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

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ClinicalTrials.gov Identifier: NCT04315948
Recruitment Status : Active, not recruiting
First Posted : March 20, 2020
Last Update Posted : July 27, 2021
Sponsor:
Information provided by (Responsible Party):
Institut National de la Santé Et de la Recherche Médicale, France

Tracking Information
First Submitted Date  ICMJE March 13, 2020
First Posted Date  ICMJE March 20, 2020
Last Update Posted Date July 27, 2021
Actual Study Start Date  ICMJE March 22, 2020
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 18, 2020)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 23, 2021)
  • 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
  • National Early Warning Score 2 (NEWS-2 score) [ Time Frame: Days 3, 8, 15, and 29 ]
    Change from baseline in NEWS-2.
  • Number of oxygenation free days in the first 28 days [ Time Frame: 29 days ]
  • Incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial. [ Time Frame: 29 days ]
  • Ventilator free days in the first 28 days [ Time Frame: 29 days ]
  • Incidence of new mechanical ventilation use during the trial. [ Time Frame: 29 days ]
  • Need for mechanical ventilation or death by Day 15 [ Time Frame: Day 15 ]
    Proportion of patients with mechanical ventilation or death at day 15
  • Hospitalization [ Time Frame: 29 days ]
    Time to hospital discharge (days).
  • Mortality [ Time Frame: In hospital, Days 28, 90, 180, 365, 456 ]
    Rate of mortality
  • Occurrence of new hospitalization [ Time Frame: Days 90, 180 and 365 ]
  • Occurrence of confirmed re-infection with SARS-CoV-2 [ Time Frame: Days 90, 180 and 365 ]
  • Cumulative incidence of serious adverse events (SAEs) [ Time Frame: 29 days ]
  • Cumulative incidence of Grade 1- 2 hypersensitivity- related and infusion related AEs until D29 visit [ Time Frame: 29 days ]
  • Cumulative incidence of Grade 3 and 4 adverse events (AEs) [ Time Frame: 29 days ]
  • Number of participants with a discontinuation or temporary suspension of study drugs (for any reason) [ Time Frame: 29 days ]
  • Cumulative incidence of AEs of Special Interest [ Time Frame: 29 days ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 18, 2020)
  • Percentage of subjects reporting each severity rating on a 7-point on an ordinal scale [ Time Frame: Days 3, 5, 8, 11, 15 and 29 ]
    • Time to an improvement of one category from admission on an ordinal scale.
    • Subject clinical status on an ordinal scale at days 3, 5, 8, 11, and 29.
    • Mean change in the ranking on an ordinal scale from baseline to days 3, 5, 8, 11, 15 and 29 from baseline.
  • The time to discharge or to a NEWS of ≤ 2 and maintained for 24 hours, whichever occurs first. [ Time Frame: Days 3, 5, 8, 11, 15 and 29 ]
    • Change from baseline to days 3, 5, 8, 11, 15, and 29 in NEWS.
  • Number of oxygenation free days in the first 28 days [ Time Frame: 29 days ]
  • Incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial. [ Time Frame: 29 days ]
  • Duration of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial. [ Time Frame: 29 days ]
  • Ventilator free days in the first 28 days [ Time Frame: 29 days ]
  • Incidence of new mechanical ventilation use during the trial. [ Time Frame: 29 days ]
  • Hospitalization [ Time Frame: 29 days ]
    • Duration of hospitalization (days).
  • Mortality [ Time Frame: Day 28 ]
    Rate of mortality
  • Cumulative incidence of serious adverse events (SAEs) [ Time Frame: 29 days ]
  • Cumulative incidence of Grade 3 and 4 adverse events (AEs) [ Time Frame: 29 days ]
  • Number of participants with a discontinuation or temporary suspension of study drugs (for any reason) [ Time Frame: 29 days ]
  • Changes from baseline in blood white cell count [ Time Frame: 29 days ]
  • Changes from baseline in haemoglobin [ Time Frame: 29 days ]
  • Changes from baseline in platelets [ Time Frame: 29 days ]
  • Changes from baseline in creatinine [ Time Frame: 29 days ]
  • Changes from baseline in prothrombine time [ Time Frame: 29 days ]
  • Changes from baseline in international normalized ratio (INR) [ Time Frame: 29 days ]
  • Changes from baseline in glucose [ Time Frame: 29 days ]
  • Changes from baseline in total bilirubin [ Time Frame: 29 days ]
  • Changes from baseline in alanine aminotransferase (ALT) [ Time Frame: 29 days ]
  • Changes from baseline in aspartate aminotransferase (AST) [ Time Frame: 29 days ]
Current Other Pre-specified Outcome Measures
 (submitted: April 22, 2021)
  • Percent of subjects with SARS-CoV-2 detectable in nasopharyngeal sample [ Time Frame: Days 3, 5, 8, 11, 15, 29 ]
  • Quantitative SARS-CoV-2 virus in nasopharyngeal sample [ Time Frame: Days 3, 5, 8, 11, 15, 29 ]
  • Quantitative SARS-CoV-2 virus in blood [ Time Frame: Days 3, 8 ]
Original Other Pre-specified Outcome Measures
 (submitted: March 18, 2020)
  • Percent of subjects with SARS-CoV-2 detectable in nasopharyngeal sample [ Time Frame: Days 3, 5, 8, 11, 15, 29 ]
  • Quantitative SARS-CoV-2 virus in nasopharyngeal sample [ Time Frame: Days 3, 5, 8, 11, 15, 29 ]
  • Quantitative SARS-CoV-2 virus in blood [ Time Frame: Days 3, 5, 8 and 11 ]
 
