Effect of Intravenous Interferon β-1a on Death and Days Free From Mechanical Ventilation Among Patients With Moderate to Severe Acute Respiratory Distress Syndrome: A Randomized Clinical Trial | Critical Care Medicine | JAMA | JAMA Network
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Visual Abstract. Effect of interferon β-1a on Death and Days Free From Mechanical Ventilation in Moderate to Severe ARDS
Effect of interferon β-1a on Death and Days Free From Mechanical Ventilation in Moderate to Severe ARDS
Figure 1.  Recruitment, Randomization, and Analysis Population
Recruitment, Randomization, and Analysis Population

ARDS indicates acute respiratory distress syndrome; CHF, chronic heart failure; COPD, chronic obstructive pulmonary disease; ECLS, extracorporeal life support; ECMO, extracorporeal membrane oxygenation; HFOV, high-frequency oscillatory ventilation; IFN, interferon; NIV, noninvasive ventilation; NYHA, New York Heart Association; and RRT, renal replacement therapy.

aRecruitment between December 2015 and December 2017.

bExclusion criteria as recorded by the study sites (≥1 criteria may have been recorded for a single patient).

cReasons for ineligibility not recorded at study sites.

Figure 2.  Days Alive and Free of Mechanical Ventilation
Days Alive and Free of Mechanical Ventilation

Death (A) and days free of mechanical ventilation (B) shown as proportion of patients over time from randomization to day 28. The median observation times for ventilator-free days were 18 days (interquartile range [IQR], 8-28) in the interferon β-1a and 19.5 days (IQR, 8-28) in the placebo group. The median observation times for survival to day 28 were 28 days (IQR, 24.5-28) in the interferon β-1a group and 28 days (IQR, 28-28) in the placebo group.

Table 1.  Characteristics of the Patients at Baselinea
Characteristics of the Patients at Baselinea
Table 2.  Primary and Secondary Outcomesa
Primary and Secondary Outcomesa
Supplement 3.

eMethods.

eFigure 1. Number of Study Patients in the Full Analysis Set (FAS), and Safety Analyses (Safety)

eFigure 2. Kaplan-Meier Survival Estimates of All-cause Mortality up to Day 360

eFigure 3. Blood Myxovirus Resistance Protein A (MxA) Levels During Study Days 1-14

eFigure 4. Cluster of Differentiation 73 (CD73) Serum Levels During Study Days 1-14

eFigure 5. Association of Corticosteroids at Baseline With Mortality

eFigure 6. Adjusted OR for 28 Day Mortality According to the Country

eTable 1. Dosing and Follow-up of the Patients

eTable 2. Physiological Data at Randomization

eTable 3. PaO2/FiO2 Ratio on Study Days 0-7

eTable 4. PEEP (cm H2O) on Study Days 0-7

eTable 5. Fraction of Inspired Oxygen (FiO2) on Study Days 0-7

eTable 6. Tidal Volume (mL) on Study Days 0-1

eTable 7. NMBAs Administered During First 28 Days

eTable 8. Corticosteroids Administered During First 28 Days

eTable 9. Renal Replacement Therapy at Least Once During First 28 Days

eTable 10. ECMO Therapy at Least Once During First 28 Days

eTable 11. Prone Position at Least Once During First 28 Days

eTable 12. Prone Positioning on Study Days 0-28

eTable 13. Long-term Efficacy Period Day 90: Patient Status

eTable 14. Intention-to-Treat Analysis of D28 Mortality

eTable 15. Related Treatment-Emergent Adverse Events Occurring in >3% of Patients in Any Treatment Group (Safety Population)

eTable 16. Number (%) of Study Subjects (>3%) in Any Treatment Group With Serious Adverse Events (Safety Population)

eTable 17. Discontinuations Due to Treatment-Emergent Adverse Events – (Safety Population)

eTable 18. Subgroup Analysis With Logistic Regression for Day 28 Mortality

eTable 19. Short-term Follow-up Period (Day 1-28 [LOP]): SOFA Score Summary (FAS Population)

