International experts have made a weak recommendation for the use of remdesivir in patients with severe COVID-19, advising continuation of patient enrolment for ongoing clinical trials of remdesivir to enable the collection of additional data.
The expert recommendation is based on a new study referred to as a “living systematic review”. Living systematic reviews are designed to enable timely access to high quality, up-to-date data emerging from studies in fast moving areas, such as COVID-19 research. Living systematic reviews can also be updated to reflect emerging evidence, up to two years after the original publication date.
The antiviral remdesivir has received worldwide attention as an existing drug with the potential to be repurposed as a treatment for COVID-19. It is currently being investigated in numerous international clinical studies and administered in various formulations (intravenous infusion and inhalation).
Current regulatory guidance on remdesivir use in COVID-19 patients
On May 4, the US Food and Drug Administration (FDA) issued an emergency use authorization for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease. Almost two months later, on June 26, the European Medicine Agency (EMA), issued a press release announcing that the human medicines committee (CHMP) had recommended granting conditional marketing authorization to Veklury® (remdesivir) for “the treatment of COVID-19 in adults and adolescents from 12 years of age with pneumonia who require supplemental oxygen”.
Comparing the effects of different drugs for COVID-19
The BMJ living systematic review article compared the effects of several different treatments for COVID-19, using the US Centers for Disease Control and Prevention (CDC) COVID-19 Research Articles Downloadable Database.
23 randomized clinical trials were included in the analysis. The trials that were assessed included patients with either a suspected, probable or confirmed diagnosis of COVID-19 and were designed to compare drugs against each other, against no intervention, or a placebo or standard care.
Siemieniuk, et al. cautioned that “the certainty of the evidence for most of the comparisons was very low”, also noting that “the effectiveness of most interventions is uncertain because most of the randomized controlled trials so far have been small and have important study limitations.” The authors also stressed that randomized trials in patients with COVID-19 have not yet provided definitive information regarding potential adverse effects for most interventions.
In summary, the current iteration of the living systematic review and network meta-analysis found that:
- Glucocorticoids were the only intervention shown to probably reduce both mortality and the need for mechanical ventilation.
- Remdesivir was the only intervention in which moderate certainty exists in terms of benefits for time to symptom resolution and duration of mechanical ventilation. Uncertainty remains as to whether remdesivir has any effect on mortality.
- Remdesivir may be effective in reducing recovery time in patients diagnosed with severe disease, however, the authors note “certainty of the evidence is low.”
- Remdesivir probably has no impact on the need for mechanical ventilation and may have little/no effect on the length of a patient’s stay in hospital.
- Hydroxychloroquine may raise the risk of adverse events, leading to drug discontinuation in comparison with the other interventions included in the review.
Remdesivir for severe COVID-19: Rapid recommendation
The living systematic review noted two randomized trials of remdesivir whereby 1300 participants were enrolled. Analysis of the trial data indicated evidence of low certainty, in terms of remdesivir’s ability to reduce recovery time and mortality in patients with severe disease. This information, coupled with findings from the ACTT-1 randomized controlled trial of remdesivir recently published in the New England Journal, triggered the drafting of “Remdesivir for severe COVID-19: a clinical practice guideline”.
The guideline was created by an international panel of recovered COVID-19 patients, intensivists, internists, infectious disease experts, public health specialists, family physicians, pharmacists, and methodologists. The panel concluded that a weak recommendation should be given for the use of remdesivir in severe COVID-19.
Due to the limited quantity of data, they also supported the “continuation of active enrolment of patients into ongoing randomized controlled trials examining remdesivir.”
The panel advised that the following questions should be considered a priority for future research:
- If remdesivir is to be used in patients with severe disease, what is the optimal dose, time of starting treatment, and duration of therapy?
- Is remdesivir best given alone or in combination with other therapeutics?
- Are there specific subgroups of patients most likely to receive benefit from treatment with remdesivir?
The rapid emergence of new evidence regarding the efficacy and safety of various COVID-19 treatments coupled with patient population data will almost certainly fuel the generation of additional guidelines.
Siemieniuk, et al. (2020). Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ DOI: http://dx.doi.org/10.1136 bmj.m2980
Rachwerg, et al. (2020). Remdesivir for severe covid-19: a clinical practice guideline. BMJ. DOI: http://dx.doi.org/10.1136/bmj.m2924
Macdonald, et al. (2020). Living systematic reviews at The BMJ. BMJ. DOI: http://dx.doi.org/10.1136/bmj.m2925