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Michael W Konstan - One of the best experts on this subject based on the ideXlab platform.
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Lumacaftor-ivacaftor_survival_model_appendix – Supplemental material for Modeling long-term health outcomes of patients with cystic fibrosis homozygous for F508del-CFTR treated with Lumacaftor/ivacaftor
2019Co-Authors: Jaime L. Rubin, Michael W Konstan, Lasair O’callaghan, Christopher Pelligra, Alexandra Ward, Jack K. Ishak, Conor Chandler, Theodore G. LiouAbstract:Supplemental material, Lumacaftor-ivacaftor_survival_model_appendix for Modeling long-term health outcomes of patients with cystic fibrosis homozygous for F508del-CFTR treated with Lumacaftor/ivacaftor by Jaime L. Rubin, Lasair O’Callaghan, Christopher Pelligra, Michael W. Konstan, Alexandra Ward, Jack K. Ishak, Conor Chandler and Theodore G. Liou in Therapeutic Advances in Respiratory Disease
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Modeling long-term health outcomes of patients with cystic fibrosis homozygous for treated with Lumacaftor/ivacaftor
SAGE Publishing, 2019Co-Authors: Jaime L. Rubin, Michael W Konstan, Lasair O’callaghan, Christopher Pelligra, Alexandra Ward, Jack K. Ishak, Conor Chandler, Theodore G. LiouAbstract:Background: Lumacaftor/ivacaftor combination therapy is efficacious and generally safe for patients with cystic fibrosis (CF) homozygous for the F508del-CF transmembrane conductance regulator (CFTR) mutation. However, long-term survival benefits of Lumacaftor/ivacaftor (LUM/IVA) cannot yet be quantified. Simulation models can provide predictions about long-term health outcomes. In this study, we aimed to project long-term health outcomes of LUM/IVA plus standard care (SC) in patients with CF homozygous for F508del-CFTR . Methods: This modeling study was an individual patient simulation in US patients aged ⩾6 years with CF, homozygous for F508del-CFTR . The primary outcome was projected survival among (a) a cohort of patients who ever initiated LUM/IVA, accounting for treatment discontinuations, and (b) a cohort of patients who remain on continuous LUM/IVA. Patient characteristics and model parameters were derived from clinical trials: VX14-809-109, VX13-809-011B, TRAFFIC/TRANSPORT, and PROGRESS; published literature; and the US CF Foundation Patient Registry. Results: Lumacaftor/ivacaftor + SC is expected to increase median survival by 6.1 years versus SC alone, accounting for treatment discontinuations. The incremental median predicted survival versus SC assuming initiation of LUM/IVA at ages 6, 12, 18, and 25 years was 17.7, 12.6, 8.0, and 3.8 years, respectively. Assuming lifetime treatment with LUM/IVA, incremental median survival was predicted to be 7.8 years longer in the LUM/IVA + SC cohort. Initiating LUM/IVA at ages 6, 12, 18, and 25 years and assuming lifetime treatment resulted in incremental median predicted survival of 23.4, 18.2, 11.0, and 4.8 years, respectively. Conclusions: Lumacaftor/ivacaftor is projected to increase survival for patients with CF. Initiation at an early age and treatment persistence result in further increments in projected survival
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Lumacaftor ivacaftor treatment of patients with cystic fibrosis heterozygous for f508del cftr
Annals of the American Thoracic Society, 2017Co-Authors: Steven M. Rowe, Gautham Marigowda, Susanna A Mccolley, Ernst Rietschel, David Waltz, Michael W Konstan, Scott C Bell, Xiaolei Li, Michael P BoyleAbstract:Rationale: In a prior study, Lumacaftor/ivacaftor treatment (≤28 d) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function.Objectives: To evaluate an optimized Lumacaftor/ivacaftor dosing regimen with a longer duration in a cohort of patients heterozygous for F508del-CFTR.Methods: Patients aged 18 years or older with a confirmed CF diagnosis and percent predicted FEV1 (ppFEV1) of 40 to 90 were randomized to Lumacaftor/ivacaftor (400 mg/250 mg every 12 h) or placebo daily for 56 days. Primary outcomes were change in ppFEV1 at Day 56 and safety. Other disease markers were evaluated.Measurements and Main Results: Of 126 patients, 119 (94.4%) completed the study. Lumacaftor/ivacaftor was well tolerated, although chest tightness and dyspnea occurred more frequently with active treatment than with placebo (27.4% vs. 14.3% and 14.5% vs. 6.3%, respectively). Mean (SD) ppFEV1 values at baseline were 62.9 (14.3) in the active treatment group and 60.1 (14.0) in the placebo ...
