Multi-centre, Adaptive, Randomized Trial of the Safety and Efficacy of Treatments of COVID-19 in Hospitalized Adults
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 1,552
- 试验地点
- 108
- 主要终点
- Percentage of subjects reporting each severity rating on a 7-point ordinal scale
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
- 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
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
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
干预措施: Standard of care (Other)
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
干预措施: Remdesivir (Drug)
Standard of care with placebo
Standard of care with placebo since April, 2021 n=620
干预措施: Placebo (Other)
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
干预措施: Hydroxychloroquine (Drug)
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
干预措施: Lopinavir/ritonavir (Drug)
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
干预措施: AZD7442 (Drug)
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
干预措施: Standard of care (Other)
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
干预措施: Standard of care (Other)
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
干预措施: Standard of care (Other)
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
干预措施: Standard of care (Other)
Standard of care alone
Standard of care alone before March, 2021.
干预措施: Standard of care (Other)
Standard of care with placebo
Standard of care with placebo since April, 2021 n=620
干预措施: Standard of care (Other)
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
干预措施: Interferon Beta-1A (Drug)
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
干预措施: Lopinavir/ritonavir (Drug)
结局指标
主要结局
Percentage of subjects reporting each severity rating on a 7-point ordinal scale
时间窗: 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.
次要结局
- Cumulative incidence of Grade 3 and 4 adverse events (AEs)(29 days)
- Number of oxygenation free days in the first 28 days(29 days)
- Occurrence of new hospitalization(Days 90, 180 and 365)
- Ventilator free days in the first 28 days(29 days)
- Hospitalization(29 days)
- National Early Warning Score 2 (NEWS-2 score)(Days 3, 8, 15, and 29)
- Incidence of new mechanical ventilation use during the trial.(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)
- Status on an ordinal scale(Days 29, 90, 180 and 365)
- Mortality(In hospital, Days 29, 90, 180, 365, 456)
- 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)
- 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)