Pub Date : 2024-08-30DOI: 10.1016/S2213-2600(24)00222-4
Surinder S Birring, Linda Cardozo, Roger Dmochowski, Peter Dicpinigaitis, Amna Afzal, Carmen La Rosa, Susan Lu, Allison Martin Nguyen, Ruji Yao, Paul A Reyfman
Background: Approximately two-thirds of women with chronic cough have cough-induced stress urinary incontinence (CSUI). We aimed to evaluate the efficacy and safety of gefapixant in reducing CSUI episodes in women with refractory or unexplained chronic cough.
Methods: This phase 3b, double-blind, randomised, placebo-controlled trial done at 90 sites in 12 countries enrolled women aged 18 years or older who had chronic cough for at least 1 year, a diagnosis of refractory or unexplained chronic cough, a cough severity visual analogue scale score of 40 mm or more (100 mm maximum), and CSUI for 3 months or more. Participants were randomised 1:1 to oral gefapixant or placebo for 12 weeks. The primary outcome was percentage change from baseline in daily CSUI episodes (7-day average) at week 12. This study is registered with ClinicalTrials.gov (NCT04193176).
Findings: From May 10, 2020, to Sept 2, 2022, 375 participants were randomised to and treated with gefapixant 45 mg twice daily (n=185) or placebo (n=190). Mean age was 56·4 years (SD 11·4), with mean chronic cough duration of 5·2 years (SD 6·6) and SUI duration of 4·0 years (SD 5·9). Least-squares mean percentage change from baseline in daily CSUI episodes was -52·8% (95% CI -58·4 to -47·1%) for gefapixant and -41·1% (-46·7 to -35·4%) for placebo (estimated treatment difference: -11·7% [95% CI -19·7 to -3·7]; p=0·004). 129 (70%) of 185 participants who received gefapixant and 71 (37%) of 190 participants who received placebo had at least one adverse event. Safety and tolerability were consistent with previous trials of gefapixant; the most frequent adverse events were taste related.
Interpretation: Gefapixant 45 mg twice daily is the first treatment to show efficacy versus placebo in reducing CSUI episodes in participants with refractory or unexplained chronic cough.
Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co.
{"title":"Efficacy and safety of gefapixant in women with chronic cough and cough-induced stress urinary incontinence: a phase 3b, randomised, multicentre, double-blind, placebo-controlled trial.","authors":"Surinder S Birring, Linda Cardozo, Roger Dmochowski, Peter Dicpinigaitis, Amna Afzal, Carmen La Rosa, Susan Lu, Allison Martin Nguyen, Ruji Yao, Paul A Reyfman","doi":"10.1016/S2213-2600(24)00222-4","DOIUrl":"https://doi.org/10.1016/S2213-2600(24)00222-4","url":null,"abstract":"<p><strong>Background: </strong>Approximately two-thirds of women with chronic cough have cough-induced stress urinary incontinence (CSUI). We aimed to evaluate the efficacy and safety of gefapixant in reducing CSUI episodes in women with refractory or unexplained chronic cough.</p><p><strong>Methods: </strong>This phase 3b, double-blind, randomised, placebo-controlled trial done at 90 sites in 12 countries enrolled women aged 18 years or older who had chronic cough for at least 1 year, a diagnosis of refractory or unexplained chronic cough, a cough severity visual analogue scale score of 40 mm or more (100 mm maximum), and CSUI for 3 months or more. Participants were randomised 1:1 to oral gefapixant or placebo for 12 weeks. The primary outcome was percentage change from baseline in daily CSUI episodes (7-day average) at week 12. This study is registered with ClinicalTrials.gov (NCT04193176).