NEJM: Remdesivir for the Treatment of Covid-19-Final Report


With the development of the global epidemic, remdesivir has received continuous attention from the industry and the public. Earlier, preliminary results of a global clinical trial called ACTT-1 sponsored by the American Institute of Allergy and Infectious Diseases (NIAID) showed that remdesivir significantly accelerated the recovery time of hospitalized patients with COVID-19.

The final report of the ACTT-1 trial was officially published in the New England Journal of Medicine (NEJM) on Oct. 8, helping us to gain a fuller and clearer understanding of the effects of the drug remdesivir on COVID-19 patients. Mr. Daniel O’Day, Chairman and CEO of Gilead Scientific, said in an open letter, “the final report provides new information and expands the benefits of remdesivir, and every finding in the study is critical to managing the COVID-19 pandemic and for health care workers to make decisions to communicate with patients.”
Let’s first review the experimental design of ACTT-1. This is an adaptively designed, randomized, double-blind, placebo-controlled global phase 3 clinical trial. The trial began on February 21, 2020, and ended on April 19, 2020, and was carried out in 73 clinical centers in many countries and regions around the world. The patients were confirmed by the nucleic acid test as COVID-19 hospitalized adult patients with evidence of lower respiratory tract infection. Patients were randomly divided into two groups at 1:1. Patients in the Remdesivir group received up to 10 days of treatment with a dose of 200 mg, on the first day followed by 100 mg, per day. The control group received matched placebo, and all patients received supportive treatment according to the standards of their hospitals.
In this final report, 1062 patients were randomly divided into two groups: remdesivir (n = 541) and placebo (n = 521). The final data conveys three important messages:

1. Remdesiviraccelerated the patient’s recovery. According to the severity of the disease, the effect of patients receiving remdesivirtreatment is also different.

  • Overall, the median recovery time of patients in the remdesivirgroup was 10 days, that of patients in the placebo group was 15 days, and that of patients treated with Remdesivir was 29% faster.
  • Among patients with severe illness, patients in the remdesivirgroup recovered 31% faster (the median recovery time was 11 days and vs 18 days), and these patients accounted for 90.1% of the total number of patients in the trial.
  • Patients whose symptoms were assessed as requiring hospitalization and low-flow oxygen inhalation had the most significant recovery benefits at the time of joining the study, with an acceleration of 45%.
  • Patients who took the medicine earlier recovered more quickly. The recovery of patients treated with remdesivirwithin 10 days of onset was significantly accelerated by 37%, and that of patients treated with drugs 10 days after onset was 20% faster and was not statistically significant.
  • After considering the effects of glucocorticoid or hydroxychloroquine, remdesivir still showed the effect of accelerating the recovery of patients.

2. Remdesivirreduced the risk of progression of the disease. According to the ordinal table of 8 types of symptoms, patients in the remdesivir group had a 50% higher chance of clinical symptom improvement on the 15th day.

3. Throughout the study, remdesivirshowed a trend to reduce patient mortality.

Among all subjects, on the 15th day, the mortality rate was 6.7% in the remdesivir group and 11.9% in the placebo group, and 11.4% in the remdesivir group and 15.2% in the placebo group on the 29th day. The risk of death in the remdesivir group was reduced by 27% but was not statistically significant.
It is worth noting that among the patients who needed to be hospitalized and inhaled low-flow oxygen before the trial (which was also the largest category of patients in the trial, accounting for 40%), the risk of death in the Remdesivir group was significantly reduced by 70%.
In addition, in terms of safety, 131 (24.6%) of the 532 patients who received remdesivir had serious adverse events, and 163 (31.6%) of the 516 patients who received the placebo had serious adverse events.

“For COVID-19 hospitalized patients, we should not underestimate the importance of accelerating recovery by 5-7 days,” Mr. Daniel O’Day said, “Because this will not only reduce the physical challenges that COVID-19 itself brings to patients, but also reduce the risk of secondary infection caused by prolonged hospitalization, ease the emotional burden on patients and their families. On the other hand, reducing disease progression also prevents patients from entering a critical stage of disease deterioration, because once a ventilator is needed, patients have a lower chance of survival.” The benefits of these patients will also be translated into savings in medical resources. In addition, the question of whether remdesivir can reduce COVID-19 mortality has also been answered, providing valuable information for clinical practice.

At present, Remdesivir has been approved or authorized for emergency use in more than 50 countries and regions around the world for COVID-19 treatment. The research team also pointed out in the discussion section of the paper that the mortality rate of COVID-19 is still high, and it is clear that antiviral therapy alone is not enough to treat all patients. As a result, studies will continue to evaluate the efficacy of remdesivir in combination with immune response regulators, such as ACTT-2 and ACTT-3 trials, which are being evaluated in combination with JAK inhibitors baricitinib or interferon β-1a. At the same time, we still need multiple treatments and multiple combination strategies to continuously improve the prognosis of patients with COVID-19.

References

1. Beigel, J. H., Tomashek, K. M., Dodd, L. E., Mehta, A. K., Zingman, B. S., Kalil, A. C., … & Lopez de Castilla, D. (2020). Remdesivir for the treatment of Covid-19—preliminary report.New England Journal of Medicine.

2. Beigel, J. H., Tomashek, K. M., Dodd, L. E., Mehta, A. K., Zingman, B. S., Kalil, A. C., … & Lopez de Castilla, D. (2020). Remdesivir for the Treatment of Covid-19-Final Report.New England Journal of Medicine.

3. Wilt, T. J., Kaka, A. S., MacDonald, R., Greer, N., Obley, A., & Duan-Porter, W. (2020). Remdesivir for Adults With COVID-19: A Living Systematic Review for an American College of Physicians Practice Points.Annals of Internal Medicine.