数字化用药依从性和肺功能测量在指导未控制哮喘治疗中的应用（INCA Sun）：一项多中心、单盲、随机临床试验
2023/04/21
摘要
背景：数字工具评估未控制哮喘患者的依从性和肺功能的临床价值尚不清楚。本研究旨在比较运用数字化获取的用药依从性、吸入器使用方法和峰流量数据与现有方法指导治疗决策的效果。
方法：本研究在爱尔兰、北爱尔兰和英格兰的10个重症哮喘诊所进行为期32周的前瞻性、多中心、单盲、平行、随机对照试验。受试者年龄18岁及以上，罹患未控制哮喘，哮喘控制测试（ACT）评分在19分及以下，尽管接受高剂量吸入性糖皮质激素治疗，但在过去一年内至少有一次严重急性发作。根据呼出气一氧化氮（FeNO）浓度和招募站点进行分层，采用计算机生成的排列块大小（2、4和6）的随机分配序列，按1：1将患者随机分配至活动组或对照组。在对照组中，受试者不知道自己的用药依从性和吸入器错误使用相关数据。统计学家单盲进行统计分析。在进行为期1周的试验期前，两组患者在8周内接受了三次护士主导的教育随访（第7天、第4周和第8周）和三次医师主导的治疗调整随访（第8、20和32周）。在活动组中，医师随访期间的治疗调整基于吸入器用药依从性、每日两次的数字化最大呼气峰流量（ePEF）、患者报告的哮喘控制和急性加重情况的数字化数据。在对照组中，治疗调整基于用药补充率（用药依从性的一种度量）、ACT问卷评估的哮喘控制状况以及急性加重情况和吸入器使用方法的可视化管理。两组均使用数字化的吸入器依从性评估（INCA）和PEF。主要结局为在32周结束时需要净增加治疗的患者比例和意向性治疗人群中最后12周内的依从性率。安全性分析包括所有同意参加试验的患者。该试验已在ClinicalTrials.gov注册，编号为NCT02307669，已完成。
结果：在2015年10月25日至2020年1月26日期间，共有425名患者接受了纳入资格评估，其中220名同意参加研究，213名接受随机分配（活动组108名，对照组105名），200名完成了研究（活动组102名，对照组98名）。在32周的意向治疗分析中，与基线相比，14名（14％）活动组患者和31名（32％）对照组患者的治疗有净增加（比值比[OR] 0.31 [95％ CI 0.15-0.64]，p = 0.0015），11名（11％）活动组患者和21名（21％）对照组患者需要补充生物治疗（0.42 [0.19-0.95]，p = 0.038），调整了研究地点、年龄、性别和基线FeNO。19名活动组患者中有3名（16％）和25名对照组患者中有11名（44％）需要将吸入剂的氟替卡松丙酸盐剂量从500μg/天增加到1000μg/天（每天500μg，调整后的OR 0.23 [0.06-0.87]，p = 0.026）。83名活动组患者中的26名（31％）和73名对照组患者中的13名（18％）患者需要将吸入剂的氟替卡松丙酸盐剂量从每天1000μg减少到每天500μg（调整后的OR 2.43 [1.13-5.20]，p = 0.022）。在20-32周的实际平均依从性中，活动组的平均依从性为64.9％（SD 23.5），而对照组为55.5％（26.8），两组之间的差异为11.1％ [95％ CI 4.4-17.9]，p = 0.0012。共收到29个严重不良事件（活动组16个[55％]，对照组13个[45％]）报告，其中11件确认为呼吸系统事件。所报告不良事件与研究干预、沙美特罗-氟替卡松吸入剂的使用或数字PEF或INCA的使用均无因果关联。
结论：数字化数据支持的基于证据的医疗管理可适度改善患者用药依从性并显著减轻患者治疗负担。
Use of digital measurement of medication adherence and lung function to guide the management of uncontrolled asthma (INCA Sun): a multicentre, single-blinded, randomised clinical trial.
