Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial

McKone, Edward F.; Tullis, Elizabeth; Braeckel, Eva Van; Wainwright, Claire; Ahluwalia, Neil; Bruinsma, Bote G.; Harris, Christopher; Lam, Anna; Lou, Yiyue; Moskowitz, Samuel M.; Tian, Simon; Yuan, Jason X.‐J.; Waltz, David A.; Mall, Marcus; Aurora, Paul; Verhulst, Stijn; Watson, Danie; Lorenz, Michael; Roehmel, Jobst; Gleiber, Wolfgang; Naehrig, Susanne; Stehling, Florian; Sutharsan, Sivagurunathan; Koningsbruggen-Rietschel, Silke van; Fischer, Rainald; Downey, D.G.; Haworth, Charles; Duckers, J.; Legg, Julian; Barry, Peter J.; Thursfield, Rebecca; Doe, Simon; Hilliard, Tom; MacGregor, Gordon; Nash, Edward F.; Withers, Nicholas; Peckham, Daniel; Barr, Helen L.; Lee, Timothy J.; Gray, Robert D.; Vermeulen, François; Vanderhelst, Eef; Robinson, Philip; Smith, Daniel; Mulrennan, Siobhain; Clements, Barry; Wark, Peter

doi:10.1016/s2213-2600(21)00454-9

Cited by 73 publications

(59 citation statements)

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“…In parallel to the improvement in CFAbd-Scores, ppFEV 1 increased by 13% and BMI and weight in adults increased by 8 and 9%, respectively, with ETI, as might be expected from previous studies (Heijerman et al, 2019;Middleton et al, 2019;Sutharsan et al, 2021). Significant improvements in children's BMI-for age z-scores and weight were also observed during a 22-week follow-up.…”

Section: Discussionsupporting

confidence: 84%

Elexacaftor-Tezacaftor-Ivacaftor Treatment Reduces Abdominal Symptoms in Cystic Fibrosis-Early results Obtained With the CF-Specific CFAbd-Score

et al. 2022

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Background: The novel and highly effective CFTR modulator combination of elexacaftor-tezacaftor-ivacaftor (ETI) has been shown to improve lung function and body weight in people with Cystic Fibrosis (pwCF) carrying a F508del mutation. However, the impact of these modulators on gastrointestinal (GI) symptoms is relatively unknown. Therefore, the CFAbd-Score was developed and validated following FDA recommendations for development of a PROM including focus groups, multidisciplinary CF specialists, people with CF and their families. The aim of this study was to assess effects of ETI on GI symptoms using the CFAbd-Score.Methods: Gastrointestinal symptoms were prospectively assessed in pwCF using the CFAbd-Score before and up to 26 weeks during therapy. The CFAbd-Score was also administered to a healthy control (HC) group. The one-sided questionnaire includes 28 items grouped in five domains. Data analysis included calculation of scores with a weighting tool, developed according to FDA recommendations.Results: A total of 107 pwCF attended in four CF centres in Germany and four centres in the UK completed the CFAbd-Score on at least two occasions. Results were compared to those obtained from the questionnaire of 45 HCs. Despite differences in demographics, age and proportion of pancreatic insufficiency between German and UK patients, analyses based on linear mixed-effects models at week 24 of ETI therapy revealed that estimated marginal means (EMMs) of total CFAbd-Scores significantly reduced (mean ± SE: 14.9 ± 1.2→10.6 ± 1.4; p < 0.01). Also EMMs of all five domains significantly declined (“pain” 16.3 ± 1.6→10.2 ± 2.3, “GERD” 15.8 ± 1.8→8.2 ± 1.9, “disorders of bowel movement” 20.9 ± 1.5→16.0 ± 1.7, “disorders of appetite” 7.9 ± 1.1→2.6 ± 1.1 and “quality of life impairment” 10.1 ± 1.92→3.9 ± 1.9). However, during 24 weeks, CF participants’ symptoms mostly still did not reach the reference levels of HCs.Discussion: Using the CFAbd-Score, the first PROM specifically developed for assessment of CF-related abdominal symptoms, we demonstrate comprehensive improvements in GI symptoms after initiation of the highly effective modulator therapy ETI.

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Section: Discussionsupporting

confidence: 84%

Elexacaftor-Tezacaftor-Ivacaftor Treatment Reduces Abdominal Symptoms in Cystic Fibrosis-Early results Obtained With the CF-Specific CFAbd-Score

et al. 2022

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“…Although the RCT excluded patients with more advanced (ppFEV 1 < 40%) pulmonary disease at the time of screening, a subgroup of 10 enrolled patients had ppFEV 1 < 40% on day 1 of the study, but no result is reported about this little subgroup. A further phase IIIB RCT including F/F pwCF was conducted for 24 weeks, with a fast improvement of ppFEV 1 (11.2) after 4 weeks of treatment with ETI that sustained through to 24 weeks [13]. Our patients, all but one treated with L/I before beginning TCT, showed a similar increase in pulmonary function in the first 4 weeks of ETI treatment (mean improvement of ppFEV 1 12.1) that was sustained through to 24 and 48 weeks (mean improvements of ppFEV 1 15.3 and 14.5, respectively).…”

Section: Discussionmentioning

confidence: 99%

Elexacaftor/Tezacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for the F508del Mutation and Advanced Lung Disease: A 48-Week Observational Study