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Lumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for F508del‐CFTR
Annals of the American Thoracic Society, 2017Co-Authors: Steven M. Rowe, Gautham Marigowda, Susanna A Mccolley, Ernst Rietschel, David Waltz, Michael W Konstan, Scott C Bell, Xiaolei Li, Michael P BoyleAbstract:Rationale: In a prior study, Lumacaftor/ivacaftor treatment (≤28 d) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function.Objectives: To evaluate an optimized Lumacaftor/ivacaftor dosing regimen with a longer duration in a cohort of patients heterozygous for F508del-CFTR.Methods: Patients aged 18 years or older with a confirmed CF diagnosis and percent predicted FEV1 (ppFEV1) of 40 to 90 were randomized to Lumacaftor/ivacaftor (400 mg/250 mg every 12 h) or placebo daily for 56 days. Primary outcomes were change in ppFEV1 at Day 56 and safety. Other disease markers were evaluated.Measurements and Main Results: Of 126 patients, 119 (94.4%) completed the study. Lumacaftor/ivacaftor was well tolerated, although chest tightness and dyspnea occurred more frequently with active treatment than with placebo (27.4% vs. 14.3% and 14.5% vs. 6.3%, respectively). Mean (SD) ppFEV1 values at baseline were 62.9 (14.3) in the active treatment group and 60.1 (14.0) in the placebo ...
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assessment of safety and efficacy of long term treatment with combination Lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the f508del cftr mutation progress a phase 3 extension study
The Lancet Respiratory Medicine, 2017Co-Authors: Michael W Konstan, R.b Moss, Gautham Marigowda, David Waltz, Barry Lubarsky, Edward F Mckone, J Rubin, Xiaohong Huang, S. Tian, Stefanie J MillarAbstract:Summary Background The 24-week safety and efficacy of Lumacaftor/ivacaftor combination therapy was shown in two randomised controlled trials (RCTs)—TRAFFIC and TRANSPORT—in patients with cystic fibrosis who were aged 12 years or older and homozygous for the F508del-CFTR mutation. We aimed to assess the long-term safety and efficacy of extended Lumacaftor/ivacaftor therapy in this group of patients in PROGRESS, the long-term extension of TRAFFIC and TRANSPORT. Methods PROGRESS was a phase 3, parallel-group, multicentre, 96-week study of patients who completed TRAFFIC or TRANSPORT in 191 sites in 15 countries. Patients were eligible if they were at least 12 years old with cystic fibrosis and homozygous for the F508del-CFTR mutation. Exclusion criteria included any comorbidity or laboratory abnormality that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering the study drug to the participant, history of drug intolerance, and history of poor compliance with the study drug. Patients who previously received active treatment in TRANSPORT or TRAFFIC remained on the same dose in PROGRESS. Patients who had received placebo in TRANSPORT or TRAFFIC were randomly assigned (1:1) to receive Lumacaftor (400 mg every 12 h)/ivacaftor (250 mg every 12 h) or Lumacaftor (600 mg once daily)/ivacaftor (250 mg every 12 h). The primary outcome was to assess the long-term safety of combined therapy. The estimated annual rate of decline in percent predicted FEV 1 (ppFEV 1 ) in treated patients was compared with that of a matched registry cohort. Efficacy analyses were based on modified intention-to-treat, such that data were included for all patients who were randomly assigned and received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01931839. Findings Between Oct 24, 2013, and April 7, 2016, 1030 patients from the TRANSPORT and TRAFFIC studies enrolled in PROGRESS, and 1029 received at least one dose of study drug. 340 patients continued treatment with Lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h; 176 patients who had received placebo in the TRANSPORT or TRAFFIC studies initiated treatment with Lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h, the commercially available dose, for which data are presented. The most common adverse events were infective pulmonary exacerbations, cough, increased sputum, and haemoptysis. Modest blood pressure increases seen in TRAFFIC and TRANSPORT were also observed in PROGRESS. For patients continuing treatment, the mean change from baseline in ppFEV 1 was 0·5 (95% CI −0·4 to 1·5) at extension week 72 and 0·5 (−0·7 to 1·6) at extension week 96; change in BMI was 0·69 (0·56 to 0·81) at extension week 72 and 0·96 (0·81 to 1·11) at extension week 96. The annualised pulmonary exacerbation rate in patients continuing treatment through extension week 96 (0·65, 0·56 to 0·75) remained lower than the placebo rate in TRAFFIC and TRANSPORT. The annualised rate of ppFEV 1 decline was reduced in Lumacaftor/ivacaftor-treated patients compared with matched controls (−1·33, −1·80 to −0·85 vs −2·29, −2·56 to −2·03). The efficacy and safety profile of the Lumacaftor 600 mg once daily/ivacaftor 250 mg every 12 h groups was generally similar to that of the Lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h groups. Interpretation The long-term safety profile of Lumacaftor/ivacaftor combination therapy was consistent with previous RCTs. Benefits continued to be observed with longer-term treatment, and Lumacaftor/ivacaftor was associated with a 42% slower rate of ppFEV 1 decline than in matched registry controls. Funding Vertex Pharmaceuticals Incorporated.
David Waltz - One of the best experts on this subject based on the ideXlab platform.
