Trial of Treatments for COVID-19 in Hospitalized Adults

Corona Virus Infection Clinical Trial

— DisCoVeRy  

Official title:

Multi-centre, Adaptive, Randomized Trial of the Safety and Efficacy of Treatments of COVID-19 in Hospitalized Adults

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04315948
• Other study ID #: C20-15
• Secondary ID: 101015736
• Status: Completed
• Phase: Phase 3
• Start date: March 22, 2020
• Est. completion date: September 25, 2023

Study information

• Verified date: November 2023
• Source: Institut National de la Santé Et de la Recherche Médicale, France
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

DisCoVeRy is a randomized controlled trial among adults (≥18-year-old) hospitalized for COVID-19. This study is an adaptive, randomized, open or blinded, depending on the drug to be evaluated, clinical trial to evaluate the safety and efficacy of possible therapeutic agents in hospitalized adult patients diagnosed with COVID-19. The study is a multi-centre/country trial that will be conducted in various sites in Europe with Inserm as sponsor. The study will compare different investigational therapeutic agents to a control group managed with the SoC including corticosteroids and anticoagulants. There will be interim monitoring to allow early stopping for safety and to introduce new therapies as they become available. If one therapy proves to be superior to others in the trial, this treatment may become part of the SoC for comparison(s) with new experimental treatment(s).

In previous versions of the DisCoVeRy protocol, remdesivir, lopinavir/ritonavir with or without interferon ß-1a and hydroxychloroquine were evaluated as potential treatments for COVID-19. These treatments have been discontinued based on analyses review by both DSMC/DSMB, the Solidarity Executive Group and the DisCoVeRy steering committee.

This version of the protocol, therefore, describes a randomized blinded placebo-controlled trial among adults (≥18-year-old) hospitalized for COVID-19 that randomly allocates them (1:1 ratio) between 2 arms: SoC + placebo versus SoC + AZD7442.

Randomization will be stratified by region (according to the administrative definition in each country), antigenic status (positive or negative) obtained from the result of a rapid antigen test on nasopharyngeal swab performed at enrolment and vaccination initiation (yes or no).

The primary analyses will be conducted on patients with antigen-positive results. A positive antigenic test is evidence of high viral shedding consistent with a recently started or uncontrolled infection. Overall, the number of antigen-negative patients will be at most 30% of all included subjects. The number of patients with vaccination (partly or fully) will be limited to 20% of all participants, split evenly between antigen positive and antigen negative patients (i.e. vaccinated patients can make up at most 20% of antigene positive patients and 20% of antigene negative patients). Sensitivity analyses will be performed in all patients, stratified by antigenic status and vaccination initiation.

A global independent data and safety monitoring board (DSMB) monitors interim data to make recommendations about early study closure or changes to conduct, including adding or removing treatment arms. However, the current version of the protocol does not allow for efficacy or futility analysis, and the ability to add trial arms will be limited by the study being blinded and placebo-controlled during the investigation of AZD7442.

Description:

DisCoVeRy is a randomized controlled trial among adults (≥18-year-old) hospitalized for COVID-19. This study is an adaptive, randomized, open or blinded, depending on the drug to be evaluated, clinical trial to evaluate the safety and efficacy of possible therapeutic agents in hospitalized adult patients diagnosed with COVID-19. The study is a multi-centre/country trial that will be conducted in various sites in Europe with Inserm as sponsor. The study will compare different investigational therapeutic agents to a control group managed with the SoC including corticosteroids and anticoagulants. There will be interim monitoring to allow early stopping for safety and to introduce new therapies as they become available. If one therapy proves to be superior to others in the trial, this treatment may become part of the SoC for comparison(s) with new experimental treatment(s).

In previous versions of the DisCoVeRy protocol, remdesivir, lopinavir/ritonavir with or without interferon ß-1a and hydroxychloroquine were evaluated as potential treatments for COVID-19. These treatments have been discontinued based on analyses review by both DSMC/DSMB, the Solidarity Executive Group and the DisCoVeRy steering committee.

This version of the protocol, therefore, describes a randomized blinded placebo-controlled trial among adults (≥18-year-old) hospitalized for COVID-19 that randomly allocates them (1:1 ratio) between 2 arms: SoC + placebo versus SoC + AZD7442.

