Trial NCT02735707
Publication Arabi Y, 2021 (published paper)
Dates: 4/8/2020 to 11/19/2020
Funding: Mixed (The European Union through the Platform for European Preparedness Against emerging Epidemics (PREâPARE) 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 | â¥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 1 Lopinavir-Ritonavir | |
| Control Standard care | |
| Control Hydroxychloroquine | |
| Control Hydroxychloroquine+Lopinavir+Ritonavir | |
| Participants | |
| Randomized 726 participants n1=268/ n2=377/ n3=52/ n4=29/ | |
| Characteristics of participants N=726 Mean age : 60.5 488 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 available |
Protocol Yes. In English Statistical plan Yes Data-sharing stated NR |
| 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. |