Methylprednisolone vs. Dexamethasone in COVID-19 Pneumonia (MEDEAS RCT)

Phase 3

Completed

• Conditions: Covid19; Viral Pneumonia Human Coronavirus; Severe Acute Respiratory Syndrome
• Interventions: Drug: Dexamethasone; Drug: Methylprednisolone

• Registration Number: NCT04636671
• Lead Sponsor: University of Trieste

Brief Summary

Low-dose glucocorticoid treatment is the only intervention shown to significantly reduce mortality in cases of COVID-19 pneumonia requiring oxygen supplementation or ventilatory support. In particular, a large UK randomized controlled trial (RECOVERY trial) demonstrated the efficacy of dexamethasone at a dosage of 6mg/day for 10 days in reducing mortality compared to usual therapy, with a greater impact on patients requiring mechanical ventilation (36% reduction) or oxygen therapy (18% reduction) than on those who did not need respiratory support (doi: 10.1056/NEJMoa2021436). However, there is still paucity of information guiding glucocorticoid administration in severe pneumonia/ARDS and no evidence of the superiority of a steroid drug -nor of a therapeutic scheme- compared to the others, which led to a great heterogeneity of treatment protocols and misinterpretation of available findings. In a recent longitudinal observational study conducted in Italian respiratory high-dependency units, a protocol with prolonged low-dose methylprednisolone demonstrated a 71% reduction in mortality and the achievement of other secondary endpoints such as an increase in ventilation-free days by study day 28 in a subgroup of patients with severe pneumonia and high levels of systemic inflammation (doi: 10.1093/ofid/ofaa421). The treatment was well tolerated and did not affect viral shedding from the airways. In light of these data, the present study aims to compare the efficacy of a methylprednisolone protocol and that of a dexamethasone protocol based on previous evidence in increasing survival by day 28, as well as in reducing the need and duration for mechanical ventilation, among hospitalized patients requiring noninvasive respiratory support (oxygen supplementation and/or noninvasive ventilation).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-11-18
• Study First Submitted QC: 2020-11-18
• Study First Posted: 2020-11-19
• Study Start: 2021-04-14
• Status Verified: 2022-05
• Primary Completion: 2022-05-04
• Study Completion: 2022-05-04
• Last Update Submitted: 2022-05-16
• Last Update Posted: 2022-05-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 690

Inclusion Criteria

1. Able to understand and sign the informed consent
2. SARS-CoV-2 positive on at least one upper respiratory swab or bronchoalveolar lavage
3. PaO2 <= 60 mmHg or SpO2 <= 90% or on oxygen therapy (any), CPAP or NPPV at randomization
4. Age >= 18 years old at randomization

Exclusion Criteria

1. On invasive mechanical ventilation (either intubated or tracheostomized)
2. Heart failure as the main cause of acute respiratory failure
3. On long-term oxygen or home mechanical ventilation
4. Decompensated liver cirrhosis
5. Immunosuppression (i.e., cancer on treatment, post-organ transplantation, HIV-positive, on immunosuppressant therapy)
6. On chronic steroid therapy or other immunomodulant therapy (e.g., azathioprine, methotrexate, mycophenolate, convalescent/hyperimmune plasma)
7. Chronic renal failure with dialysis dependence
8. Progressive neuro-muscular disorders
9. Cognitively impaired, dementia or decompensated psychiatric disorder
10. Quadriplegia/Hemiplegia or quadriparesis/hemiparesis
11. Do-not-resuscitate order
12. Participating in other clinical trial including experimental compound with proved or expected activity against SARS-CoV-2 infection
13. Any other condition that in the opinion of the investigator may significantly impact with patient's capability to comply with protocol intervention
14. Refuse to participate in the study or absence of signed informed consent form.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dexamethasone	Dexamethasone	A. Dexamethasone (DM) 6 mg IV in 30 minutes or PO from day 1 to day 10 or until hospital discharge (if sooner). B. After day 10 study treatment is interrupted.
Methylprednisolone	Methylprednisolone	A. On day 1, loading dose of methylprednisolone (MP) 80 mg IV in 30 minutes, promptly followed by continuous infusion of MP 80 mg/day in 240 mL of normal saline at 10 mL/h. B. From day 2 to day 8: infusion of MP 80 mg/day in 240 mL of normal saline at 10 mL/h. C. From day 9 and beyond: 1. If not intubated patient and PaO2/FiO2 \> 200, taper to MP 20 mg IV in 30 minutes three times a day for 3 days, then MP 20 mg IV twice daily for 3 days, then MP 20 mg IV once daily for 2 days, then switch to MP 16 mg/day PO for 2 days, then MP 8mg/day PO for 2 days, then MP 4mg/day PO for 2 days; 2. If intubated patient or PaO2/FiO2 \<= 200 with at least 5 cmH2O CPAP, continue infusion of MP 80 mg/day in 240 mL of normal saline at 10 mL/h until PaO2/FiO2 \> 200 then taper as in a)

Primary Outcome Measures

Name	Time	Method
Survival	28 days	Survival proportion at 28 days in both arms

Secondary Outcome Measures

Name	Time	Method
Disease progression	Day 3, 7 and 14	WHO clinical progression scale at study day 3, 7 and 14 in both arms
Reduction in the need for mechanical ventilation	28 days	Number of days free from mechanical ventilation (either noninvasive or invasive) by study day 28 in both arms
Length of hospitalization	From date of randomization until the date of hospital discharge, assessed up to 60 days	Number of days of hospitalization for patients discharged alive in both arms
Need for tracheostomy	Day 28	Proportion of patients requiring tracheostomy in both arms
Reduction in systemic inflammation markers	Day 3, 7 and 14	C-reactive protein level (mg/L) at study day 3, 7 and 14 in both arms
Amelioration of oxygenation	Day 3, 7 and 14	PaO2/FiO2 ratio (mmHg) at study day 3, 7 and 14 in both arms

Trial Locations

Locations (1)

Marco Confalonieri; 🇮🇹 Trieste, TS, Italy