Randomization will be stratified by region (according to the administrative definition in each country), antigenic status (positive or negative) obtained from the result of a rapid antigen test on nasopharyngeal swab performed at enrolment and vaccination initiation (yes if at least one injection of any vaccine against SARS-CoV-2 was reveived prior to enrolment whatever the delay or no).

The primary analyses will be conducted on patients with antigen-positive results. A positive antigenic test is evidence of high viral shedding consistent with a recently started or uncontrolled infection. Overall, the number of antigen-negative patients will be at most 30% of all included subjects. The number of patients with vaccination (partly or fully) will be limited to 20% of all participants, split evenly between antigen positive and antigen negative patients (i.e. vaccinated patients can make up at most 20% of antigene positive patients and 20% of antigene negative patients). Sensitivity analyses will be performed in all patients, stratified by antigenic status and vaccination initiation.

A global independent data and safety monitoring board (DSMB) monitors interim data to make recommendations about early study closure or changes to conduct, including adding or removing treatment arms. However, the current version of the protocol does not allow for efficacy or futility analysis, and the ability to add trial arms will be limited by the study being blinded and placebo-controlled during the investigation of AZD7442.

All subjects will undergo a series of efficacy and safety assessments, including laboratory assays.

Subjects will be assessed at baseline, and at Days 3, 8 and 15 while hospitalized. Patients will be contacted by phone at Day 15 for evaluation of the Primary Endpoint if they have been discharged prior to Day 15-, and 14-days following hospital discharge for efficacy assessment.

Further follow-up assessments will be organized at Days 29, 90, 180, 365 and 456.

If discharged from the hospital, days 29 and 90 assessments will be organized as outpatients' consultations for all. For Days 180 and 365 assessments, a subset of 25% of patients enrolled in centers with available resources and selected at Day 90 will be evaluated during a medical consultation, while the other will be contacted by phone. For Day 456, all patients will be contacted by phone.

Nasopharyngeal swabs (NP) or lower respiratory tract samples will be obtained at baseline (Day 1 pre-treatment) and at Days 3, 8, 15 (while hospitalized) and 29 (while hospitalized or, if discharged from the hospital, in the outpatient setting).

Blood samples will be obtained at baseline (Day 1 pre-treatment) and at Days 3, 8, 15 (while hospitalized), at Days 29 and 90, and at Days 180 and 365 (for the subset of patients evaluated during a medical consultation at these times).

Thoracic computed tomography (CT)-scan will be obtained at baseline, depending on the centre's imagery capacities.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1552
• Est. completion date: September 25, 2023
• Est. primary completion date: July 9, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Adult =18 years of age at the time of enrolment

2. Hospitalized patients with any of the following criteria:

1. the presence of pulmonary rales/crackles on clinical exam OR

2. SpO2 = 94% on room air OR

3. requirement of supplementary oxygen including high flow oxygen devices or non-invasive ventilation

3. A time between onset of symptoms and randomization of less than 11 days

4. A positive SARS-CoV-2 PCR performed on a NP swab within the 5 days preceding randomization

5. The result of a rapid antigen test performed on a NP swab within the 6 hours preceding randomization

6. Contraceptive use by men or women.

1. Male participants: Contraception for male participants is required; to avoid the transfer of any fluids, all male participants must use a condom from Day 1 and agree to continue for 90 days following administration of IMP.

2. Female participants: Women of child-bearing potential must agree to use contraception for 365 days following administration of IMP

Exclusion Criteria:

1. Refusal to participate expressed by patient or legally authorized representative

2. Need for invasive mechanical ventilation and/or ECMO at the time of enrolment

3. Spontaneous blood ALT/AST levels > 5 times the upper limit of normal

4. Glomerular filtration rate (GFR) < 15 mL/min or requiring maintenance dialysis

5. Pregnancy or breast-feeding

6. Anticipated transfer to another hospital, which is not a study site within 72 hours following randomization

7. Known history of allergy or reaction to any component of the study drug formulation.

8. Previous hypersensitivity, infusion-related reaction, or severe adverse reaction following administration of monoclonal or polyclonal antibodies.

9. Any prior receipt of investigational or licensed other mAb/biologic indicated for the prevention of SARS-CoV-2 infection or COVID-19, and for those not vaccinated, expected receipt of vaccine in the 30 days following hospital discharge, according to current recommendation in each country.