Hale EM, Greene G, Mulvey C, Mokoka MC, van Boven JFM, Cushen B, Sulaiman I, Brennan V, Kerr PJ, Reilly RB, Hughes C, Kent BD, Jackson DJ, Butler M, Counihan I, Hayes J, Faul J, Kelly M, Convery R, Nanzer Kelly AM, Fitzgerald JM, Murphy DM, Heaney LG, Costello RW; INCA Research Team.
Abstract
BACKGROUND:The clinical value of using digital tools to assess adherence and lung function in uncontrolled asthma is not known. We aimed to compare treatment decisions guided by digitally acquired data on adherence, inhaler technique, and peak flow with existing methods.
METHODS:A 32-week prospective, multicentre, single-blinded, parallel, randomly controlled trial was done in ten severe asthma clinics across Ireland, Northern Ireland, and England. Participants were 18 years or older, had uncontrolled asthma, asthma control test (ACT) score of 19 or less, despite treatment with high-dose inhaled corticosteroids, and had at least one severe exacerbation in the past year despite high-dose inhaled corticosteroids. Patients were randomly assigned in a 1:1 ratio to the active group or the control group, by means of a computer-generated randomisation sequence of permuted blocks of varying sizes (2, 4, and 6) stratified by fractional exhaled nitric oxide (FeNO) concentration and recruitment site. In the control group, participants were masked to their adherence and errors in inhaler technique data. A statistician masked to study allocation did the statistical analysis. After a 1-week run-in period, both groups attended three nurse-led education visits over 8 weeks (day 7, week 4, and week 8) and three physician-led treatment adjustment visits at weeks 8, 20, and 32. In the active group, treatment adjustments during the physician visits were informed by digital data on inhaler adherence, twice daily digital peak expiratory flow (ePEF), patient-reported asthma control, and exacerbation history. Treatment was adjusted in the control group on the basis of pharmacy refill rates (a measure of adherence), asthma control by ACT questionnaire, and history of exacerbations and visual management of inhaler technique. Both groups used a digitally enabled Inhaler Compliance Assessment (INCA) and PEF. The primary outcomes were asthma medication burden measured as proportion of patients who required a net increase in treatment at the end of 32 weeks and adherence rate measured in the last 12 weeks by area under the curve in the intention-to-treat population. The safety analyses included all patients who consented for the trial. The trial is registered with ClinicalTrials.gov, NCT02307669 and is complete.
RESULTS:Between Oct 25, 2015, and Jan 26, 2020, of 425 patients assessed for eligibility, 220 consented to participate in the study, 213 were randomly assigned (n=108 in the active group; n=105 in the control group) and 200 completed the study (n=102 in the active group; n=98 in the control group). In the intention-to-treat analysis at week 32, 14 (14%) active and 31 (32%) control patients had a net increase in treatment compared with baseline (odds ratio [OR] 0.31 [95% CI 0.15-0.64], p=0.0015) and 11 (11%) active and 21 (21%) controls required add-on biological therapy (0.42 [0.19-0.95], p=0.038) adjusted for study site, age, sex, and baseline FeNO. Three (16%) of 19 active and 11 (44%) of 25 control patients increased their medication from fluticasone propionate 500 μg daily to 1000 μg daily (500 μg twice a day; adjusted OR 0.23 [0.06-0.87], p=0.026). 26 (31%) of 83 active and 13 (18%) of 73 controls reduced their medication from fluticasone propionate 1000 μg once daily to 500 μg once daily (adjusted OR 2.43 [1.13-5.20], p=0.022. Week 20-32 actual mean adherence was 64.9% (SD 23.5) in the active group and 55.5% (26.8) in the control group (between-group difference 11.1% [95% CI 4.4-17.9], p=0.0012). A total of 29 serious adverse events were recorded (16 [55%] in the active group, and 13 [45%] in the control group), 11 of which were confirmed as respiratory. None of the adverse events reported were causally linked to the study intervention, to the use of salmeterol-fluticasone inhalers, or the use of the digital PEF or INCA.
CONCLUSIONS:Evidence-based care informed by digital data led to a modest improvement in medication adherence and a significantly lower treatment burden.