Carnovale

Iacotucci

Terlizzi

et al. 2022

JCM

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Background: Elexacaftor/tezacaftor/ivacaftor (ETI) is the newest cystic fibrosis transmembrane conductance regulator (CFTR) modulator drug approved for the treatment of patients with cystic fibrosis (pwCF) aged ≥6 years with at least one copy of the F508del mutation (F) in the CFTR gene or another mutation that is responsive to treatment with ETI. This study determined the effectiveness and safety of ETI in a cohort of severely affected pwCF with an F/F genotype. Methods: Retrospective observational study in F/F pwCF treated for 48 weeks, enrolled in an ETI managed access program available to subjects with advanced lung disease (ppFEV1 < 40). Twenty-six patients from three centres were included. The main outcomes included lung function, sweat chloride concentration (SCC), nutrition, frequency of pulmonary exacerbations (PEx), CFQ-R, and safety. Results: ppFEV1 improved by 12.06 (95%CI 8.54, 15.57) from baseline after 4 weeks of treatment with ETI, 15.32 (11.3, 19.34) after 24 weeks, and 14.48 (10.64, 18.32) after 48 weeks. The increase in FEV1 was accompanied by a decrease in SCC, improvement of BMI, and noticeable reduction in PEx. An overall good safety profile was observed. Conclusions: In F/F pwCF with advanced lung disease with an F/F genotype, ETI was safe and associated with clinical improvement.

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“…Four studies were excluded for overlapping patients or being single arm studies, and four studies were excluded for being preclinical studies or experiments. Finally, six RCTs were included in the final analysis ( Davies et al, 2018 ; Keating et al, 2018 : Heijerman et al, 2019 ; Middleton et al, 2019 ; Barry et al, 2021 ; Sutharsan et al, 2021 ), all of which were multicenter RCTs. The main characteristics of the included studies are shown in Table 1 .…”

Section: Resultsmentioning

confidence: 99%

“…The main characteristics of the included studies are shown in Table 1 . Five included studies used the same triple combination therapy ( Keating et al, 2018 ; Heijerman et al, 2019 ; Middleton et al, 2019 ; Barry et al, 2021 ; Sutharsan et al, 2021 ) (elexacaftor-tezacaftor-ivacaftor, ELX-TEZ-IVA), and one study ( Davies et al, 2018 ) used VX659-TEZ-IVA as the triple combination therapy. Two studies ( Davies et al, 2018 ; Keating et al, 2018 ) used triple placebo or active-control as the comparator, three studies used only active control as the comparator ( Heijerman et al, 2019 ; Barry et al, 2021 ; Sutharsan et al, 2021 ), and one study used only triple placebo as the comparator ( Middleton et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

“…In fact, researchers expect highly effective therapies to be available for all patients with CF, regardless of their variants, in the near future ( Middleton and Taylor-Cousar, 2021 ). Third, the results from the included studies were mostly short-term; however, two included studies ( Middleton et al, 2019 ; Sutharsan et al, 2021 ) used triple therapy for a relatively long period (24 weeks). Additional long-term results remain necessary to confirm the results.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy and Safety of Triple Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Patients With Cystic Fibrosis: A Meta-Analysis of Randomized Controlled Trials

Wang

et al. 2022

Front. Pharmacol.

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Background: Cystic fibrosis is a rare, recessive, progressive genetic disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Small molecules have recently been developed to treat the molecular consequences of CFTR mutations and restore CFTR protein function. However, the data on triple combination therapy (mainly from Vertex Pharmaceuticals, which is most tested in clinical trials) are limited. This meta-analysis was aimed to assess the efficacy and safety of this therapy according to different mutation genotypes and comparators.Methods: Relevant publications were identified through searching several medical databases before 31 December 2021. The primary outcomes of ppFEV1, sweat chloride concentration and Cystic Fibrosis Questionnaire-Revised (CFQ-R) score were pooled and analyzed. The secondary outcomes were adverse events in triple combination therapy.Results: Six randomized controlled trials were eligible for analysis. The total outcome of the ppFEV1 change was higher with triple combination therapy than triple placebo or active control (mean difference, MD, 13.6% and 8.74%, respectively). The pooled result of sweat chloride concentrations with triple combination therapy was lower than that of triple placebo or active control (MD, −44.13 and −39.26, respectively). The pooled estimate of the CFQ-R score was higher with triple combination therapy than triple placebo or active control (MD, 19.8% and 14.63%, respectively). No clear differences in adverse events were found between triple combination therapy and the control (placebo or active control).Conclusion: CFTR modulators in triple combination achieve better clinical results than placebo and active control, and result in comparable adverse events.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021293402, identifier PROSPERO 2021 CRD42021293402.

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Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial

Cited by 73 publications

References 30 publications

Elexacaftor-Tezacaftor-Ivacaftor Treatment Reduces Abdominal Symptoms in Cystic Fibrosis-Early results Obtained With the CF-Specific CFAbd-Score

Elexacaftor-Tezacaftor-Ivacaftor Treatment Reduces Abdominal Symptoms in Cystic Fibrosis-Early results Obtained With the CF-Specific CFAbd-Score

Elexacaftor/Tezacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for the F508del Mutation and Advanced Lung Disease: A 48-Week Observational Study

Efficacy and Safety of Triple Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Patients With Cystic Fibrosis: A Meta-Analysis of Randomized Controlled Trials

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