Dupilumab对2型哮喘患者呼出一氧化氮、黏液栓和功能性呼吸成像的影响（VESTIGE）：一项随机、双盲、安慰剂对照
2025/03/03
Dupilumab对2型哮喘患者呼出一氧化氮、黏液栓和功能性呼吸成像的影响（VESTIGE）：一项随机、双盲、安慰剂对照的4期试验
摘要
背景：哮喘是一种以慢性气道炎症和黏液分泌过多为特征的呼吸道疾病。VESTIGE研究使用功能性呼吸成像技术评估了Dupilumab对气道结构和功能变化的影响，包括黏液栓的形成。
方法：VESTIGE是一项在14个国家的72个研究场所或学术中心进行的随机、双盲、安慰剂对照的4期试验。我们招募了18至70岁的成年患者，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/μL，且呼出一氧化氮分数[FeNO]≥25亿分之几[ppb]），他们正在接受中等剂量至高剂量的吸入性糖皮质激素与其他控制药物联合治疗。患者通过交互式语音网络响应技术以2:1的比例（区块大小为6）随机分配，接受每2周一次300毫克皮下注射的Dupilumab附加治疗或体积匹配的安慰剂，直至第24周。随机分组按吸入性糖皮质激素剂量水平和地区（美国与非美国）进行分层。参与者和研究者，包括评估结果的研究者，均对分组分配不知情。主要终点是第24周时FeNO浓度低于25 ppb的患者比例，以及从基线到第24周在总肺活量（TLC）时气道体积（特定区域气道体积校正肺体积，[s]iVaw）的百分比变化，均在意向治疗人群中进行评估。安全性在所有接受至少一剂研究药物或安慰剂的患者中进行评估。该试验已在ClinicalTrials.gov注册，编号为NCT04400318，且已完成。
发现：患者招募从2020年7月18日持续至2023年1月6日。患者（平均年龄50.4岁[标准差12.6]；68名[62%]为女性，41名[38%]为男性）被随机分配接受Dupilumab 300毫克（n=72）或安慰剂（n=37）。在第24周，接受Dupilumab治疗的患者比接受安慰剂的患者更有可能使FeNO浓度低于25 ppb（72名患者中有41名[57%]，37名患者中有4名[11%]；比值比：9.8[95%CI 3.1至30.8]；p<0.001）。与安慰剂相比，Dupilumab治疗使（s）iVaw在TLC处从基线到第24周的数值有所增加，尽管差异并不显著（从基线到第24周的最小二乘[LS]平均百分比变化：Dupilumab为19.7%[SE 8.1]，安慰剂为-2.0%[11.5]；与安慰剂相比的LS平均差异：21.8%[95%CI-7.7至51.3]；p=0.14）。安全性与Dupilumab的报告安全性特征一致。在接受Dupilumab治疗的72名患者中有11名（15%），接受安慰剂的37名患者中有4名（11%）报告了与研究干预相关的治疗中出现的不良事件；在干预期间没有发生死亡。
解释：这项研究的完整结果表明，Dupilumab减少了气道炎症和黏液栓塞，改善了气道体积和气流，这对应于肺功能的改善和哮喘控制的改善。这项研究突出了成像技术评估疾病负担、监测进展和评估治疗反应的潜力，这可以为未控制的中度至重度2型哮喘患者的临床决策提供宝贵的见解。
背景：哮喘是一种以慢性气道炎症和黏液分泌过多为特征的呼吸道疾病。VESTIGE研究使用功能性呼吸成像技术评估了Dupilumab对气道结构和功能变化的影响，包括黏液栓的形成。
方法：VESTIGE是一项在14个国家的72个研究场所或学术中心进行的随机、双盲、安慰剂对照的4期试验。我们招募了18至70岁的成年患者，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/μL，且呼出一氧化氮分数[FeNO]≥25亿分之几[ppb]），他们正在接受中等剂量至高剂量的吸入性糖皮质激素与其他控制药物联合治疗。患者通过交互式语音网络响应技术以2:1的比例（区块大小为6）随机分配，接受每2周一次300毫克皮下注射的Dupilumab附加治疗或体积匹配的安慰剂，直至第24周。随机分组按吸入性糖皮质激素剂量水平和地区（美国与非美国）进行分层。参与者和研究者，包括评估结果的研究者，均对分组分配不知情。主要终点是第24周时FeNO浓度低于25 ppb的患者比例，以及从基线到第24周在总肺活量（TLC）时气道体积（特定区域气道体积校正肺体积，[s]iVaw）的百分比变化，均在意向治疗人群中进行评估。安全性在所有接受至少一剂研究药物或安慰剂的患者中进行评估。该试验已在ClinicalTrials.gov注册，编号为NCT04400318，且已完成。
发现：患者招募从2020年7月18日持续至2023年1月6日。患者（平均年龄50.4岁[标准差12.6]；68名[62%]为女性，41名[38%]为男性）被随机分配接受Dupilumab 300毫克（n=72）或安慰剂（n=37）。在第24周，接受Dupilumab治疗的患者比接受安慰剂的患者更有可能使FeNO浓度低于25 ppb（72名患者中有41名[57%]，37名患者中有4名[11%]；比值比：9.8[95%CI 3.1至30.8]；p<0.001）。与安慰剂相比，Dupilumab治疗使（s）iVaw在TLC处从基线到第24周的数值有所增加，尽管差异并不显著（从基线到第24周的最小二乘[LS]平均百分比变化：Dupilumab为19.7%[SE 8.1]，安慰剂为-2.0%[11.5]；与安慰剂相比的LS平均差异：21.8%[95%CI-7.7至51.3]；p=0.14）。安全性与Dupilumab的报告安全性特征一致。在接受Dupilumab治疗的72名患者中有11名（15%），接受安慰剂的37名患者中有4名（11%）报告了与研究干预相关的治疗中出现的不良事件；在干预期间没有发生死亡。
解释：这项研究的完整结果表明，Dupilumab减少了气道炎症和黏液栓塞，改善了气道体积和气流，这对应于肺功能的改善和哮喘控制的改善。这项研究突出了成像技术评估疾病负担、监测进展和评估治疗反应的潜力，这可以为未控制的中度至重度2型哮喘患者的临床决策提供宝贵的见解。
（中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校）
（Lancet Respir Med. 2025 Feb 10:S2213-2600(24)00362-X. doi: 10.1016/S2213-2600(24)00362-X.）
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
Mario Castro, Alberto Papi, Celeste Porsbjerg, Njira L Lugogo, Christopher E Brightling, Francisco-Javier González-Barcala, Arnaud Bourdin, Mykola Ostrovskyy, Maria Staevska, Pai-Chien Chou, Liliana Duca, Ana Margarida Pereira, Charles Fogarty, Rufai Nadama, Mei Zhang, Amelie Rodrigues, Xavier Soler, Harry J Sacks, Yamo Deniz, Paul J Rowe, Lucía de Prado Gómez, Juby A Jacob-Nara