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safety pharmacokinetics and pharmacodynamics of Lumacaftor and ivacaftor combination therapy in children aged 2 5 years with cystic fibrosis homozygous for f508del cftr an open label phase 3 study
The Lancet Respiratory Medicine, 2019Co-Authors: John Mcnamara, Chonghua Li, Gautham Marigowda, Linda T Wang, Susanna A Mccolley, David Waltz, David Stiles, Caroline A. Owen, S. Tian, Gregory S SawickiAbstract:Summary Background The efficacy, safety, and tolerability of Lumacaftor and ivacaftor are established in patients aged 6 years and older with cystic fibrosis, homozygous for the F508del-CFTR mutation. We assessed the safety, pharmacokinetics, pharmacodynamics, and efficacy of Lumacaftor and ivacaftor in children aged 2–5 years. Methods In this multicentre, phase 3, open-label, two-part study, we enrolled children aged 2–5 years, weighing at least 8 kg at enrolment, with a confirmed diagnosis of cystic fibrosis who were homozygous for the F508del-CFTR mutation. Children received Lumacaftor 100 mg and ivacaftor 125 mg (bodyweight Findings The study was done from May 13, 2016, to Sept 8, 2017. 12 children enrolled in part A, 11 of whom completed the 15-day treatment period and enrolled in part B. 60 children enrolled in part B, 56 of whom completed the 24-week treatment period. Safety and pharmacokinetics were consistent with the well characterised safety profile of Lumacaftor and ivacaftor. In part B, most children (59 [98%] of 60 children) had one or more treatment-emergent adverse events; most events were mild to moderate in severity. The most common adverse events were cough (38 [63%] of 60), vomiting (17 [28%]), pyrexia (17 [28%]), and rhinorrhoea (15 [25%]). Serious adverse events occurred in four children: infective pulmonary exacerbation of cystic fibrosis (n=2), gastroenteritis viral (n=1), and constipation (n=1). Three (5%) of 60 children discontinued treatment because of elevated serum aminotransferase concentrations. Mean sweat chloride concentrations decreased by 31·7 mmol/L, biomarkers of pancreatic function improved (fecal elastase-1 concentrations increased and serum immunoreactive trypsinogen concentrations decreased), and growth parameters increased at week 24. Interpretation Lumacaftor and ivacaftor were generally safe and well tolerated in children aged 2–5 years with cystic fibrosis for 24 weeks. Efficacy findings also suggest that early intervention with Lumacaftor and ivacaftor has the potential to modify the course of disease. Funding Vertex Pharmaceuticals Incorporated.
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efficacy and safety of Lumacaftor and ivacaftor in patients aged 6 11 years with cystic fibrosis homozygous for f508del cftr a randomised placebo controlled phase 3 trial
The Lancet Respiratory Medicine, 2017Co-Authors: Felix Ratjen, C E Milla, Gautham Marigowda, Jane C Davies, David Waltz, Xiaohong Huang, S. Tian, Sanja Stanojevic, Paul Robinson, Margaret RosenfeldAbstract:Summary Background Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of Lumacaftor and ivacaftor in patients with cystic fibrosis aged 6–11 years homozygous for F508del-CFTR . Methods In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV 1 ) of 70 or more, and lung clearance index 2·5 (LCI 2·5 ) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight ( vs ≥25 kg) and ppFEV 1 severity ( vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg Lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute change in LCI 2·5 from all study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473. Findings Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive Lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the Lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of Lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI 2·5 from baseline over all study visits up to and including the week 24 visit, least squares mean difference was −1·09 units (95% CI −1·43 to −0·75, p 1 from all study visits until week 24 was 2·4 (95% CI 0·4–4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 [43%]) or moderate (98 [48%]). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the Lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the Lumacaftor and ivacaftor group and 11 (11%) of 101 patients in the placebo group. Interpretation Treatment with Lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI 2·5 and ppFEV 1 , versus placebo in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR . The overall safety profile was consistent with previous phase 3 studies of Lumacaftor and ivacaftor. Funding Vertex Pharmaceuticals.
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Lumacaftor ivacaftor in patients aged 6 11 years with cystic fibrosis and homozygous for f508del cftr
American Journal of Respiratory and Critical Care Medicine, 2017Co-Authors: C E Milla, Gautham Marigowda, David Waltz, Margaret Rosenfeld, Felix RatjenAbstract:Rationale: Combination Lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged 12 years and older with cystic fibrosis and homozygous for F508del-CFTR, but it has not been assessed in younger patients.Objectives: In this open-label phase III trial, we evaluated the safety, tolerability, pharmacodynamics, and efficacy of Lumacaftor/ivacaftor combination therapy in patients aged 6–11 years with cystic fibrosis who were homozygous for F508del-CFTR.Methods: Patients (N = 58) received 200 mg Lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications.Measurements and Main Results: Lumacaftor/ivacaftor was well tolerated; the safety profile was generally similar to that observed in larger Lumacaftor/ivacaftor trials with older patients. Four patients discontinued (two because of drug-related adverse events: elevated liver transaminases, n = 1; rash, n = 1). No safety concerns were associated with spirometry. N...
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Lumacaftor ivacaftor treatment of patients with cystic fibrosis heterozygous for f508del cftr
Annals of the American Thoracic Society, 2017Co-Authors: Steven M. Rowe, Gautham Marigowda, Susanna A Mccolley, Ernst Rietschel, David Waltz, Michael W Konstan, Scott C Bell, Xiaolei Li, Michael P BoyleAbstract:Rationale: In a prior study, Lumacaftor/ivacaftor treatment (≤28 d) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function.Objectives: To evaluate an optimized Lumacaftor/ivacaftor dosing regimen with a longer duration in a cohort of patients heterozygous for F508del-CFTR.Methods: Patients aged 18 years or older with a confirmed CF diagnosis and percent predicted FEV1 (ppFEV1) of 40 to 90 were randomized to Lumacaftor/ivacaftor (400 mg/250 mg every 12 h) or placebo daily for 56 days. Primary outcomes were change in ppFEV1 at Day 56 and safety. Other disease markers were evaluated.Measurements and Main Results: Of 126 patients, 119 (94.4%) completed the study. Lumacaftor/ivacaftor was well tolerated, although chest tightness and dyspnea occurred more frequently with active treatment than with placebo (27.4% vs. 14.3% and 14.5% vs. 6.3%, respectively). Mean (SD) ppFEV1 values at baseline were 62.9 (14.3) in the active treatment group and 60.1 (14.0) in the placebo ...
