Which severe COVID-19 patients could benefit from high dose dexamethasone? A Bayesian post-hoc reanalysis of the COVIDICUS randomized clinical trial
Authors: Chevret Sylvie , Bouadma Lila , Dupuis Claire , Burdet Charles , Timsit Jean-François ,   the COVIDICUS RCT group, Beldjoudi Naima , Chevret Sylvie , Burdet Charles , Alloux Céline , Amerali Fadila , Andriss Béatrice , Baghli Kamyl , Brocvielle Hélène , Capelle Florence , Chibane Ines , Dalibey Sarra , Ettalhaoui Nadia , Lamri Sabrine , Maurer Yohan , Mintsa Jean-Marc , Oubahim Alice , Tellier Marie-Capucine , Zemihi Imane , Bouadma Lila , Abdel-Nabey Moustafa , Azzouguen Billal , Belkessa Ghenima , De Montmollin Etienne , Deiler Veronique , Dupuis Claire , Fallet Aline , Franchineau Guillaume , Girard Tiphaine , Grinea Alexandra , Jaquet Pierre , Kramer Laura , Lamara Fariza , Lefevre Lucie , Marzouk Mehdi , Patrier Juliette , Presente Simona , Sayagh Faiza , Sinnah Fabrice , Sonneville Romain , Wicky Paul-Henri , Zmihi Sylia , Cohen Yves , Barget Nathalie , Belmokhtar Rawan , Brahmi Sabrina , Djabra Naoual , Ebstein Nathan , Fliss Souha , Gourbdji Amina , Juguet William , Messani Fadhila , Rambaud Thomas , Rathouin Vanessa , Rebai Mani , Rigal Marthe , Schmidt Julien , Soulie Marie , Tandjaoui-Lombiotte Yacine , Winchenne Anaïs , Ziol Marianne , Arrestier Romain , Bagate François , Benais Morgan , Bendib Ines , Lan LE , Benelli Brice , Berti Enora , Bertier Astrid , Carteaux Guillaume , Carvalho Muriel , Cavaleiro Pedro , Deprost Nicolas , Hartman Otto , Haudebourg Anne-Fleur , Lefebvre De Nailly Delphine , Lopinto Julien , Mahiou Sabrina , Masi Paul , Michaud Gaël , Nait-Chabane Luiza , Ouali Fariza , Perier François , Razazi Keyvan , Sadaoui Thiziri , Thiemele Alaki , Tuffet Samuel , Autron Flavien , Boddaert Pauline , Brice Sylvie , Caplan Morgan , Cerf Amélie , Cousin Nicolas , Cuvelliez Marie , Delcourte Claire , Durand Arthur , Favory Raphaël , El Kalioubie Ahmed , Gaudel Myrtille , Gaudet Alexandre , Goutay Julien , Houard Marion , Jaillette Emmanuelle , Jourdain Mercé , Ledoux Geoffrey , Mariller Laure , Millot Guillaume , Moreau Anne-Sophie , Niles Christopher , Nseir Saad , Onimus Thierry , Preau Sébastien , Roucou Aurélie , Rouze Anahita , Saura Ouriel , Simonnet Arthur , Tortuyaux Romain , Merdji Hamid , Allam Hayat , Cattelan Jessy , Clere-Jehl Raphaël , Helms Julie , Hilt Kévin , Hutt-Clauss Anne , Kummerlen Christine , Meziani Ferhat , Monnier Alexandra , Rahmani Hassène , Studer Antoine , Thiebaut Leonie , Han Hew Wai Aurélie , Cerf Charles , Cortier David , Devaquet Jérôme , Fremont Dimitri , Galliot Richard , Juster Fabienne , Le-Marchand Mathilde , Le-Meur Lucie , Neuville Mathilde , Roux Emmanuel , Tachon Guillaume , Vassord-Dang Camille , Zuber Benjamin , Bruel Cédric , Aroulanda Marie-José , Berthet-Delteil Bryan , Courtiade-Malher Juliette , De Chevigny Alix , Fontaine Candice , Fournier Julien , Garrigou Sonia , Jardin-Szucs Meryam , Philippart François , Renet Sophie , Sacco Emmanuelle , Tran Marc , Guitton Christophe , Bolle Delphine , Callahan Jean-Christophe , Chudeau Nicolas , Darreau Cédric , Guillarme Séverine , Landais Mickael , Latrouite Laurent , Le Moal Charlène , Lebasnier Eliott , Leroyer Marie-Hélène , Marnai Rémy , Meunier Juliette , Naveau Catherine , Saint-Martin Marjorie , Robert Alain , Tirot Patrice , Schwebel Carole , Bougnaud Joanna , Candille Clara , Collomb-Muret Roselyne , Cordier Charlotte , Galerneau Louis-Marie , Gerard Côme , Nicolas Pierre , Refes Amel , Rigault Guillaume , Sigaud Florian , Terzi Nicolas , Terzi Ester , Turbil Emmanuelle , Vallod Yann , Dupuis Claire , Adda Mireille , Bachelier Claire , Bereiziat Marine , Bernard Lise , Bouzgarrou Radhia , Calvet Laure , Couhault Pierre , Coupez Elisabeth , Duee Frédéric , Gilard Armelle , Girard Tiphaine , Grapin Kévin , Kinda Francis , Laurichesse Guillaume , Liteaudon Jean-Mathias , Souweine Bertrand , Thouy François , Marzouk Mehdi , Declercq Hervé , Descamps Dominique , Dewatine Anne , Janowski Sabine , Senis Catherine , Vinsonneau Christophe , Kipnis Eric , Bignon Anne , Bommenel Tchadie , Brice Sylvie , Huriez Claude , Duprey Matthieu , Garcon Pierre , Hammami Afef , Issad Andréa , Jaccod-Deneuville Marie-Odile , Kachmar Safaâ , Van-Vong Ly , Zarka Jonathan , Megarbane Bruno , Deye Nicolas , Jacob Aude , Malissin Isabelle , M’Rad Aymen , Voicu Sebastian , Geri Guillaume , Chambrin-Lauvray Hélène , Douache Ouarda , Godement Mathieu , Jouffroy Romain , Jullien Edouard , Petit Matthieu , Vieillard-Baron Antoine , Cariou Alain , Boyer Alexandre , Pavese Patricia , Giraudeau Bruno 
Published: August 2023

