Interferon beta-1a fails to benefit patients with ARDS

Treatment with IV recombinant human interferon beta-1a failed to improve outcomes in mechanically ventilated patients with moderate or severe acute respiratory distress syndrome, according to data published in JAMA.

Previous results from a pilot, open-label, nonrandomized phase 1/2 study demonstrated an association between lower 28-day mortality and treatment with interferon beta-1a (IFN-beta-1a) in patients with ARDS. As a result, researchers decided to perform the INTEREST study — a randomized, double-blind, parallel-group trial conducted at 74 ICUs in eight European countries from 2015 to 2017. A total of 301 patients (mean age, 57 years; 34.2% women) with moderate or severe ARDS, as defined by the Berlin definition, were enrolled in the study and randomly assigned IV IFN-beta-1a 10 g or placebo once daily for 6 days.

For patients to qualify for inclusion in INTEREST, the radiological and partial pressure of oxygen, arterial/fraction of inspired oxygen criteria for ARDS had to be met within 24 hours and the administration of the first dose of the study drug had to occur within 48 hours of the ARDS diagnosis. Additionally, medical monitors confirmed patient eligibility before randomization by having the enrolling clinician match the patient’s chest X-ray against a panel of unlabeled chest X-rays to ensure the imaging was consistent with ARDS.

A score combining death and number of ventilator-free days at day 28, with the score ranging from –1 for death to 27 if the patient was no longer on ventilation on the first day, served as the primary outcome.

No significant differences

Of those enrolled, 296 patients — 144 in the intervention arm and 152 in the placebo arm — were included in the primary analysis. At 28 days, the primary composite outcome of death and ventilator-free days at day 28 did not differ significantly between the intervention and placebo arms (median, 10 vs. 8.5 days, respectively), and the same was true for the secondary outcome of 28-day mortality (26.4% vs. 23%, respectively). There were also no significant differences between study arms in a number of other secondary outcomes, including 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.

“These results do not support the use of IFN-beta-1a in the management of ARDS,” the researchers wrote.

The researchers also performed additional exploratory post hoc analyses due to high use of corticosteroids at baseline. Results from these analyses showed that mortality at 28 days was 50% in the intervention arm and 28.3% in the placebo arm among those taking corticosteroids at randomization (OR = 2.53; 95% CI, 1.12-5.72) vs. 10.6% and 14.8%, respectively, among those not taking corticosteroids at randomization (OR = 0.78; 95% CI, 0.37-1.65; P for interaction = .04).

In terms of safety, treatment-related adverse events occurred in 74 patients, including 41 in the IFN-beta-1a arm and 33 in the placebo arm. The number of serious adverse events, adverse events and patients with any serious and/or any adverse events were similar between study arms, according to the researchers.

Potential issues

The researchers noted that the lack of benefit of IFN-beta-1a treatment may be related to the fact that the study was underpowered to detect clinical benefit and “relied heavily on an optimistic mortality assumption based on a small, nonrandomized phase 1/2 trial.”

“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-beta-1a signaling through its transcription factors IRF3 and IRF9,” they wrote.

In an accompanying editorial, Manu Shankar-Hari, MD, MSc, PhD, from the School of Immunology and Microbial Sciences at Kings College London and Guy’s and St. Thomas’ NHS Foundation Trust, ICU Support Offices at St. Thomas’ Hospital, and Carolyn S. Calfee, MD, MAS, from the division of pulmonary, critical care, allergy and sleep medicine, departments of medicine and anesthesia and Cardiovascular Research Institute at the University of California, San Francisco, also highlighted the study’s limitations but wrote that clinical trials of pharmacologic agents for ARDS have been negative in general.

“The current model for ARDS drug trials is typically focused around modifying one or more pathways related to alveolar epithelial injury, pulmonary endothelial injury or the systemic immune response,” they wrote, noting that not these may not be the only causal pathways to outcomes in all patients with ARDS. “Therefore, ARDS should be considered as a multipathway illness, with the ARDS to outcome relationship a multicausality relationship and every causal mechanism representing the joint action of a multitude of component causes. The pathways that determine outcome may differ between patients. This heterogeneity suggests the importance of highlighting two essential concepts in early-phase trials, prognostic and predictive enrichment and surrogate outcomes, both of which need additional development in ARDS.”

Unfortunately, surrogate outcomes in early-phase trials usually include biomarkers or physiologic changes and make predicting a drug’s effect on outcomes difficult, according to Shankar-Hari and Calfee.

“The ideal surrogate outcome would represent the single causal pathway of ARDS to patient-centered outcomes (such as mortality), the effect of treatment on the surrogate outcome mirrors the likely effect of treatment on patient-centered outcome and the entire effect of the treatment on the patient-centered outcomes is mediated through its effect on the surrogate outcome,” they wrote. “ARDS research currently lacks such surrogate outcomes, as causal pathways are extrapolated between nonideal surrogate outcomes and patient-centered outcomes in the context of incomplete knowledge. In the future, early-phase trials of novel pharmacotherapies in ARDS should develop treatment-specific surrogate outcomes, include enrichment strategies and test patient-centered outcomes as primary outcomes to potentially break this pattern of relentlessly ‘negative’ clinical trials.” – by Melissa Foster

Disclosures: The INTEREST study was sponsored by Faron Pharmaceuticals and supported in part by the European Union Seventh Framework Program. Ranieri reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Calfee reports she has received grants from GlaxoSmithKline and the NIH; grants and personal fees from Bayer and Roche/Genentech; and personal fees from CSL Behring and Quark. Shankar-Hari reports no relevant financial disclosures.