1.
Ranieri  VM, Rubenfeld  GD, Thompson  BT,  et al; ARDS Definition Task Force.  Acute respiratory distress syndrome: the Berlin Definition.  JAMA. 2012;307(23):2526-2533.PubMedGoogle Scholar
2.
Matthay  MA, Zemans  RL, Zimmerman  GA,  et al.  Acute respiratory distress syndrome.  Nat Rev Dis Primers. 2019;5(1):18. doi:10.1038/s41572-019-0069-0PubMedGoogle ScholarCrossref
3.
Bellani  G, Laffey  JG, Pham  T,  et al; LUNG SAFE Investigators; ESICM Trials Group.  Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.  JAMA. 2016;315(8):788-800. doi:10.1001/jama.2016.0291PubMedGoogle ScholarCrossref
4.
Ohta  A, Sitkovsky  M.  Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage.  Nature. 2001;414(6866):916-920. doi:10.1038/414916aPubMedGoogle ScholarCrossref
5.
Thompson  LF, Eltzschig  HK, Ibla  JC,  et al.  Crucial role for ecto-5′-nucleotidase (CD73) in vascular leakage during hypoxia.  J Exp Med. 2004;200(11):1395-1405. doi:10.1084/jem.20040915PubMedGoogle ScholarCrossref
6.
Kiss  J, Yegutkin  GG, Koskinen  K, Savunen  T, Jalkanen  S, Salmi  M.  IFN-beta protects from vascular leakage via up-regulation of CD73.  Eur J Immunol. 2007;37(12):3334-3338. doi:10.1002/eji.200737793PubMedGoogle ScholarCrossref
7.
Aeffner  F, Woods  PS, Davis  IC.  Activation of A1-adenosine receptors promotes leukocyte recruitment to the lung and attenuates acute lung injury in mice infected with influenza A/WSN/33 (H1N1) virus.  J Virol. 2014;88(17):10214-10227. doi:10.1128/JVI.01068-14PubMedGoogle ScholarCrossref
8.
Bellingan  G, Maksimow  M, Howell  DC,  et al.  The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study.  Lancet Respir Med. 2014;2(2):98-107. doi:10.1016/S2213-2600(13)70259-5PubMedGoogle ScholarCrossref
9.
Bellingan  G, Brealey  D, Mancebo  J,  et al.  Comparison of the efficacy and safety of FP-1201-lyo (intravenously administered recombinant human interferon beta-1a) and placebo in the treatment of patients with moderate or severe acute respiratory distress syndrome: study protocol for a randomized controlled trial.  Trials. 2017;18(1):536. doi:10.1186/s13063-017-2234-7PubMedGoogle ScholarCrossref
10.
Ferguson  ND, Fan  E, Camporota  L,  et al.  The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material.  Intensive Care Med. 2012;38(10):1573-1582. doi:10.1007/s00134-012-2682-1PubMedGoogle ScholarCrossref
11.
Knaus  WA, Draper  EA, Wagner  DP, Zimmerman  JE.  APACHE II: a severity of disease classification system.  Crit Care Med. 1985;13(10):818-829. doi:10.1097/00003246-198510000-00009PubMedGoogle ScholarCrossref
12.
Brower  RG, Matthay  MA, Morris  A, Schoenfeld  D, Thompson  BT, Wheeler  A; Acute Respiratory Distress Syndrome Network.  Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.  N Engl J Med. 2000;342(18):1301-1308. doi:10.1056/NEJM200005043421801PubMedGoogle ScholarCrossref
13.
Guérin  C, Reignier  J, Richard  JC,  et al; PROSEVA Study Group.  Prone positioning in severe acute respiratory distress syndrome.  N Engl J Med. 2013;368(23):2159-2168. doi:10.1056/NEJMoa1214103PubMedGoogle ScholarCrossref
14.
Wiedemann  HP, Wheeler  AP, Bernard  GR,  et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network.  Comparison of two fluid-management strategies in acute lung injury.  N Engl J Med. 2006;354(24):2564-2575. doi:10.1056/NEJMoa062200PubMedGoogle ScholarCrossref
15.
Thompson  BT, Ranieri  VM.  Steroids are part of rescue therapy in ARDS patients with refractory hypoxemia: no.  Intensive Care Med. 2016;42(5):921-923. doi:10.1007/s00134-016-4255-1PubMedGoogle ScholarCrossref
16.
Finkelstein  DM, Schoenfeld  DA.  Combining mortality and longitudinal measures in clinical trials.  Stat Med. 1999;18(11):1341-1354. doi:10.1002/(SICI)1097-0258(19990615)18:11<1341::AID-SIM129>3.0.CO;2-7PubMedGoogle ScholarCrossref
17.
Vallittu  AM, Erälinna  JP, Ilonen  J, Salmi  AA, Waris  M.  MxA protein assay for optimal monitoring of IFN-beta bioactivity in the treatment of MS patients.  Acta Neurol Scand. 2008;118(1):12-17. doi:10.1111/j.1600-0404.2007.00968.xPubMedGoogle ScholarCrossref
18.
Vincent  JL, Moreno  R, Takala  J,  et al.  The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure: on behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.  Intensive Care Med. 1996;22(7):707-710. doi:10.1007/BF01709751PubMedGoogle ScholarCrossref
19.
Maksimow  M, Kyhälä  L, Nieminen  A,  et al.  Early prediction of persistent organ failure by soluble CD73 in patients with acute pancreatitis*.  Crit Care Med. 2014;42(12):2556-2564. doi:10.1097/CCM.0000000000000550PubMedGoogle ScholarCrossref
20.
Flammer  JR, Dobrovolna  J, Kennedy  MA,  et al.  The type I interferon signaling pathway is a target for glucocorticoid inhibition.  Mol Cell Biol. 2010;30(19):4564-4574. doi:10.1128/MCB.00146-10PubMedGoogle ScholarCrossref
21.
Diez  D, Goto  S, Fahy  JV,  et al.  Network analysis identifies a putative role for the PPAR and type 1 interferon pathways in glucocorticoid actions in asthmatics.  BMC Med Genomics. 2012;5:27. doi:10.1186/1755-8794-5-27PubMedGoogle ScholarCrossref
22.
Rubenfeld  GD, Caldwell  E, Granton  J, Hudson  LD, Matthay  MA.  Interobserver variability in applying a radiographic definition for ARDS.  Chest. 1999;116(5):1347-1353. doi:10.1378/chest.116.5.1347PubMedGoogle ScholarCrossref
23.
Meade  MO, Cook  RJ, Guyatt  GH,  et al.  Interobserver variation in interpreting chest radiographs for the diagnosis of acute respiratory distress syndrome.  Am J Respir Crit Care Med. 2000;161(1):85-90. doi:10.1164/ajrccm.161.1.9809003PubMedGoogle ScholarCrossref
24.
Beitler  JR, Sarge  T, Banner-Goodspeed  VM,  et al; EPVent-2 Study Group.  Effect of titrating positive end-expiratory pressure (PEEP) with an esophageal pressure-guided strategy vs an empirical high PEEP-Fio2 strategy on death and days free from mechanical ventilation among patients with acute respiratory distress syndrome: a randomized clinical trial.  JAMA. 2019;321(9):846-857. doi:10.1001/jama.2019.0555PubMedGoogle ScholarCrossref
25.
McCoy  CE, Carpenter  S, Pålsson-McDermott  EM, Gearing  LJ, O’Neill  LA.  Glucocorticoids inhibit IRF3 phosphorylation in response to Toll-like receptor-3 and -4 by targeting TBK1 activation.  J Biol Chem. 2008;283(21):14277-14285. doi:10.1074/jbc.M709731200PubMedGoogle ScholarCrossref
26.
Englert  JA, Cho  MH, Lamb  AE,  et al.  Whole blood RNA sequencing reveals a unique transcriptomic profile in patients with ARDS following hematopoietic stem cell transplantation.  Respir Res. 2019;20(1):15. doi:10.1186/s12931-019-0981-6PubMedGoogle ScholarCrossref
Original Investigation
February 17, 2020

Effect of Intravenous Interferon β-1a on Death and Days Free From Mechanical Ventilation Among Patients With Moderate to Severe Acute Respiratory Distress Syndrome: A Randomized Clinical Trial

Author Affiliations
  • 1Alma Mater Studiorum–Università di Bologna, Dipartimento di Scienze Mediche e Chirurgiche, Anesthesia and Intensive Care Medicine, Policlinico di Sant’Orsola, Bologna, Italy
  • 2Division of Intensive Care, Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 3Faron Pharmaceuticals Ltd, Turku, Finland
  • 4Manchester University NHS Foundation Trust, Wythenshawe Hospital, Manchester, United Kingdom
  • 5Critical Care, University College London Hospitals, NHS Foundation Trust and National Institute for Health Research Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London, London, United Kingdom
  • 6Department of Intensive Care, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
  • 7Department of Intensive Care/SODIR Research Group–VHIR Hospital Universitari Vall d’Hebron UCI, Barcelona, Spain
  • 8Médecine Intensive-Réanimation CHU d’Angers, Université d’Angers, Angers, France
  • 9Dipartimento di scienze diagnostiche e integrate, Università degli studi di Genova, Genova, Italy
  • 10Anesthesiology and Operative Intensive Care Medicine, Universitätsmedizin Göttingen, Göttingen, Germany
  • 11Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
  • 12Université de Strasbourg (UNISTRA), Faculté de Médecine, Hôpitaux universitaires de Strasbourg, Nouvel Hôpital Civil, Service de réanimation, Strasbourg, France
  • 13Azienda Ospedaliera San Gerardo, Milan, Italy
  • 14Department of Intensive Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 15Corporacion Sanitaria Universitaria Parc Tauli CIBER Enfermedades Respiratorias Autonomous University of Barcelona, Sabadell, Spain
  • 16Medicity research Laboratory, University of Turku, Turku, Finland
JAMA. 2020;323(8):725-733. doi:10.1001/jama.2019.22525
Key Points

Question  Does treatment with systemic interferon β-1a provide clinical benefit in adults with moderate or severe acute respiratory distress syndrome?

Findings  In this randomized clinical trial that included 301 patients, intravenous interferon β-1a administered for 6 days, compared with placebo, resulted in no significant difference in a composite score that included death and number of ventilator-free days over 28 days (median, 10.0 vs 8.5 days).

Meaning  These results do not support the use of interferon β-1a in the management of moderate or severe acute respiratory distress syndrome.

Abstract

Importance  Acute respiratory distress syndrome (ARDS) is associated with high mortality. Interferon (IFN) β-1a may prevent the underlying event of vascular leakage.

