Trial of Treatments for COVID-19 in Hospitalized Adults
- Conditions
- Corona Virus Infection
- Interventions
- Drug: Lopinavir/ritonavirDrug: RemdesivirDrug: HydroxychloroquineOther: Standard of careOther: PlaceboDrug: Interferon Beta-1ADrug: AZD7442
- Registration Number
- NCT04315948
- Lead Sponsor
- Institut National de la Santé Et de la Recherche Médicale, France
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1552
-
Adult ≥18 years of age at the time of enrolment
-
Hospitalized patients with any of the following criteria:
- the presence of pulmonary rales/crackles on clinical exam OR
- SpO2 ≤ 94% on room air OR
- requirement of supplementary oxygen including high flow oxygen devices or non-invasive ventilation
-
A time between onset of symptoms and randomization of less than 11 days
-
A positive SARS-CoV-2 PCR performed on a NP swab within the 5 days preceding randomization
-
The result of a rapid antigen test performed on a NP swab within the 6 hours preceding randomization
-
Contraceptive use by men or women.
- 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.
- Female participants: Women of child-bearing potential must agree to use contraception for 365 days following administration of IMP
- Refusal to participate expressed by patient or legally authorized representative
- Need for invasive mechanical ventilation and/or ECMO at the time of enrolment
- Spontaneous blood ALT/AST levels > 5 times the upper limit of normal
- Glomerular filtration rate (GFR) < 15 mL/min or requiring maintenance dialysis
- Pregnancy or breast-feeding
- Anticipated transfer to another hospital, which is not a study site within 72 hours following randomization
- Known history of allergy or reaction to any component of the study drug formulation.
- Previous hypersensitivity, infusion-related reaction, or severe adverse reaction following administration of monoclonal or polyclonal antibodies.
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Hydroxychloroquine (stopped on May 24, 2020) Standard of care 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 Standard of care alone Standard of care Standard of care alone before March, 2021. Standard of care with placebo Placebo Standard of care with placebo since April, 2021 n=620 Lopinavir/ritonavir (stopped on June 29, 2020) Lopinavir/ritonavir 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 AZD7442 Standard of care 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 Lopinavir/ritonavir plus Interferon ß-1a (stopped on June 29) Standard of care 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 Remdesivir Standard of care 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 Standard of care with placebo Standard of care Standard of care with placebo since April, 2021 n=620 Lopinavir/ritonavir (stopped on June 29, 2020) Standard of care 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 Lopinavir/ritonavir plus Interferon ß-1a (stopped on June 29) Lopinavir/ritonavir 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 Remdesivir 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 Lopinavir/ritonavir plus Interferon ß-1a (stopped on June 29) Interferon Beta-1A 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 Hydroxychloroquine (stopped on May 24, 2020) Hydroxychloroquine 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 AZD7442 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
- Primary Outcome Measures
Name Time Method Percentage of subjects reporting each severity rating on a 7-point ordinal scale 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
Name Time Method Ventilator free days in the first 28 days 29 days National Early Warning Score 2 (NEWS-2 score) Days 3, 8, 15, and 29 Change from baseline in NEWS-2.
Incidence of new mechanical ventilation use during the trial. 29 days Hospitalization 29 days Time to hospital discharge (days).
