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

Sponsor

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04977960

Collaborator

University of Milan (Other), IRCCS Azienda Ospedaliero-Universitaria di Bologna (Other)

180

Enrollment

Arms

Anticipated Duration (Months)

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
COVID-19 Acute Respiratory Distress Syndrome	Drug: Potassium Canrenoate	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

180 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Open label, 1:1 randomized parallel arms, Simon's two stage design, single centre.Open label, 1:1 randomized parallel arms, Simon's two stage design, single centre.

Masking:

None (Open Label)

Primary Purpose:

Treatment

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.

Anticipated Study Start Date :

Sep 1, 2022

Anticipated Primary Completion Date :

May 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

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 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	Drug: Potassium Canrenoate potassium canrenoate for 7 days in addition to maximal medical treatment Other Names: Canrenone

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 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

Drug: Potassium Canrenoate

potassium canrenoate for 7 days in addition to maximal medical treatment

Other Names:

Canrenone

Outcome Measures

Primary Outcome Measures

in-hospital death [At the event (discharge or 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 [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 [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 [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 [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 [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 [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 [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 [at 48 hours and 168 hours (7th day) from randomization]
CRP levels, IL-6, Ddimer and Ferritin
Change in respiratory parameters [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 [at 7 days after randomization]
Changes in [K+]hematic, renin, AngII, Ang1-7, Ang1-9, aldosterone and structurally related steroids [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) [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts 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