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Multi-centre, Adaptive, Randomized Trial of the Safety and Efficacy of Treatments of COVID-19 in Hospitalized Adults

Trial Profile

Multi-centre, Adaptive, Randomized Trial of the Safety and Efficacy of Treatments of COVID-19 in Hospitalized Adults

Status: Recruiting
Phase of Trial: Phase III

Latest Information Update: 17 May 2020

At a glance

  • Drugs Hydroxychloroquine (Primary) ; Interferon beta-1a (Primary) ; Interferon beta-1a (Primary) ; Lopinavir/ritonavir (Primary) ; Remdesivir (Primary)
  • Indications COVID 2019 infections
  • Focus Therapeutic Use
  • Acronyms DisCoVeRy
  • Most Recent Events

    • 30 Apr 2020 According to a Faron Pharmaceuticals media release, over 90 countries involved in this trial.
    • 27 Apr 2020 According to a Faron Pharmaceuticals media release, the Company will donate supplies of its investigational intravenous (IV) interferon (IFN) beta-1a for 2,000 patients in the World Health Organization's (WHO) Solidarity trial.
    • 23 Mar 2020 Status changed from not yet recruiting to recruiting.

Trial Overview

Purpose

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 + Lopinavir/Ritonavir plus interferon ß-1a versus SoC + Hydroxychloroquine. 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.

Primary Endpoints

Percentage of subjects reporting each severity rating on a 7-point ordinal scale

description: Not hospitalized, no limitations on activities
Not hospitalized, limitation on activities;
Hospitalized, not requiring supplemental oxygen;
Hospitalized, requiring supplemental oxygen;
Hospitalized, on non-invasive ventilation or high flow oxygen devices;
Hospitalized, on invasive mechanical ventilation or ECMO;
Death.
time_frame: Day 15

Other Endpoints

Percentage of subjects reporting each severity rating on a 7-point on an ordinal scale

description: 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.
time_frame: Days 3, 5, 8, 11, 15 and 29

The time to discharge or to a NEWS of ≤ 2 and maintained for 24 hours, whichever occurs first.

description: • Change from baseline to days 3, 5, 8, 11, 15, and 29 in NEWS.
time_frame: Days 3, 5, 8, 11, 15 and 29

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

description: • Duration of hospitalization (days).
time_frame: 29 days

Mortality

description: Rate of mortality
time_frame: In hospital, Day 28, Day 90

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 blood electrolytes (including kaliemia)

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

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

Plasma concentration of lopinavir

description: 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
time_frame: Days 1, 3, 5, 8 and 11

Plasma concentration of hydroxychloroquine

description: 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
time_frame: Days 1, 3, 5, 8 and 11 [1]

Diseases Treated

Indication Qualifiers Patient Segments
COVID 2019 infections treatment -

Subjects

  • Subject Type patients
  • Number

    Planned: 3300

  • Sex male & female
  • Age Group ≥ 18 years; adult; elderly

Patient 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

Patient 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 - 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

Trial Details

Identifiers

Identifier Owner
NCT04315948 ClinicalTrials.gov: US National Institutes of Health
EudraCT2020-000936-23 European Clinical Trials Database
C20-15 -

Organisations

  • Affiliations Faron Pharmaceuticals

Trial Dates

  • Initiation Dates

    Planned : 01 Mar 2020

    Actual : 22 Mar 2020

  • Primary Completion Dates

    Planned : 01 Mar 2023

  • End Dates

    Planned : 01 Mar 2023

Other Details

  • Design multicentre; open; parallel; prospective; randomised
  • Phase of Trial Phase III
  • Location Europe; France; Luxembourg
  • Focus Therapeutic Use

Interventions

Drugs Route Formulation
HydroxychloroquinePrimary Drug Oral Tablet
Interferon beta-1aPrimary Drug Intravenous
-
Interferon beta-1aPrimary Drug Subcutaneous Injection
Lopinavir/ritonavirPrimary Drug Oral Solution, Suspension, Tablet
RemdesivirPrimary Drug Intravenous Infusion

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.)

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 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.)

Lopinavir/ritonavir plus Interferon ß-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 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.)

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 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.)

Standard of care

Standard of care. n=620 Other: Standard of care (Standard of care.)

