Corona Virus Infection
Conditions
Keywords
COVID-19, SARS-CoV-2, Pneumonia
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.
Interventions
DRUGRemdesivir
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.
DRUGLopinavir/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).
DRUGInterferon 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.
DRUGHydroxychloroquine
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).
OTHERStandard of care
Standard of care
DRUGAZD7442
AZD7442 will be supplied as separate vials of AZD8895 and AZD1061 containing 150 mg colorless to slightly yellow, clear to opalescent solutions for injection.
OTHERPlacebo
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.
Sponsors
Institut National de la Santé Et de la Recherche Médicale, France
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, 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
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Incidence of new mechanical ventilation use during the trial. | 29 days | — |
| Cumulative incidence of Grade 3 and 4 adverse events (AEs) | 29 days | — |
| Number of participants with a discontinuation or temporary suspension of study drugs (for any reason) | 29 days | — |
| Cumulative incidence of AEs of Special Interest | 29 days | — |
| Need for mechanical ventilation or death by Day 15 | Day 15 | Proportion of patients with mechanical ventilation or death at day 15 |
| Hospitalization | 29 days | Time to hospital discharge (days). |
| 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 |
| National Early Warning Score 2 (NEWS-2 score) | Days 3, 8, 15, and 29 | Change from baseline in NEWS-2. |
| Number of oxygenation free days in the first 28 days | 29 days | — |
| Incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial. | 29 days | — |
| Ventilator free days in the first 28 days | 29 days | — |
| Mortality | In hospital, Days 29, 90, 180, 365, 456 | Rate of mortality |
| Occurrence of new hospitalization | Days 90, 180 and 365 | — |
| Occurrence of confirmed re-infection with SARS-CoV-2 | Days 90, 180 and 365 | — |
| Cumulative incidence of serious adverse events (SAEs) | 29 days | — |
| Cumulative incidence of Grade 1- 2 hypersensitivity- related and infusion related AEs until D29 visit | 29 days | — |
Other
| Measure | Time frame |
|---|---|
| Quantitative SARS-CoV-2 virus in blood | Days 3, 8 |
| Quantitative SARS-CoV-2 virus in nasopharyngeal sample | Days 3, 5, 8, 11, 15, 29 |
| Percent of subjects with SARS-CoV-2 detectable in nasopharyngeal sample | Days 3, 5, 8, 11, 15, 29 |
Countries
Austria, Belgium, France, Greece, Luxembourg, Norway, Portugal
Outcome results
None listed