The Adaptive COVID-19 Treatment Trial-1 (ACTT-1) in a real-world population: a comparative observational study

© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Background The recently published ‘Adaptive COVID-19 Treatment Trial’ (ACTT-1) showed that remdesivir is a promising treatment option against coronavirus disease 2019 (COVID-19) [1]. Consequently, remdesivir is now being evaluated for implementation in clinical practice worldwide. Randomized clinical trials (RCTs) are the current golden standard for procuring evidence of a drug’s efficacy, but in order to predict effectiveness and safety in daily clinical practice, it is important to complement the results from RCTs with an evaluation of their transferability to a real-world setting. To bridge the evidentiary gap between clinical research and clinical practice, the U.S. Food and Drug Administration recognizes the need for harnessing ‘Real-World Data’ and observational methods to generate evidence of effectiveness to support regulatory decisions concerning drugs [2].

Randomized clinical trials (RCTs) are the current golden standard for procuring evidence of a drug's efficacy, but in order to predict effectiveness and safety in daily clinical practice, it is important to complement the results from RCTs with an evaluation of their transferability to a real-world setting.
To bridge the evidentiary gap between clinical research and clinical practice, the U.S. Food and Drug Administration recognizes the need for harnessing 'Real-World Data' and observational methods to generate evidence of effectiveness to support regulatory decisions concerning drugs [2].

Objective
The aim of the present study was to examine whether the evidence generated in the ACTT-1 could be applied to a real-world population by comparing characteristics of the included patients and their outcomes in order to evaluate the transferability of the trial's outcomes to the patients eligible for remdesivir treatment in clinical practice.

Methods and findings
Data for the present study were extracted from hospital electronic health records of all patients with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test in the Capital Region of Denmark admitted to a hospital between March 1 and May 5, 2020. Patients' eligibility was assessed using inclusion and exclusion criteria from ACCT-1. Index time for baseline characteristics and start of follow-up was defined as 24 h after admission or time of first positive SARS-CoV-2 test result, whichever came last based on an assumption that most patients would have been included in the ACCT-1 trial prior to this timepoint. We assessed mortality and time to discharge as a comparable outcome to time to recovery in ACCT-1, during the first 29 days. Indirect standardization was used to weight the cohort to the same eight-point ordinal severity baseline score as the placebo group in the ACTT-1.
We identified 1053 patients admitted with COVID-19. Four hundred and seventy-four patients were ineligible according to inclusion criteria (385 due to mild disease) and exclusion criteria (84 due to severe chronic kidney disease). The remaining 579 patients had complete follow-up. Compared to the placebo group in the ACTT-1, the patients in the present study were older and less obese and fewer required high-flow oxygen, non-invasive ventilation (NIV) or ventilator treatment ( Table 1). The overall study population had a shorter duration to discharge and Open Access *Correspondence: tonny.studsgaard.petersen@regionh.dk 1 Department of Clinical Pharmacology, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospital, Bispebjerg Bakke 23, indgang 20 C, 2. sal, 2400 Copenhagen, NV, Denmark Full list of author information is available at the end of the article increased mortality compared to the ACTT-1 placebo group (Fig. 1). Adjusting for differences in baseline severity by weighting the study population increased the time to discharge and to a lesser degree mortality. Twenty-two deaths, of 148, occurred after discharge.

Discussion
Overall, our study shows that patient characteristics and outcomes in the ACTT-1 differ from the present realworld population. The most pronounced differences are a doubled mortality rate and a larger proportion of patients only requiring supplemental oxygen in the Danish realworld cohort. The increased mortality rate is likely due to the cohorts higher age [3].
In the ACTT-1, the most significant reduction in mortality and an increase in recovery rate were reported for the subgroup of patients only requiring supplemental oxygen. Hence, the observed differences with the present cohort may indicate a potentially larger absolute mortality reduction by remdesivir in a real-world population compared to the ACTT-1, assuming the relative mortality reduction observed in the supplemental oxygen subgroup in the ACTT-1 persists.
Due to the observational nature of the present study, results should be interpreted with caution. We believe, however, that the results are an important supplemental tool to better evaluate the possible impact of introducing remdesivir in clinical practice.

Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.