Abstract
Background:Asthma is a respiratory disease characterised by chronic airway inflammation and mucus hypersecretion. VESTIGE used functional respiratory imaging to assess changes in airway structure and function, including mucus plugging, in response to dupilumab.
Methods:VESTIGE was a randomised, double-blind, placebo-controlled, phase 4 trial done at 72 research sites or academic centres in 14 countries. 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. 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. Randomisation was stratified by inhaled corticosteroids dose level and region (USA vs non-USA). Participants and investigators, including those assessing outcomes, were masked to group assignment. 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-treat population. Safety was assessed in all patients who received at least one dose of study drug or placebo. The trial is registered with ClinicalTrials.gov, NCT04400318, and is completed.
Findings:Patient recruitment occurred from July 18, 2020, to Jan 6, 2023. 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). 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). Treatment with dupilumab versus placebo led to a numerical increase in (s)iVawat 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). Safety was consistent with the reported safety profile for dupilumab. 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.
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. 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.
Abstract
Background:Asthma is a respiratory disease characterised by chronic airway inflammation and mucus hypersecretion. VESTIGE used functional respiratory imaging to assess changes in airway structure and function, including mucus plugging, in response to dupilumab.
Methods:VESTIGE was a randomised, double-blind, placebo-controlled, phase 4 trial done at 72 research sites or academic centres in 14 countries. 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. 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. Randomisation was stratified by inhaled corticosteroids dose level and region (USA vs non-USA). Participants and investigators, including those assessing outcomes, were masked to group assignment. 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-treat population. Safety was assessed in all patients who received at least one dose of study drug or placebo. The trial is registered with ClinicalTrials.gov, NCT04400318, and is completed.
Findings:Patient recruitment occurred from July 18, 2020, to Jan 6, 2023. 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). 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). Treatment with dupilumab versus placebo led to a numerical increase in (s)iVawat 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). Safety was consistent with the reported safety profile for dupilumab. 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.
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. 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.
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表型分析系统性糖皮质激素在哮喘发作管理中的反应（PRISMA）
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