Critical Care, University College Hospital, London, UK; Department of Medicine, University College London and NIHR University College London Hospitals Biomedical Research Centre, UK.
Faron Pharmaceuticals, Turku, Finland.
Lancet Respir Med. 2014 Feb;2(2):98-107. doi: 10.1016/S2213-2600(13)70259-5. Epub 2013 Dec 23.
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.
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.
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).
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.
急性呼吸窘迫综合征（ARDS）早期会出现肺血管渗漏。死亡率很高（35-45%），但目前尚无有效的药物治疗方法。细胞外 5'-核苷酸酶（CD73）产生的抗炎性腺苷有助于维持内皮屏障功能。我们测试了干扰素-β-1a（IFN-β-1a）是否可以减少 ARDS 患者的血管渗漏和死亡率，IFN-β-1a 可增加 CD73 的合成。
在体外研究中，我们首先证明 IFN-β-1a 可诱导培养的人肺组织样本中 CD73 的上调。然后，我们在一项开放标签研究（包括剂量递增和扩展阶段）中测试了静脉内人重组 IFN-β-1a（FP-1201）在 ARDS 患者中的安全性、耐受性和疗效。我们从英国的 8 个重症监护病房招募了患者。合格的患者年龄在 18 岁或以上，患有 ARDS，并且正在接受辅助通气治疗。我们在第一阶段，即剂量递增阶段，确定了最佳耐受剂量（OTD）。一旦确定，我们将静脉内 FP-1201 的 OTD 剂量给予所有随后入组的患者，持续 6 天。我们评估了接受 OTD 的所有患者与未接受治疗的患者（对照组包括研究中的患者，但由于在剂量递增后的安全窗口期内筛选，因此未接受治疗）的 28 天死亡率（我们的主要终点）。这项试验在 ClinicalTrials.gov 注册，编号为 NCT00789685，在欧盟临床试验注册中心（EudraCT）注册，编号为 2008-000140-13。
IFN-β-1a 在第 1 天（p=0.04）和第 4 天（p=0.004）时使肺培养物中 CD73 阳性血管的数量分别增加了四倍和 14.3 倍。对于临床试验，在 2009 年 2 月 23 日至 2011 年 4 月 7 日期间，我们确定了 150 名患者，其中 37 名患者入组并接受了治疗。对照组由 59 名入组接受研究但未接受治疗的患者组成。治疗组和对照组的人口统计学特征和疾病严重程度没有差异。最佳耐受 FP-1201 剂量为每天 10μg，持续 6 天。到第 28 天，治疗组的 37 名患者中有 3 名（8%）和对照组的 59 名患者中有 19 名（32%）死亡-因此，FP-1201 治疗可使 28 天死亡率的可能性降低 81%（比值比 0.19 [95%CI 0.03-0.72]；p=0.01）。
FP-1201 上调了人肺 CD73 的表达，并与 ARDS 患者 28 天死亡率的降低相关。我们的发现需要在大型前瞻性随机试验中得到证实，但表明 FP-1201 可能是 ARDS 患者的第一种有效、机制靶向、疾病特异性的药物治疗方法。