Descriptive Information
Brief Title  ICMJE Trial of Treatments for COVID-19 in Hospitalized Adults
Official Title  ICMJE Multi-centre, Adaptive, Randomized Trial of the Safety and Efficacy of Treatments of COVID-19 in Hospitalized Adults
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) and antigenic status (positive or negative), obtained from the result of a rapid antigen test on nasopharyngeal swab performed at enrolment.

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. Sensitivity analyses will be performed in all patients, stratified by antigenic status.

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) and antigenic status (positive or negative), obtained from the result of a rapid antigen test on nasopharyngeal swab performed at enrolment.

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. Sensitivity analyses will be performed in all patients, stratified by antigenic status.

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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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
Condition  ICMJE Corona Virus Infection
Intervention  ICMJE
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
Study Arms  ICMJE
  • 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

    Interventions:
    • Drug: Remdesivir
    • Other: 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

    Interventions:
    • Drug: Lopinavir/ritonavir
    • Other: 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

    Interventions:
    • Drug: Lopinavir/ritonavir
    • Drug: Interferon Beta-1A
    • Other: 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
    Interventions:
    • Drug: Hydroxychloroquine
    • Other: Standard of care
  • Active Comparator: Standard of care alone
    Standard of care alone before March, 2021.
    Intervention: Other: 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

    Interventions:
    • Other: Standard of care
    • Drug: AZD7442
  • Active Comparator: Standard of care with placebo
    Standard of care with placebo since April, 2021 n=620
    Interventions:
    • Other: Standard of care
    • Other: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: April 22, 2021)
2416
Original Estimated Enrollment  ICMJE
 (submitted: March 18, 2020)
3200
Estimated Study Completion Date  ICMJE March 2023
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 9 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 not required; however, 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 vaccine or other mAb/biologic indicated for the prevention of SARS-CoV-2 infection or COVID-19 or expected receipt 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Belgium,   France,   Luxembourg,   Norway,   Portugal
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04315948
Other Study ID Numbers  ICMJE C20-15
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Supporting Materials: 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
Responsible Party Institut National de la Santé Et de la Recherche Médicale, France
Study Sponsor  ICMJE Institut National de la Santé Et de la Recherche Médicale, France
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Florence Ader, MD Hospices Civils de Lyon
PRS Account Institut National de la Santé Et de la Recherche Médicale, France
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP