Trial of Treatments for COVID-19 in Hospitalized Adults (DisCoVeRy)

• ClinicalTrials.gov Identifier: NCT04315948
• Recruitment Status: Completed
• First Posted: March 20, 2020
• Last Update Posted: November 29, 2023
• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France
• Information provided by (Responsible Party): Institut National de la Santé Et de la Recherche Médicale, France

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Corona Virus Infection	Drug: Remdesivir; Drug: Lopinavir/ritonavir; Drug: Interferon Beta-1A; Drug: Hydroxychloroquine; Other: Standard of care; Drug: AZD7442; Other: Placebo	Phase 3

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1552 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

From March 22, 2020 to May 24, 2020, the study randomized participants 1:1:1:1:1 to standard of care alone (control) or with investigational product added.

From May 24, 2020 to June 29, 2020, the study randomized participants 1:1:1:1 to standard of care alone (control) or with investigational product added.

From June 29, 2020 to January 19,2021, the study randomized participants 1:1 to standard of care alone (control) or with investigational product added.

Since April, 2021, the study will randomize participants 1:1 to standard of care with placebo (control) or standard of care with investigational product added.

• Masking: Triple (Participant, Investigator, Outcomes Assessor)

Masking Description

• the treatment arm SOC + hydroxychloroquine has been ceased since May 24, 2020;
• the treatment arm SOC + lopinavir / Ritonavir and lopinavir / ritonavir + interferon ß-1a has been ceased since June 29, 2020
• the treatment arm SOC + remdesivir has been ceased since January 19, 2021
• the treatment arm SOC + AZD7442

• Primary Purpose: Treatment
• Official Title: Multi-centre, Adaptive, Randomized Trial of the Safety and Efficacy of Treatments of COVID-19 in Hospitalized Adults
• Actual Study Start Date: March 22, 2020
• Actual Primary Completion Date: July 9, 2022
• Actual Study Completion Date: September 25, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Remdesivir; Remdesivir will be administered as a 200 mg intravenous loading dose on Day 1, followed by a 100 mg once-daily intravenous maintenance dose for the duration of the hospitalization up to a 10 days total course. n=475	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.; Other: Standard of care; Standard of care
Experimental: Lopinavir/ritonavir (stopped on June 29, 2020); Lopinavir/ritonavir (400 lopinavir mg/100 mg ritonavir) will be administered every 12 h for 14 days in tablet form. For patients who are unable to take medications by mouth, the lopinavir/ritonavir (400 lopinavir mg/100 mg ritonavir) will be administered as a 5-ml suspension every 12 h for 14 days via a pre-existing or newly placed nasogastric tube. n=620	Drug: 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).; Other: Standard of care; Standard of care
Experimental: Lopinavir/ritonavir plus Interferon ß-1a (stopped on June 29); Lopinavir/ritonavir (400 lopinavir mg/100 mg ritonavir) will be administered every 12 h for 14 days in tablet form. For patients who are unable to take medications by mouth, the lopinavir/ritonavir (400 lopinavir mg/100 mg ritonavir) will be administered as a 5-ml suspension every 12 h for 14 days via a pre-existing or newly placed nasogastric tube. Interferon ß1a will be administered subcutaneously at the dose of 44 µg for a total of 3 doses in 6 days (day 1, day 3, day 6). n=620	Drug: 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).; Drug: 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.; Other: Standard of care; Standard of care
Experimental: Hydroxychloroquine (stopped on May 24, 2020); Hydroxychloroquine will be administered orally as a loading dose of 400 mg twice daily for one day followed by 400 mg once daily for 9 days. The loading dose of hydroxychloroquine through a nasogastric tube will be increased to 600 mg twice a day for one day, followed by a maintenance dose of 400 mg once a day for 9 days n=620	Drug: 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
Active Comparator: Standard of care alone; Standard of care alone before March, 2021.	Other: Standard of care; Standard of care
Experimental: AZD7442; Participants randomized to the AZD7442 group will receive a total dose of 600 mg AZD7442 via a co-administered (300 mg AZD8895 and 300 mg AZD1061) single IV infusion on Day 1. n=620	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.
Active Comparator: Standard of care with placebo; Standard of care with placebo since April, 2021 n=620	Other: Standard of care; Standard of care; 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.

