Effect of dupilumab on exhaled nitric oxide, mucus plugs, and functional respiratory imaging in patients with type 2 asthma (VESTIGE): a randomised, double-blind, placebo-controlled, phase 4 trial.

VESTIGE used functional respiratory imaging to assess changes in airway structure and function, including mucus plugging, in response to dupilumab.

VESTIGE研究使用功能性呼吸成像技术评估了在使用dupilumab治疗后气道结构和功能的变化，包括粘液栓塞的情况。

Methods

VESTIGE was a randomised, double-blind, placebo-controlled, phase 4 trial done at 72 research sites or academic centres in 14 countries.

VESTIGE是一项在14个国家的72个研究地点或学术中心进行的随机、双盲、安慰剂对照的4期临床试验。

We recruited adult patients (aged 18-70 years) with physician-diagnosed, uncontrolled, moderate-to-severe type 2 asthma (blood eosinophil count ≥300 cells/μL and fractional exhaled nitric oxide [FeNO] ≥25 parts per billion [ppb]) being treated with medium-dose to high-dose inhaled corticosteroids combined with other controller medications.

我们招募了成年患者（年龄在18-70岁之间），这些患者被医生诊断为未控制的中度至重度2型哮喘（血液嗜酸性粒细胞计数≥300个细胞/μL和呼出气一氧化氮分数[FeNO]≥25十亿分之[ppb]），正在接受中等剂量至高剂量吸入性皮质类固醇和其他控制药物的治疗。

Patients were randomly assigned (2:1; block size of 6) via interactive voice-web response technology to receive add-on dupilumab 300 mg subcutaneously once every 2 weeks or volume-matched placebo up to week 24.

患者通过交互式语音-网络响应技术随机分配（2:1; 块大小为6），每两周接受一次300毫克的dupilumab皮下注射或相匹配的安慰剂，直至第24周。

Randomisation was stratified by inhaled corticosteroids dose level and region (eastern Europe vs the rest of the world).

随机化按吸入性皮质类固醇剂量水平和区域（东欧与世界其他地区）进行分层。

Participants and investigators, including those assessing outcomes, were masked to group assignment.

参与者和研究人员，包括那些评估结果的研究人员，对组别分配进行了盲法处理。

The primary endpoints were the proportion of patients with a FeNO concentration below 25 ppb at week 24, and percentage change from baseline to week 24 in airway volumes (specific regional airway volumes corrected for lung volume, [s]iVaw) at total lung capacity (TLC), both assessed in the intention-to-treatpopulation.

主要终点是第24周时，患者中FeNO浓度低于25 ppb的比例，以及从基线到第24周在总肺容量（TLC）时气道体积（校正肺容量的特定区域气道体积，[s]iVaw）的百分比变化，这两项均在意向治疗人群中评估。

Safety was assessed in all patients who received at least one dose of study drug or placebo.

所有接受至少一次研究药物或安慰剂的患者均进行了安全性评估。

The trial is registered with ClinicalTrials.gov, NCT04400318, and is completed.

该试验已在ClinicalTrials.gov注册，注册号为NCT04400318，并已完成。

Results

Patient recruitment occurred from July 18, 2020, to Jan 6, 2023.

患者招募发生在2020年7月18日至2023年1月6日。

Patients (mean age 50·4 years [SD 12·6]; 68 [62%] female and 41 [38%] male) were randomly assigned to receive dupilumab 300 mg (n=72) or placebo (n=37).

患者（平均年龄50.4岁[标准差12.6]；68名[62%]女性和41名[38%]男性）被随机分配接受300毫克度普利尤单抗（n=72）或安慰剂（n=37）。

At week 24, patients in the dupilumab group were significantly more likely than those in the placebo group to have a FeNO concentration below 25 ppb (41 [57%] of 72 patients vs four [11%] of 37; odds ratio: 9·8 [95% CI 3·1 to 30·8]; p<0·001).

在第24周时，与安慰剂组相比，接受度普利尤单抗治疗的患者更有可能出现FeNO浓度低于25 ppb（72名患者中有41名[57%]，而37名患者中有4名[11%]；比值比：9·8 [95% 置信区间3·1至30·8]；p<0·001）。

Treatment with dupilumab versus placebo led to a numerical increase in (s)iVaw at TLC from baseline to week 24, although the difference was not significant (least squares [LS] mean percentage change from baseline to week 24: 19·7% [SE 8·1] for dupilumab and -2·0% [11·5] for placebo; LS mean difference vs placebo: 21·8% [95% CI -7·7 to 51·3]; p=0·14).

从基线到第24周，接受度普利尤单抗治疗与接受安慰剂治疗相比，(s)iVaw在TLC时有所增加，尽管差异不显著（最小二乘法[LS]平均百分比变化从基线到第24周：度普利尤单抗为19·7% [标准误8·1]，安慰剂为-2·0% [11·5]；与安慰剂相比LS平均差异：21·8% [95% 置信区间-7·7至51·3]；p=0·14）。

Safety was consistent with the reported safety profile for dupilumab.

安全性与 dupilumab 已报告的安全性档案一致。

Treatment-emergent adverse events related to study intervention were reported in 11 (15%) of 72 patients who received dupilumab and four (11%) of 37 who received placebo; no deaths occurred during the intervention period.

与研究干预相关的治疗后不良事件在 72 名接受 dupilumab 治疗的患者中有 11 例（15%），而在接受安慰剂的 37 名患者中有 4 例（11%）；干预期间没有发生死亡事件。

interpretation

The full results of this study indicate that dupilumab reduced airway inflammation and mucus plugging, and improved airway volume and flow, corresponding to improved lung function and asthma control.

本研究的完整结果表明，度普利尤单抗减少了气道炎症和粘液栓塞，并改善了气道体积和气流，对应于肺功能和哮喘控制的改善。

This study highlights the potential of imaging technology to assess disease burden, monitor progression, and evaluate therapeutic responses, which can provide valuable insights to guide clinical decision making for patients with uncontrolled, moderate-to-severe type 2 asthma.

本研究强调了影像技术评估疾病负担、监测进展和评估治疗反应的潜力，这可以为临床决策提供宝贵的见解，以指导未控制的中度至重度2型哮喘患者。

funding

Sanofi and Regeneron Pharmaceuticals.

赛诺菲和再生元制药公司。