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Lumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for F508del‐CFTR
Annals of the American Thoracic Society, 2017Co-Authors: Steven M. Rowe, Gautham Marigowda, Susanna A Mccolley, Ernst Rietschel, David Waltz, Michael W Konstan, Scott C Bell, Xiaolei Li, Michael P BoyleAbstract:Rationale: In a prior study, Lumacaftor/ivacaftor treatment (≤28 d) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function.Objectives: To evaluate an optimized Lumacaftor/ivacaftor dosing regimen with a longer duration in a cohort of patients heterozygous for F508del-CFTR.Methods: Patients aged 18 years or older with a confirmed CF diagnosis and percent predicted FEV1 (ppFEV1) of 40 to 90 were randomized to Lumacaftor/ivacaftor (400 mg/250 mg every 12 h) or placebo daily for 56 days. Primary outcomes were change in ppFEV1 at Day 56 and safety. Other disease markers were evaluated.Measurements and Main Results: Of 126 patients, 119 (94.4%) completed the study. Lumacaftor/ivacaftor was well tolerated, although chest tightness and dyspnea occurred more frequently with active treatment than with placebo (27.4% vs. 14.3% and 14.5% vs. 6.3%, respectively). Mean (SD) ppFEV1 values at baseline were 62.9 (14.3) in the active treatment group and 60.1 (14.0) in the placebo ...
Gautham Marigowda - One of the best experts on this subject based on the ideXlab platform.
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safety pharmacokinetics and pharmacodynamics of Lumacaftor and ivacaftor combination therapy in children aged 2 5 years with cystic fibrosis homozygous for f508del cftr an open label phase 3 study
The Lancet Respiratory Medicine, 2019Co-Authors: John Mcnamara, Chonghua Li, Gautham Marigowda, Linda T Wang, Susanna A Mccolley, David Waltz, David Stiles, Caroline A. Owen, S. Tian, Gregory S SawickiAbstract:Summary Background The efficacy, safety, and tolerability of Lumacaftor and ivacaftor are established in patients aged 6 years and older with cystic fibrosis, homozygous for the F508del-CFTR mutation. We assessed the safety, pharmacokinetics, pharmacodynamics, and efficacy of Lumacaftor and ivacaftor in children aged 2–5 years. Methods In this multicentre, phase 3, open-label, two-part study, we enrolled children aged 2–5 years, weighing at least 8 kg at enrolment, with a confirmed diagnosis of cystic fibrosis who were homozygous for the F508del-CFTR mutation. Children received Lumacaftor 100 mg and ivacaftor 125 mg (bodyweight Findings The study was done from May 13, 2016, to Sept 8, 2017. 12 children enrolled in part A, 11 of whom completed the 15-day treatment period and enrolled in part B. 60 children enrolled in part B, 56 of whom completed the 24-week treatment period. Safety and pharmacokinetics were consistent with the well characterised safety profile of Lumacaftor and ivacaftor. In part B, most children (59 [98%] of 60 children) had one or more treatment-emergent adverse events; most events were mild to moderate in severity. The most common adverse events were cough (38 [63%] of 60), vomiting (17 [28%]), pyrexia (17 [28%]), and rhinorrhoea (15 [25%]). Serious adverse events occurred in four children: infective pulmonary exacerbation of cystic fibrosis (n=2), gastroenteritis viral (n=1), and constipation (n=1). Three (5%) of 60 children discontinued treatment because of elevated serum aminotransferase concentrations. Mean sweat chloride concentrations decreased by 31·7 mmol/L, biomarkers of pancreatic function improved (fecal elastase-1 concentrations increased and serum immunoreactive trypsinogen concentrations decreased), and growth parameters increased at week 24. Interpretation Lumacaftor and ivacaftor were generally safe and well tolerated in children aged 2–5 years with cystic fibrosis for 24 weeks. Efficacy findings also suggest that early intervention with Lumacaftor and ivacaftor has the potential to modify the course of disease. Funding Vertex Pharmaceuticals Incorporated.
