• 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)

Protocol

Yes. In English

Statistical plan

Yes

Data-sharing willing stated in the publication:

Yes

• 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)

Protocol

Yes. In English

Statistical plan

Yes

Data-sharing willing stated in the publication:

Yes

• Physician decision that involvement in the trial was not in the patient’s best interest, presence of any condition that would not allow the protocol to be followed safely, known allergy or hypersensitivity to lopinavir–ritonavir, known severe liver disease (e.g., cirrhosis, with an alanine aminotransferase level >5× the upper limit of the normal range or an aspartate aminotransferase level >5× the upper limit of the normal range), use of medications that are contraindicated with lopinavir–ritonavir and that could not be replaced or stopped during the trial period (see the Supplementary Appendix, available with the full text of this article at NEJM.org)
• pregnancy or breast-feeding, or known HIV infection, because of concerns about the development of resistance to lopinavir–ritonavir if used without combining with other antiretrovirals.

Protocol

Yes. In language other than English

Statistical plan

NR

Data-sharing willing stated in the publication:

Yes

• Report:
  Patients with severe hepatic insufficiency or who were using medicinal products that are highly dependent on cytochrome P450 3A4 for clearance and for whom elevated plasma concentrations would be associated with serious or life-threatening events (in line with the summary of product characteristics).
  
  Registry:
  If the attending clinician believes that there is a specific contra-indication to one of the active drug treatment arms or that the patient should definitely be receiving one of the active drug treatment arms then that arm will not be available for randomisation for that patient. For patients who lack capacity, an advanced directive or behaviour that clearly indicates that they would not wish to participate in the trial would be considered sufficient reason to exclude them from the trial.

Protocol

Yes. In English

Statistical plan

Yes

Data-sharing willing stated in the publication:

• The only exclusions were patients without clear consent to follow-up

Protocol

Yes. In English

Statistical plan

NR

Data-sharing willing stated in the publication:

Yes

• 1) Known or suspected to be allergic to LPV/r or Umifenovir
• 
  2) Having severe nausea, vomiting, diarrhea or other complaints affecting oral intake or absorption in the digestive tract
• 
  3) Taking other drugs that may interact with LPV/r or Umifenovir
• 
  4) Having serious underlying diseases, including but not limited to heart, lung, or kidney disease, liver malfunction, or mental diseases affecting treatment compliance
• 
  5) Complicating with pancreatitis or hemophilia prior to the trial
• 
  6) Pregnant or lactating women
• 
  7) Having the suspected or confirmed history of alcohol or substance use disorder
• 
  8) Having participated in other drug trials in the past month
• 
  9) Deemed otherwise unsuitable for the study by the researchers.

Protocol

NR

Statistical plan

NR

Data-sharing willing stated in the publication:

No