A REMAP CAP randomised controlled trial

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected more than 175 million people across the globe and caused more than 3.8 million deaths to date [1].

Recent trials involving steroids and other immunomodulators have shown benefits and contributed to improved care.

Given the emerging nature of the virus, several repurposed agents were also considered as potential antiviral agents for COVID-19. Lopinavir-ritonavir and hydroxychloroquine were proposed based on data from severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS) treatments.

The Randomised, Embedded, Multifactorial Adaptive Platform (REMAP‑CAP) trial is the largest randomised clinical trial (RCT) in critically ill patients with COVID‑19 to report the effects of lopinavir‑ritonavir, hydroxychloroquine and combination therapy of lopinavir‑ritonavir and hydroxychloroquine compared with no antiviral therapy.

The main aim was to see whether these medications would improve organ support free days in critically-ill patients with COVID-19.

Inclusion criteria were set as per prior REMAP-CAP trial standards of patients who were ≥ 18 years old with suspected or confirmed COVID-19 and receiving respiratory or cardiovascular organ support within critical care areas.

Exclusion criteria were again as per prior standards, including imminent death, imminent discharge, previous REMAP-CAP involvement, hypersensitivity to agents being used, known HIV, severe liver failure, pregnancy and recent amiodarone use.

Using a concealed online randomisation system, patients were randomised to a medication group or the control group.

694 patients were involved in the trial, split across the groups – lopinavir‐ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362).

Results included

• Median organ support free days: more days organ support free in the medication groups vs control;
• In-hospital mortality: higher in the medication groups vs control;
• High probabilities of harm in all medication groups (98.5% in Lopinivir-Ritonavir, 99.4% in hydroxychloroquine, 99.8% in combination therapy).

STUDY STRENGTHS & LIMITATIONS

Strengths

• REMAP-CAP uses a novel and innovative adaptive trial design to evaluate several treatment options simultaneously and efficiently.
• REMAP-CAP uses a Bayesian design with no prespecified sample size; enrolment in any intervention continues until a pre-defined statistical trigger is met at an adaptive analysis.
• Well-designed, multi-national randomised pragmatic study.
• Despite small sample groups, a strong signal observed resulted in a high probability of harm from the medications.

Limitations

• It was underpowered, mainly because of the large population excluded from the study due to enrolment in one or more REMAP‑CAP domains.
• Limited group sizes may have reduced the detection of adverse events.
• Only critically ill patients studied – would there be benefit in including patients prior to critical care admission?

TAKE-HOME MESSAGES

The Randomised, Embedded, Multifactorial Adaptive Platform (REMAP‑CAP) trial is the largest randomised clinical trial in critically ill patients with COVID‑19 to report the effects of lopinavir‑ritonavir, hydroxychloroquine and combination therapy, finding that all three reduced survival compared to no COVID‑19 antiviral therapy (control care group).

As a result, these medications have no utility in the care of these patients currently. It is unclear why these medications do not transfer their in-vitro effect across into clinical situations.

These results for these medications concur with other studies and literature in this field in hospitalised patients [2], [3].

This article review was prepared and submitted by Rami Mohamed (IMT2) and Andrew Martin (Consultant in ICM), Adult Critical Care Department, Manchester Royal infirmary (UK) on behalf of the ESICM Journal Review Club.

[2] Arabi Y.M. et al.; REMAP-CAP Investigators. Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial. Intensive Care Med. 2021 Aug;47(8):867-886. Epub 2021 Jul 12. PMID: 34251506; PMCID: PMC8274471.

[3] RECOVERY Collaborative Group, Horby P et al. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020 Nov 19;383(21):2030-2040. Epub 2020 Oct 8. PMID: 33031652; PMCID: PMC7556338.