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efficacy and safety of Lumacaftor and ivacaftor in patients aged 6 11 years with cystic fibrosis homozygous for f508del cftr a randomised placebo controlled phase 3 trial
The Lancet Respiratory Medicine, 2017Co-Authors: Felix Ratjen, C E Milla, Gautham Marigowda, Jane C Davies, David Waltz, Xiaohong Huang, S. Tian, Sanja Stanojevic, Paul Robinson, Margaret RosenfeldAbstract:Summary Background Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of Lumacaftor and ivacaftor in patients with cystic fibrosis aged 6–11 years homozygous for F508del-CFTR . Methods In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV 1 ) of 70 or more, and lung clearance index 2·5 (LCI 2·5 ) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight ( vs ≥25 kg) and ppFEV 1 severity ( vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg Lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute change in LCI 2·5 from all study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473. Findings Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive Lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the Lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of Lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI 2·5 from baseline over all study visits up to and including the week 24 visit, least squares mean difference was −1·09 units (95% CI −1·43 to −0·75, p 1 from all study visits until week 24 was 2·4 (95% CI 0·4–4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 [43%]) or moderate (98 [48%]). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the Lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the Lumacaftor and ivacaftor group and 11 (11%) of 101 patients in the placebo group. Interpretation Treatment with Lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI 2·5 and ppFEV 1 , versus placebo in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR . The overall safety profile was consistent with previous phase 3 studies of Lumacaftor and ivacaftor. Funding Vertex Pharmaceuticals.
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Lumacaftor ivacaftor in patients aged 6 11 years with cystic fibrosis and homozygous for f508del cftr
American Journal of Respiratory and Critical Care Medicine, 2017Co-Authors: C E Milla, Gautham Marigowda, David Waltz, Margaret Rosenfeld, Felix RatjenAbstract:Rationale: Combination Lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged 12 years and older with cystic fibrosis and homozygous for F508del-CFTR, but it has not been assessed in younger patients.Objectives: In this open-label phase III trial, we evaluated the safety, tolerability, pharmacodynamics, and efficacy of Lumacaftor/ivacaftor combination therapy in patients aged 6–11 years with cystic fibrosis who were homozygous for F508del-CFTR.Methods: Patients (N = 58) received 200 mg Lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications.Measurements and Main Results: Lumacaftor/ivacaftor was well tolerated; the safety profile was generally similar to that observed in larger Lumacaftor/ivacaftor trials with older patients. Four patients discontinued (two because of drug-related adverse events: elevated liver transaminases, n = 1; rash, n = 1). No safety concerns were associated with spirometry. N...
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Lumacaftor ivacaftor treatment of patients with cystic fibrosis heterozygous for f508del cftr
Annals of the American Thoracic Society, 2017Co-Authors: Steven M. Rowe, Gautham Marigowda, Susanna A Mccolley, Ernst Rietschel, David Waltz, Michael W Konstan, Scott C Bell, Xiaolei Li, Michael P BoyleAbstract:Rationale: In a prior study, Lumacaftor/ivacaftor treatment (≤28 d) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function.Objectives: To evaluate an optimized Lumacaftor/ivacaftor dosing regimen with a longer duration in a cohort of patients heterozygous for F508del-CFTR.Methods: Patients aged 18 years or older with a confirmed CF diagnosis and percent predicted FEV1 (ppFEV1) of 40 to 90 were randomized to Lumacaftor/ivacaftor (400 mg/250 mg every 12 h) or placebo daily for 56 days. Primary outcomes were change in ppFEV1 at Day 56 and safety. Other disease markers were evaluated.Measurements and Main Results: Of 126 patients, 119 (94.4%) completed the study. Lumacaftor/ivacaftor was well tolerated, although chest tightness and dyspnea occurred more frequently with active treatment than with placebo (27.4% vs. 14.3% and 14.5% vs. 6.3%, respectively). Mean (SD) ppFEV1 values at baseline were 62.9 (14.3) in the active treatment group and 60.1 (14.0) in the placebo ...
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Lumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for F508del‐CFTR
Annals of the American Thoracic Society, 2017Co-Authors: Steven M. Rowe, Gautham Marigowda, Susanna A Mccolley, Ernst Rietschel, David Waltz, Michael W Konstan, Scott C Bell, Xiaolei Li, Michael P BoyleAbstract:Rationale: In a prior study, Lumacaftor/ivacaftor treatment (≤28 d) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function.Objectives: To evaluate an optimized Lumacaftor/ivacaftor dosing regimen with a longer duration in a cohort of patients heterozygous for F508del-CFTR.Methods: Patients aged 18 years or older with a confirmed CF diagnosis and percent predicted FEV1 (ppFEV1) of 40 to 90 were randomized to Lumacaftor/ivacaftor (400 mg/250 mg every 12 h) or placebo daily for 56 days. Primary outcomes were change in ppFEV1 at Day 56 and safety. Other disease markers were evaluated.Measurements and Main Results: Of 126 patients, 119 (94.4%) completed the study. Lumacaftor/ivacaftor was well tolerated, although chest tightness and dyspnea occurred more frequently with active treatment than with placebo (27.4% vs. 14.3% and 14.5% vs. 6.3%, respectively). Mean (SD) ppFEV1 values at baseline were 62.9 (14.3) in the active treatment group and 60.1 (14.0) in the placebo ...
Gary Connett - One of the best experts on this subject based on the ideXlab platform.
