Trial of Treatments for COVID-19 in Hospitalized Adults
Status:
Recruiting
Sponsors
Institut National de la Santé Et de la Recherche Médicale, France
Abstract:
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.
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.
Condition or disease:Corona Virus Infection
Intervention/treatment:
Drug: Remdesivir
Drug:
Drug: Lopinavir/ritonavir plus Interferon ß-1a (stopped on June 29)
Drug: Hydroxychloroquine (stopped on May 24, 2020)
Other:
Phase:Phase 3
Study design:
Study Type:Interventional
Allocation:Randomized
: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.
Primary Purpose:Treatment
Masking:None (Open Label)
: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
Arm group:
ArmIntervention/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.
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
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 plus Interferon ß-1a (stopped on June 29)
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.
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 (stopped on May 24, 2020)
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).
Active Comparator: Standard of care
Standard of care. n=620
Eligibility Criteria:
Ages Eligible for Study:18 Years to 18 Years
Sexes Eligible for Study:All
Accepts Healthy Volunteers:Yes
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

Outcome:
Primary Outcome Measures
1. Percentage of subjects reporting each severity rating on a 7-point ordinal scale [Day 15]
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.
Secondary Outcome Measures
1. Percentage of subjects reporting each severity rating on a 7-point on an ordinal scale [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. [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 [29 days]
4. Incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial. [29 days]
5. Duration of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial. [29 days]
6. Ventilator free days in the first 28 days [29 days]
7. Incidence of new mechanical ventilation use during the trial. [29 days]
8. Hospitalization [29 days]
• Duration of hospitalization (days).
9. Mortality [In hospital, Day 28, Day 90]
Rate of mortality
10. Cumulative incidence of serious adverse events (SAEs) [29 days]
11. Cumulative incidence of Grade 3 and 4 adverse events (AEs) [29 days]
12. Number of participants with a discontinuation or temporary suspension of study drugs (for any reason) [29 days]
13. Changes from baseline in blood white cell count [29 days]
14. Changes from baseline in haemoglobin [29 days]
15. Changes from baseline in platelets [29 days]
16. Changes from baseline in creatinine [29 days]
17. Changes from baseline in blood electrolytes (including kaliemia) [29 days]
18. Changes from baseline in prothrombine time [29 days]
19. Changes from baseline in international normalized ratio (INR) [29 days]
20. Changes from baseline in glucose [29 days]
21. Changes from baseline in total bilirubin [29 days]
22. Changes from baseline in alanine aminotransferase (ALT) [29 days]
23. Changes from baseline in aspartate aminotransferase (AST) [29 days]
Other Outcome Measures
1. Percent of subjects with SARS-CoV-2 detectable in nasopharyngeal sample [Days 3, 5, 8, 11, 15, 29]
2. Quantitative SARS-CoV-2 virus in nasopharyngeal sample [Days 3, 5, 8, 11, 15, 29]
3. Quantitative SARS-CoV-2 virus in blood [Days 3, 5, 8 and 11]
4. Plasma concentration of lopinavir [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 [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
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