NEJM Oct 2020. DOI:10.1056/NEJMoa2007764
Beigel J.H, Tomashek K.M., Dodd A.K et al.
Aims of the Study
To identify whether Remdesivir is a suitable and effective therapy for the treatment of Coronavirus disease 2019 (Covid-19)
Design and Location
An international, double blind randomised, placebo-controlled trial conducted over 60 sites. Principal investigators were based in the United States although sites were found in multiple countries globally.
– 18yo or older, hospitalised with a lower respiratory tract infection and Covid-19 positive assay
– Severely deranged liver or kidney function
– Allergy to study product, pregnancy or breast feeding
– Anticipated hospital discharge date within 72 hours of enrolment
Patients were randomised to either Remdesivir for ten days (200mg loading dose then 100mg maintenance) or placebo. Patients clinical status were categorised into eight ordinal groups, ranging from not hospitalised up to being mechanically ventilated or had died. Patients were followed up for 28 days recording their clinical status, NEWS (National Early Warning Score) and which clinical category they fell into.
Time to recovery (defined as the first day following enrolment the patient was felt to be safe for discharge from hospital).
Note: Original primary outcome was defined as the patient’s clinical status at day 15, however early in the study it became clear this was too short a timeframe and therefore this was changed to 28 days.
Multiple. This included mortality at 14 and 28 days, number of days of supplemental oxygen and invasive ventilation. Also included were how quickly patient ordinal category improved from baseline score and total number of days hospitalised.
Just over a thousand patients were included in the study, with 541 patients in the treatment arm vs 521 in the placebo. Overall, patients in the Remdesivir group had a shorter time to recovery compared to placebo (median time to recovery being 10 vs 15 days). If only looking at the 85% of patients who were labelled as ‘severe’ disease at baseline (requiring either supplemental oxygen, assisted ventilation or saturating at less than 94% on room air) the difference with Remdesivir was more marked – median time to recovery was 11 vs 18 days.
The rate ratio (comparing rate of recovery of treatment arm vs placebo) overall was 1.31. Of interest patients treated with Remdesivir also had a reduced number of days requiring oxygen therapy, reduced intubation days and had a shorter time to discharge.
Remdesivir treatment also appeared to be influenced by the clinical status of the patient at baseline. Those in hospital requiring only supplemental oxygen had the best response to Remdesivir – a rate ratio of 1.45. Those that were hospitalised but not on oxygen and those requiring non-invasive ventilation had rate ratios of 1.29 and 1.09 respectively. The only group with an equivocal/worse outcome were patients already requiring mechanical ventilation at baseline, with a rate ratio of 0.98 vs placebo.
This study was performed in the midst of one the most significant medical crisis of the modern era. It has been run in conjunction with a number of other large international trials looking at treatment options for the Covid-19 pandemic. Interestingly, because of the positive early results in May it was decided to release results early, enabling countries to start using the medication whilst the study was still being performed.
The study itself was well run and has a high level of evidence. There were however obvious constraints to performing a study during a pandemic, with training, site visits and monitoring having to be performed remotely. The authors also stressed they felt releasing the positive results early, enabling clinicians to request their patients to be added to the ‘treatment’ arm, resulted in minimal bias and changes to the overall outcomes.
Overall, the study showed a clear benefit for the use of Remdesivir in the treatment of Covid-19 pneumonia. With the biggest difference seen in patients in patients with less ‘severe’ disease at baseline. However, it difficult to conclusively state that Remdesivir is not effective if started in more severe disease/ if patients are already requiring mechanical ventilation. These patients potentially could take longer than 28 days to improve and therefore further work is needed over a longer period to see if the drug is effective in these patients
Sub-group analysis of patients also being treated with steroids also showed promise and that these could be potentially be used in combination. Further work is currently being undertaken looking at Remdesivir in combination with other immune modulators.
Summary by Dr J Blake, Journal Club Meeting 15th October 2020