</p><p><strong>Findings: </strong>From May 10, 2020, to Sept 2, 2022, 375 participants were randomised to and treated with gefapixant 45 mg twice daily (n=185) or placebo (n=190). Mean age was 56·4 years (SD 11·4), with mean chronic cough duration of 5·2 years (SD 6·6) and SUI duration of 4·0 years (SD 5·9). Least-squares mean percentage change from baseline in daily CSUI episodes was -52·8% (95% CI -58·4 to -47·1%) for gefapixant and -41·1% (-46·7 to -35·4%) for placebo (estimated treatment difference: -11·7% [95% CI -19·7 to -3·7]; p=0·004). 129 (70%) of 185 participants who received gefapixant and 71 (37%) of 190 participants who received placebo had at least one adverse event. Safety and tolerability were consistent with previous trials of gefapixant; the most frequent adverse events were taste related.</p><p><strong>Interpretation: </strong>Gefapixant 45 mg twice daily is the first treatment to show efficacy versus placebo in reducing CSUI episodes in participants with refractory or unexplained chronic cough.</p><p><strong>Funding: </strong>Merck Sharp & Dohme, a subsidiary of Merck & Co.</p>","PeriodicalId":51307,"journal":{"name":"Lancet Respiratory Medicine","volume":null,"pages":null},"PeriodicalIF":38.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/S2213-2600(24)00248-0
Imran Howell, Aleksandra Howell, Ian Pavord
{"title":"Navigating uncertainty: asthma biologics during pregnancy.","authors":"Imran Howell, Aleksandra Howell, Ian Pavord","doi":"10.1016/S2213-2600(24)00248-0","DOIUrl":"https://doi.org/10.1016/S2213-2600(24)00248-0","url":null,"abstract":"","PeriodicalId":51307,"journal":{"name":"Lancet Respiratory Medicine","volume":null,"pages":null},"PeriodicalIF":38.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/S2213-2600(24)00174-7
Jennifer Naftel, David J Jackson, Matthew Coleman, Grainne d'Ancona, Liam G Heaney, Paddy Dennison, Apostolos Bossios, Hitasha Rupani
Uncontrolled asthma is associated with an increased risk of adverse perinatal outcomes. Asthma biologics reduce exacerbation frequency, are steroid sparing, and improve quality of life in people with severe asthma. However, evidence for the use and safety of asthma biologics during pregnancy is scarce, largely because pregnant women were excluded from clinical trials. To help to support clinical teams, we conducted an international modified Delphi study. 141 panellists from 32 countries who were involved in the care of people with severe asthma completed two rounds of online surveys covering key areas surrounding the use of asthma biologics in pregnancy. The results from this international Delphi study emphasise risk versus benefit discussions and shared clinical decision making, with consensus among panellists that asthma biologics can be used during conception and throughout pregnancy, initiated during pregnancy in line with prescribing criteria for non-pregnant people, and initiated or continued during breastfeeding. Collating data through international registries remains essential to inform clinical guidelines.
{"title":"An international consensus on the use of asthma biologics in pregnancy.","authors":"Jennifer Naftel, David J Jackson, Matthew Coleman, Grainne d'Ancona, Liam G Heaney, Paddy Dennison, Apostolos Bossios, Hitasha Rupani","doi":"10.1016/S2213-2600(24)00174-7","DOIUrl":"https://doi.org/10.1016/S2213-2600(24)00174-7","url":null,"abstract":"<p><p>Uncontrolled asthma is associated with an increased risk of adverse perinatal outcomes. Asthma biologics reduce exacerbation frequency, are steroid sparing, and improve quality of life in people with severe asthma. However, evidence for the use and safety of asthma biologics during pregnancy is scarce, largely because pregnant women were excluded from clinical trials. To help to support clinical teams, we conducted an international modified Delphi study. 