LungenClinic Grosshansdorf, Grosshansdorf, Germany; Department of Medicine, Christian Albrechts University Kiel, Kiel, Germany.
Pulmonary Research Institute, Grosshansdorf, Germany.
Lancet Respir Med. 2018 Nov;6(11):827-836. doi: 10.1016/S2213-2600(18)30331-X. Epub 2018 Sep 14.
The clinical effects of roflumilast, a selective phosphodiesterase-4 inhibitor, are well established, but little is known about the anti-inflammatory mechanisms underlying the drug's efficacy. The aim of the ROflumilast Biopsy European Research Trial (ROBERT) was to assess the anti-inflammatory effects of roflumilast on bronchial mucosal inflammation in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and chronic bronchitis.
ROBERT was a randomised, double-blind, placebo-controlled trial done at 18 sites in five countries. Eligible patients were aged 40-80 years, had COPD, and had had a chronic productive cough for 3 months in each of the two previous years. Patients also had to have a post-bronchodilator predicted FEV 30-80% and a post-bronchodilator FEV/forced vital capacity ratio of 70% or less. Patients entered a 6-week run-in period before being randomly assigned (1:1) via a computerised central randomisation system to roflumilast 500 μg once daily or placebo for 16 weeks, in addition to bronchodilator therapy (inhaled corticosteroids were not permitted). Randomisation was stratified by concomitant use of long-acting β agonist. Both participants and investigators were masked to group assignment. Roflumilast and placebo were supplied as identical yellow, triangular tablets. Airway inflammation was assessed by quantification of inflammatory cells in bronchial biopsy samples and induced sputum samples. The primary endpoint was the change in the number of CD8 inflammatory cells in bronchial biopsy submucosa from randomisation to week 16 in the intention-to-treat population. Changes in cell counts of additional inflammatory markers, including eosinophils, were assessed as secondary endpoints. This trial is registered with ClinicalTrials.gov, number NCT01509677, and is closed to new participants, with follow-up completed.
Between Jan 4, 2012, and Feb 11, 2016, 158 patients were randomly assigned: 79 to the roflumilast group, and 79 to the placebo group. At week 16, the change in the number of CD8 cells in the bronchial submucosa did not differ significantly between the roflumilast and placebo groups (treatment ratio 1·03 [95% CI 0·82-1·30]; p=0·79). However, compared with placebo, roflumilast was associated with a significant reduction in eosinophils in bronchial biopsy samples at week 16 (treatment ratio 0·53 [95% CI 0·34-0·82]; p=0·0046). Significant reductions in both absolute (p=0·0042) and differential (p=0·0086) eosinophil cell counts in induced sputum were also noted with roflumilast compared with placebo, but peripheral blood eosinophil counts were not significantly affected. We noted no other significant effects of roflumilast on bronchial mucosal inflammatory cells. The most common (ie, occurring in >5% patients) moderate adverse events were worsening of COPD (three [4%] patients in the roflumilast group vs seven [9%] in the placebo group), cough (six [8%] vs four [5%]), diarrhoea (four [5%] vs three [4%]), and nasopharyngitis (three [4%] vs five [6%]). Severe adverse events included worsening of COPD, which occurred in four (5%) patients in the roflumilast group and two (3%) in the placebo group. No deaths occurred during the study. Serious adverse events occurred in eight (10%) patients in the roflumilast group and five (6%) in the placebo group.
16 weeks of treatment with roflumilast did not affect the number of CD8 cells in bronchial submucosa compared with placebo. However, we noted significant reductions in eosinophil cell counts in bronchial biopsy samples and induced sputum, generating the hypothesis that the effect of roflumilast in COPD could be mediated by an effect on lung eosinophils.
Takeda and AstraZeneca.
磷酸二酯酶-4 抑制剂罗氟司特的临床疗效已得到充分证实，但对于该药疗效的抗炎机制知之甚少。ROflumilast 活检欧洲研究试验（ROBERT）的目的是评估罗氟司特对中重度慢性阻塞性肺疾病（COPD）和慢性支气管炎患者支气管黏膜炎症的抗炎作用。
ROBERT 是一项在五个国家的 18 个地点进行的随机、双盲、安慰剂对照试验。符合条件的患者年龄在 40-80 岁之间，患有 COPD，并且在过去两年的每个季度都有慢性产痰咳嗽 3 个月。患者还必须在支气管扩张剂后预测 FEV 为 30-80%，并且在支气管扩张剂后 FEV/用力肺活量比值为 70%或更低。患者在进入 16 周的随机分组（1:1）之前进行了 6 周的导入期，通过计算机化的中央随机分组系统，将患者随机分为罗氟司特 500μg 每日一次或安慰剂组，同时给予支气管扩张剂治疗（不允许使用吸入性皮质类固醇）。随机分组按长效β激动剂的同时使用进行分层。参与者和研究人员均对分组情况进行了掩蔽。罗氟司特和安慰剂均为相同的黄色三角形片剂。通过支气管活检样本和诱导痰样本中炎性细胞的定量评估气道炎症。主要终点是在意向治疗人群中从随机分组到第 16 周时支气管活检黏膜下 CD8 炎性细胞的数量变化。还评估了包括嗜酸性粒细胞在内的其他炎症标志物的细胞计数变化作为次要终点。该试验在 ClinicalTrials.gov 上注册，编号为 NCT01509677，现已对新参与者关闭，随访已完成。
2012 年 1 月 4 日至 2016 年 2 月 11 日期间，共 158 名患者被随机分配：79 名患者接受罗氟司特治疗，79 名患者接受安慰剂治疗。在第 16 周时，罗氟司特组和安慰剂组支气管黏膜下 CD8 细胞数量的变化无显著差异（治疗比 1.03 [95%CI 0.82-1.30]；p=0.79）。然而，与安慰剂相比，罗氟司特治疗与支气管活检样本中嗜酸性粒细胞的显著减少相关，在第 16 周时（治疗比 0.53 [95%CI 0.34-0.82]；p=0.0046）。与安慰剂相比，罗氟司特治疗还显著降低了诱导痰中的绝对（p=0.0042）和差异（p=0.0086）嗜酸性粒细胞计数。我们还注意到，罗氟司特治疗对支气管黏膜炎症细胞没有其他显著影响。最常见（即发生在>5%患者中）的中度不良事件是 COPD 恶化（罗氟司特组 3 例[4%]，安慰剂组 7 例[9%]）、咳嗽（6 例[8%]，4 例[5%]）、腹泻（4 例[5%]，3 例[4%]）和鼻咽炎（3 例[4%]，5 例[6%]）。严重不良事件包括 COPD 恶化，罗氟司特组 4 例（5%），安慰剂组 2 例（3%）。研究期间无死亡病例。严重不良事件发生在罗氟司特组 8 例（10%）和安慰剂组 5 例（6%）。
与安慰剂相比，16 周的罗氟司特治疗并未影响支气管黏膜下 CD8 细胞的数量。然而，我们注意到支气管活检样本和诱导痰中的嗜酸性粒细胞计数显著减少，这产生了罗氟司特在 COPD 中的作用可能通过对肺嗜酸性粒细胞的作用来介导的假设。
武田和阿斯利康。
