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Review
. 2022 Oct;162(4):804-814.
doi: 10.1016/j.chest.2022.04.145. Epub 2022 Apr 30.

Oxygen-Free Days as an Outcome Measure in Clinical Trials of Therapies for COVID-19 and Other Causes of New-Onset Hypoxemia

Ari Moskowitz  1 , Matthew S Shotwell  2 , Kevin W Gibbs  3 , Michelle Harkins  4 , Yves Rosenberg  5 , James Troendle  5 , Lisa H Merck  6 , D Clark Files  3 , Marjolein de Wit  7 , Kristin Hudock  8 , B Taylor Thompson  9 , Michelle N Gong  1 , Adit A Ginde  10 , David J Douin  11 , Samuel M Brown  12 , Eileen Rubin  13 , Meghan Morrison Joly  14 , Li Wang  2 , Christopher J Lindsell  2 , Gordon R Bernard  15 , Matthew W Semler  16 , Sean P Collins  17 , Wesley H Self  18 ; Fourth Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4) Host Tissue Investigators
Affiliations
Review

Oxygen-Free Days as an Outcome Measure in Clinical Trials of Therapies for COVID-19 and Other Causes of New-Onset Hypoxemia

Ari Moskowitz et al. Chest. 2022 Oct.

Abstract

Mortality historically has been the primary outcome of choice for acute and critical care clinical trials. However, undue reliance on mortality can limit the scope of trials that can be performed. Large sample sizes are usually needed for trials powered for a mortality outcome, and focusing solely on mortality fails to recognize the importance that reducing morbidity can have on patients' lives. The COVID-19 pandemic has highlighted the need for rapid, efficient trials to rigorously evaluate new therapies for hospitalized patients with acute lung injury. Oxygen-free days (OFDs) is a novel outcome for clinical trials that is a composite of mortality and duration of new supplemental oxygen use. It is designed to characterize recovery from acute lung injury in populations with a high prevalence of new hypoxemia and supplemental oxygen use. In these populations, OFDs captures two patient-centered consequences of acute lung injury: mortality and hypoxemic lung dysfunction. Power to detect differences in OFDs typically is greater than that for other clinical trial outcomes, such as mortality and ventilator-free days. OFDs is the primary outcome for the Fourth Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4) Host Tissue platform, which evaluates novel therapies targeting the host response to COVID-19 among adults hospitalized with COVID-19 and new hypoxemia. This article outlines the rationale for use of OFDs as an outcome for clinical trials, proposes a standardized method for defining and analyzing OFDs, and provides a framework for sample size calculations using the OFD outcome.

Keywords: COVID-19; acute lung injury; oxygen; respiratory failure.

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Figures

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Graphical abstract
Figure 1
Figure 1
Standardized script used in the Fourth Accelerating COVID-19 Therapeutic Interventions and Vaccines Host Tissue Platform to ascertain oxygen use after hospital discharge for the calculation of oxygen-free days for patients not receiving oxygen at baseline (before the acute illness). For patients who did use oxygen at baseline, similar questions are asked to ascertain oxygen use above baseline. These questions are asked by telephone, text message, or another telecommunication method during study visits after the patient has been discharged from the hospital. Answers to these questions are used to understand if the patient used oxygen after hospital discharge, and if so, when the final liberation from oxygen occurred.
Figure 2
Figure 2
A, B, Histograms showing (A) oxygen-free days and (B) ventilator-free days among the first 698 participants in the Passive Immunity Trial for Our Nation trial, a randomized trial of COVID-19 convalescent plasma vs placebo among adults hospitalized with COVID-19 and hypoxemia in the United States.
See this image and copyright information in PMC

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