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

Covid19 Clinical Trial

— MEDEAS  

Official title:

Randomized Controlled Trial of Methylprednisolone Versus Dexamethasone in COVID-19 Pneumonia (MEDEAS Trial)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04636671
• Other study ID #: MEDEAS1
• Status: Completed
• Phase: Phase 3
• Start date: April 14, 2021
• Est. completion date: May 4, 2022

Study information

• Verified date: May 2022
• Source: University of Trieste
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 690
• Est. completion date: May 4, 2022
• Est. primary completion date: May 4, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• COVID-19
• Covid19
• Pneumonia
• Pneumonia, Viral
• Severe Acute Respiratory Syndrome
• Viral Pneumonia Human Coronavirus

Intervention

Drug:
• Methylprednisolone
Per-protocol methylprednisolone administration and tapering (see arm description)
• Dexamethasone
Per-protocol dexamethasone administration (see arm description)

Locations

Country	Name	City	State
Italy	Marco Confalonieri	Trieste	TS

Sponsors (3)

Lead Sponsor	Collaborator
University of Trieste	Centro di Riferimento Oncologico - Aviano, National Institute for the Infectious Diseases (L. Spallanzani) - Rome

Country where clinical trial is conducted

Italy, 

References & Publications (7)

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. — View 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. — View 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. Review. — View 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. — View 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, Davì 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. — View 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, Jüni P, Landray MJ, Le Gouge A, Leclerc M, Lim WS, Machado FR, McArthur C, Meziani F, Møller 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. — View 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. Review. Erratum in: Lancet Infect Dis. 2020 Oct;20(10):e250. — View Citation

Outcome

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