141 panellists from 32 countries who were involved in the care of people with severe asthma completed two rounds of online surveys covering key areas surrounding the use of asthma biologics in pregnancy. The results from this international Delphi study emphasise risk versus benefit discussions and shared clinical decision making, with consensus among panellists that asthma biologics can be used during conception and throughout pregnancy, initiated during pregnancy in line with prescribing criteria for non-pregnant people, and initiated or continued during breastfeeding. Collating data through international registries remains essential to inform clinical guidelines.</p>","PeriodicalId":51307,"journal":{"name":"Lancet Respiratory Medicine","volume":null,"pages":null},"PeriodicalIF":38.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1016/S2213-2600(24)00249-2
Pierre-Régis Burgel
{"title":"Expanding the indication of CFTR modulator combinations for people with cystic fibrosis with non-F508del variants.","authors":"Pierre-Régis Burgel","doi":"10.1016/S2213-2600(24)00249-2","DOIUrl":"https://doi.org/10.1016/S2213-2600(24)00249-2","url":null,"abstract":"","PeriodicalId":51307,"journal":{"name":"Lancet Respiratory Medicine","volume":null,"pages":null},"PeriodicalIF":38.7,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1016/S2213-2600(24)00205-4
George M Solomon, Rachel W Linnemann, Rachel Rich, Ashleigh Streby, Brian Buehler, Eric Hunter, Kadambari Vijaykumar, William R Hunt, John J Brewington, Andras Rab, Shasha P Bai, Adrianna L Westbrook, Carmel McNicholas-Bevensee, Jong Hong, Candela Manfredi, Cristina Barilla, Shingo Suzuki, Brian R Davis, Eric J Sorscher
<p><strong>Background: </strong>CFTR modulators are approved for approximately 90% of people with cystic fibrosis in the USA and provide substantial clinical benefit. N1303K (Asn1303Lys), one of the most common class 2 CFTR defects, has not been approved for these therapies by any regulatory agency. Preclinical investigation by our laboratories showed N1303K CFTR activation with elexacaftor-tezacaftor-ivacaftor (ETI). In this trial, we evaluate whether ETI improves CFTR function, measured by sweat chloride and other clinical outcomes, in people with cystic fibrosis and CFTR<sup>N1303K</sup>.</p><p><strong>Methods: </strong>In this prospective, open-label, single-arm trial, participants aged 12 years or older with cystic fibrosis encoding at least one N1303K variant and at least one CFTR<sup>N1303K</sup> allele who were ineligible for modulator therapy by US Food and Drug Administration labelling were given ETI for 28 days followed by a 28-day washout period at two cystic fibrosis centres in the USA. Participants received two orally administered pills of 100 mg elexacaftor, 50 mg tezacaftor, and 75 mg ivacaftor once daily in the morning, and 150 mg ivacaftor once daily in the evening. The primary endpoint was mean change in sweat chloride from baseline up to day 28 compared with mixed-effects models. Secondary endpoints were changes in percentage of predicted FEV<sub>1</sub> (ppFEV<sub>1</sub>), Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain, BMI, and weight after ETI therapy. Safety was assessed in all participants who received at least one dose of the study drug and primary and secondary analyses were performed in all participants who took the study drug per protocol. The trial was registered at ClinicalTrials.gov (NCT03506061) and remains open for reporting purposes.