10. Any medical condition which, in the judgment of the investigator, could interfere with the interpretation of the trial results or that preludes to protocol adherence.

Related Conditions & MeSH terms

• Corona Virus Infection
• Coronavirus Infections
• COVID-19

Intervention

Drug:
• Remdesivir
The lyophilized formulation of Remdesivir is a preservative-free, white to off-white or yellow, lyophilized solid containing 100 mg of Remdesivir to be reconstituted with 19 mL of sterile water for injection and diluted into IV infusion fluids prior to IV infusion. Following reconstitution, each vial contains a 5 mg/mL Remdesivir concentrated solution with sufficient volume to allow withdrawal of 20 mL (100 mg of remdesivir). It is supplied as a sterile product in a single-use, 30 mL, Type 1 clear glass vial.
• Lopinavir/ritonavir
The oral tablets of lopinavir/ritonavir contain 200 mg lopinavir, 50 mg ritonavir. They have a yellow colour, film-coated, ovaloid shape debossed with the "a" logo and the code KA. The oral solution for patients who cannot swallow is a light yellow to orange colored liquid containing 400 mg lopinavir and 100 mg ritonavir per 5 mL (80 mg lopinavir and 20 mg ritonavir per mL).
• Interferon Beta-1A
IFN-ß-1a is supplied as a sterile solution containing no preservative available in a prefilled syringe. It will be provided as a single-dose prefilled graduated syringe with 44 µg per 0.5 mL. The liquid should be clear to slightly yellow. Do not use if the liquid is cloudy, discolored or contains particles. Use a different syringe.
• Hydroxychloroquine
Hydroxychloroquine is supplied as film-coated 200 mg tablets. Hydroxychloroquine sulfate tablets are presented as white or whitish, peanut-shaped, oblong or round film-coated tablets containing 200 mg of hydroxychloroquine sulfate (equivalent to 155 mg base).

Other:
• Standard of care
Standard of care

Drug:
• AZD7442
AZD7442 will be supplied as separate vials of AZD8895 and AZD1061 containing 150 mg colorless to slightly yellow, clear to opalescent solutions for injection.

Other:
• Placebo
Since April, 2021, the placebo will be a 0.9% (w/v) NaCl solution for infusion also called saline. The placebo will be supplied as a single 10-mL, clear and colorless vial.

