Background: Pulmonary vascular leakage occurs early in acute respiratory distress syndrome (ARDS). Mortality is high (35-45%), but no effective pharmacotherapy exists. Production of anti-inflammatory adenosine by ecto-5'-nucleotidase (CD73) helps maintain endothelial barrier function. We tested whether interferon-beta-1a (IFN-beta-1a), which increases CD73 synthesis, can reduce vascular leakage and mortality in patients with ARDS.
Methods: In ex-vivo studies, we first established that IFN-beta-1a induced CD73 up-regulation in cultured human lung tissue samples. We then tested the safety, tolerability, and efficacy of intravenous human recombinant IFN-beta-1a (FP-1201) in patients with ARDS in an open-label study (comprising dose-escalation and expansion phases). We recruited patients from eight intensive care units in the UK. Eligible patients were aged 18 years or older, had ARDS, and were being treated with assisted ventilation. We established an optimal tolerated dose (OTD) in the first, dose-escalation phase. Once established, we gave all subsequently enrolled patients the OTD of intravenous FP-1201 for 6 days. We assessed 28-day mortality (our primary endpoint) in all patients receiving the OTD versus 28-day mortality in a group of patients who did not receive treatment (this control group comprised patients in the study but who did not receive treatment because they were screened during the safety windows after dose escalation). This trial is registered with ClinicalTrials.gov, number NCT00789685, and the EU Clinical Trials Register EudraCT, number 2008-000140-13.
Findings: IFN-beta-1a increased the number of CD73-positive vessels in lung culture by four times on day 1 (p=0·04) and by 14·3 times by day 4 (p=0·004). For the clinical trial, between Feb 23, 2009, and April 7, 2011, we identified 150 patients, of whom 37 were enrolled into the trial and given treatment. The control group consisted of 59 patients who were recruited to take part in the study, but who did not receive treatment. Demographic characteristics and severity of illness did not differ between treatment and control groups. The optimal tolerated FP-1201 dose was 10 μg per day for 6 days. By day 28, 3 (8%) of 37 patients in the treatment cohort and 19 (32%) of 59 patients in the control cohort had died-thus, treatment with FP-1201 was associated with an 81% reduction in odds of 28-day mortality (odds ratio 0·19 [95% CI 0·03-0·72]; p=0·01).
Interpretation: FP-1201 up-regulates human lung CD73 expression, and is associated with a reduction in 28-day mortality in patients with ARDS. Our findings need to be substantiated in large, prospective randomised trials, but suggest that FP-1201 could be the first effective, mechanistically targeted, disease-specific pharmacotherapy for patients with ARDS.
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