Spironolactone and Dexamethasone in Patients Hospitalized With COVID-19

Study Overview
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Brief Summary
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The Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) is a rapidly spreading infection of the respiratory tract. Most infected patients have either asymptomatic disease or mild symptoms. However, a proportion of patients, especially elderly men or patients with comorbidities, are at risk of developing acute respiratory distress syndrome (ARDS). ARDS, alongside clotting abnormalities, is known to be a major contributor to SARS-CoV-2-related mortality and admission to intensive care units, with evidenced effective preventative treatment options lacking. In this study, the investigators test a novel hypothesis that the use of a combination of spironolactone and dexamethasone at low doses will improve the clinical progression of the infection evaluated by the 6-point ordinal scale in patients with moderate and severe disease by blocking exocytosis of the Weibel-Palade bodies from endothelial cells.

Official Title
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Spironolactone and Dexamethasone in Patients Hospitalized With Moderate-to-severe COVID-19 (SPIDEX-II): a Randomized Clinical Trial

Conditions
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Coronavirus Infection, Pneumonia, Viral

Intervention / Treatment
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* Drug: Spironolactone + Dexamethasone
* Drug: Standard-of-care SARS-CoV-2 treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or above; Signed informed consent; PCR-confirmed diagnosis of SARS-CoV-2 infection Presenting with moderate-to-severe disease (scores 4-6 on WHO ordinal scale) Exclusion Criteria: Women of childbearing age without a negative urine pregnancy test, currently pregnant or breastfeeding women; Severe heart failure (NYHA4), severe renal failure (eGFR < 30 ml/min/1.73 m2), severe liver failure (ALT/AST ratio > 5 norms), severe anemia (haemoglobin < 30 g/l) Participating in another clinical trial Severe electrolyte imbalance (hyperkalemia > 5.0 mmol/l, hyponatremia < 120 mmol/l) Hypersensitivity or contraindications to the study drugs (spironolactone and dexamethasone) Renal dialysis Severe uncontrolled diabetes mellitus Patient receiving one of the following medications that cannot be substituted over the trial duration: ACE inhibitors, amiloride, eplerenone, cortisone acetate, potassium canrenoate, triamterene

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>After randomisation (Day 1): Spironolactone [100 mg 1x/day] + dexamethasone [2 mg 2x/day, 12/12h] Days 2-12*: Spironolactone [50 mg 2x/day, 12/12h] + dexamethasone [2 mg 2x/day, 12/12h] Days 13-20: Spironolactone [25 mg 2x/day, 12/12h] Days 21-28: Spironolactone [25 mg 1x/day] Standard treatment is according to the treatment protocol for 2019-nCoV infection. *In case of cortisol levels above 100 nmol/L on days 3 and 4, the dexamethasone dose should be increased to 3 mg in the morning and in the evening (total 6 mg per day). | Drug: Spironolactone + Dexamethasone<br>* Low doses of orally administered spironolactone and dexamethasone<br>|
| Active Comparator: Control<br>Patients receiving standard-of-care treatment for SARS-CoV-2 infection as regulated by the relevant guidelines of the Ministry of Healthcare of the Russian Federation | Drug: Standard-of-care SARS-CoV-2 treatment<br>* Standard-of-care SARS-CoV-2 treatment administered according to the local guidelines<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the clinical status | Clinical status at day 14 post-randomization defined by a 6-point ordinal scale score (6 being the worst score) | Day 14 post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-day all-cause mortality | All-cause mortality at 28 days post-randomization | 28 days post-randomization | 
| Oxygen-free days | The number of days without oxygen support of any type | 28 days post-randomization | 
| Ventilator-free days | The number of days without invasive mechanical ventilation | 28 days post-randomization | 
| Invasive mechanical ventilation | The number of patients requiring invasive mechanical ventilation during hospitalization and the number of days spent on newly-administered invasive mechanical ventilation | 28 days post-randomization | 
| Time to discharge | The number of days from hospitalization to discharge | 28 days post-randomization | 
| Length of ICU stay | The number of days spent in the intensive care unit | 28 days post-randomization | 
| New ICU admission | The number of patients requiring transfer to ICU and the number of days spent in the ICU post-transfer | 28 days post-randomization | 
| Long-COVID development | The number of patients with signs and symptoms that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis (Post-COVID-19 syndrome as defined by the relevant NICE guidance) | 60 and 90 days post-admission | 
| Evaluation of the clinical status | Clinical status at day 7 post-randomization defined by a 6-point ordinal scale score (6 being the worst score) | Day 7 post-randomization |