Objective  To determine the efficacy and adverse events of IFN-β-1a in patients with moderate to severe ARDS.

Design, Setting, and Participants  Multicenter, randomized, double-blind, parallel-group trial conducted at 74 intensive care units in 8 European countries (December 2015-December 2017) that included 301 adults with moderate to severe ARDS according to the Berlin definition. The radiological and partial pressure of oxygen, arterial (Pao2)/fraction of inspired oxygen (Fio2) criteria for ARDS had to be met within a 24-hour period, and the administration of the first dose of the study drug had to occur within 48 hours of the diagnosis of ARDS. The last patient visit was on March 6, 2018.

Interventions  Patients were randomized to receive an intravenous injection of 10 μg of IFN-β-1a (144 patients) or placebo (152 patients) once daily for 6 days.

Main Outcomes and Measures  The primary outcome was a score combining death and number of ventilator-free days at day 28 (score ranged from −1 for death to 27 if the patient was off ventilator on the first day). There were 16 secondary outcomes, including 28-day mortality, which were tested hierarchically to control type I error.

Results  Among 301 patients who were randomized (mean age, 58 years; 103 women [34.2%]), 296 (98.3%) completed the trial and were included in the primary analysis. At 28 days, the median composite score of death and number of ventilator-free days at day 28 was 10 days (interquartile range, −1 to 20) in the IFN-β-1a group and 8.5 days (interquartile range, 0 to 20) in the placebo group (P = .82). There was no significant difference in 28-day mortality between the IFN-β-1a vs placebo groups (26.4% vs 23.0%; difference, 3.4% [95% CI, −8.1% to 14.8%]; P = .53). Seventy-four patients (25.0%) experienced adverse events considered to be related to treatment during the study (41 patients [28.5%] in the IFN-β-1a group and 33 [21.7%] in the placebo group).

Conclusions and Relevance  Among adults with moderate or severe ARDS, intravenous IFN-β-1a administered for 6 days, compared with placebo, resulted in no significant difference in a composite score that included death and number of ventilator-free days over 28 days. These results do not support the use of IFN-β-1a in the management of ARDS.

Trial Registration  ClinicalTrials.gov Identifier: NCT02622724

Introduction

Acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure characterized by hypoxemia, pulmonary edema not explained by cardiac failure or fluid overload, and diffuse bilateral radiographic opacities occurring in the presence of a predisposing factor.1,2 No approved drug therapy for ARDS exists. Thus, treatment for ARDS is based on management of the underlying disease and supportive care. Despite substantial progress in ventilatory strategies, the hospital mortality rate of ARDS remains approximately 40%.3 The key pathophysiological event underlying ARDS is an uncontrolled inflammatory response resulting in injury to the epithelium and endothelium of the alveolar-capillary barrier with increased pulmonary vascular leakage.1,2

Adenosine has anti-inflammatory properties and is one of the physiological regulators, reducing endothelial cell permeability.4 Cluster of differentiation 73 (CD73) is the enzyme expressed on endothelial and epithelial cells that regulates adenosine production by converting extracellular adenosine monophosphate to active adenosine.5 Interferon (IFN) β-1a has been shown to upregulate CD73, prevent vascular leakage,6 and inhibit leukocyte recruitment.7 A pilot open-label nonrandomized phase 1/2 study showed that administration of recombinant human IFN-β-1a was associated with significantly lower 28-day mortality compared with nontreatment in patients with ARDS.8

This trial was conducted to test the hypothesis that treatment with intravenous recombinant human IFN-β-1a would improve outcomes in patients with ARDS.

Methods

The trial was approved by the national regulatory authorities and central/local ethics boards, and written informed consent was obtained in accordance with local processes. The study design, protocol, and statistical analysis plan (SAP) have been previously published9 and are available in Supplement 1 (study protocol) and Supplement 2 (SAP). The study was monitored by an independent data monitoring committee.

Eligibility Criteria

Patients were eligible for inclusion if they were older than 18 years of age, were intubated and mechanically ventilated, and had moderate or severe ARDS based on the Berlin definition.1 The radiological and partial pressure of oxygen, arterial (Pao2)/fraction of inspired oxygen (Fio2) criteria had to be met within a 24-hour period, and the administration of the first dose of the study drug had to occur within 48 hours of the diagnosis of ARDS.

Major exclusion criteria were occurrence of invasive or noninvasive ventilation for more than 48 hours prior to the diagnosis of ARDS; an underlying diagnosis that could adversely affect survival, impair weaning from the ventilator, or compromise adherence to the protocol; administration of any form of IFN prior to study enrollment, or known hypersensitivity to natural or recombinant IFN or to any of the excipients; or use of any form of extracorporeal lung support.9 Detailed enrollment criteria have been provided in Supplement 3.

To ensure appropriate enrollment, the medical monitors (P.N. or N.P.) confirmed the eligibility of every patient prior to randomization. The enrolling clinician had to match the patient’s chest x-ray against a panel of unlabeled chest x-rays.10 If the closest chest x-ray match corresponded to a chest x-ray inconsistent or equivocal for ARDS, the enrolling clinician could repeat the match using a new chest x-ray eventually available from standard clinical management until the time to diagnosis did not exceed 48 hours from the start of mechanical ventilation.

Severity of disease was assessed by the Acute Physiology and Chronic Health Evaluation (APACHE) II score (range, 0-71).11

Randomization and Study Drug

Randomization was performed with an automated, centralized computer-generated 24-hour randomization service. Patients were randomly assigned to study groups in a 1:1 ratio with the use of permuted blocks (block size, 2), stratification according to the severity of ARDS (moderate or severe), and country. All parties involved in the study remained blinded for the study treatment throughout the study. Patients received either intravenous 10-μg FP-1201-lyo (IFN-β-1a) or placebo once daily for 6 days. The placebo consisted of the same excipients as FP-1201-lyo, except IFN-β-1a. Administration of the first dose had to take place within 48 hours of ARDS diagnosis.

Study Measurements and Procedures

Apart from administration of the study drug, participating intensive care units (ICUs) were encouraged to manage patients according to best practice as expressed in the protocol.9 Specifically, mechanical ventilation had to be provided using a lung-protective strategy.12 Use of higher vs lower positive end-expiratory pressure, prone positioning, recruitment maneuvers, and extracorporeal lung support had to follow best evidence.12,13 Weaning followed a predefined protocol.12 Fluid management was unrestricted during episodes of shock, but for patients not in shock, a conservative fluid approach was recommended.14 A recommendation was also given to avoid the use of glucocorticoids for the treatment of ARDS.15

Outcome Measures

The primary outcome was a composite end point incorporating 28-day survival and the number of ventilator-free days in patients at 28 days.16 Ventilator-free days were scored as the number of ventilator-free calendar days in those alive at day 28. For those who died within 28 days, the score was set at −1; for 28-day survivors, the score ranged between 0 (alive still on the ventilator at day 28) and 27 (alive and successfully extubated on day 1).9

Secondary end points (16 total) included all-cause mortality at 28 (and mortality in the ICU up to day 28 and mortality in hospital up to day 28), 90, and 180 days; organ failure–free days alive (mechanical ventilation–free days alive, renal support–free days alive, vasoactive support–free days alive, organ failure–free days alive) and ICU-free days alive within 28 days; the total number of days spent in the hospital; and the presence of neutralizing antibodies to IFN-β-1a at baseline and at day 28 and pharmacodynamic biomarker myxovirus resistance protein A (MxA, ng/mL),17 a specific biomarker of IFN-β-1a activity. Organ function was assessed using Sequential Organ Failure Assessment (SOFA) scores (a score ranging from 0 to 4 for each organ system, where higher scores indicate more severe organ dysfunction).18 Assessment of quality of life, respiratory functioning, and neurological functioning was scheduled at day 180, and these outcomes are not reported in this article.

