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

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.

Active, not recruiting
Corona Virus Infection

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.
Remdesivir

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).
Lopinavir/ritonavir (stopped on June 29, 2020)
Lopinavir/ritonavir plus Interferon ß-1a (stopped on June 29)

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.
Lopinavir/ritonavir plus Interferon ß-1a (stopped on June 29)

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).
Hydroxychloroquine (stopped on May 24, 2020)

Other: Standard of care
Standard of care.
Hydroxychloroquine (stopped on May 24, 2020)
Lopinavir/ritonavir (stopped on June 29, 2020)
Lopinavir/ritonavir plus Interferon ß-1a (stopped on June 29)
Remdesivir
Standard of care

Eligibility 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

Eligibility Gender
All
Eligibility Age
Minimum: 18 Years
Countries
Austria
Belgium
France
Luxembourg
Portugal

Florence Ader, MD
Study Chair
Hospices Civils de Lyon

Institut National de la Santé Et de la Recherche Médicale, France
NCT Number
Keywords
Covid-19
SARS-CoV-2
Pneumonia
MeSH Terms
Coronavirus Infections
Severe Acute Respiratory Syndrome
Interferons
Ritonavir
Lopinavir
Interferon-beta
Interferon beta-1a
Hydroxychloroquine