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Lumacaftor-ivacaftor in the treatment of cystic fibrosis: design, development and place in therapy
Drug design development and therapy, 2019Co-Authors: Gary ConnettAbstract:Lumacaftor-ivacaftor is a combination of two small molecule therapies targeting the basic defect in cystic fibrosis (CF) at a cellular level. It is a precision medicine and its effects are specific to individuals with two copies of the p.Phe508del gene mutation. The drug combination works by restoring functioning CF transmembrane conductance regulator (CFTR) protein in cell surface membranes and was the first CFTR modulator licensed for the homozygous p.Phe508del genotype. The drug is a combination of a CFTR corrector and potentiator. Lumacaftor, the corrector, works by increasing the trafficking of CFTR proteins to the outer cell membrane. Ivacaftor, the potentiator, works by enabling the opening of what would otherwise be a dysfunctional chloride channel. In vivo Lumacaftor-ivacaftor improves Phe508del-CFTR activity in airways, sweat ducts and intestine to approximately 10-20% of normal CFTR function with greater reductions in sweat chloride levels in children versus adults. Its use results in a modest improvement in lung function and a decreased rate of subsequent decline. Perhaps more importantly, those treated report increased levels of well-being and their rate of respiratory exacerbations is significantly improved. This review traces the development and use of this combination of CFTR modulators, the first licensed drug for treating the homozygous p.Phe508del CF genotype at the intracellular level by correcting the protein defect.
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the use of Lumacaftor ivacaftor to treat acute deterioration in paediatric cystic fibrosis
Paediatric Respiratory Reviews, 2018Co-Authors: James A. Hammond, Gary ConnettAbstract:Abstract Lumacaftor/ivacaftor is a precision medicine targeting the defective cystic fibrosis transmembrane regulator (CFTR) protein in cystic fibrosis (CF) patients homozygous for Phe508del genotype. Whilst there is evidence for efficacy in children aged 6–11 years who are stable with good lung function, there are little data about the use of this medication for children with acute deterioration in this age group. We describe the use of this drug to treat a child with an unusually severe exacerbation of CF lung disease and review the potential of Lumacaftor/ivacaftor as a rescue therapy in the paediatric CF population.
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The use of Lumacaftor/ivacaftor to treat acute deterioration in paediatric cystic fibrosis
Paediatric Respiratory Reviews, 2018Co-Authors: James A. Hammond, Gary ConnettAbstract:Abstract Lumacaftor/ivacaftor is a precision medicine targeting the defective cystic fibrosis transmembrane regulator (CFTR) protein in cystic fibrosis (CF) patients homozygous for Phe508del genotype. Whilst there is evidence for efficacy in children aged 6–11 years who are stable with good lung function, there are little data about the use of this medication for children with acute deterioration in this age group. We describe the use of this drug to treat a child with an unusually severe exacerbation of CF lung disease and review the potential of Lumacaftor/ivacaftor as a rescue therapy in the paediatric CF population.
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efficacy and safety of Lumacaftor and ivacaftor in patients aged 6 11 years with cystic fibrosis homozygous for f508del cftr a randomised placebo controlled phase 3 trial
The Lancet Respiratory Medicine, 2017Co-Authors: Felix Ratjen, C E Milla, Gautham Marigowda, Jane C Davies, David Waltz, Xiaohong Huang, S. Tian, Sanja Stanojevic, Paul Robinson, Margaret RosenfeldAbstract:Summary Background Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of Lumacaftor and ivacaftor in patients with cystic fibrosis aged 6–11 years homozygous for F508del-CFTR . Methods In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV 1 ) of 70 or more, and lung clearance index 2·5 (LCI 2·5 ) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight ( vs ≥25 kg) and ppFEV 1 severity ( vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg Lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute change in LCI 2·5 from all study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473. Findings Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive Lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the Lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of Lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI 2·5 from baseline over all study visits up to and including the week 24 visit, least squares mean difference was −1·09 units (95% CI −1·43 to −0·75, p 1 from all study visits until week 24 was 2·4 (95% CI 0·4–4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 [43%]) or moderate (98 [48%]). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the Lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the Lumacaftor and ivacaftor group and 11 (11%) of 101 patients in the placebo group. Interpretation Treatment with Lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI 2·5 and ppFEV 1 , versus placebo in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR . The overall safety profile was consistent with previous phase 3 studies of Lumacaftor and ivacaftor. Funding Vertex Pharmaceuticals.