Adverse events (serious and nonserious) occurring between informed consent and day 28 (definitions of adverse events are available in the protocol provided as Supplement 1) were recorded.

To assess biological activity of the study drug, an exploratory end point, soluble biomarker CD73 (ng/mL)19 was measured during study days 1 through 14 with a previously developed enzyme-linked immunosorbent assay (described in Supplement 3). CD73 is the molecular target of IFN-β-1a.19 Both MxA and CD73 range from 0 ng/mL upwards to a nonspecified maximum and have stable baseline values that may be affected by inflammatory and hypoxic insults.18,19 The method for determining anti–IFN-β-1a antibodies is described in eMethods in the Supplement 3.

Sample Size Calculation

We planned to enroll 300 patients, providing 90% power and a 2-sided Mann-Whitney U test at the significance level of .05 assuming that (1) the mortality rate at 28 days is 30% in the control group and 15% in the IFN-β-1a group; (2) 20% of the patients survive but with no ventilator-free days in the control group; (3) patients receiving IFN-β-1a have 3 ventilator-free days more than patients treated with placebo (including the mortality difference); and (4) 5% of patients drop out and a further 4% of the remaining patients will not be evaluable for the primary efficacy analysis (PASS software version 11; NCSS LLC). The mortality of the active group was assumed to be around 10% according to the prior phase 2 study,8 but was further increased to 15% to have a more conservative estimate. Similarly, the mortality of the control group was presumed to be around 35%,1,3 but was further reduced to 30% considering that mortality in prospective randomized trials tends to be lower than in historical cohorts.

Statistical Analysis

All analyses were conducted in accordance with a predefined SAP unless otherwise specified.9 The number of given study drug doses and major protocol violations blind to treatment allocation were verified to allow selection of patients for per-protocol analysis. Any resulting deviations from the planned analyses had to be justified and reported (blinded changes in the SAP prior to unblinded data analysis are in the final SAP available as Supplement 2). Missing data were not imputed for primary efficacy data.

Primary efficacy and adverse event analyses were conducted using the full analysis set (FAS) according to the received treatment. The FAS population consisted of all randomized patients who received at least 1 dose of the study drug. No statistical analyses were performed for adverse events between groups.

To determine differences in the treatment effect in the study population, we performed nonparametric analysis using the van Elteren test, adjusting for the country and ARDS severity according to the Berlin Definition.16 To avoid type I error due to multiple comparisons of secondary end points, a hierarchical approach was used and end points in the hierarchy below a nonsignificant end point should be interpreted as exploratory only (testing hierarchy for the secondary end points presented in the eMethods in Supplement 3). Kaplan-Meier survival curves including log-rank test were used to assess mortality up to day 360.

For pharmacodynamic marker MxA and exploratory pharmacodynamic marker CD73, the difference between groups was analyzed as a change from baseline by analysis of covariance model with treatment, ARDS severity, and country as fixed effect factors, and baseline as a covariate.

For post hoc analyses, the associations of etiology of ARDS, APACHE II, SOFA score, ARDS severity, Pao2/Fio2 ratio, weight, vasopressor use, days taking vasopressors, sex, age, and prerandomization steroid use against 28-day mortality were explored, and the Breslow-Day test was used to test for interaction. Homogeneity of treatment effect was also assessed by calculating odds ratios (ORs) and associated 95% CIs by ARDS severity and by country and an analysis was also performed that included center as a random effect. A post hoc analysis of 28-day mortality was conducted using all randomized patients and imputing worst-case scenario for the randomized but not dosed patients (ie, patients in the IFN-β-1a group counted as deaths and placebo patients counted as survivors until day 28).

All data derivations, manipulations, and reporting procedures were done using SAS version 9.4 (SAS Institute) in a Windows 7 operating system. All statistical tests were performed as 2-sided and at a significance level of .05.

Results
Patients

Patients were enrolled between December 2015 and December 2017 at 47 of 74 available study sites. Of the 2211 patients with moderate or severe ARDS, 301 patients were randomized to receive IFN-β-1a or placebo. Five patients (2 in the IFN-β-1a group and 3 in the control group) were randomized but not dosed for the following reasons: 3 patients improved their status not meeting any more criteria for moderate ARDS; 1 patient was taken to emergency surgery before dosing; and 1 patient experienced a technical problem on computerized drug allocation program that prevented dosing. Primary analyses were conducted on the FAS (296 patients, of whom 144 received IFN-β-1a and 152 placebo; Figure 1; eFigure 1 in Supplement 3).

Adherence to the Protocol and Missing Data

The occurrence of significant protocol deviations was similar between the treatment groups (66 and 68 study patients in the active and placebo groups, respectively). There were no missing data for mortality and ventilator-free days at day 28 in the FAS population. No data were gathered from the 5 randomized patients (2 in the placebo group and 3 in the IFN-β-1a group) who did not receive study drug.

Demographic Variables and the Study Treatments

At baseline, 28 of 144 IFN-β-1a–treated patients (19.4%) had severe ARDS compared with 35 of 152 placebo-treated patients (23.0%) (Table 1). Baseline characteristics and concomitant treatments were comparable between the study groups (Table 1). A total of 44 patients (31%) in the IFN-β-1a group and 60 (39%) in the placebo group were taking corticosteroids at baseline.

During the 6-day treatment period, patients received a mean (SD) of 5.5 (1.3) doses of the study drug in the IFN-β-1a group and 5.7 (1.0) in the placebo group (eTable 1 in Supplement 3). Daily physiological parameters are presented in eTables 2-6 in Supplement 3.

Concomitant Treatment

During the first 28 days, neuromuscular-blocking agents (77.8% vs 75.5%), corticosteroids (54.2% vs 64.5%), renal replacement therapy (30.6% vs 35.5%), extracorporeal membrane oxygenation therapy (3.5% vs 3.3%), and prone positioning (43.1% vs 48.0%) were used in comparable proportions of patients in the IFN-β-1a and placebo groups, respectively (eTables 7-12 in Supplement 3).

Primary and Secondary Outcomes

The primary composite outcome measure of death and number of ventilator-free days at day 28 did not significantly differ between the IFN-β-1a and placebo groups (median, 10 days [interquartile range {IQR}, −1 to 20] vs 8.5 [IQR, 0 to 20], respectively; P = .82). Consistent results were observed in terms of ICU mortality, 28-day hospital mortality (outside the ICU), 90-day mortality, organ failure–free days, days alive without ICU care, and number of days in the hospital (Table 2). The Kaplan-Meier survival curves for mortality and ventilator-free days up to day 28 are presented in Figure 2 (see also eFigure 2 for 360-day mortality and eTable 13 for demographic data and mortality in Supplement 3). A post hoc analysis of 28-day mortality among the 301 randomized patients and imputing worst-case scenario for the 5 randomized but not dosed patients (2 patients in the IFN-β-1a group counted as deaths and 3 placebo patients counted as survivors until day 28) showed similar results (eTable 14 in Supplement 3). One patient tested positive for neutralizing anti–IFN-β-1a antibodies at randomization and no positive patients were detected on the last study day in the ICU.