Locations

Country	Name	City	State
Austria	Medizinische Universität Innsbruck	Innsbruck
Austria	Kepler Universitätsklinikum Linz	Linz
Austria	Landeskrankenhaus Salzburg Universitätsklinikum der Paracelsus Medizinischen Privatuniversität	Salzburg
Belgium	Hôpital Erasme - Cliniques universitaires de Bruxelles	Brussels
Belgium	Hôpital Saint Luc	Brussels
Belgium	Hôpital La Citadelle	Liège
Belgium	Pôle Hospitalier Jolimont / site de Mons-Warquignies	Mons
France	Centre Hospitalier Universitaire Amiens-Picardie	Amiens
France	Centre Hospitalier Regional Metz-Thionville	Ars-Laquenexy
France	Centre Hospitalier Régional Universitaire de Besançon	Besançon
France	Centre Hospitalier Universitaire de Bordeaux	Bordeaux
France	CHU APHP Ambroise-Paré	Boulogne-Billancourt
France	Centre Hospitalier Andrée Rosemon	Cayenne
France	Hospices Civil	Colmar
France	APHP - hôpital Henri-Mondor	Créteil
France	Centre Hospitalier Universitaire Dijon-Bourgogne	Dijon
France	Centre Hospitalier Annecy Genevois	Épagny
France	Centre Hospitalier Universitaire de Martinique	Fort De France
France	AP-HP Hôpital Bicêtre	Kremlin-Bicêtre
France	Centre Hospitalo-Universitaire de Grenoble	La Tronche
France	Centre Hospitalier Régional Universitaire de Lille	Lille
France	Hospices Civils de Lyon	Lyon
France	Centre Hospitalier Universitaire de Montpellier	Montpellier
France	Groupe Hospitalier de la Région de Mulhouse Sud Alsace	Mulhouse
France	Centre Hospitalier Régional et Universitaire de Nancy	Nancy
France	Centre Hospitalier Universitaire de Nantes	Nantes
France	Centre Hospitalo-Universitaire de Nice	Nice
France	CHU Nîmes	Nîmes
France	APHP - Hôpital Bichat Claude Bernard	Paris
France	APHP - Hôpital Cochin	Paris
France	APHP - Hôpital Lariboisière	Paris
France	APHP - Hôpital Necker	Paris
France	APHP - Hôpital Saint Antoine	Paris
France	APHP - Hôpital Saint Louis	Paris
France	APHP - Hôpital Tenon	Paris
France	APHP - Hôpital Universitaire Pitié Salpêtrière	Paris
France	APHP- Hôpital Européen Georges-Pompidou	Paris
France	Hôpital Paris Saint-Joseph et Marie Lannelongue	Paris
France	CHU Poitiers	Poitiers
France	CH Cornouaille	Quimper
France	CHU de Reims	Reims
France	Centre Hospitalier Universitaire de Rennes	Rennes
France	Hopital DELAFONTAINE	Saint-Denis
France	Centre Hospitalier Universitaire de Saint Etienne	Saint-Étienne
France	Hôpital d'Instruction des Armées BEGIN	Saint-Mandé
France	Centre Hospitalier Régional Universitaire de Strasbourg	Strasbourg
France	Centre Hospitalier Universitaire de Toulouse	Toulouse
France	Centre Hospitalier Universitaire de Toulouse	Toulouse
France	Centre Hospitalier de Tourcoing	Tourcoing
France	Centre Hospitalier Universitaire de Tours	Tours
France	CH Bretagne Atlantique	Vannes
France	CH Bretagne Atlantique	Vannes
Greece	Evaggelismos General Hospital	Athens
Greece	General University Hospital of Patras	Patras
Luxembourg	Centre Hospitalier Luxembourg	Luxembourg
Luxembourg	Hôpitaux Robert Schuman	Luxembourg
Norway	Akershus Unniversity Hospital	Oslo
Norway	Lovisenberg Diaconal Hospital	Oslo
Norway	Oslo University Hospital	Oslo
Portugal	Hospital de Cascais	Cascais
Portugal	CHULN- Hospital de Santa Maria	Lisboa
Portugal	Centro Hospitalar Universitário de São João, EPE	Porto

Sponsors (1)

Lead Sponsor	Collaborator
Institut National de la Santé Et de la Recherche Médicale, France

Countries where clinical trial is conducted

Austria,  Belgium,  France,  Greece,  Luxembourg,  Norway,  Portugal, 

References & Publications (16)

Ader F, Bouscambert-Duchamp M, Hites M, Peiffer-Smadja N, Mentre F, Burdet C; DisCoVeRy Study Group. Final results of the DisCoVeRy trial of remdesivir for patients admitted to hospital with COVID-19. Lancet Infect Dis. 2022 Jun;22(6):764-765. doi: 10.101 — View Citation

Ader F, Bouscambert-Duchamp M, Hites M, Peiffer-Smadja N, Poissy J, Belhadi D, Diallo A, Le MP, Peytavin G, Staub T, Greil R, Guedj J, Paiva JA, Costagliola D, Yazdanpanah Y, Burdet C, Mentre F; DisCoVeRy Study Group. Remdesivir plus standard of care vers — View Citation

Ader F, Peiffer-Smadja N, Poissy J, Bouscambert-Duchamp M, Belhadi D, Diallo A, Delmas C, Saillard J, Dechanet A, Mercier N, Dupont A, Alfaiate T, Lescure FX, Raffi F, Goehringer F, Kimmoun A, Jaureguiberry S, Reignier J, Nseir S, Danion F, Clere-Jehl R, — View Citation

Ader F; Discovery French Trial Management Team. Protocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults. BMJ Open. 2020 Sep 21;10(9):e041437. doi: 10.1136/bmjopen-2020-041437. — View Citation

Ader F; DisCoVeRy Study Group. An open-label randomized, controlled trial of the effect of lopinavir and ritonavir, lopinavir and ritonavir plus interferon-beta-1a, and hydroxychloroquine in hospitalized patients with COVID-19: final results. Clin Microbi — View Citation

