypotensive events
    Description
    defined as systolic blood pressure constantly <90 mmHg and diastolic blood pressure constantly <60 mmHg)
    Time Frame
    From the date of randomization until three days after the end of IMP administration (10 days after randomization)
    Title
    Number of hyperkaliemias events
    Description
    defined as [K+]hematic >5.1 mEq/L
    Time Frame
    From the date of randomization until three days after the end of IMP administration (10 days after randomization)
    Title
    Number of renal failures
    Description
    defined as eGFR <30 ml/min
    Time Frame
    From the date of randomization until three days after the end of IMP administration (10 days after randomization)
    Title
    Change in Sequential Organ Failure Assessment (SOFA) score from randomization to 7 days after randomization
    Description
    A score from 0 (better outcome) to 4 (worst outcome) for six different systems (respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems) will be assessed and recorded in CRF
    Time Frame
    7 days after randomization
    Title
    Change in inflammatory status
    Description
    CRP levels, IL-6, Ddimer and Ferritin
    Time Frame
    at 48 hours and 168 hours (7th day) from randomization
    Title
    Change in respiratory parameters
    Description
    Heart Rate, Blood Pressure (mmHg), PaO2/FiO2 (mmHg), alveolar-arterial gradient (mmHg)
    Time Frame
    at 48 hours and 168 hours (7th day) from randomization
    Title
    Changes in features of pulmonary interstitial disease measured by chest X-Ray
    Time Frame
    at 7 days after randomization
    Title
    Changes in [K+]hematic, renin, AngII, Ang1-7, Ang1-9, aldosterone and structurally related steroids
    Description
    [K+]hematic will be expressed as mEq/L Plasmatic Renin Activity will be expressed as µUI/mL Hematic Concentration of AngII, Ang1-7, Ang1-9, aldosterone and structurally related steroids will be expressed as ng/mL
    Time Frame
    at randomization and at 48 and 168 hours (7th day) from randomization
    Title
    Correlation between levels of [K+]hematic, renin, AngII, Ang1-7, Ang1-9, aldosterone and structurally related steroids, at basal level (randomization) and clinical outcomes (in-hospital death, need of invasive mechanical ventilation, SOFA score)
    Description
    [K+]hematic will be expressed as mEq/L Plasmatic Renin Activity will be expressed as µUI/mL Hematic Concentration of AngII, Ang1-7, Ang1-9, aldosterone and structurally related steroids will be expressed as ng/mL
    Time Frame
    at randomization and at 48 and 168 hours (7th day) from randomization

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    80 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Age 18 - 80 y.o. Since over eighties are very fragile patients, a lot of confounding unpredictable events may interfere with the trial analyses; thus, these patients will be excluded from this exploratory proof-of-concept trial; COVID-19 diagnosis through swab within 14 days from the beginning of symptoms Hospitalization for moderate to severe ARDS (as determined by PaO2/FiO2 ≤300 mmHg at admission) Serum concentration of potassium ≤4.5 mEq/L Consent to participate Exclusion Criteria: Invasive mechanical ventilation I.v. hydratation with Darrow's solution or half-strength Darrow's solution underway Acute cardiovascular event (acute myocardial infarction, acute ischaemic stroke) Current malignant disease Creatinine >1.8 mg/dL (for women) and >2.0 mg/dL (for men) or glomerular filtration rate <50 mL/mm Systolic blood pressure <110 mmHg and/or diastolic blood pressure <60 mmHg Known or suspected hypersensitivity to canrenone Hyponatremia Anuria Familial history of porphyria Pregnancy and breastfeeding known or suspected hypersensitivity to canrenone Inclusion in any other pharmacological clinical trials
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Marco Vicenzi, MD
    Phone
    +390255033537
    Email
    marco.vicenzi@policlinico.mi.it
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Marco Vicenzi, MD
    Organizational Affiliation
    Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No

    Learn more about this trial

    Efficacy of Canrenone as add-on Treatment in Moderate to Severe ARDS in COVID-19

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