Trial Centres

Investigators

Investigator Centre Name Trial Centre Country
André CABIE Centre Hospitalier Universitaire de Martinique France
Armand MEKONTSO DESSAP APHP - hôpital Henri-Mondor France
Benoit PILMIS Hôpital Paris Saint-Joseph et Marie Lannelongue France
Béatrice RIU-POULENC Centre Hospitalier Universitaire de Toulouse France
Clément DUBOST Hôpital d'Instruction des Armées BEGIN France
Cyrille CHABARTIER Centre Hospitalier Universitaire de Martinique France
Cécile FICKO Hôpital d'Instruction des Armées BEGIN France
Céline ROBERT Centre Hospitalier Regional Metz-Thionville France
David BOUGON Centre Hospitalier Annecy Genevois France
David LEBEAUX APHP- Hôpital Européen Georges-Pompidou France
Denis GAROT Centre Hospitalier Universitaire de Tours France
Denis MALVY Centre Hospitalier Universitaire de Bordeaux France
Didier GRUSON Centre Hospitalier Universitaire de Bordeaux France
Elisabeth BOTELHO-NEVERS Centre Hospitalier Universitaire de Saint Etienne France
Eric SENNEVILLE Centre Hospitalier de Tourcoing France
Fanny BOUNES - VARDON Centre Hospitalier Universitaire de Toulouse France
Ferhat MEZIANI Centre Hospitalier Régional Universitaire de Strasbourg France
Flora CROCKETT Hopital DELAFONTAINE France
Florence ADER Hospices Civils de Lyon France
Florence Ader, MD
+33 (0)4 72 07 15 60 florence.ader@chu-lyon.fr
show details
Hospices Civils de Lyon France
François BENEZIT Centre Hospitalier Universitaire de Rennes France
François DANION Centre Hospitalier Régional Universitaire de Strasbourg France
François GOEHRINGER Centre Hospitalier Régional et Universitaire de Nancy France
François Raffi Centre Hospitalier Universitaire de Nantes France
François-Xavier Lescure APHP - Hôpital Bichat Claude Bernard France
Guillaume MARTIN BLONDEL Centre Hospitalier Universitaire de Toulouse France
Guillaume THIERY Centre Hospitalier Universitaire de Saint Etienne France
Hafid AIT TOUFELLA APHP - Hôpital Saint Antoine France
Hélène Espérou, MD
+33 1 44 23 60 70 helene.esperou@inserm.fr
show details
-
Jean DELLAMONICA Centre Hospitalo-Universitaire de Nice France
Jean Reignier Centre Hospitalier Universitaire de Nantes France
Jean-Christophe NAVELLOU Centre Hospitalier Régional Universitaire de Besançon France
Jean-Christophe RICHARD Hospices Civils de Lyon France
Jean-François Timsit APHP - Hôpital Bichat Claude Bernard France
Jean-Luc DIEHL APHP- Hôpital Européen Georges-Pompidou France
Jean-Paul MIRA APHP - Hôpital Cochin France
Jean-Philippe LANOIX Centre Hospitalier Universitaire Amiens-Picardie France
Jean-Pierre QUENOT Centre Hospitalier Universitaire Dijon-Bourgogne France
Jerome ABOAB Hopital DELAFONTAINE France
Jerome Le Pavec Hôpital Paris Saint-Joseph et Marie Lannelongue France
Johan COURJEON Centre Hospitalo-Universitaire de Nice France
Joy MOOTIEN Groupe Hospitalier de la Région de Mulhouse Sud Alsace France
Julien MAYAUX APHP - Hôpital Universitaire Pitié Salpêtrière France
Julien Poissy Centre Hospitalier Régional Universitaire de Lille France
Kada KLOUCHE Centre Hospitalier Universitaire de Montpellier France
Karine Faure Centre Hospitalier Régional Universitaire de Lille France
Karine LACOMBE APHP - Hôpital Saint Antoine France
Kevin BOUILLER Centre Hospitalier Régional Universitaire de Besançon France
Lionel PIROTH Centre Hospitalier Universitaire Dijon-Bourgogne France
Louis BERNARD Centre Hospitalier Universitaire de Tours France
Marc BERNIA Hôpitaux Robert Schuman Luxembourg
Nicolas TERZI Centre Hospitalo-Universitaire de Grenoble France
Odile LAUNAY APHP - Hôpital Cochin France
Olivier EPAULARS Centre Hospitalo-Universitaire de Grenoble France
Olivier HINSCHBERGER Groupe Hospitalier de la Région de Mulhouse Sud Alsace France
Rostane GACI Centre Hospitalier Regional Metz-Thionville France
Samy FIGUEIREDO AP-HP Hôpital Bicêtre France
Stéphane JAUREGUIBERRY AP-HP Hôpital Bicêtre France
Sébastien GALLIEN APHP - hôpital Henri-Mondor France
Sébastien GIBOT Centre Hospitalier Régional et Universitaire de Nancy France
Thérèse STAUB Centre Hospitalier Luxembourg Luxembourg
Valérie POURCHER APHP - Hôpital Universitaire Pitié Salpêtrière France
Vanessa JEAN-MICHEL Centre Hospitalier de Tourcoing France
Vincent LEMOING Centre Hospitalier Universitaire de Montpellier France
Violaine TOLSMA Centre Hospitalier Annecy Genevois France
Yoann ZERBIB Centre Hospitalier Universitaire Amiens-Picardie France
Yves LE TULZO Centre Hospitalier Universitaire de Rennes France