Adverse Events

The numbers of serious adverse events, adverse events, and patients with any serious and/or any adverse event were comparable between study groups (Table 2). In total, 265 study patients (89.5%) experienced adverse events during the study. Overall, the number and percentage of study patients experiencing at least 1 adverse event were similar in the treatment groups (131 patients [91.0%] in the IFN-β-1a group compared with 134 patients [88.2%] in the placebo group). In total, 74 patients (25%) experienced adverse events considered to be related to treatment during the study (41 patients [28.5%] in the IFN-β-1a group and 33 [21.7%] in the placebo group). The most common adverse events considered to be related to treatment were pyrexia (13 patients [9.0%]) and rhabdomyolysis (5 patients [3.5%]) in the IFN-β-1a group and pyrexia (5 patients [3.3%]) and transaminases increased (6 patients [3.9%]) in the placebo group (eTables 15-17 in Supplement 3).

Biological Effect

The median baseline level for MxA was 0 ng/mL (IQR, 0 to 0) and 0 ng/mL (IQR, 0 to 2.6) for the IFN-β-1a and placebo groups, respectively. Levels of MxA (eFigure 3 in Supplement 3) from days 1 through 14 were significantly different between the treatment groups (difference of baseline change between groups, 23.8 ng/mL [95% CI, 12.8 to 34.8]; P < .001). The median baseline level for CD73 was 0 ng/mL (IQR, 0 to 4.6) and 0 ng/mL (IQR, 0 to 5.3) for the IFN-β-1a and placebo groups, respectively. There was no significant difference between treatment groups for CD73 levels for study days 1 through 14 (difference, 0.7 ng/mL [95% CI, −1.1 to 2.4]; P = .46) (eFigure 4 in Supplement 3).

Post Hoc Analysis

Due to high use of corticosteroids at baseline (described in detail in eTable 8 in Supplement 3), we performed additional exploratory post hoc analyses revealing that mortality at day 28 (IFN-β-1a vs placebo) was 50.0% and 28.3% in patients taking corticosteroids at randomization (OR, 2.53 [95% CI, 1.12-5.72]) and 10.6% and 14.8% in patients not taking corticosteroids at randomization (OR, 0.78 [95% CI, 0.37-1.65]; P = .04 for interaction between baseline glucocorticoids and treatment group (Breslow-Day test for interaction) (eTable 18 and eFigure 5 in Supplement 3). The adjusted ORs for 28-day mortality by country are presented in eFigure 6 in Supplement 3. Additionally, statistical analyses examining the site effect are provided in eMethods in Supplement 3.

Discussion

In this international multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial comprising patients with moderate or severe ARDS, IFN-β-1a compared with placebo did not improve ventilator-free survival within 28 days.

This study was based on the strong biological plausibility of IFN-β-1a as a treatment for ARDS, given its ability to increase extracellular adenosine by activation of CD73 on epithelial and endothelial cells. Adenosine is one of the physiological regulators of endothelial cell permeability,4 which also accelerates alveolar fluid reabsorption.5 Administration of IFN-β-1a upregulates CD73 via de novo synthesis, prevents vascular leakage, and inhibits leukocyte recruitment in animal models.6,7 Prior clinical data suggested efficacy for IFN-β-1a in ARDS. In a small phase 1/2 open-label nonrandomized study, an 81% reduction in 28-day mortality was observed in patients with ARDS treated with IFN-β-1a.8

In the current double-blind and randomized clinical trial, no significant differences in outcomes between the placebo and IFN-β-1a groups could be detected. Aside from lack of efficacy, one possible explanation is that the study was underpowered to detect any clinical benefit. Another possible explanation for these negative results may be in the extensive use of systemic corticosteroids in the trial, as previous experimental studies have shown that concomitant steroid treatment inhibits the effect of IFN-β-1a signaling through its transcription factors IRF3 and IRF9.20,21 In the current study, there was evidence of decreased IFN-β-1a effect with no increase in soluble CD73 levels in IFN-β-1a–treated patients.

Although numbers of adverse events were comparable between study groups, it should be noted that in the IFN-β-1a group, 5 patients (3.5%) experienced treatment-related rhabdomyolysis. Because this clinical condition is rare in patients with ARDS, further studies are required to evaluate the role of IFN-β-1a in this clinical context. In addition, it is possible that the use of IFN-β-1a in combination with glucocorticoids was associated with increased mortality, which should be carefully considered in all future IFN-β-1a studies.

The major strength of the trial lies in its design and practices ensuring greater adherence to the Berlin definition in identifying critically ill adult patients with hypoxemia who were likely to have pulmonary edema caused by injury of the endothelial-alveolar barrier. To improve the reliability of the chest x-ray criterion for ARDS,22,23 clinicians blindly associated the patient’s chest x-ray with a set of radiograms previously defined as consistent, inconsistent, or equivocal for ARDS.10 Inconsistencies were assessed and adjudicated by a medical monitor.

Limitations

This study had several limitations. First, the study may have been underpowered to detect a significant effect in 28-day ventilator-free survival because it relied heavily on an optimistic mortality assumption based on a small nonrandomized phase 1/2 trial. Second, in the primary composite outcome measure of death and number of ventilator-free days at day 28, mortality was assigned an arbitrary value of −1.24 Ventilator-free days already incorporates mortality as 0, making the new score almost identical to ventilator-free days and giving only limited additional value to mortality. Third, the higher-than-expected use of glucocorticoids represents a potential limitation of the present study because glucocorticoids may interfere with the biological effect of IFN-β-1a.20,21,25,26

Conclusions

Among adults with moderate or severe ARDS, intravenous IFN-β-1a administered for 6 days, compared with placebo, resulted in no significant difference in a composite score that included death and number of ventilator-free days over 28 days. These results do not support the use of IFN-β-1a in the management of ARDS.

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Article Information

Corresponding Author: Geoff Bellingan, MD, PhD, University College London Hospitals, NHS Foundation Trust, 250 Euston Rd, London NW1 2PG, United Kingdom (geoff.bellingan1@nhs.net).

Accepted for Publication: January 20, 2020.

Published Online: February 17, 2020. doi:10.1001/jama.2019.22525

Author Contributions: Drs Ranieri and Bellingan had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ranieri, Nightingale, Brealey, Mancebo, Mercat, Patroniti, Quintel, Vincent, Artigas-Raventos, Maksimow, Piippo, M. Jalkanen, Bellingan.

Acquisition, analysis, or interpretation of data: Ranieri, Pettilä, Karvonen, J. Jalkanen, Nightingale, Brealey, Mancebo, Ferrer, Mercat, Patroniti, Quintel, Vincent, Cerny, Okkonen, Meziani, Bellani, MacCallum, Creteur, Kluge, Artigas-Raventos, Elima, S. Jalkanen, M. Jalkanen, Bellingan.

