Clinical trial NCT04315948: Trial of Treatments for COVID-19 in Hospitalized Adults
Official title: Multi-centre, Adaptive, Randomized Trial of the Safety and Efficacy of Treatments of COVID-19 in Hospitalized Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Corona Virus Infection
Keywords: COVID-19
SARS-CoV-2
Pneumonia
Lead sponsor: Institut National de la Santé Et de la Recherche Médicale, France
Sponsor class: OTHER_GOV
First posted: 2020-03-20
Enrollment: 1552
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Percentage of subjects reporting each severity rating on a 7-point ordinal scale
timeFrame: Day 15
Secondary outcomes:
measure: Status on an ordinal scale
timeFrame: Days 29, 90, 180 and 365
measure: National Early Warning Score 2 (NEWS-2 score)
timeFrame: Days 3, 8, 15, and 29
measure: Number of oxygenation free days in the first 28 days
timeFrame: 29 days
measure: Incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial.
timeFrame: 29 days
measure: Ventilator free days in the first 28 days
timeFrame: 29 days
measure: Incidence of new mechanical ventilation use during the trial.
timeFrame: 29 days
measure: Need for mechanical ventilation or death by Day 15
timeFrame: Day 15
measure: Hospitalization
timeFrame: 29 days
measure: Mortality
timeFrame: In hospital, Days 29, 90, 180, 365, 456
measure: Occurrence of new hospitalization
timeFrame: Days 90, 180 and 365
measure: Occurrence of confirmed re-infection with SARS-CoV-2
timeFrame: Days 90, 180 and 365
measure: Cumulative incidence of serious adverse events (SAEs)
timeFrame: 29 days
measure: Cumulative incidence of Grade 1- 2 hypersensitivity- related and infusion related AEs until D29 visit
timeFrame: 29 days
measure: Cumulative incidence of Grade 3 and 4 adverse events (AEs)
timeFrame: 29 days
measure: Number of participants with a discontinuation or temporary suspension of study drugs (for any reason)
timeFrame: 29 days
measure: Cumulative incidence of AEs of Special Interest
timeFrame: 29 days
Other outcomes:
measure: Percent of subjects with SARS-CoV-2 detectable in nasopharyngeal sample
timeFrame: Days 3, 5, 8, 11, 15, 29
measure: Quantitative SARS-CoV-2 virus in nasopharyngeal sample
timeFrame: Days 3, 5, 8, 11, 15, 29
measure: Quantitative SARS-CoV-2 virus in blood
timeFrame: Days 3, 8
Locations:
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
city: Linz
country: Austria
facility: Kepler Universitätsklinikum Linz
city: Salzburg
country: Austria
facility: Landeskrankenhaus Salzburg Universitätsklinikum der Paracelsus Medizinischen Privatuniversität
city: Brussels
country: Belgium
facility: Hôpital Erasme - Cliniques universitaires de Bruxelles
city: Brussels
country: Belgium
facility: Hôpital Saint Luc
city: Liège
country: Belgium
facility: Hôpital La Citadelle
city: Mons
country: Belgium
facility: Pôle Hospitalier Jolimont / site de Mons-Warquignies
city: Amiens
country: France
facility: Centre Hospitalier Universitaire Amiens-Picardie
city: Ars-Laquenexy
country: France
facility: Centre Hospitalier Regional Metz-Thionville
city: Besançon
country: France
facility: Centre Hospitalier Régional Universitaire de Besançon
city: Bordeaux
country: France
facility: Centre Hospitalier Universitaire de Bordeaux
city: Boulogne-Billancourt
country: France
facility: CHU APHP Ambroise-Paré
city: Cayenne
country: France
facility: Centre Hospitalier Andrée Rosemon
city: Colmar
country: France
facility: Hospices Civil
city: Créteil
country: France
facility: APHP - hôpital Henri-Mondor
city: Dijon
country: France
facility: Centre Hospitalier Universitaire Dijon-Bourgogne
city: Fort De France
country: France