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assessment of safety and efficacy of long term treatment with combination Lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the f508del cftr mutation progress a phase 3 extension study
The Lancet Respiratory Medicine, 2017Co-Authors: Michael W Konstan, R.b Moss, Gautham Marigowda, David Waltz, Barry Lubarsky, Edward F Mckone, J Rubin, Xiaohong Huang, S. Tian, Stefanie J MillarAbstract:Summary Background The 24-week safety and efficacy of Lumacaftor/ivacaftor combination therapy was shown in two randomised controlled trials (RCTs)—TRAFFIC and TRANSPORT—in patients with cystic fibrosis who were aged 12 years or older and homozygous for the F508del-CFTR mutation. We aimed to assess the long-term safety and efficacy of extended Lumacaftor/ivacaftor therapy in this group of patients in PROGRESS, the long-term extension of TRAFFIC and TRANSPORT. Methods PROGRESS was a phase 3, parallel-group, multicentre, 96-week study of patients who completed TRAFFIC or TRANSPORT in 191 sites in 15 countries. Patients were eligible if they were at least 12 years old with cystic fibrosis and homozygous for the F508del-CFTR mutation. Exclusion criteria included any comorbidity or laboratory abnormality that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering the study drug to the participant, history of drug intolerance, and history of poor compliance with the study drug. Patients who previously received active treatment in TRANSPORT or TRAFFIC remained on the same dose in PROGRESS. Patients who had received placebo in TRANSPORT or TRAFFIC were randomly assigned (1:1) to receive Lumacaftor (400 mg every 12 h)/ivacaftor (250 mg every 12 h) or Lumacaftor (600 mg once daily)/ivacaftor (250 mg every 12 h). The primary outcome was to assess the long-term safety of combined therapy. The estimated annual rate of decline in percent predicted FEV 1 (ppFEV 1 ) in treated patients was compared with that of a matched registry cohort. Efficacy analyses were based on modified intention-to-treat, such that data were included for all patients who were randomly assigned and received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01931839. Findings Between Oct 24, 2013, and April 7, 2016, 1030 patients from the TRANSPORT and TRAFFIC studies enrolled in PROGRESS, and 1029 received at least one dose of study drug. 340 patients continued treatment with Lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h; 176 patients who had received placebo in the TRANSPORT or TRAFFIC studies initiated treatment with Lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h, the commercially available dose, for which data are presented. The most common adverse events were infective pulmonary exacerbations, cough, increased sputum, and haemoptysis. Modest blood pressure increases seen in TRAFFIC and TRANSPORT were also observed in PROGRESS. For patients continuing treatment, the mean change from baseline in ppFEV 1 was 0·5 (95% CI −0·4 to 1·5) at extension week 72 and 0·5 (−0·7 to 1·6) at extension week 96; change in BMI was 0·69 (0·56 to 0·81) at extension week 72 and 0·96 (0·81 to 1·11) at extension week 96. The annualised pulmonary exacerbation rate in patients continuing treatment through extension week 96 (0·65, 0·56 to 0·75) remained lower than the placebo rate in TRAFFIC and TRANSPORT. The annualised rate of ppFEV 1 decline was reduced in Lumacaftor/ivacaftor-treated patients compared with matched controls (−1·33, −1·80 to −0·85 vs −2·29, −2·56 to −2·03). The efficacy and safety profile of the Lumacaftor 600 mg once daily/ivacaftor 250 mg every 12 h groups was generally similar to that of the Lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h groups. Interpretation The long-term safety profile of Lumacaftor/ivacaftor combination therapy was consistent with previous RCTs. Benefits continued to be observed with longer-term treatment, and Lumacaftor/ivacaftor was associated with a 42% slower rate of ppFEV 1 decline than in matched registry controls. Funding Vertex Pharmaceuticals Incorporated.
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efficacy and safety of Lumacaftor ivacaftor combination therapy in patients with cystic fibrosis homozygous for phe508del cftr by pulmonary function subgroup a pooled analysis
The Lancet Respiratory Medicine, 2016Co-Authors: Stuart J Elborn, Gautham Marigowda, Michael P Boyle, David Waltz, Bonnie W Ramsey, Michael W Konstan, Xiaohong Huang, Claire E WainwrightAbstract:Summary Background Lumacaftor/ivacaftor combination therapy has shown clinical benefits in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation; however, pretreatment lung function is a confounding factor that potentially affects the efficacy and safety of this therapy. We aimed to assess the efficacy and safety of Lumacaftor/ivacaftor therapy in these patients, defined by specific categories of lung function. Methods Both trials (TRAFFIC and TRANSPORT) included in this pooled analysis were multinational, randomised, double-blind, placebo-controlled, parallel-group, phase 3 studies. Eligible patients from 187 participating centres in North America, Australia, and the European Union (both trials) were aged 12 years or older with a confirmed diagnosis of cystic fibrosis, homozygous for the Phe508del CFTR mutation, and with a percent predicted FEV 1 (ppFEV 1 ) of 40–90 at the time of screening. Patients were randomly assigned with an interactive web response system (1:1:1) to receive placebo, Lumacaftor (600 mg once daily) plus ivacaftor (250 mg every 12 h), or Lumacaftor (400 mg every 12 h) plus ivacaftor (250 mg every 12 h) for 24 weeks. Prespecified subgroup analyses of pooled efficacy and safety data by lung function, as measured by ppFEV 1 , were done for patients with baseline ppFEV 1 ( 1 ( 1 at week 24 analysed in all randomised patients who received at least one dose of study drug. Both trials are registered with ClinicalTrials.gov (TRAFFIC: NCT01807923; TRANSPORT: NCT01807949). Findings Both trials were done between April, 2013, and April, 2014. Of the 1108 patients included in the efficacy analysis, 81 patients had a ppFEV 1 that decreased to lower than 40 between screening and baseline and 1016 had a ppFEV 1 of 40 or higher at baseline. At screening, 730 had a ppFEV 1 of less than 70, and 342 had a ppFEV 1 of 70 or higher. Improvements in the absolute change from baseline at week 24 in ppFEV 1 were observed with both Lumacaftor/ivacaftor doses in the subgroup with baseline ppFEV 1 levels lower than 40 (least-squares mean difference vs placebo was 3·7 percentage points [95% CI 0·5–6·9; p=0·024] in the Lumacaftor [600 mg/day]–ivacaftor group and 3·3 percentage points [0·2–6·4; p=0·036] in the Lumacaftor [400 mg/12 h]–ivacaftor group). Improvements in ppFEV 1 compared with placebo were also reported in the subgroup with baseline ppFEV 1 levels of 40 or higher (3·3 percentage points [2·3–4·4; p 1 compared with placebo were observed in subgroups with screening ppFEV 1 levels lower than 70 and ppFEV 1 levels of 70 or higher. Increases in body-mass index and reduction in number of pulmonary exacerbation events were observed in both Lumacaftor/ivacaftor dose groups compared with placebo across all lung function subgroups. Treatment was generally well tolerated, although the incidence of some respiratory adverse events was higher with Lumacaftor/ivacaftor than with placebo in all subgroups. In patients with baseline ppFEV 1 levels lower than 40, these adverse events included cough, dyspnoea, and abnormal respiration. Interpretation These analyses confirm that Lumacaftor/ivacaftor combination therapy benefits patients with cystic fibrosis homozygous for Phe508del CFTR who have varying degrees of lung function impairment. Funding Vertex Pharmaceuticals.