Outcome Measures

Primary Outcome Measures :

1. Percentage of subjects reporting each severity rating on a 7-point ordinal scale [ Time Frame: Day 15 ]
   1. Not hospitalized, no limitations on activities
   2. Not hospitalized, limitation on activities;
   3. Hospitalized, not requiring supplemental oxygen;
   4. Hospitalized, requiring supplemental oxygen;
   5. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
   6. Hospitalized, on invasive mechanical ventilation or ECMO;
   7. Death.

Secondary Outcome Measures :

1. Status on an ordinal scale [ Time Frame: Days 29, 90, 180 and 365 ]
   Percentage of subjects reporting each severity rating on a 7-point on an ordinal scale
2. National Early Warning Score 2 (NEWS-2 score) [ Time Frame: Days 3, 8, 15, and 29 ]
   Change from baseline in NEWS-2.
3. Number of oxygenation free days in the first 28 days [ Time Frame: 29 days ]
4. Incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial. [ Time Frame: 29 days ]
5. Ventilator free days in the first 28 days [ Time Frame: 29 days ]
6. Incidence of new mechanical ventilation use during the trial. [ Time Frame: 29 days ]
7. Need for mechanical ventilation or death by Day 15 [ Time Frame: Day 15 ]
   Proportion of patients with mechanical ventilation or death at day 15
8. Hospitalization [ Time Frame: 29 days ]
   Time to hospital discharge (days).
9. Mortality [ Time Frame: In hospital, Days 29, 90, 180, 365, 456 ]
   Rate of mortality
10. Occurrence of new hospitalization [ Time Frame: Days 90, 180 and 365 ]
11. Occurrence of confirmed re-infection with SARS-CoV-2 [ Time Frame: Days 90, 180 and 365 ]
12. Cumulative incidence of serious adverse events (SAEs) [ Time Frame: 29 days ]
13. Cumulative incidence of Grade 1- 2 hypersensitivity- related and infusion related AEs until D29 visit [ Time Frame: 29 days ]
14. Cumulative incidence of Grade 3 and 4 adverse events (AEs) [ Time Frame: 29 days ]
15. Number of participants with a discontinuation or temporary suspension of study drugs (for any reason) [ Time Frame: 29 days ]
16. Cumulative incidence of AEs of Special Interest [ Time Frame: 29 days ]

Other Outcome Measures:

1. Percent of subjects with SARS-CoV-2 detectable in nasopharyngeal sample [ Time Frame: Days 3, 5, 8, 11, 15, 29 ]
2. Quantitative SARS-CoV-2 virus in nasopharyngeal sample [ Time Frame: Days 3, 5, 8, 11, 15, 29 ]
3. Quantitative SARS-CoV-2 virus in blood [ Time Frame: Days 3, 8 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Austria

Medizinische Universität Innsbruck

Innsbruck, Austria, 6020

Kepler Universitätsklinikum Linz

Linz, Austria

Landeskrankenhaus Salzburg Universitätsklinikum der Paracelsus Medizinischen Privatuniversität