背景：数字工具评估未控制哮喘患者的依从性和肺功能的临床价值尚不清楚。本研究旨在比较运用数字化获取的用药依从性、吸入器使用方法和峰流量数据与现有方法指导治疗决策的效果。
方法：本研究在爱尔兰、北爱尔兰和英格兰的10个重症哮喘诊所进行为期32周的前瞻性、多中心、单盲、平行、随机对照试验。受试者年龄18岁及以上，罹患未控制哮喘，哮喘控制测试（ACT）评分在19分及以下，尽管接受高剂量吸入性糖皮质激素治疗，但在过去一年内至少有一次严重急性发作。根据呼出气一氧化氮（FeNO）浓度和招募站点进行分层，采用计算机生成的排列块大小（2、4和6）的随机分配序列，按1：1将患者随机分配至活动组或对照组。在对照组中，受试者不知道自己的用药依从性和吸入器错误使用相关数据。统计学家单盲进行统计分析。在进行为期1周的试验期前，两组患者在8周内接受了三次护士主导的教育随访（第7天、第4周和第8周）和三次医师主导的治疗调整随访（第8、20和32周）。在活动组中，医师随访期间的治疗调整基于吸入器用药依从性、每日两次的数字化最大呼气峰流量（ePEF）、患者报告的哮喘控制和急性加重情况的数字化数据。在对照组中，治疗调整基于用药补充率（用药依从性的一种度量）、ACT问卷评估的哮喘控制状况以及急性加重情况和吸入器使用方法的可视化管理。两组均使用数字化的吸入器依从性评估（INCA）和PEF。主要结局为在32周结束时需要净增加治疗的患者比例和意向性治疗人群中最后12周内的依从性率。安全性分析包括所有同意参加试验的患者。该试验已在ClinicalTrials.gov注册，编号为NCT02307669，已完成。
结果：在2015年10月25日至2020年1月26日期间，共有425名患者接受了纳入资格评估，其中220名同意参加研究，213名接受随机分配（活动组108名，对照组105名），200名完成了研究（活动组102名，对照组98名）。在32周的意向治疗分析中，与基线相比，14名（14％）活动组患者和31名（32％）对照组患者的治疗有净增加（比值比[OR] 0.31 [95％ CI 0.15-0.64]，p = 0.0015），11名（11％）活动组患者和21名（21％）对照组患者需要补充生物治疗（0.42 [0.19-0.95]，p = 0.038），调整了研究地点、年龄、性别和基线FeNO。19名活动组患者中有3名（16％）和25名对照组患者中有11名（44％）需要将吸入剂的氟替卡松丙酸盐剂量从500μg/天增加到1000μg/天（每天500μg，调整后的OR 0.23 [0.06-0.87]，p = 0.026）。83名活动组患者中的26名（31％）和73名对照组患者中的13名（18％）患者需要将吸入剂的氟替卡松丙酸盐剂量从每天1000μg减少到每天500μg（调整后的OR 2.43 [1.13-5.20]，p = 0.022）。在20-32周的实际平均依从性中，活动组的平均依从性为64.9％（SD 23.5），而对照组为55.5％（26.8），两组之间的差异为11.1％ [95％ CI 4.4-17.9]，p = 0.0012。共收到29个严重不良事件（活动组16个[55％]，对照组13个[45％]）报告，其中11件确认为呼吸系统事件。所报告不良事件与研究干预、沙美特罗-氟替卡松吸入剂的使用或数字PEF或INCA的使用均无因果关联。
结论：数字化数据支持的基于证据的医疗管理可适度改善患者用药依从性并显著减轻患者治疗负担。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Lancet Respir Med. 2023 Mar 21:S2213-2600(22)00534-3. doi: 10.1016/S2213-2600(22)00534-3.)
(Lancet Respir Med. 2023 Mar 21:S2213-2600(22)00534-3. doi: 10.1016/S2213-2600(22)00534-3.)
Use of digital measurement of medication adherence and lung function to guide the management of uncontrolled asthma (INCA Sun): a multicentre, single-blinded, randomised clinical trial.