Amstutz A, Speich B, Mentre F, Rueegg CS, Belhadi D, Assoumou L, Burdet C, Murthy S, Dodd LE, Wang Y, Tikkinen KAO, Ader F, Hites M, Bouscambert M, Trabaud MA, Fralick M, Lee TC, Pinto R, Barratt-Due A, Lund-Johansen F, Muller F, Nevalainen OPO, Cao B, Bonnett T, Griessbach A, Taji Heravi A, Schonenberger C, Janiaud P, Werlen L, Aghlmandi S, Schandelmaier S, Yazdanpanah Y, Costagliola D, Olsen IC, Briel M. Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials. Lancet Respir Med. 2023 May;11(5):453-464. doi: 10.1016/S2213-2600(22)00528-8. Epub 2023 Feb 21. Erratum In: Lancet Respir Med. 2023 Aug;11(8):e77. — View Citation

EU-Response investigators group; Diallo A, Troseid M, Simensen VC, Boston A, Demotes J, Olsen IC, Chung F, Paiva JA, Hites M, Ader F, Arribas JR, Baratt-Due A, Melien O, Tacconelli E, Staub T, Greil R, Tsiodras S, Briel M, Esperou H, Mentre F, Eustace J, Saillard J, Delmas C, LeMestre S, Dumousseaux M, Costagliola D, Rottingen JA, Yazdanpanah Y. Accelerating clinical trial implementation in the context of the COVID-19 pandemic: challenges, lessons learned and recommendations from DisCoVeRy and the EU-SolidAct EU response group. Clin Microbiol Infect. 2022 Jan;28(1):1-5. doi: 10.1016/j.cmi.2021.10.011. Epub 2021 Nov 8. No abstract available. — View Citation

Fougerou-Leurent C, Delmas C, Saillard J, Dumousseaux M, Ferrane A, Mercier N, Terzic V, Le Mestre S, Dechanet A, Belhadi D, Metois A, Burdet C, Mentre F, Noret M, Diallo A, Petrov-Sanchez V, Couffin-Cadiergues S, Hites M, Ader F, Esperou H. Ensuring quality control in a COVID-19 clinical trial during the pandemic: The experience of the Inserm C20-15 DisCoVeRy study. Contemp Clin Trials. 2023 Aug;131:107267. doi: 10.1016/j.cct.2023.107267. Epub 2023 Jun 9. — View Citation

Le MP, Peiffer-Smadja N, Guedj J, Neant N, Mentre F, Ader F, Yazdanpanah Y, Peytavin G. Rationale of a loading dose initiation for hydroxychloroquine treatment in COVID-19 infection in the DisCoVeRy trial. J Antimicrob Chemother. 2020 Sep 1;75(9):2376-2380. doi: 10.1093/jac/dkaa191. — View Citation

Le MP, Peiffer-Smadja N, Guedj J, Neant N, Mentre F, Ader F, Yazdanpanah Y, Peytavin G; C-20-15 DisCoVeRy French Steering Committee. Rationale of a loading dose initiation for hydroxychloroquine treatment in COVID-19 infection in the DisCoVeRy trial-authors' response. J Antimicrob Chemother. 2021 Jan 1;76(1):277-279. doi: 10.1093/jac/dkaa415. No abstract available. — View Citation

Lingas G, Neant N, Gaymard A, Belhadi D, Peytavin G, Hites M, Staub T, Greil R, Paiva JA, Poissy J, Peiffer-Smadja N, Costagliola D, Yazdanpanah Y, Wallet F, Gagneux-Brunon A, Mentre F, Ader F, Burdet C, Guedj J, Bouscambert-Duchamp M. Effect of remdesivi — View Citation

Mercier N, Belhadi D, DeChanet A, Delmas C, Saillard J, Dumousseaux M, Le Mestre S, Fougerou-Leurent C, Ferrane A, Burdet C, Esperou H, Ader F, Hites M, Peiffer-Smadja N, Poissy J, Andrejak C, Paiva JA, Tacconelli E, Staub T, Greil R, Costagliola D, Mentre F, Yazdanpanah Y, Diallo A; DisCoVeRy Safety Working group. Management of pharmacovigilance during the COVID-19 pandemic crisis by the safety department of an academic sponsor: Lessons learnt and challenges from the EU DisCoVeRy clinical trial. Pharmacol Res Perspect. 2023 Jun;11(3):e01072. doi: 10.1002/prp2.1072. — View Citation

