Covid-19 living Data

Lopinavir-Ritonavir vs Hydroxychloroquine (RCT)

Hospitalized patients

FOREST PLOTS -2021-07-29

Studies description

Trial NCT04315948
Publication DisCoVeRy - Ader F, medRxiv (2022) (preprint)
Dates: 2020-03-22 to 2020-06-29
Funding: Mixed (Programme Hospitalier de Recherche Clinique, DIM One Health Île-de-France, REACTing, INSERM. GILEAD, SANOFI, MERCK and ABBVIE (drug provision) )
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / France, Luxembourg Follow-up duration (days): 90
Inclusion criteria	Adult ≥18 years of age at time of enrolment 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 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 Women of childbearing potential must agree to use contraception for the duration of the study
Exclusion criteria	Refusal to participate expressed by patient or legally authorized representative if they are present Spontaneous blood alanine transferase (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 Corrected QT interval superior to 500 milliseconds (as calculated with the Fridericia formula)
Interventions
	Treatment Lopinavir-Ritonavir Lpv/R: 400/100 mg orally or by nasogastric tube every 12h for 14 days LPV/r+IFN beta-1a Lpv/R: 400/100 mg orally or by nasogastric tube every 12h for 14 days IFN beta-1a: 44 mcg subcutaneously on days 1, 3 and 6 Hydroxychloroquine 400 mg orally twice on day 1 then 400 mg once daily for 9 days
	Control Standard care
Participants
	Randomized participants : Lopinavir-Ritonavir=150 LPV/r+IFN beta-1a=150 Hydroxychloroquine=151 Standard care=152
	Characteristics of participants N= 603 Mean age : NR 421 males Severity : Mild: n=21 / Moderate: n=354 / Severe: n=62 Critical: n=156
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 avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: 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 journal/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 publication/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. On 26th of April, 2022, this study was updated based on the preprint reporting final results.

Trial NCT02735707
Publication Arabi Y, Intensive Care Med (2021) (published paper)
Dates: 2020-04-08 to 2020-11-19
Funding: Mixed (The European Union through the Platform for European Preparedness Against emerging Epidemics (PRE‑PARE) consortium and Horizon 2020 research and innovation program (the Rapid European Covid-19 Emergency Research response (RECOVER) consortium; the Australian National Health and Medical Research Council; the Health Research Council of New Zealand; Canadian Institutes of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant; the U.K. NIHR and the NIHR Imperial Biomedical Research Centre; the Health Research Board of Ireland; the UPMC Learning While Doing Program; the Breast Cancer Research Foundation; the French Ministry of Health; the Minderoo Foundation; Amgen; Eisai; the Global Coalition for Adaptive Research; the Wellcome Trust Innovations Project)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Australia, Canada, France, Germany, Ireland, Netherlands, New Zealand, Portugal, Saudi Arabia, UK, USA Follow-up duration (days): 90
Inclusion criteria	≥18 years old admitted with suspected or confrmed COVID-19 receiving respiratory or cardiovascular organ failure support in an intensive care unit (ICU). Organ support included the provision of invasive mechanical ventilation, noninvasive mechanical ventilation, high-fow nasal cannulae with a fow rate of at least 30 L per minute and a fractional inspired oxygen concentration of 0.4 or higher, or the infusion of vasopressor or inotropes for shock
Exclusion criteria	Death was deemed to be imminent during the next 24 h AND one or more of the patient, substitute decision-maker, or attending physician are not committed to full active treatment expected to be discharged from hospital the same day or the following day more than 14 days have elapsed while admitted to hospital with symptoms of an acute illness due to suspected or proven pandemic infection previous participation in this REMAP-CAP within the last 90 days known hypersensitivity to lopinavir-ritonavir and hydroxychloroquine receiving lopinavir-ritonavir or hydroxychloroquine as a usual medication prior to this hospitalization known human immunodefciency (HIV) infection (an exclusion criterion from receiving lopinavir-ritonavir) severe liver failure (an exclusion criterion from lopinavir-ritonavir) known or suspected pregnancy receiving amiodarone as a usual medication prior to this hospitalization or any administration of amiodarone within the 72 h prior to the assessment of eligibility (an exclusion criterion from lopinavir-ritonavir) high clinical risk of sustained ventricular dysrhythmia (an exclusion criterion from hydroxychloroquine)
Interventions
	Treatment Lopinavir-Ritonavir 400 mg + 100 mg orally twice daily for 5-14 days or ICU discharge Hydroxychloroquine Initial dose: two oral 800 mg doses 6 h apart - Maintenance dose: 400 mg orally twice daily for 6 days HCQ+LPV/r 400 mg Lopinavir + 100 mg Ritonavir orally twice daily for 5-14 days or ICU discharge + HCQ two 800 mg oral doses 6 h apart, then 400 mg orally twice daily for 6 days
	Control Standard care
Participants
	Randomized participants : Lopinavir-Ritonavir=268 Hydroxychloroquine=52 HCQ+LPV/r=29 Standard care=377
	Characteristics of participants N= 726 Mean age : NR 488 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=0 Critical: n=694
Primary outcome
	In the register All-cause mortality [ Time Frame: Day 90 ]; Days alive and not receiving organ support in ICU [ Time Frame: Day 21 ]
	In the report composite ordinal scale of the number of respiratory and cardiovascular organ support-free days (OSFD) and in-hospital mortality with death assigned the worst outcome, up to day 21
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: 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 published article, the supplementary appendix with protocol and statistical analysis plan, and study registry were used in data extraction and risk of bias assessment. This was a multi-country adaptive platform trial (REMAP-CAP) with no pre-defined sample size. This paper reported on critically ill patients and four of the trial's intervention arms. The interventions arms reported were added to the registry (15 April 2020) one week after the start of recruitment to the arms (8 April 2020), but the domain-specific protocol amendment was dated before start of recruitment (1 April 2020). There were no substantive differences between the published article and the registry, protocol and statistical analysis plan in population, procedures, interventions and outcomes. Enrollment into the hydroxychloroquine and combination therapy study arms was halted before reaching any pre-specifed internal trigger but based on external evidence, consequently, these arms had much smaller sample sizes compared to the other arms.