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Efficacy and safety of Lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup: a pooled analysis.
The Lancet Respiratory Medicine, 2016Co-Authors: J. Stuart Elborn, Gautham Marigowda, Michael P Boyle, David Waltz, Bonnie W Ramsey, Michael W Konstan, Xiaohong Huang, Claire E WainwrightAbstract:Summary Background Lumacaftor/ivacaftor combination therapy has shown clinical benefits in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation; however, pretreatment lung function is a confounding factor that potentially affects the efficacy and safety of this therapy. We aimed to assess the efficacy and safety of Lumacaftor/ivacaftor therapy in these patients, defined by specific categories of lung function. Methods Both trials (TRAFFIC and TRANSPORT) included in this pooled analysis were multinational, randomised, double-blind, placebo-controlled, parallel-group, phase 3 studies. Eligible patients from 187 participating centres in North America, Australia, and the European Union (both trials) were aged 12 years or older with a confirmed diagnosis of cystic fibrosis, homozygous for the Phe508del CFTR mutation, and with a percent predicted FEV 1 (ppFEV 1 ) of 40–90 at the time of screening. Patients were randomly assigned with an interactive web response system (1:1:1) to receive placebo, Lumacaftor (600 mg once daily) plus ivacaftor (250 mg every 12 h), or Lumacaftor (400 mg every 12 h) plus ivacaftor (250 mg every 12 h) for 24 weeks. Prespecified subgroup analyses of pooled efficacy and safety data by lung function, as measured by ppFEV 1 , were done for patients with baseline ppFEV 1 ( 1 ( 1 at week 24 analysed in all randomised patients who received at least one dose of study drug. Both trials are registered with ClinicalTrials.gov (TRAFFIC: NCT01807923; TRANSPORT: NCT01807949). Findings Both trials were done between April, 2013, and April, 2014. Of the 1108 patients included in the efficacy analysis, 81 patients had a ppFEV 1 that decreased to lower than 40 between screening and baseline and 1016 had a ppFEV 1 of 40 or higher at baseline. At screening, 730 had a ppFEV 1 of less than 70, and 342 had a ppFEV 1 of 70 or higher. Improvements in the absolute change from baseline at week 24 in ppFEV 1 were observed with both Lumacaftor/ivacaftor doses in the subgroup with baseline ppFEV 1 levels lower than 40 (least-squares mean difference vs placebo was 3·7 percentage points [95% CI 0·5–6·9; p=0·024] in the Lumacaftor [600 mg/day]–ivacaftor group and 3·3 percentage points [0·2–6·4; p=0·036] in the Lumacaftor [400 mg/12 h]–ivacaftor group). Improvements in ppFEV 1 compared with placebo were also reported in the subgroup with baseline ppFEV 1 levels of 40 or higher (3·3 percentage points [2·3–4·4; p 1 compared with placebo were observed in subgroups with screening ppFEV 1 levels lower than 70 and ppFEV 1 levels of 70 or higher. Increases in body-mass index and reduction in number of pulmonary exacerbation events were observed in both Lumacaftor/ivacaftor dose groups compared with placebo across all lung function subgroups. Treatment was generally well tolerated, although the incidence of some respiratory adverse events was higher with Lumacaftor/ivacaftor than with placebo in all subgroups. In patients with baseline ppFEV 1 levels lower than 40, these adverse events included cough, dyspnoea, and abnormal respiration. Interpretation These analyses confirm that Lumacaftor/ivacaftor combination therapy benefits patients with cystic fibrosis homozygous for Phe508del CFTR who have varying degrees of lung function impairment. Funding Vertex Pharmaceuticals.
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Lumacaftor ivacaftor in patients with cystic fibrosis homozygous for phe508del cftr
The New England Journal of Medicine, 2015Co-Authors: Claire E Wainwright, Gautham Marigowda, Carla Colombo, Jane C Davies, J. Stuart Elborn, Marco Cipolli, Kris De Boeck, Bonnie W Ramsey, Xiaohong Huang, Patrick A. FlumeAbstract:A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV 1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both Lumacaftor–ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV 1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the Lumacaftor–ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the Lumacaftor–ivacaftor groups as well. The incidence of adverse events was generally similar in the Lumacaftor–ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received Lumacaftor–ivacaftor versus 1.6% among those who received placebo. CONCLUSIONS These data show that Lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.)
