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Clinical Trial
. 2020 Feb 25;323(8):725-733.
doi: 10.1001/jama.2019.22525.

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

V Marco Ranieri  1 , Ville Pettilä  2 , Matti K Karvonen  3 , Juho Jalkanen  3 , Peter Nightingale  4 , David Brealey  5 , Jordi Mancebo  6 , Ricard Ferrer  7 , Alain Mercat  8 , Nicolò Patroniti  9 , Michael Quintel  10 , Jean-Louis Vincent  11 , Marjatta Okkonen  2 , Ferhat Meziani  12 , Giacomo Bellani  13 , Niall MacCallum  5 , Jacques Creteur  11 , Stefan Kluge  14 , Antonio Artigas-Raventos  15 , Mikael Maksimow  3 , Ilse Piippo  3 , Kati Elima  16 , Sirpa Jalkanen  16 , Markku Jalkanen  3 , Geoff Bellingan  5 ; INTEREST Study Group
Affiliations
Clinical Trial

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

V Marco Ranieri et al. JAMA. .

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.

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Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. 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.
Figure 2.. 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.
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Comment in

References

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