Salzburg, Austria, 5020

Belgium

Hôpital Erasme - Cliniques universitaires de Bruxelles

Brussels, Belgium, 1070

Hôpital Saint Luc

Brussels, Belgium, 1200

Hôpital La Citadelle

Liège, Belgium, 4000

Pôle Hospitalier Jolimont / site de Mons-Warquignies

Mons, Belgium

France

Centre Hospitalier Universitaire Amiens-Picardie

Amiens, France, 80054

Centre Hospitalier Regional Metz-Thionville

Ars-Laquenexy, France, 57085

Centre Hospitalier Régional Universitaire de Besançon

Besançon, France, 25000

Centre Hospitalier Universitaire de Bordeaux

Bordeaux, France, 33000

CHU APHP Ambroise-Paré

Boulogne-Billancourt, France

Centre Hospitalier Andrée Rosemon

Cayenne, France, 97306

Hospices Civil

Colmar, France

APHP - hôpital Henri-Mondor

Créteil, France, 94010

Centre Hospitalier Universitaire Dijon-Bourgogne

Dijon, France, 21000

Centre Hospitalier Universitaire de Martinique

Fort De France, France, 97261

AP-HP Hôpital Bicêtre

Kremlin-Bicêtre, France, 94270

Centre Hospitalo-Universitaire de Grenoble

La Tronche, France, 38700

Centre Hospitalier Régional Universitaire de Lille

Lille, France, 59000

Hospices Civils de Lyon

Lyon, France, 69000

Centre Hospitalier Universitaire de Montpellier

Montpellier, France, 34000

Groupe Hospitalier de la Région de Mulhouse Sud Alsace

Mulhouse, France, 68100

Centre Hospitalier Régional et Universitaire de Nancy

Nancy, France, 54000

Centre Hospitalier Universitaire de Nantes

Nantes, France, 44000

Centre Hospitalo-Universitaire de Nice

Nice, France, 06000

CHU Nîmes

Nîmes, France

APHP - Hôpital Lariboisière

Paris, France, 75010

APHP - Hôpital Saint Louis

Paris, France, 75010

APHP - Hôpital Saint Antoine

Paris, France, 75012

APHP - Hôpital Universitaire Pitié Salpêtrière

Paris, France, 75013

APHP - Hôpital Cochin

Paris, France, 75014

Hôpital Paris Saint-Joseph et Marie Lannelongue

Paris, France, 75014

APHP - Hôpital Necker

Paris, France, 75015

APHP- Hôpital Européen Georges-Pompidou

Paris, France, 75015

APHP - Hôpital Bichat Claude Bernard

Paris, France, 75018

APHP - Hôpital Tenon

Paris, France, 75020

CHU Poitiers

Poitiers, France

CH Cornouaille

Quimper, France

CHU de Reims

Reims, France, 51100

Centre Hospitalier Universitaire de Rennes

Rennes, France, 35033

Hopital DELAFONTAINE

Saint-Denis, France, 93200

Hôpital d'Instruction des Armées BEGIN

Saint-Mandé, France, 94160

Centre Hospitalier Universitaire de Saint Etienne

Saint-Étienne, France, 42055

Centre Hospitalier Régional Universitaire de Strasbourg

Strasbourg, France, 67000

Centre Hospitalier Universitaire de Toulouse

Toulouse, France, 31000

Centre Hospitalier Universitaire de Toulouse

Toulouse, France, 31300

Centre Hospitalier de Tourcoing

Tourcoing, France, 59208

Centre Hospitalier Universitaire de Tours

Tours, France, 37000

CH Bretagne Atlantique

Vannes, France, 56000

CH Bretagne Atlantique

Vannes, France

Centre Hospitalier Annecy Genevois

Épagny, France, 74370

Greece

Evaggelismos General Hospital

Athens, Greece

General University Hospital of Patras

Patras, Greece

Luxembourg

Centre Hospitalier Luxembourg

Luxembourg, Luxembourg, L-1210

Hôpitaux Robert Schuman

Luxembourg, Luxembourg, L-2450

Norway

Akershus Unniversity Hospital

Oslo, Norway

Lovisenberg Diaconal Hospital

Oslo, Norway

Oslo University Hospital

Oslo, Norway

Portugal

Hospital de Cascais

Cascais, Portugal

CHULN- Hospital de Santa Maria

Lisboa, Portugal

Centro Hospitalar Universitário de São João, EPE

Porto, Portugal

Sponsors and Collaborators

Institut National de la Santé Et de la Recherche Médicale, France

Investigators

• Study Chair: Florence Ader, MD; Hospices Civils de Lyon

More Information

Publications of Results:

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, Allum E, Alotaibi A, Alvarez-Moreno CA, Appadoo S, Asiri A, Aukrust P, Barratt-Due A, Bellani S, Branca M, Cappel-Porter HBC, Cerrato N, Chow TS, Como N, Eustace J, Garcia PJ, Godbole S, Gotuzzo E, Griskevicius L, Hamra R, Hassan M, Hassany M, Hutton D, Irmansyah I, Jancoriene L, Kirwan J, Kumar S, Lennon P, Lopardo G, Lydon P, Magrini N, Maguire T, Manevska S, Manuel O, McGinty S, Medina MT, Mesa Rubio ML, Miranda-Montoya MC, Nel J, Nunes EP, Perola M, Portoles A, Rasmin MR, Raza A, Rees H, Reges PPS, Rogers CA, Salami K, Salvadori MI, Sinani N, Sterne JAC, Stevanovikj M, Tacconelli E, Tikkinen KAO, Trelle S, Zaid H, Rottingen JA, Swaminathan S. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021 Feb 11;384(6):497-511. doi: 10.1056/NEJMoa2023184. Epub 2020 Dec 2.

