Covid-19 Living Data

Trial NCT04315948; EudraCT
Publication Ader F, DisCoVeRy, Clin Microbiol Infect, 2021 (published paper)
Dates: 3/22/2020 to 6/29/2020
Funding: Mixed (Programme Hospitalier de Recherche Clinique, DIM One Health Ãle-de-France, REACTing, INSERM. GILEAD, SANOFI, MERCK and ABBVIE (drug provision) )
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / France, Luxembourg Follow-up duration (days): 29
Inclusion criteria	1. Adult ≥18 years of age at time of enrolment; 2. 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; 3. Hospitalized patients with illness of any duration, and at least one of the following: - Clinical assessment (evidence of rales/crackles on physical examination) AND SpO2 ≤ 94% on room air, OR - Acute respiratory failure requiring supplemental oxygen, high flow oxygen devices, non-invasive ventilation, and/or mechanical ventilation; 4. Women of childbearing potential must agree to use contraception for the duration of the study.
Exclusion criteria	1. Refusal to participate expressed by patient or legally authorized representative if they are present; 2. Spontaneous blood alanine transferase (ALT)/AST levels > 5 times the upper limit of normal; 3. Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR < 30 mL/min); 4. Pregnancy or breast-feeding; 5. Anticipated transfer to another hospital, which is not a study site within 72 hours; 6. Patients previously treated with one of the antivirals evaluated in the trial (i.e. remdesivir, interferon beta-1a, lopinavir/ritonavir, hydroxychloroquine) in the past 29 days; 7. Contraindication to any study medication including allergy; 8. 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); 9. Use of medications that are contraindicated with hydroxychloroquine: citalopram, escitalopram, hydroxyzine, domperidone, piperaquine; 10. Human immunodeficiency virus infection under highly active antiretroviral therapy (HAART); 11. History of severe depression or attempted suicide or current suicidal ideation; 12. Corrected QT interval superior to 500 milliseconds (as calculated with the Fridericia formula).
Interventions

	Treatment 1 Lopinavir-Ritonavir (400 mg+100 mg) Co-Intervention: Standard care Duration : 14 days
	Control Lopinavir-Ritonavir+Interferon beta-1a (400 mg+100 mg/44 mcg) Co-Intervention: Standard care Duration : 14 days
	Control Hydroxychloroquine (400 mg) Co-Intervention: Standard care Duration : 10 days
	Control Standard care
	Participants
		Randomized 603 participants n₁=150/ n₂=150/ n₃=151/ n₄=152/
Characteristics of participants N=603 Mean age : NR 418 males Severity : Mild: n=27 / Moderate: n=341/ Severe: n=63 Critical: n=152
Primary outcome
	In the register Percentage of subjects reporting each severity rating on a 7-point ordinal scale [ Time Frame: Day 15 ]: a. Not hospitalized, no limitations on activities; b. Not hospitalized, limitation on activities; c. Hospitalized, not requiring supplemental oxygen; d. Hospitalized, requiring supplemental oxygen; e. Hospitalized, on non-invasive ventilation or high flow oxygen devices; f. Hospitalized, on invasive mechanical ventilation or ECMO; g. Death.
	In the report Clinical status at day 15 as measured on the 7-point ordinal scale of the WHO Master Protocol (v3.0, March 3, 2020)
Documents available	Protocol Yes. In English Statistical plan Yes Data-sharing stated Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the pre-print article and its supplementary materials, the study registry and published protocol were used in data extraction and risk of bias assessment. DisCoVeRy is an adaptive, add-on trial of the WHO Solidarity trial. The same treatments are evaluated in DisCoVeRy and in Solidarity. Solidarity has three endpoints which are also secondary endpoints of DisCoVeRy: (1) mortality during hospitalization (the primary endpoint of Solidarity), (2) length of hospital stay and (3) time to mechanical ventilation or transfer to intensive care. There were no substantive differences between the protocol, registry and pre-print in study population, procedures, interventions or outcomes. The 3 intervention arms presented here were terminated early. Quote: "The present analysis is based on the protocol v7.0 of April, 5th 2020,(14) with two secondary outcomes added in protocol v9.0 of June, 29th 2020...On May 25th 2020, following a safety warning on hydroxychloroquine use(19), enrollment in the hydroxychloroquine arm was suspended at the request of the French Agency of drug Security (Agence Nationale de Sécurité du Médicament). On June 13th, based on the interim analysis of the Solidarity data, the Solidarity and DisCoVeRy trial DSMBs recommended to definitely stop the hydroxychloroquine arm due to futility. This decision was endorsed by the DisCoVeRy steering committee on June 17th. The Solidarity DSMB advised to stop the lopinavir/ritonavir arm due to futility on June, 23th. Thereafter, the DisCoVeRy DSMB further advised to stop both the lopinavir/ritonavir-containing arms due to additional safety concern on June, 25th. This decision was endorsed by the DisCoVeRy steering committee on June 27th with subsequent interruption on June, 29th." The pre-planned remdesivir arm is continuing and currently enrolling. This was substantially underpowered as <25% of the pre-stated sample size was randomized. On 1st of May, 2021, this study was updated based on the published report.