Neant N, Lingas G, Gaymard A, Belhadi D, Hites M, Staub T, Greil R, Paiva JA, Poissy J, Peiffer-Smadja N, Costagliola D, Yazdanpanah Y, Bouscambert-Duchamp M, Gagneux-Brunon A, Ader F, Mentre F, Wallet F, Burdet C, Guedj J; DisCoVeRy study group. Associat — View Citation

Terzic V, Levoyer L, Figarella M, Bigagli E, Mercier N, De Gastines L, Gibowski S, Troseid M, Demotes J, Olsen IC, Hites M, Ader F, Lopez JRA, Mentre F, Esperou H, Costagliola D, Rottingen JA, Poissy J, Roze JC, Warris A, O'Leary J, Fernandes RM, Assoumou L, Hankard R, Turner MA, Yazdanpanah Y, Diallo A; EU-Response safety group; c4c safety group. Implementation of a centralized pharmacovigilance system in academic pan-European clinical trials: Experience from EU-Response and conect4children consortia. Br J Clin Pharmacol. 2023 Apr;89(4):1318-1328. doi: 10.1111/bcp.15669. Epub 2023 Feb 8. — View Citation

Troseid M, Hentzien M, Ader F, Cardoso SW, Arribas JR, Molina JM, Mueller N, Hites M, Bonnet F, Manuel O, Costagliola D, Grinsztejn B, Olsen IC, Yazdapanah Y, Calmy A; EU RESPONSE; COMBINE. Immunocompromised patients have been neglected in COVID-19 trials: a call for action. Clin Microbiol Infect. 2022 Sep;28(9):1182-1183. doi: 10.1016/j.cmi.2022.05.005. Epub 2022 May 25. No abstract available. — View Citation

WHO Solidarity Trial Consortium; Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Abdool Karim Q, Alejandria MM, Hernandez Garcia C, Kieny MP, Malekzadeh R, Murthy S, Reddy KS, Roses Periago M, Abi Hanna P, Ader F, Al-Bader AM, Alhasawi A, — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percent of subjects with SARS-CoV-2 detectable in nasopharyngeal sample		Days 3, 5, 8, 11, 15, 29
Other	Quantitative SARS-CoV-2 virus in nasopharyngeal sample		Days 3, 5, 8, 11, 15, 29
Other	Quantitative SARS-CoV-2 virus in blood		Days 3, 8
Primary	Percentage of subjects reporting each severity rating on a 7-point ordinal scale	Not hospitalized, no limitations on activities; Not hospitalized, limitation on activities; Hospitalized, not requiring supplemental oxygen; Hospitalized, requiring supplemental oxygen; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, on invasive mechanical ventilation or ECMO; Death.	Day 15
Secondary	Status on an ordinal scale	Percentage of subjects reporting each severity rating on a 7-point on an ordinal scale	Days 29, 90, 180 and 365
Secondary	National Early Warning Score 2 (NEWS-2 score)	Change from baseline in NEWS-2.	Days 3, 8, 15, and 29
Secondary	Number of oxygenation free days in the first 28 days		29 days
Secondary	Incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial.		29 days
Secondary	Ventilator free days in the first 28 days		29 days
Secondary	Incidence of new mechanical ventilation use during the trial.		29 days
Secondary	Need for mechanical ventilation or death by Day 15	Proportion of patients with mechanical ventilation or death at day 15	Day 15
Secondary	Hospitalization	Time to hospital discharge (days).	29 days
Secondary	Mortality	Rate of mortality	In hospital, Days 29, 90, 180, 365, 456
Secondary	Occurrence of new hospitalization		Days 90, 180 and 365
Secondary	Occurrence of confirmed re-infection with SARS-CoV-2		Days 90, 180 and 365
Secondary	Cumulative incidence of serious adverse events (SAEs)		29 days
Secondary	Cumulative incidence of Grade 1- 2 hypersensitivity- related and infusion related AEs until D29 visit		29 days
Secondary	Cumulative incidence of Grade 3 and 4 adverse events (AEs)		29 days
Secondary	Number of participants with a discontinuation or temporary suspension of study drugs (for any reason)		29 days
Secondary	Cumulative incidence of AEs of Special Interest		29 days