A Large, Simple Trial Leading to Complex Questions | NEJM

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the lack of known effective treatments for coronavirus disease 2019 (Covid-19) have caused an unprecedented situation for patients and clinicians — regimens with uncertain value are being used worldwide while being evaluated in clinical studies. The writing committee for the World Health Organization (WHO) trial Solidarity1 now reports in the Journal interim results regarding four pharmacologic treatments that have generated substantial interest: regimens based on remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a. At 405 hospitals in 30 countries representing all six WHO regions, 11,330 adults were randomly assigned to receive either one of these regimens — as available — or to receive hospital-specific standard care. The report provides rate ratios for death over a 28-day period for each regimen as compared with standard care: remdesivir, 0.95 (95% confidence interval [CI], 0.81 to 1.11); hydroxychloroquine, 1.19 (95% CI, 0.89 to 1.59); lopinavir, 1.00 (95% CI, 0.79 to 1.25); and interferon beta-1a, 1.16 (95% CI, 0.96 to 1.39).

Large, simple randomized trials such as Solidarity focus on easily measured definitive outcomes that can be collected quickly and accurately. In 7 months from the beginning of enrollment to publication, the Solidarity trial answered the critically important question of possible mortality benefits of four highly touted regimens. It has informed the research agenda for the treatment of Covid-19. For three of the four drugs that were studied (hydroxychloroquine, lopinavir, and interferon beta-1a), there is no evidence of benefit. The benefit with the fourth (remdesivir) may be its ability to change the course of hospitalization in some patients, but the results of the Solidarity trial tell us not to expect substantially reduced mortality. The next set of questions regarding remdesivir can be answered only in placebo-controlled trials with complex data. Should remdesivir be reserved for the treatment of patients with selected risk factors? What is a more effective timing for the use of remdesivir, and should it be used in combination with other agents? How is the course of hospitalization affected by the type and level of care delivered in particular settings? Detailed examination of these questions within the Solidarity trial would have undermined the very simplicity that made it possible. How to answer these more complicated and nuanced questions quickly remains a challenge for the scientific community. It will not be simple to achieve clarity on when and how — or even whether — to use remdesivir.