使用呼出型一氧化氮(RAACENO)作为生物标志物来减少儿童哮喘发作，为治疗策略提供信息:一项多中心、平行、随机、对照、
2022/03/17
使用呼出型一氧化氮(RAACENO)作为生物标志物来减少儿童哮喘发作，为治疗策略提供信息:一项多中心、平行、随机、对照、3期试验
摘要
背景：部分呼出型一氧化氮(FeNO)在指导哮喘治疗方面的益处尚不确定。我们评估了在哮喘患儿的症状指导治疗中加入FeNO与单纯症状指导治疗的疗效比较。
方法：RAACENO是一项多中心、平行、随机、对照的3期临床试验，在英国的35个二级保健中心和17个初级保健招募站点(只有7个初级保健站点成功招募了患者)进行。哮喘确诊患者，年龄在6-15岁之间，常规吸入糖皮质激素，并在招募前的12个月内至少因一次哮喘加重接受口服糖皮质激素治疗可纳入组。参与者被随机分配到FeNO和症状指导治疗组(干预)或单独症状指导治疗组(标准治疗)，使用24小时的内部、基于网络的随机系统。参与者和临床和研究团队没有被掩蔽到组分配。基于网络的算法根据哮喘控制测试(ACT)或儿童ACT (CACT)评分给出了治疗建议;目前哮喘治疗;在过去3个月内坚持学习治疗;和FeNO的使用情况(干预组)。随访时间为3个月，每次随访12个月。主要转归是随机分组后12个月内口服糖皮质激素治疗的任何哮喘加重，评估的是有意治疗人群。本研究在国际标准随机对照试验注册中心(ISRCTN67875351)注册。
结果：在2017年6月22日和2019年8月8日之间，535名儿童被评估为合格，20名不合格，6名被排除在随机化后。509名儿童被招募，在基线时，参与者的平均年龄为10.1岁(SD 2.6)，308名(60.5%)为男性。中位FeNO为21 ppb (IQR 10-48)，平均预测FEV为89.6% (SD 18.0)，每日吸入皮质类固醇的中位剂量为400 μg布地奈德当量(IQR 400 - 1000)。在509名参与者中，有256人(50.3%)哮喘得到部分或完全控制。509名参与者中有506人(99%)出现了主要结局，255名干预组参与者中有123人(48.2%)出现了主要结局，251名标准护理组参与者中有129人(51.4%)出现了主要结局，意向治疗调整优势比(OR)为0.88 (95% CI为0.61至1.27;p = 0·49)。与接受标准治疗的参与者相比，接受干预的参与者发生主要结局的比例调整后的差异为-3%(- 11.9%至5.6%)。在1771次评估中，有377次(21.3%)没有遵循算法建议。509名参与者中有27人(5.3%)报告了不良事件(15人在标准护理组，12人在干预组)。最常见的不良事件是皮肤点刺试验后瘙痒(每组有8名参与者报告)。
结论：我们发现，在症状引导的哮喘治疗中添加FeNO并没有导致易于哮喘加重的儿童哮喘加重的减少。哮喘症状仍然是指导治疗决定的唯一工具。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Lancet Respir Med. 2022 Jan 28;S2213-2600(21)00486-0. doi: 10.1016/S2213-2600(21)00486-0.）
（Lancet Respir Med. 2022 Jan 28;S2213-2600(21)00486-0. doi: 10.1016/S2213-2600(21)00486-0.）
Reducing asthma attacks in children using exhaled nitric oxide (RAACENO) as a biomarker to inform treatment strategy: a multicentre, parallel, randomised, controlled, phase 3 trial
Turner S, Cotton S, Wood J, et al.
Abtract
BACKGROUND:The benefit of fractional exhaled nitric oxide (FeNO) in guiding asthma treatment is uncertain. We evaluated the efficacy of adding FeNO to symptom-guided treatment in children with asthma versus only symptom-guided treatment.
METHODS:RAACENO was a multicenter, parallel, randomized, controlled, phase 3 trial done in 35 secondary care centers and 17 primary care recruitment sites (only seven primary care sites managed to recruit patients) in the UK. Patients with a confirmed asthma diagnosis, aged 6–15 years, prescribed inhaled corticosteroids, and who received a course of oral corticosteroids for at least one asthma exacerbation during the 12 months before recruitment were included. Participants were randomly assigned to either FeNO plus symptom-guided treatment (intervention) or symptom-guided treatment alone (standard care) using a 24 h in-house, web-based randomization system. Participants and the clinical and research teams were not masked to the group allocation. A web-based algorithm gave treatment recommendations based on the Asthma Control Test (ACT) or Childhood ACT (CACT) score; current asthma treatment; adherence to study treatment in the past 3 months; and use of FeNO (in the intervention group). Follow-up occurred at 3- month intervals for 12 months. The primary outcome was any asthma exacerbation treated with oral corticosteroids in the 12 months afer randomization, assessed in the intention-to-treat population. This study is registered with the International Standard Randomized Controlled Trial Registry, ISRCTN67875351.
RESULTS: Between June 22, 2017, and Aug 8, 2019, 535 children were assessed for eligibility, 20 were ineligible and six were excluded post randomization. 509 children were recruited and at baseline, the mean age of participants was 10.1 years (SD 2.6), and 308 (60.5%) were male. The median FeNO was 21 ppb (IQR 10–48), mean predicted FEV was 89.6% (SD 18.0), and median daily dose of inhaled corticosteroids was 400 μg budesonide equivalent (IQR 400– 1000). Asthma was partly or fully controlled in 256 (50.3%) of 509 participants. The primary outcome, which was available for 506 (99%) of 509 participants, occurred in 123 (48.2%) of 255 participants in the intervention group and 129 (51.4%) of 251 in the standard care group, the intention-to-treat adjusted odds ratio (OR) was 0.88 (95% CI 0.61 to 1.27; p=0.49). The adjusted difference in the percentage of participants who received the intervention in whom the primary outcome occurred compared with those who received standard care was −3·1% (−11.9% to 5.6%). In 377 (21.3%) of 1771 assessments, the algorithm recommendation was not followed. Adverse events were reported by 27 (5.3%) of 509 participants (15 in the standard care group and 12 in the intervention group). The most common adverse event was itch after skin prick testing (reported by eight participants in each group).
CONCLUSIONS: We found that the addition of FeNO to symptom-guided asthma treatment did not lead to reduced exacerbations among children prone to asthma exacerbation. Asthma symptoms remain the only tool for guiding treatment decisions.
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