Drafting of the manuscript: Ranieri, Pettilä, Karvonen, J. Jalkanen, Patroniti, Vincent, Artigas-Raventos, M. Jalkanen, Bellingan.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ranieri, Karvonen, J. Jalkanen, Patroniti.

Obtained funding: Ranieri, Maksimow, S. Jalkanen, M. Jalkanen, Bellingan.

Administrative, technical, or material support: Ranieri, Pettilä, Karvonen, J. Jalkanen, Nightingale, Brealey, Ferrer, Mercat, Patroniti, Quintel, Bellani, MacCallum, Kluge, Maksimow, Piippo, S. Jalkanen, M. Jalkanen, Bellingan.

Supervision: Ranieri, Pettilä, Karvonen, Brealey, Mercat, Patroniti, Vincent, Meziani, MacCallum, Creteur, Maksimow, Piippo, S. Jalkanen, M. Jalkanen, Bellingan.

Conflict of Interest Disclosures: Drs Karvonen, J. Jalkanen, Maksimow, Piippo, and M. Jalkanen are employees and shareholders of the sponsor Faron Pharmaceuticals Ltd. Dr S. Jalkanen is a shareholder of the Faron Pharmaceuticals Ltd. Dr Mancebo reported receiving personal fees from Faron Pharmaceuticals during the conduct of the study and personal fees from Medtronic, travel and hotel expenses for attending a meeting from IMT Medical, and grants from the Canadian Institutes of Health Research and Covidien (Medtronic) outside the submitted work. Dr Ferrer reported receiving personal fees from Faron Pharmaceuticals during the conduct of the study. Dr Mercat reported receiving personal fees from Faron Pharmaceuticals during the conduct of the study and personal fees from Medtronic, Dräger Medical, Fisher-Paykel, and Air Liquide Medical; grants from Fisher-Paykel; and grants and nonfinancial support from General Electric outside the submitted work. Dr Patroniti reported receiving personal fees from Faron Pharmaceuticals during the conduct of the study. Dr Quintel reported receiving personal fees from Faron Pharmaceuticals during the conduct of the study and personal fees from Sphere Medical, Fresenius, Medtronic, and Baxter outside the submitted work. Dr Vincent reported receiving grants from Faron Pharmaceuticals during the conduct of the study. Dr Bellani reported receiving grants and personal fees from Draeger Medical, personal fees and nonfinancial support from GE Healthcare, and personal fees from Hamilton and Getinge, and having equity ownership and being president of ReviewerCredits outside the submitted work. Dr Artigas-Raventos reported receiving grants from Grifols during the conduct of the study and personal fees from Lilly Foundation outside the submitted work. Dr Maksimow reported receiving grants from FP7 EC framework and shares from Faron Pharmaceuticals during the conduct of the study; in addition, Dr Maksimow had a patent No. 10293030 issued and patent No. 10247730 issued. Dr S. Jalkanen reported receiving grants from the European Union during the conduct of the study and owning stock in Faron Pharmaceuticals outside the submitted work; in addition, Dr S. Jalkanen had a patent to US 7534423 issued. Dr M. Jalkanen reported receiving grants from the European Commission during the conduct of the study and personal fees from Faron Pharmaceuticals outside the submitted work; in addition, Dr M. Jalkanen had a patent to intravenous use of inteferon β issued and with royalties paid and is an owner of Faron shares traded at London AIM under ticker FARN. Dr Bellingan reported receiving grants from European Union FP7 grant funding and travel and accommodation expenses to attend meetings from Faron Pharmaceuticals during the conduct of the study; Dr Bellingan previously served as the secretary for the European Society of Intensive Care Medicine. No other disclosures were reported.

Funding/Support: The INTEREST Study was sponsored by Faron Pharmaceuticals Ltd (Turku, Finland) and supported, in part, by the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement No. 305853.

Role of the Funder/Sponsor: Faron Pharmaceuticals participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; but the sponsor did not control the decision to submit the manuscript for publication.