Hale EM, Greene G, Mulvey C, Mokoka MC, van Boven JFM, Cushen B, Sulaiman I, Brennan V, Kerr PJ, Reilly RB, Hughes C, Kent BD, Jackson DJ, Butler M, Counihan I, Hayes J, Faul J, Kelly M, Convery R, Nanzer Kelly AM, Fitzgerald JM, Murphy DM, Heaney LG, Costello RW; INCA Research Team.
Abstract
BACKGROUND:The clinical value of using digital tools to assess adherence and lung function in uncontrolled asthma is not known. We aimed to compare treatment decisions guided by digitally acquired data on adherence, inhaler technique, and peak flow with existing methods.
METHODS:A 32-week prospective, multicentre, single-blinded, parallel, randomly controlled trial was done in ten severe asthma clinics across Ireland, Northern Ireland, and England. Participants were 18 years or older, had uncontrolled asthma, asthma control test (ACT) score of 19 or less, despite treatment with high-dose inhaled corticosteroids, and had at least one severe exacerbation in the past year despite high-dose inhaled corticosteroids. Patients were randomly assigned in a 1:1 ratio to the active group or the control group, by means of a computer-generated randomisation sequence of permuted blocks of varying sizes (2, 4, and 6) stratified by fractional exhaled nitric oxide (FeNO) concentration and recruitment site. In the control group, participants were masked to their adherence and errors in inhaler technique data. A statistician masked to study allocation did the statistical analysis. After a 1-week run-in period, both groups attended three nurse-led education visits over 8 weeks (day 7, week 4, and week 8) and three physician-led treatment adjustment visits at weeks 8, 20, and 32. In the active group, treatment adjustments during the physician visits were informed by digital data on inhaler adherence, twice daily digital peak expiratory flow (ePEF), patient-reported asthma control, and exacerbation history. Treatment was adjusted in the control group on the basis of pharmacy refill rates (a measure of adherence), asthma control by ACT questionnaire, and history of exacerbations and visual management of inhaler technique. Both groups used a digitally enabled Inhaler Compliance Assessment (INCA) and PEF. The primary outcomes were asthma medication burden measured as proportion of patients who required a net increase in treatment at the end of 32 weeks and adherence rate measured in the last 12 weeks by area under the curve in the intention-to-treat population. The safety analyses included all patients who consented for the trial. The trial is registered with ClinicalTrials.gov, NCT02307669 and is complete.
RESULTS:Between Oct 25, 2015, and Jan 26, 2020, of 425 patients assessed for eligibility, 220 consented to participate in the study, 213 were randomly assigned (n=108 in the active group; n=105 in the control group) and 200 completed the study (n=102 in the active group; n=98 in the control group). In the intention-to-treat analysis at week 32, 14 (14%) active and 31 (32%) control patients had a net increase in treatment compared with baseline (odds ratio [OR] 0.31 [95% CI 0.15-0.64], p=0.0015) and 11 (11%) active and 21 (21%) controls required add-on biological therapy (0.42 [0.19-0.95], p=0.038) adjusted for study site, age, sex, and baseline FeNO. Three (16%) of 19 active and 11 (44%) of 25 control patients increased their medication from fluticasone propionate 500 μg daily to 1000 μg daily (500 μg twice a day; adjusted OR 0.23 [0.06-0.87], p=0.026). 26 (31%) of 83 active and 13 (18%) of 73 controls reduced their medication from fluticasone propionate 1000 μg once daily to 500 μg once daily (adjusted OR 2.43 [1.13-5.20], p=0.022. Week 20-32 actual mean adherence was 64.9% (SD 23.5) in the active group and 55.5% (26.8) in the control group (between-group difference 11.1% [95% CI 4.4-17.9], p=0.0012). A total of 29 serious adverse events were recorded (16 [55%] in the active group, and 13 [45%] in the control group), 11 of which were confirmed as respiratory. None of the adverse events reported were causally linked to the study intervention, to the use of salmeterol-fluticasone inhalers, or the use of the digital PEF or INCA.
CONCLUSIONS:Evidence-based care informed by digital data led to a modest improvement in medication adherence and a significantly lower treatment burden.
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