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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: COVID-19 Acute Respiratory Distress Syndrome
• Intervention / Treatment: Drug: Potassium Canrenoate

• Study Type: Interventional
• Enrollment (Anticipated): 180
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Marco Vicenzi, MD; Phone Number: +390255033537; Email: marco.vicenzi@policlinico.mi.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 daysceftriaxone: 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	Drug: Potassium Canrenoate; potassium canrenoate for 7 days in addition to maximal medical treatment; Other Names: Canrenone

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
• Collaborators: IRCCS Azienda Ospedaliero-Universitaria di Bologna; University of Milan
• Investigators: Principal Investigator: Marco Vicenzi, MD, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): September 1, 2022
• Primary Completion (ANTICIPATED): May 1, 2023
• Study Completion (ANTICIPATED): December 1, 2023

Study Registration Dates

• First Submitted: July 21, 2021
• First Submitted That Met QC Criteria: July 22, 2021
• First Posted (ACTUAL): July 27, 2021

Study Record Updates

• Last Update Posted (ACTUAL): May 20, 2022
• Last Update Submitted That Met QC Criteria: May 16, 2022
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: COVID-19; potassium canrenoate
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; COVID-19; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Canrenoic Acid; Canrenone
• Other Study ID Numbers: MINECRAFT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No