Group Information: The INTEREST Study Group members are as follows: Jacques Creteur, MD; CUB–Hôpital Erasme Route de Lennik, BruxellesBelgium: Maxime Van Cutsem, MD; CHU Charleroi–Site Hospital Civil Marie Curie Chaussée de Bruxelles, Charleroi Belgium: Pierre Damas, MD; Centre Hospitalier Universitaire de Liège Domaine Universitaire du Sart Tilman–Bâtiment B35 Liège, Belgium: Johan Decruyenaere, MD; UZ GentDe Pintelaan, Oost-Vlaanderen Belgium: Pierre Bulpa, MD, and Alain-Michel Dive, MD; CHU Dinant Godinne UCL–Namur Avenue Docteur Gaston –Therasse, Belgium: Philippe Jorens, MD; UZ Antwerpen Wilrijkstraat, Antwerpen Belgium: Herbert Spapen, MD, and Patrick Honoré, MD; UZ Brussel Campus Jette, Laarbeeklaan, Belgium: Frantisek Duska, MD; Fakultni nemocnice Kralovske Vinohrady Srobarova Czech Republic: Vladimir Cerny, MD; Hospital Usti nad Labem Socialni pece Usti nad LabemCzech Republic: Pavel Dostal, MD; Fakultni nemocnice Hradec Kralove Sokolska 581 Kinika anesteziologie, resuscitace a intenzivni mediciny Hradec Kralove, Czech Republic: Marjatta Okkonen, MD; Helsinki University Hospital, Intensive Care Unit, Helsinki, Finland: Sari Karlsson, MD; Tampere University Hospital, Intensive Care Unit Tampere, Finland: Stepani Bendel, MD, and Ilkka Parviainen, MD; Kuopio University Hospital, Intensive Care Unit Kuopio, Finland: Mika Valtonen, MD; Turku University Hospital, Intensive Care Unit Turku, Finland: Alain Mercat, MD; CHU Angers–Service de Réanimation Médicale, Angers, France: Gaëtan Beduneau, MD; CHU Charles Nicolle–ICU, Rouen, France: Thierry Boulain, MD; CHR Orleans–ICU, Orléans, France: Delphine Chatellier, MD; CHU Poitiers–Service de Réanimation Médicate, Poitiers, France: Jean-Daniel Chiche, MD; Hôpital Cochin Réanimation Médicale, Paris, France: Alain Combes, MD; Hôpital de la Pitié Salpétrière, Réanimation Médicale Paris, France: Claude Guerin, MD; Hôpital de La Croix Rousse, Rhône, France: Ferhat Meziani, MD; Nouvel Hopital Civil de Strasbourg, Réanimation Médicale, Strasbourg, France: Christian Richard, MD; CHU de Bicêtre, Réanimation, Médicale, Le Kremlin-Bicêtre France: Christophe Guervilly, MD; CHU Marseille Nord, Réanimation Médicale, Chemin des Bourrely, Marseille, Bouches-du-Rhône, France: Erwan L’Her, MD; CHU Brest la Cavale, Réanimation Médicale, Brest, France: Stephan Ehrmann, MD; CHU Bretonneau–Service de Réanimation Médicale, Tours, France: Christophe Guitton, MD; Centre Hospitalier Le Mans, Le Mans, France: Arnaud Gacouin, MD; Hôpital Pontchaillou, Rennes Ille-et-Vilaine, France: Gérard Audibert, MD; CHRU Nancy, Service de Réanimation, Chirurgicale Polyvalente, Nancy, Meurthe-et-Moselle, France: Michael Quintel, MD; Klinik für Anästhesiologie, Universitätsmedizin Göttingen, Göttingen, Germany: Ulrich Peter Jaschinski, MD; Klinik für Anästhesiologie, Klinikum AugsburgAugsburg, Germany: Christian Karagiannidis, MD; Kliniken der Stadt Köln, Lungenklinik Merheim, Köln, Germany: Stefan Kluge, MD; Universitätsklinikum Hamburg-Eppendorf, Klinik für Intensivmedizin, Hamburg, Germany: Sven Laudi, MD; Universitatsklinikum Leipzig, Dep. of Anaesthesiology, Leipzig, Germany: Christian Putensen, MD; Klinik füer Anästhesiologie, Universitätsklinikum Bonn, Bonn, Germany: Maximillian Ragaller, MD; Universitätsklinikum Carl Gustav Carus, Klinik für Anästhesiologie und Intensivtherapie, Dresden, Germany: Steffen Weber Carstens, MD; Charité Berlin Campus, Virchow-Klinikum, Berlin, Germany: Giacomo Bellani, MD; Dip. Emergenza, Ospedale San Gerardo, Monza, Italy: Massimo Antonelli, MD; Reparto di Rianimazione, Terapia Intensiva e Tossicologia, Fondazione Policlinico A. Gemelli–Largo A. Gemelli, Rome, Italy: Francesco Della Corte, MD; Dipartimento di Emergenza, Urgenza, Anestesia e Rianimazione, AOU Maggiore della Carità-Corso Mazzini, Novara, Italy: Vito Fanelli, MD; Dipartimento di Anestesia e Rianimazione, AOU Città della Salute e della, Scienza–Corso Bramante, Turin, Italy: Francesco Alessandri, MD, and Andrea Morelli, MD; Reparto di Anestesia e Rianimazione, Univ. degli Studi di Roma “La Sapienza”–Rome, Italy: Antonio Maria Pesenti, MD; IRCCS Cà Granda Ospedale, Maggiore Policlinico, Milan, Italy: Carlo Alberto Volta, MD; Azienda Ospedaliero-Universitaria Sant'Anna, Anestesia-Terapia Intensiva, Dip. Emergenza, Ferrara, Italy: Antoni-Jordi Betbese Roig, MD; Hospital de La Santa Creu i Sant Pau, Barcelona, Spain: Antonio Artigas Raventós, MD; Corporació Sanitària Parc Tauli, Barcelona, Spain: Joan Ramon Badia, MD; Hospital Clinic de Barcelona, Barcelona, Spain: Jesus Blanco Varela, MD; Hospital Universitario Rio Hortega, Valladolid, Spain: Ricard Ferrer, MD; Hospital Universitari Vall, d'Hebron, Barcelona, Spain: Mireia Ferreruela Serlavós, MD; Hospital Universitario Son Espases Ctra. de Valldemossa 79, Balears Spain: Federico Gordo Vidal, MD; Hospital Universitario del Henares, Madrid, Spain: Sonia Lopez Cuenca, MD; Hospital Universitario de, Getafe, Madrid, Spain: Maria del Mar Fernandez, MD; Hospital Mutua de Terrassa Placa Dr. Robert, Barcelona, Spain: Sergio Ruiz-Santana, MD; Hospital de Gran Canaria, Doctor Negrin, Barranco De Lane Ballena S/n, Unidad Medicina Intensiva, Las Palmas de Gran Canaria, Spain: Joan Ramon Masclans, MD; Hospital del Mar Passeig Marítim 25-28, Barcelona, Spain: Jose Sanchez-Izquierdo Riera, MD; Hospital Universitario 12 de Octubre, Unidad de Cuidados Intensivos, UCI Polivalente, Spain: Manuel Sánchez Sánchez, MD; Hospital Universitario La Paz, Servicio de Medicina Intensiva, Madrid, Spain: Paula Ramirez, MD; Hospital Universitari I, Politecnic La Fe de Valencia, Valencia, Spain: Pilar Ricart, MD; Hospital Universitario Germans, Trias i Pujol,Carretera De Canyet S/n Badalona, Cataluña, Spain: Niall MacCallum, MD; University College London, Hospital, London, United Kingdom: Luigi Camporota, MD; Guy’s and St Thomas’ NHS Foundation Trust–Guy’s Hospital, London, United Kingdom: Susannah Leaver, MD and Maurizio Cecconi, MD; St George’s Hospital, London, United Kingdom: Rebecca Cusack, MD; Southampton General Hospital, Southampton, United Kingdom: Philip Hopkins, MD; Kings College Hospital, NHS Foundation TrustLondon, United Kingdom: David Pogson, MD; Queen Alexandra Hospital, Portsmouth, Hampshire, United Kingdom: Sanjoy Shah, MD; Bristol Royal Infirmary, Bristol, United Kingdom: Martin Stotz, MD; Imperial College Healthcare NHS Trust, St Mary’s Hospital, London, United Kingdom; Charing Cross Hospital, London, United Kingdom; and Hammersmith Hospital, London, United Kingdom: Kallirroi Kefala, MD; Ward 118 Intensive Care Unit, Royal Infirmary of Edinburgh Edinburgh, Scotland, United Kingdom: Daniel Harvey, MD; Nottingham University Hospitals NHS Trust, Queens Medical Centre, Nottingham, United Kingdom: Parvez Moondi, MD; Norfolk and Norwich Foundation Trust University Hospital, Norwich, United Kingdom: Shondipon Laha, MD; Lancashire Teaching Hospital, NHS Foundation Trust, Royal Preston Hospital, Preston, United Kingdom: Matthew Wise, MD; Cardiff and Vale NHS Trust, University Hospital of Wales, Cardiff, United Kingdom.

Meeting Presentation: This study was presented at the Society of Critical Care Medicine’s 49th Critical Care Congress; February 17, 2020; Orlando, Florida.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank the study investigators, study coordinators, and support staff across all sites for entrusting us to conduct this study; contract research organizations for the clinical conduct of the study; and Data Magik Ltd (Salisbury, United Kingdom) and 4Pharma Ltd (Turku, Finland) for data management and statistics.

Additional Information: Members of the independent data monitoring committee included Arthur Slutsky, MD (chair), University of Toronto, Toronto, Ontario, Canada; Taylor Thompson, MD, Harvard University, Boston, Massachusetts; Peter Suter, MD, Geneva University, Geneva, Switzerland; and Simon Weeden (unblinded biostatistician), PPD Ltd, Scotland, United Kingdom.

