1. Within the Adaptive COVID-19 Treatment Trial (ACCT) series, improvement in standard of care (SOC) alone contributed to better recovery and survival in patients hospitalized with coronavirus disease 2019 (COVID-19).
2. Changes in the patient cohort composition contributed to improved outcomes from ACTT-1 to ACTT-2.
Evidence Rating Level: 2 (Good)
Study Rundown: The SOC for patients hospitalized with severe COVID-19 has evolved rapidly, including changes in airway management, prone positioning, and the use of antivirals, anticoagulants, corticosteroids, and other immunomodulators. It is unclear what impact these changes have had on the recovery and survival of COVID-19 patients. The current study was a post hoc observational analysis of patient groups who received remdesivir in the sequential randomized controlled trials ACTT-1, ACTT-2, ACTT-3, and ACTT-4. These trials spanned from 2020 to 2021. ACTT-1 compared remdesivir plus SOC against a control of placebo plus SOC, whereas in ACTT-2 and ACTT-4 remdesivir plus SOC was the control group. Another analysis was performed for patient groups in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone and SOC. The results suggested that changes in patient characteristics largely explained the improved outcomes from ACTT-1 to ACTT-2, but the improvement from ACTT-2 to ACTT-3 was likely due to better SOC. Study limitations included incomplete consideration of confounders such as various biomarkers and restriction to a 28-day outcome interval. Overall, this study demonstrated that SOC improvement impacted outcomes of patients hospitalized with COVID-19 and supported excluding non-concurrent controls from the analysis of platform trials.
In-Depth [prospective cohort]: The current study was a post hoc observation analysis of patient groups who received remdesivir in ACTT-1, ACTT-2, ACTT-3, and ACTT-4. The study examined the 28-day mortality and recovery outcomes of patients who received remdesivir plus SOC in ACTT-1, ACTT-2, and ACTT-3. Recovery outcome was defined as discharge from the hospital or cessation of supplemental oxygen and medical care. Furthermore, a secondary analysis was repeated for patients who received remdesivir plus dexamethasone plus SOC. SOC evolution involved reduced hydroxychloroquine and empirical antibiotic use and more conservative intubation practice between ACTT-1 and ACTT-2 as well as increased dexamethasone use and further decreased azithromycin use between ACTT-2 and ACTT-3. While the recovery and mortality outcomes were better in ACTT-2 than ACTT-1, adjusted hazard ratios (HRs) were close to 1 and did not reach statistical significance (HR for recovery, 1.04; 95% Confidence Interval [CI], 0.92 to 1.17; HR for mortality, 0.90; 95% CI, 0.53 to 0.97). Furthermore, patient composition varied appreciably between ACTT-1 and ACTT-2, including in age, race, disease severity, 4C Mortality Score, and need for intubation, which was purported to partially account for improvements. Outcomes improved to a greater extent from ACTT-2 to ACTT-3 (HR for recovery, 1.43; 95% CI, 1.12 to 1.64; HR for mortality, 0.45; 95% CI, 0.21 to 0.97). After accounting for other exploratory factors such as case surges and variant trends, the SOC change of increased dexamethasone use (11% to 77%) was likely to contribute to these outcome improvements. The outcomes between the groups from ACTT-3 and ACTT-4 did not differ significantly. The study highlighted two main shortcomings regarding the inclusion of non-concurrent controls in platform trials: variation in participant characteristics and rapidly evolving SOC, both of which can alter clinical outcomes.
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