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

Study Overview
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Brief Summary
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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.

Official Title
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MINECRAFT Study: MINEralcorticoid Receptor Antagonism With CanRenone As eFfective Treatment in Moderate to Severe ARDS in COVID-19, a Phase 2 Clinical Trial.

Conditions
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COVID-19 Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Drug: Potassium Canrenoate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Reference group<br>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 | |
| Experimental: Experimental Group<br>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 | Drug: Potassium Canrenoate<br>* potassium canrenoate for 7 days in addition to maximal medical treatment<br>* Other names: Canrenone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| in-hospital death | patients discharged to a long-term care facility will be classified as discharged alive | At the event (discharge or death) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Need of invasive mechanical ventilation throughout hospitalization | Researchers will record if mechanical ventilation has been required during hospitalization (YES) or not (NO) | at discharge or death | 
| Duration of hospitalization for alive patients | from randomization to discharge | From date of randomization until the date discharge or in-hospital death from any cause, whichever came first, assessed up to 48 months | 
| Drug intolerance | measured as number of AR and SAR | From the date of randomization until three days after the end of IMP administration (10 days after randomization) | 
| Number of hypotensive events | defined as systolic blood pressure constantly <90 mmHg and diastolic blood pressure constantly <60 mmHg) | From the date of randomization until three days after the end of IMP administration (10 days after randomization) | 
| Number of hyperkaliemias events | defined as [K+]hematic >5.1 mEq/L | From the date of randomization until three days after the end of IMP administration (10 days after randomization) | 
| Number of renal failures | defined as eGFR <30 ml/min | From the date of randomization until three days after the end of IMP administration (10 days after randomization) | 
| 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 | 7 days after randomization | 
| Change in inflammatory status | CRP levels, IL-6, Ddimer and Ferritin | at 48 hours and 168 hours (7th day) from randomization | 
| Change in respiratory parameters | Heart Rate, Blood Pressure (mmHg), PaO2/FiO2 (mmHg), alveolar-arterial gradient (mmHg) | at 48 hours and 168 hours (7th day) from randomization | 
| Changes in features of pulmonary interstitial disease measured by chest X-Ray |  | at 7 days after randomization | 
| 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 | at randomization and at 48 and 168 hours (7th day) from randomization | 
| 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 | at randomization and at 48 and 168 hours (7th day) from randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, potassium canrenoate