References
1.
Ranieri  VM, Rubenfeld  GD, Thompson  BT,  et al; ARDS Definition Task Force.  Acute respiratory distress syndrome: the Berlin Definition.  JAMA. 2012;307(23):2526-2533.PubMedGoogle Scholar
2.
Matthay  MA, Zemans  RL, Zimmerman  GA,  et al.  Acute respiratory distress syndrome.  Nat Rev Dis Primers. 2019;5(1):18. doi:10.1038/s41572-019-0069-0PubMedGoogle ScholarCrossref
3.
Bellani  G, Laffey  JG, Pham  T,  et al; LUNG SAFE Investigators; ESICM Trials Group.  Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.  JAMA. 2016;315(8):788-800. doi:10.1001/jama.2016.0291PubMedGoogle ScholarCrossref
4.
Ohta  A, Sitkovsky  M.  Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage.  Nature. 2001;414(6866):916-920. doi:10.1038/414916aPubMedGoogle ScholarCrossref
5.
Thompson  LF, Eltzschig  HK, Ibla  JC,  et al.  Crucial role for ecto-5′-nucleotidase (CD73) in vascular leakage during hypoxia.  J Exp Med. 2004;200(11):1395-1405. doi:10.1084/jem.20040915PubMedGoogle ScholarCrossref
6.
Kiss  J, Yegutkin  GG, Koskinen  K, Savunen  T, Jalkanen  S, Salmi  M.  IFN-beta protects from vascular leakage via up-regulation of CD73.  Eur J Immunol. 2007;37(12):3334-3338. doi:10.1002/eji.200737793PubMedGoogle ScholarCrossref
7.
Aeffner  F, Woods  PS, Davis  IC.  Activation of A1-adenosine receptors promotes leukocyte recruitment to the lung and attenuates acute lung injury in mice infected with influenza A/WSN/33 (H1N1) virus.  J Virol. 2014;88(17):10214-10227. doi:10.1128/JVI.01068-14PubMedGoogle ScholarCrossref
8.
Bellingan  G, Maksimow  M, Howell  DC,  et al.  The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study.  Lancet Respir Med. 2014;2(2):98-107. doi:10.1016/S2213-2600(13)70259-5PubMedGoogle ScholarCrossref
9.
Bellingan  G, Brealey  D, Mancebo  J,  et al.  Comparison of the efficacy and safety of FP-1201-lyo (intravenously administered recombinant human interferon beta-1a) and placebo in the treatment of patients with moderate or severe acute respiratory distress syndrome: study protocol for a randomized controlled trial.  Trials. 2017;18(1):536. doi:10.1186/s13063-017-2234-7PubMedGoogle ScholarCrossref
10.
Ferguson  ND, Fan  E, Camporota  L,  et al.  The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material.  Intensive Care Med. 2012;38(10):1573-1582. doi:10.1007/s00134-012-2682-1PubMedGoogle ScholarCrossref
11.
Knaus  WA, Draper  EA, Wagner  DP, Zimmerman  JE.  APACHE II: a severity of disease classification system.  Crit Care Med. 1985;13(10):818-829. doi:10.1097/00003246-198510000-00009PubMedGoogle ScholarCrossref
12.
Brower  RG, Matthay  MA, Morris  A, Schoenfeld  D, Thompson  BT, Wheeler  A; Acute Respiratory Distress Syndrome Network.  Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.  N Engl J Med. 2000;342(18):1301-1308. doi:10.1056/NEJM200005043421801PubMedGoogle ScholarCrossref
13.
Guérin  C, Reignier  J, Richard  JC,  et al; PROSEVA Study Group.  Prone positioning in severe acute respiratory distress syndrome.  N Engl J Med. 2013;368(23):2159-2168. doi:10.1056/NEJMoa1214103PubMedGoogle ScholarCrossref
14.
Wiedemann  HP, Wheeler  AP, Bernard  GR,  et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network.  Comparison of two fluid-management strategies in acute lung injury.  N Engl J Med. 2006;354(24):2564-2575. doi:10.1056/NEJMoa062200PubMedGoogle ScholarCrossref
15.
Thompson  BT, Ranieri  VM.  Steroids are part of rescue therapy in ARDS patients with refractory hypoxemia: no.  Intensive Care Med. 2016;42(5):921-923. doi:10.1007/s00134-016-4255-1PubMedGoogle ScholarCrossref
16.
Finkelstein  DM, Schoenfeld  DA.  Combining mortality and longitudinal measures in clinical trials.  Stat Med. 1999;18(11):1341-1354. doi:10.1002/(SICI)1097-0258(19990615)18:11<1341::AID-SIM129>3.0.CO;2-7PubMedGoogle ScholarCrossref
17.
Vallittu  AM, Erälinna  JP, Ilonen  J, Salmi  AA, Waris  M.  MxA protein assay for optimal monitoring of IFN-beta bioactivity in the treatment of MS patients.  Acta Neurol Scand. 2008;118(1):12-17. doi:10.1111/j.1600-0404.2007.00968.xPubMedGoogle ScholarCrossref
18.
Vincent  JL, Moreno  R, Takala  J,  et al.  The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure: on behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.  Intensive Care Med. 1996;22(7):707-710. doi:10.1007/BF01709751PubMedGoogle ScholarCrossref
19.
Maksimow  M, Kyhälä  L, Nieminen  A,  et al.  Early prediction of persistent organ failure by soluble CD73 in patients with acute pancreatitis*.  Crit Care Med. 2014;42(12):2556-2564. doi:10.1097/CCM.0000000000000550PubMedGoogle ScholarCrossref
20.
Flammer  JR, Dobrovolna  J, Kennedy  MA,  et al.  The type I interferon signaling pathway is a target for glucocorticoid inhibition.  Mol Cell Biol. 2010;30(19):4564-4574. doi:10.1128/MCB.00146-10PubMedGoogle ScholarCrossref
21.
Diez  D, Goto  S, Fahy  JV,  et al.  Network analysis identifies a putative role for the PPAR and type 1 interferon pathways in glucocorticoid actions in asthmatics.  BMC Med Genomics. 2012;5:27. doi:10.1186/1755-8794-5-27PubMedGoogle ScholarCrossref
22.
Rubenfeld  GD, Caldwell  E, Granton  J, Hudson  LD, Matthay  MA.  Interobserver variability in applying a radiographic definition for ARDS.  Chest. 1999;116(5):1347-1353. doi:10.1378/chest.116.5.1347PubMedGoogle ScholarCrossref
23.
Meade  MO, Cook  RJ, Guyatt  GH,  et al.  Interobserver variation in interpreting chest radiographs for the diagnosis of acute respiratory distress syndrome.  Am J Respir Crit Care Med. 2000;161(1):85-90. doi:10.1164/ajrccm.161.1.9809003PubMedGoogle ScholarCrossref
24.
Beitler  JR, Sarge  T, Banner-Goodspeed  VM,  et al; EPVent-2 Study Group.  Effect of titrating positive end-expiratory pressure (PEEP) with an esophageal pressure-guided strategy vs an empirical high PEEP-Fio2 strategy on death and days free from mechanical ventilation among patients with acute respiratory distress syndrome: a randomized clinical trial.  JAMA. 2019;321(9):846-857. doi:10.1001/jama.2019.0555PubMedGoogle ScholarCrossref
25.
McCoy  CE, Carpenter  S, Pålsson-McDermott  EM, Gearing  LJ, O’Neill  LA.  Glucocorticoids inhibit IRF3 phosphorylation in response to Toll-like receptor-3 and -4 by targeting TBK1 activation.  J Biol Chem. 2008;283(21):14277-14285. doi:10.1074/jbc.M709731200PubMedGoogle ScholarCrossref
26.
Englert  JA, Cho  MH, Lamb  AE,  et al.  Whole blood RNA sequencing reveals a unique transcriptomic profile in patients with ARDS following hematopoietic stem cell transplantation.  Respir Res. 2019;20(1):15. doi:10.1186/s12931-019-0981-6PubMedGoogle ScholarCrossref
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