facility: Centre Hospitalier Universitaire de Martinique
city: Kremlin-Bicêtre
country: France
facility: AP-HP Hôpital Bicêtre
city: La Tronche
country: France
facility: Centre Hospitalo-Universitaire de Grenoble
city: Lille
country: France
facility: Centre Hospitalier Régional Universitaire de Lille
city: Lyon
country: France
facility: Hospices Civils de Lyon
city: Montpellier
country: France
facility: Centre Hospitalier Universitaire de Montpellier
city: Mulhouse
country: France
facility: Groupe Hospitalier de la Région de Mulhouse Sud Alsace
city: Nancy
country: France
facility: Centre Hospitalier Régional et Universitaire de Nancy
city: Nantes
country: France
facility: Centre Hospitalier Universitaire de Nantes
city: Nice
country: France
facility: Centre Hospitalo-Universitaire de Nice
city: Nîmes
country: France
facility: CHU Nîmes
city: Paris
country: France
facility: APHP - Hôpital Lariboisière
city: Paris
country: France
facility: APHP - Hôpital Saint Louis
city: Paris
country: France
facility: APHP - Hôpital Saint Antoine
city: Paris
country: France
facility: APHP - Hôpital Universitaire Pitié Salpêtrière
city: Paris
country: France
facility: APHP - Hôpital Cochin
city: Paris
country: France
facility: Hôpital Paris Saint-Joseph et Marie Lannelongue
city: Paris
country: France
facility: APHP - Hôpital Necker
city: Paris
country: France
facility: APHP- Hôpital Européen Georges-Pompidou
city: Paris
country: France
facility: APHP - Hôpital Bichat Claude Bernard
city: Paris
country: France
facility: APHP - Hôpital Tenon
city: Poitiers
country: France
facility: CHU Poitiers
city: Quimper
country: France
facility: CH Cornouaille
city: Reims
country: France
facility: CHU de Reims
city: Rennes
country: France
facility: Centre Hospitalier Universitaire de Rennes
city: Saint-Denis
country: France
facility: Hopital DELAFONTAINE
city: Saint-Mandé
country: France
facility: Hôpital d'Instruction des Armées BEGIN
city: Saint-Étienne
country: France
facility: Centre Hospitalier Universitaire de Saint Etienne
city: Strasbourg
country: France
facility: Centre Hospitalier Régional Universitaire de Strasbourg
city: Toulouse
country: France
facility: Centre Hospitalier Universitaire de Toulouse
city: Toulouse
country: France
facility: Centre Hospitalier Universitaire de Toulouse
city: Tourcoing
country: France
facility: Centre Hospitalier de Tourcoing
city: Tours
country: France
facility: Centre Hospitalier Universitaire de Tours
city: Vannes
country: France
facility: CH Bretagne Atlantique
city: Vannes
country: France
facility: CH Bretagne Atlantique
city: Épagny
country: France
facility: Centre Hospitalier Annecy Genevois
city: Athens
country: Greece
facility: Evaggelismos General Hospital
city: Patras
country: Greece
facility: General University Hospital of Patras
city: Luxembourg
country: Luxembourg
facility: Centre Hospitalier Luxembourg
city: Luxembourg
country: Luxembourg
facility: Hôpitaux Robert Schuman
city: Oslo
country: Norway
facility: Akershus Unniversity Hospital
city: Oslo
country: Norway
facility: Lovisenberg Diaconal Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Cascais
country: Portugal
facility: Hospital de Cascais
city: Lisboa
country: Portugal
facility: CHULN- Hospital de Santa Maria
city: Porto
country: Portugal
facility: Centro Hospitalar Universitário de São João, EPE
Study officials:
affiliation: Hospices Civils de Lyon
name: Florence Ader, MD
role: STUDY_CHAIR
References:
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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, 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.
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