Cumulative incidence of Grade 3 and 4 adverse events (AEs) 29 days Incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial. 29 days Cumulative incidence of serious adverse events (SAEs) 29 days Cumulative incidence of AEs of Special Interest 29 days Number of oxygenation free days in the first 28 days 29 days Occurrence of new hospitalization Days 90, 180 and 365 Status on an ordinal scale Days 29, 90, 180 and 365 Percentage of subjects reporting each severity rating on a 7-point on an ordinal scale
Mortality In hospital, Days 29, 90, 180, 365, 456 Rate of mortality
Cumulative incidence of Grade 1- 2 hypersensitivity- related and infusion related AEs until D29 visit 29 days Need for mechanical ventilation or death by Day 15 Day 15 Proportion of patients with mechanical ventilation or death at day 15
Occurrence of confirmed re-infection with SARS-CoV-2 Days 90, 180 and 365 Number of participants with a discontinuation or temporary suspension of study drugs (for any reason) 29 days
Trial Locations
- Locations (60)
Centre Hospitalier Universitaire de Martinique
🇫🇷Fort De France, France
Centre Hospitalier Andrée Rosemon
🇫🇷Cayenne, France
CHU APHP Ambroise-Paré
🇫🇷Boulogne-Billancourt, France
APHP - Hôpital Universitaire Pitié Salpêtrière
🇫🇷Paris, France
Hôpitaux Robert Schuman
🇱🇺Luxembourg, Luxembourg
Centre Hospitalier Luxembourg
🇱🇺Luxembourg, Luxembourg
Oslo University Hospital
🇳🇴Oslo, Norway
Hospital de Cascais
🇵🇹Cascais, Portugal
CHULN- Hospital de Santa Maria
🇵🇹Lisboa, Portugal
Kepler Universitätsklinikum Linz
🇦🇹Linz, Austria
Akershus Unniversity Hospital
🇳🇴Oslo, Norway
Landeskrankenhaus Salzburg Universitätsklinikum der Paracelsus Medizinischen Privatuniversität
🇦🇹Salzburg, Austria
Centro Hospitalar Universitário de São João, EPE
🇵🇹Porto, Portugal
Hôpital Saint Luc
🇧🇪Brussels, Belgium
Hôpital La Citadelle
🇧🇪Liège, Belgium
Centre Hospitalier Universitaire Amiens-Picardie
🇫🇷Amiens, France
Hôpital Erasme - Cliniques universitaires de Bruxelles
🇧🇪Brussels, Belgium
Pôle Hospitalier Jolimont / site de Mons-Warquignies
🇧🇪Mons, Belgium
Centre Hospitalier Regional Metz-Thionville
🇫🇷Ars-Laquenexy, France
Centre Hospitalier Universitaire de Bordeaux
🇫🇷Bordeaux, France
Centre Hospitalier Régional Universitaire de Besançon
🇫🇷Besançon, France
APHP - hôpital Henri-Mondor
🇫🇷Créteil, France
AP-HP Hôpital Bicêtre
🇫🇷Kremlin-Bicêtre, France
Hospices Civil
🇫🇷Colmar, France
Centre Hospitalier Universitaire Dijon-Bourgogne
🇫🇷Dijon, France
Centre Hospitalier Universitaire de Montpellier
🇫🇷Montpellier, France
Hospices Civils de Lyon
🇫🇷Lyon, France
Centre Hospitalier Régional Universitaire de Lille
🇫🇷Lille, France
Centre Hospitalo-Universitaire de Grenoble
🇫🇷La Tronche, France
Groupe Hospitalier de la Région de Mulhouse Sud Alsace
🇫🇷Mulhouse, France
Centre Hospitalo-Universitaire de Nice
🇫🇷Nice, France
APHP - Hôpital Lariboisière
🇫🇷Paris, France
Centre Hospitalier Régional et Universitaire de Nancy
🇫🇷Nancy, France
Centre Hospitalier Universitaire de Nantes
🇫🇷Nantes, France
CHU Nîmes
🇫🇷Nîmes, France
APHP - Hôpital Saint Louis
🇫🇷Paris, France
APHP - Hôpital Saint Antoine
🇫🇷Paris, France
APHP - Hôpital Cochin
🇫🇷Paris, France
Hôpital Paris Saint-Joseph et Marie Lannelongue
🇫🇷Paris, France
APHP - Hôpital Necker
🇫🇷Paris, France
CHU Poitiers
🇫🇷Poitiers, France
CH Cornouaille
🇫🇷Quimper, France
APHP- Hôpital Européen Georges-Pompidou
🇫🇷Paris, France
CHU de Reims
🇫🇷Reims, France
APHP - Hôpital Tenon
🇫🇷Paris, France
APHP - Hôpital Bichat Claude Bernard
🇫🇷Paris, France
Centre Hospitalier Universitaire de Rennes
🇫🇷Rennes, France
Hopital DELAFONTAINE
🇫🇷Saint-Denis, France
Hôpital d'Instruction des Armées BEGIN
🇫🇷Saint-Mandé, France
Centre Hospitalier Universitaire de Saint Etienne
🇫🇷Saint-Étienne, France
Centre Hospitalier Annecy Genevois
🇫🇷Épagny, France
Centre Hospitalier Régional Universitaire de Strasbourg
🇫🇷Strasbourg, France
Centre Hospitalier de Tourcoing
🇫🇷Tourcoing, France
CH Bretagne Atlantique
🇫🇷Vannes, France
Centre Hospitalier Universitaire de Toulouse
🇫🇷Toulouse, France
Centre Hospitalier Universitaire de Tours
🇫🇷Tours, France
Evaggelismos General Hospital
🇬🇷Athens, Greece
General University Hospital of Patras
🇬🇷Patras, Greece
Lovisenberg Diaconal Hospital
🇳🇴Oslo, Norway
Medizinische Universität Innsbruck
🇦🇹Innsbruck, Austria
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