Abstract
Background
The respective benefits of high and low doses of dexamethasone (DXM) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and acute respiratory failure (ARF) are controversial, with two large triple-blind RCTs reaching very important difference in the effect-size. In the COVIDICUS trial, no evidence of additional benefit of high-dose dexamethasone (DXM20) was found. We aimed to explore whether some specific patient phenotypes could benefit from DXM20 compared to the standard of care 6 mg dose of DXM (DXMSoC).

Methods
We performed a post hoc exploratory Bayesian analysis of 473 patients who received either DXMSoc or DXM20 in the COVIDICUS trial. The outcome was the 60 day mortality rate of DXM20 over DXMSoC, with treatment effect measured on the hazard ratio (HR) estimated from Cox model. Bayesian analyses allowed to compute the posterior probability of a more than trivial benefit (HR < 0.95), and that of a potential harm (HR > 1.05). Bayesian measures of interaction then quantified the probability of interaction (Pr Interact) that the HR of death differed across the subsets by 20%. Primary analyses used noninformative priors, centred on HR = 1.00. Sensitivity analyses used sceptical and enthusiastic priors, based on null (HR = 1.00) or benefit (HR = 0.95) effects.

Results
Overall, the posterior probability of a more than trivial benefit and potential harm was 29.0 and 51.1%, respectively. There was some evidence of treatment by subset interaction (i) according to age (Pr Interact, 84%), with a 86.5% probability of benefit in patients aged below 70 compared to 22% in those aged above 70; (ii) according to the time since symptoms onset (Pr Interact, 99%), with a 99.9% probability of a more than trivial benefit when lower than 7 days compared to a < 0.1% probability when delayed by 7 days or more; and (iii) according to use of remdesivir (Pr Interact, 91%), with a 90.1% probability of benefit in patients receiving remdesivir compared to 19.1% in those who did not.

Conclusions
In this exploratory post hoc Bayesian analysis, compared with standard-of-care DXM, high-dose DXM may benefit patients aged less than 70 years with severe ARF that occurred less than 7 days after symptoms onset. The use of remdesivir may also favour the benefit of DXM20. Further analysis is needed to confirm these findings.
Trial registration: NCT04344730, date of registration April 14, 2020 (https://clinicaltrials.gov/ct2/show/NCT04344730?term=NCT04344730&draw=2&rank=1); EudraCT: 2020-001457-43 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-001457-43).