</p><p><strong>Findings: </strong>Between June 7, 2022, and Oct 20, 2023, 20 participants (ten male and ten female) were enrolled and received ETI treatment. One participant was lost to follow-up but was included in intention-to-treat analyses. At 28 days, the mean sweat chloride reduction was -1·1 mmol/L (95% CI -5·3 to 3·1; p=0·61) with only one participant showing a sweat chloride decrease greater than 15 mmol/L. There was a mean increase in ppFEV<sub>1</sub> from baseline at day 28 of 9·5 percentage points (6·7-12·3; p<0·0001) with 15 (75%) participants showing at least a 5% increase in ppFEV<sub>1</sub>. Improvements were also identified in mean CFQ-R respiratory domain score (20·8 increase [95% CI 11·9-29·8]; p<0·0001), BMI (0·4 kg/m<sup>2</sup> increase [0·2-0·7]; p=0·0017), and weight (1·0 kg increase [0·4-1·7]; p=0·0020) after 28 days of ETI treatment. 14 (70%) of 20 participants had adverse events (12 [60%] mild, one [5%] moderate), with one (5%) serious adverse event of hospitalisation attributed to pneumonia. No deaths were recorded in the study.</p><p><strong>Interpretation: </strong>Individuals with CFTR<sup>N1303K</sup> showed no change in sweat chlo
背景：在美国，约有 90% 的囊性纤维化患者已获准使用 CFTR 调节剂，并从中获得了巨大的临床益处。N1303K（Asn1303Lys）是最常见的 2 类 CFTR 缺陷之一，尚未被任何监管机构批准用于这些疗法。我们实验室的临床前研究显示，依来卡夫托-替扎卡夫托-依瓦卡夫托（ETI）可激活 N1303K CFTR。在这项试验中，我们将评估 ETI 是否能改善囊性纤维化和 CFTRN1303K 患者的 CFTR 功能（通过氯化汗液和其他临床结果测量）：在这项前瞻性、开放标签、单臂试验中，美国两家囊性纤维化中心为年龄在 12 岁或以上、至少有一个 N1303K 变异和至少有一个 CFTRN1303K 等位基因的囊性纤维化患者提供了 28 天的 ETI 治疗，随后是 28 天的冲洗期。参试者每天早上口服100毫克 elexacaftor、50毫克 tezacaftor和75毫克 ivacaftor，晚上口服150毫克 ivacaftor。主要终点是与混合效应模型比较从基线到第 28 天的汗液氯化物平均变化。次要终点是 ETI 治疗后预测 FEV1（ppFEV1）百分比、囊性纤维化问卷修订版（CFQ-R）呼吸领域、体重指数和体重的变化。对所有至少服用过一次研究药物的参与者进行了安全性评估，并对所有按方案服用研究药物的参与者进行了主要和次要分析。该试验已在ClinicalTrials.gov（NCT03506061）上注册，目前仍处于开放报告状态：2022年6月7日至2023年10月20日期间，20名参与者（10男10女）注册并接受了ETI治疗。一名患者失去了随访机会，但被纳入了意向治疗分析。28天后，平均汗液氯化物降幅为-1-1毫摩尔/升（95% CI -5-3至3-1；P=0-61），只有一名参与者的汗液氯化物降幅超过15毫摩尔/升。第 28 天时，ppFEV1 与基线相比平均增加了 9-5 个百分点（6-7-12-3；p1）。ETI治疗28天后，CFQ-R呼吸领域平均得分也有改善（增加20-8分[95% CI 11-9-29-8]；p2增加[0-2-0-7]；p=0-0017），体重也有改善（增加1-0千克[0-4-1-7]；p=0-0020）。20名参与者中有14人（70%）出现不良反应（12人[60%]为轻度，1人[5%]为中度），其中1人（5%）因肺炎而住院治疗。研究中没有死亡记录：CFTRN1303K患者在接受28天的ETI治疗后，汗液氯化物没有变化。然而，次要临床终点有所改善，这表明了临床疗效。我们的方法为使用体外模型系统为罕见CFTR变体的临床试验提供信息提供了支持：囊性纤维化基金会和美国国立卫生研究院。
{"title":"Evaluation of elexacaftor-tezacaftor-ivacaftor treatment in individuals with cystic fibrosis and CFTR<sup>N1303K</sup> in the USA: a prospective, multicentre, open-label, single-arm trial.","authors":"George M Solomon, Rachel W Linnemann, Rachel Rich, Ashleigh Streby, Brian Buehler, Eric Hunter, Kadambari Vijaykumar, William R Hunt, John J Brewington, Andras Rab, Shasha P Bai, Adrianna L Westbrook, Carmel McNicholas-Bevensee, Jong Hong, Candela Manfredi, Cristina Barilla, Shingo Suzuki, Brian R Davis, Eric J Sorscher","doi":"10.1016/S2213-2600(24)00205-4","DOIUrl":"https://doi.org/10.1016/S2213-2600(24)00205-4","url":null,"abstract":"<p><strong>Background: </strong>CFTR modulators are approved for approximately 90% of people with cystic fibrosis in the USA and provide substantial clinical benefit. N1303K (Asn1303Lys), one of the most common class 2 CFTR defects, has not been approved for these therapies by any regulatory agency. Preclinical investigation by our laboratories showed N1303K CFTR activation with elexacaftor-tezacaftor-ivacaftor (ETI). In this trial, we evaluate whether ETI improves CFTR function, measured by sweat chloride and other clinical outcomes, in people with cystic fibrosis and CFTR<sup>N1303K</sup>.