Centres

Centre Name Location Trial Centre Country
-
-
-
AP-HP Hôpital Bicêtre Kremlin-Bicêtre France
APHP - Hôpital Bichat Claude Bernard Paris France
APHP - Hôpital Cochin Paris France
APHP - hôpital Henri-Mondor Créteil France
APHP - Hôpital Saint Antoine Paris France
APHP - Hôpital Universitaire Pitié Salpêtrière Paris France
APHP- Hôpital Européen Georges-Pompidou Paris France
Centre Hospitalier Annecy Genevois Épagny France
Centre Hospitalier de Tourcoing Tourcoing France
Centre Hospitalier Luxembourg Luxembourg Luxembourg
Centre Hospitalier Regional Metz-Thionville Ars-Laquenexy France
Centre Hospitalier Régional et Universitaire de Nancy Nancy France
Centre Hospitalier Régional Universitaire de Besançon Besançon France
Centre Hospitalier Régional Universitaire de Lille Lille France
Centre Hospitalier Régional Universitaire de Strasbourg Strasbourg France
Centre Hospitalier Universitaire Amiens-Picardie Amiens France
Centre Hospitalier Universitaire de Bordeaux Bordeaux France
Centre Hospitalier Universitaire de Martinique Fort De France France
Centre Hospitalier Universitaire de Montpellier Montpellier France
Centre Hospitalier Universitaire de Nantes Nantes France
Centre Hospitalier Universitaire de Rennes Rennes France
Centre Hospitalier Universitaire de Saint Etienne Saint-Étienne France
Centre Hospitalier Universitaire de Toulouse Toulouse France
Centre Hospitalier Universitaire de Tours Tours France
Centre Hospitalier Universitaire Dijon-Bourgogne Dijon France
Centre Hospitalo-Universitaire de Grenoble La Tronche France
Centre Hospitalo-Universitaire de Nice Nice France
Groupe Hospitalier de la Région de Mulhouse Sud Alsace Mulhouse France
Hopital DELAFONTAINE Saint-Denis France
Hospices Civils de Lyon Lyon France
Hôpital d'Instruction des Armées BEGIN Saint-Mandé France
Hôpital Paris Saint-Joseph et Marie Lannelongue Paris France
Hôpitaux Robert Schuman Luxembourg Luxembourg
INSERM
-
France
Institut National de la Santé Et de la Recherche Médicale, France
-
-

Trial History

Event Date Event Type Comment
17 May 2020 Other trial event Last checked against European Clinical Trials Database record. Updated 17 May 2020
30 Apr 2020 Other trial event According to a Faron Pharmaceuticals media release, over 90 countries involved in this trial. Updated 04 May 2020
30 Apr 2020 Other trial event Last checked against ClinicalTrials.gov record. Updated 30 Apr 2020
27 Apr 2020 Other trial event According to a Faron Pharmaceuticals media release, the Company will donate supplies of its investigational intravenous (IV) interferon (IFN) beta-1a for 2,000 patients in the World Health Organization's (WHO) Solidarity trial. Updated 04 May 2020
24 Mar 2020 Other trial event New source identified and integrated,European Clinical Trials Database;EudraCT2020-000936-23. Updated 24 Mar 2020
23 Mar 2020 Status change - recruiting Status changed from not yet recruiting to recruiting. Updated 27 Mar 2020
23 Mar 2020 New trial record New trial record Updated 23 Mar 2020

References

  1. ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2016;.

    Available from: URL: http://clinicaltrials.gov
  2. European Clinical Trials Database. Trial-Reg 2016;.

    Available from: URL: https://www.clinicaltrialsregister.eu
  3. Faron Pharmaceuticals. Traumakine to be a part of WHO's Solidarity trial investigating potential COVID-19 treatments. Media-Rel 2020;.

    Media Release
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