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

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ClinicalTrials.gov Identifier: NCT04315948
Recruitment Status : Recruiting
First Posted : March 20, 2020
Last Update Posted : July 9, 2020
Sponsor:
Information provided by (Responsible Party):
Institut National de la Santé Et de la Recherche Médicale, France

Brief Summary:
This study is a multi-centre, adaptive, randomized, open clinical trial of the safety and efficacy of treatments for COVID-19 in hospitalized adults. The study is a multi-centre/country trial that will be conducted in various sites in Europe with Inserm as sponsor. Adults (≥18 year-old) hospitalized for COVID-19 with SpO2 ≤ 94% on room air OR acute respiratory failure requiring supplemental oxygen or ventilatory support will be randomized between 4 treatment arms, each to be given in addition to the usual standard of care (SoC) in the participating hospital: SoC alone versus SoC + Remdesivir versus SoC + Lopinavir/Ritonavir versus SoC (this treatment arm has been ceased since June 29, 2020) + Lopinavir/Ritonavir plus interferon ß-1a versus SoC (this treatment arm has been ceased since June 29, 2020) + Hydroxychloroquine (this treatment arm has been ceased since May 24, 2020). Randomization will be stratified by European region and severity of illness at enrollment (moderate disease: patients NOT requiring non-invasive ventilation NOR high flow oxygen devices NOR invasive mechanical ventilation NOR ECMO and severe disease: patients requiring non-invasive ventilation OR high flow oxygen devices OR invasive mechanical ventilation OR ECMO). The interim trial results will be monitored by a Data Monitoring Committee, and if at any stage evidence emerges that any one treatment arm is definitely inferior then it will be centrally decided that that arm will be discontinued. Conversely, if good evidence emerges while the trial is continuing that some other treatment(s) should also be being evaluated then it will be centrally decided that one or more extra arms will be added while the trial is in progress. The primary objective of the study is to evaluate the clinical efficacy and safety of different investigational therapeutics relative to the control arm in patients hospitalized with COVID-19, the primary endpoint is the subject clinical status (on a 7-point ordinal scale) at day 15.

Condition or disease Intervention/treatment Phase
Corona Virus Infection Drug: Remdesivir Drug: Lopinavir/ritonavir Drug: Interferon Beta-1A Drug: Hydroxychloroquine Other: Standard of care Phase 3

Detailed Description:
This study is a multi-centre, adaptive, randomized, open clinical trial of the safety and efficacy of treatments of COVID-19 in hospitalized adults. The study is a multi-centre/country trial that will be conducted in various sites in Europe with Inserm as sponsor. Adults (≥18 year-old) hospitalized for COVID-19 with SpO2 ≤ 94% on room air OR acute respiratory failure requiring supplemental oxygen or ventilatory support will be randomized between 4 treatment arms, each to be given in addition to the usual standard of care (SoC) in the participating hospital: SoC alone versus SoC + Remdesivir versus SoC + Lopinavir/Ritonavir versus SoC (this treatment arm has been ceased since June 29, 2020) + Lopinavir/Ritonavir plus interferon ß-1a versus SoC (this treatment arm has been ceased since June 29, 2020) + Hydroxychloroquine (this treatment arm has been ceased since May 24, 2020). Randomization will be stratified by European region and severity of illness at enrollment (moderate disease: patients NOT requiring non-invasive ventilation NOR high flow oxygen devices NOR invasive mechanical ventilation NOR ECMO and severe disease: patients requiring non-invasive ventilation OR high flow oxygen devices OR invasive mechanical ventilation OR ECMO). The interim trial results will be monitored by a Data Monitoring Committee, and if at any stage evidence emerges that any one treatment arm is definitely inferior then it will be centrally decided that that arm will be discontinued. Conversely, if good evidence emerges while the trial is continuing that some other treatment(s) should also be being evaluated then it will be centrally decided that one or more extra arms will be added while the trial is in progress. The primary objective of the study is to evaluate the clinical efficacy and safety of different investigational therapeutics relative to the control arm in patients hospitalized with COVID-19, the primary endpoint is subject clinical status (on a 7-point ordinal scale) at day 15. The secondary objectives of the study are to evaluate 1) the clinical efficacy of different investigational therapeutics through 28 days of follow-up as compared to the control arm as assessed by clinical severity (7-point ordinal scale, national early warning score, oxygenation, mechanical ventilation), hospitalization, mortality through 28 days of follow-up, in-hospital mortality and 90-day mortality 2) the safety of different investigational therapeutics through 28 days of follow-up as compared to the control arm as assessed by the cumulative incidence of serious adverse events (SAEs), the cumulative incidence of Grade 3 and 4 adverse events (AEs), the discontinuation or temporary suspension of antiviral drugs (for any reason), and the changes in blood white cell count, haemoglobin, platelets, creatinine, blood electrolytes, prothrombine time and international normalized ratio (INR), glucose, total bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) over time.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3100 participants
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.