</p><p><strong>Methods: </strong>In this prospective, open-label, single-arm trial, participants aged 12 years or older with cystic fibrosis encoding at least one N1303K variant and at least one CFTR<sup>N1303K</sup> allele who were ineligible for modulator therapy by US Food and Drug Administration labelling were given ETI for 28 days followed by a 28-day washout period at two cystic fibrosis centres in the USA. Participants received two orally administered pills of 100 mg elexacaftor, 50 mg tezacaftor, and 75 mg ivacaftor once daily in the morning, and 150 mg ivacaftor once daily in the evening. The primary endpoint was mean change in sweat chloride from baseline up to day 28 compared with mixed-effects models. Secondary endpoints were changes in percentage of predicted FEV<sub>1</sub> (ppFEV<sub>1</sub>), Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain, BMI, and weight after ETI therapy. Safety was assessed in all participants who received at least one dose of the study drug and primary and secondary analyses were performed in all participants who took the study drug per protocol. The trial was registered at ClinicalTrials.gov (NCT03506061) and remains open for reporting purposes.</p><p><strong>Findings: </strong>Between June 7, 2022, and Oct 20, 2023, 20 participants (ten male and ten female) were enrolled and received ETI treatment. One participant was lost to follow-up but was included in intention-to-treat analyses. At 28 days, the mean sweat chloride reduction was -1·1 mmol/L (95% CI -5·3 to 3·1; p=0·61) with only one participant showing a sweat chloride decrease greater than 15 mmol/L. There was a mean increase in ppFEV<sub>1</sub> from baseline at day 28 of 9·5 percentage points (6·7-12·3; p<0·0001) with 15 (75%) participants showing at least a 5% increase in ppFEV<sub>1</sub>. Improvements were also identified in mean CFQ-R respiratory domain score (20·8 increase [95% CI 11·9-29·8]; p<0·0001), BMI (0·4 kg/m<sup>2</sup> increase [0·2-0·7]; p=0·0017), and weight (1·0 kg increase [0·4-1·7]; p=0·0020) after 28 days of ETI treatment. 14 (70%) of 20 participants had adverse events (12 [60%] mild, one [5%] moderate), with one (5%) serious adverse event of hospitalisation attributed to pneumonia. No deaths were recorded in the study.</p><p><strong>Interpretation: </strong>Individuals with CFTR<sup>N1303K</sup> showed no change in sweat chlo","PeriodicalId":51307,"journal":{"name":"Lancet Respiratory Medicine","volume":null,"pages":null},"PeriodicalIF":38.7,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-20DOI: 10.1016/S2213-2600(24)00244-3
Ian D Pavord
{"title":"New thinking and a new direction in bronchiectasis.","authors":"Ian D Pavord","doi":"10.1016/S2213-2600(24)00244-3","DOIUrl":"https://doi.org/10.1016/S2213-2600(24)00244-3","url":null,"abstract":"","PeriodicalId":51307,"journal":{"name":"Lancet Respiratory Medicine","volume":null,"pages":null},"PeriodicalIF":38.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-16DOI: 10.1016/S2213-2600(24)00218-2
Molly S C Li, Stephanie P L Saw, Alfredo Addeo
{"title":"Anti-CTLA-4 in non-small-cell lung cancer: insights from the NIPPON study.","authors":"Molly S C Li, Stephanie P L Saw, Alfredo Addeo","doi":"10.1016/S2213-2600(24)00218-2","DOIUrl":"https://doi.org/10.1016/S2213-2600(24)00218-2","url":null,"abstract":"","PeriodicalId":51307,"journal":{"name":"Lancet Respiratory Medicine","volume":null,"pages":null},"PeriodicalIF":38.7,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Fatal dyspnoea at the Palace of Versailles.","authors":"Emmanuel Drouin, Serge Wasersztrum, Arnaud Chambellan","doi":"10.1016/S2213-2600(24)00270-4","DOIUrl":"https://doi.org/10.1016/S2213-2600(24)00270-4","url":null,"abstract":"","PeriodicalId":51307,"journal":{"name":"Lancet Respiratory Medicine","volume":null,"pages":null},"PeriodicalIF":38.7,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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