Clinical trial NCT04636671: Methylprednisolone vs. Dexamethasone in COVID-19 Pneumonia (MEDEAS RCT)
Official title: Randomized Controlled Trial of Methylprednisolone Versus Dexamethasone in COVID-19 Pneumonia (MEDEAS Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid19
Viral Pneumonia Human Coronavirus
Severe Acute Respiratory Syndrome
Keywords: Methylprednisolone
Dexamethasone
COVID-19
Pneumonia
Lead sponsor: University of Trieste
Sponsor class: OTHER
Collaborators: name: Centro di Riferimento Oncologico - Aviano
name: National Institute for the Infectious Diseases (L. Spallanzani) - Rome
First posted: 2020-11-19
Enrollment: 690
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open-label, randomized controlled trial
Primary purpose: TREATMENT

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).


Eligibility criteria: 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.

Primary outcomes:
measure: Survival
timeFrame: 28 days
Secondary outcomes:
measure: Reduction in the need for mechanical ventilation
timeFrame: 28 days
measure: Length of hospitalization
timeFrame: From date of randomization until the date of hospital discharge, assessed up to 60 days
measure: Need for tracheostomy
timeFrame: Day 28
measure: Reduction in systemic inflammation markers
timeFrame: Day 3, 7 and 14
measure: Amelioration of oxygenation
timeFrame: Day 3, 7 and 14
measure: Disease progression
timeFrame: Day 3, 7 and 14
Other outcomes:
Locations:
city: Trieste
country: Italy
facility: Marco Confalonieri
state: TS
Study officials:
affiliation: University of Trieste
name: Marco Confalonieri, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17.
citation: Arabi YM, Chrousos GP, Meduri GU. The ten reasons why corticosteroid therapy reduces mortality in severe COVID-19. Intensive Care Med. 2020 Nov;46(11):2067-2070. doi: 10.1007/s00134-020-06223-y. Epub 2020 Oct 7. No abstract available.
citation: WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Sterne JAC, Murthy S, Diaz JV, Slutsky AS, Villar J, Angus DC, Annane D, Azevedo LCP, Berwanger O, Cavalcanti AB, Dequin PF, Du B, Emberson J, Fisher D, Giraudeau B, Gordon AC, Granholm A, Green C, Haynes R, Heming N, Higgins JPT, Horby P, Juni P, Landray MJ, Le Gouge A, Leclerc M, Lim WS, Machado FR, McArthur C, Meziani F, Moller MH, Perner A, Petersen MW, Savovic J, Tomazini B, Veiga VC, Webb S, Marshall JC. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 2020 Oct 6;324(13):1330-1341. doi: 10.1001/jama.2020.17023.
citation: Meduri GU, Annane D, Confalonieri M, Chrousos GP, Rochwerg B, Busby A, Ruaro B, Meibohm B. Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS. Intensive Care Med. 2020 Dec;46(12):2284-2296. doi: 10.1007/s00134-020-06289-8. Epub 2020 Nov 4.
citation: Salton F, Confalonieri P, Meduri GU, Santus P, Harari S, Scala R, Lanini S, Vertui V, Oggionni T, Caminati A, Patruno V, Tamburrini M, Scartabellati A, Parati M, Villani M, Radovanovic D, Tomassetti S, Ravaglia C, Poletti V, Vianello A, Gaccione AT, Guidelli L, Raccanelli R, Lucernoni P, Lacedonia D, Foschino Barbaro MP, Centanni S, Mondoni M, Davi M, Fantin A, Cao X, Torelli L, Zucchetto A, Montico M, Casarin A, Romagnoli M, Gasparini S, Bonifazi M, D'Agaro P, Marcello A, Licastro D, Ruaro B, Volpe MC, Umberger R, Confalonieri M. Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia. Open Forum Infect Dis. 2020 Sep 12;7(10):ofaa421. doi: 10.1093/ofid/ofaa421. eCollection 2020 Oct.
citation: WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 2020 Aug;20(8):e192-e197. doi: 10.1016/S1473-3099(20)30483-7. Epub 2020 Jun 12.
citation: Dimairo M, Pallmann P, Wason J, Todd S, Jaki T, Julious SA, Mander AP, Weir CJ, Koenig F, Walton MK, Nicholl JP, Coates E, Biggs K, Hamasaki T, Proschan MA, Scott JA, Ando Y, Hind D, Altman DG; ACE Consensus Group. The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design. BMJ. 2020 Jun 17;369:m115. doi: 10.1136/bmj.m115.