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, Bouiller K, Navellou JC, Tolsma V, Cabie A, Dubost C, Courjon J, Leroy S, Mootien J, Gaci R, Mourvillier B, Faure E, Pourcher V, Gallien S, Launay O, Lacombe K, Lanoix JP, Makinson A, Martin-Blondel G, Bouadma L, Botelho-Nevers E, Gagneux-Brunon A, Epaulard O, Piroth L, Wallet F, Richard JC, Reuter J, Staub T, Lina B, Noret M, Andrejak C, Le MP, Peytavin G, Hites M, Costagliola D, Yazdanpanah Y, Burdet C, Mentre F; DisCoVeRy study group. An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19. Clin Microbiol Infect. 2021 Dec;27(12):1826-1837. doi: 10.1016/j.cmi.2021.05.020. Epub 2021 May 26.

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 versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial. Lancet Infect Dis. 2022 Feb;22(2):209-221. doi: 10.1016/S1473-3099(21)00485-0. Epub 2021 Sep 14.

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 remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial. J Antimicrob Chemother. 2022 Apr 27;77(5):1404-1412. doi: 10.1093/jac/dkac048.

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: 10.1016/S1473-3099(22)00295-X. No abstract available.

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 Microbiol Infect. 2022 Sep;28(9):1293-1296. doi: 10.1016/j.cmi.2022.04.016. Epub 2022 May 7. No abstract available.

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. Association between SARS-CoV-2 viral kinetics and clinical score evolution in hospitalized patients. CPT Pharmacometrics Syst Pharmacol. 2023 Dec;12(12):2027-2037. doi: 10.1002/psp4.13051. Epub 2023 Oct 11.

Other Publications:

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.

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.

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.

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.

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.

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.

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.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

WHO Solidarity Trial Consortium. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet. 2022 May 21;399(10339):1941-1953. doi: 10.1016/S0140-6736(22)00519-0. Epub 2022 May 2. Erratum In: Lancet. 2022 Oct 29;400(10362):1512. Lancet. 2024 Jan 13;403(10422):146.

Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.

Ansems K, Grundeis F, Dahms K, Mikolajewska A, Thieme V, Piechotta V, Metzendorf MI, Stegemann M, Benstoem C, Fichtner F. Remdesivir for the treatment of COVID-19. Cochrane Database Syst Rev. 2021 Aug 5;8(8):CD014962. doi: 10.1002/14651858.CD014962.

Taccone FS, Gorham J, Vincent JL. Hydroxychloroquine in the management of critically ill patients with COVID-19: the need for an evidence base. Lancet Respir Med. 2020 Jun;8(6):539-541. doi: 10.1016/S2213-2600(20)30172-7. Epub 2020 Apr 15. No abstract available.

• Responsible Party: Institut National de la Santé Et de la Recherche Médicale, France
• ClinicalTrials.gov Identifier: NCT04315948
• Other Study ID Numbers: C20-15; 101015736 ( Other Grant/Funding Number: H2020-EU.3.1.3. )
• First Posted: March 20, 2020
• Last Update Posted: November 29, 2023
• Last Verified: November 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Study protocol and statistical analysis plan will be available. Systematic individual patient data sharing is not intended, but all requests for the trial's data will be considered by the French DisCoVeRy Trial Management Team.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)

Time Frame

Study protocol and statistical analysis plan will be available from September 2020 with no time limit.

Other data will be available upon request after first publication of the results for at least 5 years

• Access Criteria: Study protocol and statistical analysis plan will be published. All requests for the trial's data will be considered by the French DisCoVeRy Trial Management Team that can be contacted via the principal investigator: florence.ader@chu-lyon.fr

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Institut National de la Santé Et de la Recherche Médicale, France:

COVID-19; SARS-CoV-2; Pneumonia

Additional relevant MeSH terms:

COVID-19; Coronavirus Infections; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Interferons; Ritonavir; Lopinavir; Interferon-beta; Interferon beta-1a; Remdesivir; Cilgavimab and tixagevimab drug combination; Hydroxychloroquine; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; HIV Protease Inhibitors; Viral Protease Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents