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

Overview

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.

Full Title of Study: “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

• Study Type: Interventional
• Study Design
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Primary Purpose: Treatment
  • Masking: None (Open Label)
• Study Primary Completion Date: May 2023

Interventions

• Drug: Potassium Canrenoate
  • potassium canrenoate for 7 days in addition to maximal medical treatment

Arms, Groups and Cohorts

• No Intervention: Reference group
  • 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
  • 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

Clinical Trial Outcome Measures

Primary Measures

• in-hospital death
  • Time Frame: At the event (discharge or death)
  • patients discharged to a long-term care facility will be classified as “discharged alive”

Secondary Measures

• Need of invasive mechanical ventilation throughout hospitalization
  • Time Frame: at discharge or death
  • Researchers will record if mechanical ventilation has been required during hospitalization (YES) or not (NO)
• Duration of hospitalization for alive patients
  • 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
  • from randomization to discharge
• Drug intolerance
  • Time Frame: From the date of randomization until three days after the end of IMP administration (10 days after randomization)
  • measured as number of AR and SAR
• Number of hypotensive events
  • Time Frame: From the date of randomization until three days after the end of IMP administration (10 days after randomization)
  • defined as systolic blood pressure constantly <90 mmHg and diastolic blood pressure constantly <60 mmHg)
• Number of hyperkaliemias events
  • Time Frame: From the date of randomization until three days after the end of IMP administration (10 days after randomization)
  • defined as [K+]hematic >5.1 mEq/L
• Number of renal failures
  • Time Frame: From the date of randomization until three days after the end of IMP administration (10 days after randomization)
  • defined as eGFR <30 ml/min
• Change in Sequential Organ Failure Assessment (SOFA) score from randomization to 7 days after randomization
  • Time Frame: 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
  • Time Frame: at 48 hours and 168 hours (7th day) from randomization
  • CRP levels, IL-6, Ddimer and Ferritin
• Change in respiratory parameters
  • Time Frame: at 48 hours and 168 hours (7th day) from randomization
  • Heart Rate, Blood Pressure (mmHg), PaO2/FiO2 (mmHg), alveolar-arterial gradient (mmHg)
• Changes in features of pulmonary interstitial disease measured by chest X-Ray
  • Time Frame: at 7 days after randomization
• Changes in [K+]hematic, renin, AngII, Ang1-7, Ang1-9, aldosterone and structurally related steroids
  • Time Frame: at randomization and at 48 and 168 hours (7th day) from randomization
  • [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)
  • Time Frame: at randomization and at 48 and 168 hours (7th day) from randomization
  • [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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: No

Investigator Details

• Lead Sponsor
  • Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico
• Collaborator
  • University of Milan
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Official(s)
  • Marco Vicenzi, MD, Principal Investigator, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico
• Overall Contact(s)
  • Marco Vicenzi, MD, +390255033537, marco.vicenzi@policlinico.mi.it