Since June 29, 2020, the study will randomize participants 1:1 to standard of care alone (control) or with investigational product added.

If additional arms are added to or dropped from the trial, randomization will proceed with an equal probability of assignment to each of the remaining arms.

Masking: None (Open Label)
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
Primary Purpose: Treatment
Official Title: Multi-centre, Adaptive, Randomized Trial of the Safety and Efficacy of Treatments of COVID-19 in Hospitalized Adults
Actual Study Start Date : March 22, 2020
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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=620

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.

Other: Standard of care
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

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).

Other: Standard of care
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

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.

Other: Standard of care
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
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.

Active Comparator: Standard of care
Standard of care. n=620
Other: Standard of care
Standard of care.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.
    • Time to an improvement of two categories from admission on an ordinal scale.
    • Time to discharge (categories 1 or 2 of ordinal scale) from admission.
    • 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.

  2. 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.

  3. Number of oxygenation free days in the first 28 days [ Time Frame: 29 days ]
  4. Incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial. [ Time Frame: 29 days ]
  5. Duration of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial. [ Time Frame: 29 days ]
  6. Ventilator free days in the first 28 days [ Time Frame: 29 days ]
  7. Incidence of new mechanical ventilation use during the trial. [ Time Frame: 29 days ]
  8. Hospitalization [ Time Frame: 29 days ]
    • Duration of hospitalization (days).

  9. Mortality [ Time Frame: In hospital, Day 28, Day 90 ]
    Rate of mortality

  10. Cumulative incidence of serious adverse events (SAEs) [ Time Frame: 29 days ]
  11. Cumulative incidence of Grade 3 and 4 adverse events (AEs) [ Time Frame: 29 days ]
  12. Number of participants with a discontinuation or temporary suspension of study drugs (for any reason) [ Time Frame: 29 days ]
  13. Changes from baseline in blood white cell count [ Time Frame: 29 days ]
  14. Changes from baseline in haemoglobin [ Time Frame: 29 days ]
  15. Changes from baseline in platelets [ Time Frame: 29 days ]
  16. Changes from baseline in creatinine [ Time Frame: 29 days ]
  17. Changes from baseline in blood electrolytes (including kaliemia) [ Time Frame: 29 days ]
  18. Changes from baseline in prothrombine time [ Time Frame: 29 days ]
  19. Changes from baseline in international normalized ratio (INR) [ Time Frame: 29 days ]
  20. Changes from baseline in glucose [ Time Frame: 29 days ]
  21. Changes from baseline in total bilirubin [ Time Frame: 29 days ]
  22. Changes from baseline in alanine aminotransferase (ALT) [ Time Frame: 29 days ]
  23. Changes from baseline in aspartate aminotransferase (AST) [ Time Frame: 29 days ]

Other Outcome Measures:
  1. Percent of subjects with SARS-CoV-2 detectable in nasopharyngeal sample [ Time Frame: Days 3, 5, 8, 11, 15, 29 ]
  2. Quantitative SARS-CoV-2 virus in nasopharyngeal sample [ Time Frame: Days 3, 5, 8, 11, 15, 29 ]
  3. Quantitative SARS-CoV-2 virus in blood [ Time Frame: Days 3, 5, 8 and 11 ]
  4. Plasma concentration of lopinavir [ Time Frame: Days 1, 3, 5, 8 and 11 ]
    • On Day 1, plasma concentration 4 hours after the first administration (peak), and before the second administration (trough at H12)
    • On Days 3, 5, 8 and 11, trough plasma concentration (before dose administration) while hospitalized

  5. Plasma concentration of hydroxychloroquine [ Time Frame: Days 1, 3, 5, 8 and 11 ]
    • On Day 1, plasma concentration 4 hours after the first administration (peak), and before the second administration (trough at H12)
    • On Days 3, 5, 8 and 11, trough plasma concentration (before dose administration) while hospitalized



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult ≥18 years of age at time of enrolment.
  • Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other commercial or public health assay in any specimen < 72 hours prior to randomization.
  • Hospitalized patients with illness of any duration, and at least one of the following:

    • Clinical assessment (evidence of rales/crackles on exam) AND SpO2 ≤ 94% on room air, OR
    • Acute respiratory failure requiring mechanical ventilation and/or supplemental oxygen.
  • Women of childbearing potential must agree to use contraception for the duration of the study. Acceptable birth methods control are listed in section 7.3

Exclusion Criteria:

  • Refusal to participate expressed by patient or legally authorized representative if they are present
  • Spontaneous blood ALT/AST levels > 5 times the upper limit of normal.
  • Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR < 30 mL/min)
  • Pregnancy or breast-feeding.
  • Anticipated transfer to another hospital, which is not a study site within 72 hours.
  • Patients previously treated with one of the antivirals evaluated in the trial (i.e. remdesivir, interferon ß-1a, lopinavir/ritonavir, hydroxychloroquine) in the past 29 days
  • Contraindication to any study medication including allergy

The following exclusion criteria are non applicable since lopinavir/ritonavir, lopinavir/ritonavir plus interferon ß-1a or hydroxychloroquine arm were stopped:

  • Use of medications that are contraindicated with lopinavir/ritonavir i.e. drugs whose metabolism is highly dependent on the isoform CYP3A with narrow therapeutic range (e.g. amiodarone, colchicine, simvastatine).
  • Use of medications that are contraindicated with hydroxychloroquine: citalopram, escitalopram, hydroxyzine, domperidone, pipéraquine.
  • Human immunodeficiency virus infection under highly active antiretroviral therapy (HAART).
  • History of severe depression or attempted suicide or current suicidal ideation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04315948


Contacts
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Contact: Florence Ader, MD +33 (0)4 72 07 15 60 florence.ader@chu-lyon.fr
Contact: Hélène Espérou, MD +33 1 44 23 60 70 helene.esperou@inserm.fr

Locations
Show Show 39 study locations
Sponsors and Collaborators
Institut National de la Santé Et de la Recherche Médicale, France
Investigators
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Study Chair: Florence Ader, MD Hospices Civils de Lyon
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier: NCT04315948    
Other Study ID Numbers: C20-15
First Posted: March 20, 2020    Key Record Dates
Last Update Posted: July 9, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Institut National de la Santé Et de la Recherche Médicale, France:
COVID-19
SARS-CoV-2
Pneumonia
Additional relevant MeSH terms:
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Coronavirus Infections
Severe Acute Respiratory Syndrome
Virus Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Respiratory Tract Infections
Respiratory Tract Diseases
Interferons
Ritonavir
Lopinavir
Interferon-beta
Interferon beta-1a
Hydroxychloroquine
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Antirheumatic Agents
Immunologic Factors