36 results on '"Stefanie J Millar"'
Search Results
2. Rate of Lung Function Decline in People with Cystic Fibrosis Having a Residual Function Gene Mutation
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Gregory S. Sawicki, Michael W. Konstan, Edward F. McKone, Richard B. Moss, Barry Lubarsky, Ellison Suthoff, Stefanie J. Millar, David J. Pasta, Nicole Mayer-Hamblett, Christopher H. Goss, Wayne J. Morgan, Margaret E. Duncan, and Yoojung Yang
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Pulmonary and Respiratory Medicine ,Respiratory Care - Abstract
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Approximately 5% of people with CF have residual function (RF) CFTR mutations that result in partially retained CFTR activity. Published literature on disease trajectory among those with RF mutations is limited. In this retrospective study, we characterized lung function decline across different age groups in CFTR modulator-untreated people with CF heterozygous for F508del and an RF mutation (F/RF).Rate of decline in percent predicted forced expiratory volume in 1 s (ppFEVThe estimated annualized rate of ppFEVProgressive lung function decline was observed in people with F/RF genotypes across all assessed age groups, reinforcing the importance of early intervention and clinical monitoring to preserve lung function in all people with CF.In people with cystic fibrosis, lung function typically decreases over time and is linked to the severity of the disease. How fast lung function decreases (referred to as the rate of lung function decline) in cystic fibrosis depends on the specific mutations (changes) in the CFTR gene (which causes the disease). Lung function decline has been well studied in some mutation groups, but not many previous studies have looked at lung function decline in people with one copy of the F508del-CFTR mutation (which is the most common CFTR mutation and results in little to no functional CFTR protein) and another CFTR mutation called a residual function mutation (referred to as people with F/RF genotypes). We used data from the US Cystic Fibrosis Foundation Patient Registry (which collects information on the health of people in the USA who have cystic fibrosis), to look at the rate of lung function decline in people with F/RF genotypes. We found that people with cystic fibrosis who have F/RF genotypes experience lung function loss over time. We also found that this lung function loss occurred in people of all ages with F/RF genotypes. This finding supports the importance of early treatment to help prevent lung function loss in all people with cystic fibrosis, including people with F/RF genotypes.
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- 2022
3. Disease burden in people with cystic fibrosis heterozygous for F508del and a minimal function mutation
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Kate Van Brunt, Michael W. Konstan, Jason Booth, Stefanie J. Millar, Gregory S. Sawicki, Evan Bailey, and Patrick A. Flume
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Adult ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Adolescent ,Cystic Fibrosis ,Genotype ,Osteoporosis ,Population ,Cystic Fibrosis Transmembrane Conductance Regulator ,Cystic fibrosis ,Article ,Ivacaftor ,Young Adult ,Cost of Illness ,Internal medicine ,medicine ,Humans ,Registries ,Child ,education ,Disease burden ,Retrospective Studies ,education.field_of_study ,business.industry ,medicine.disease ,Osteopenia ,Cross-Sectional Studies ,Child, Preschool ,Mutation ,Pediatrics, Perinatology and Child Health ,Cohort ,Disease Progression ,Female ,business ,Body mass index ,medicine.drug - Abstract
Background People with cystic fibrosis (CF) heterozygous for F508del-CFTR and a minimal function CFTR mutation (F/MF) that results in no CFTR protein or results in CFTR protein that is not responsive to tezacaftor, ivacaftor, and tezacaftor/ivacaftor in vitro comprise a sizeable percentage of the US CF population. This retrospective, cross-sectional, observational study aimed to characterize CF burden in this subpopulation. Methods People ≥2 years of age in the US CF Foundation Patient Registry with a CF diagnosis, F/MF genotype, and ≥1 encounters in 2017 were included. Descriptive analyses assessed lung function, nutritional parameters, microbiology, hospitalization and pulmonary exacerbation rates, and CF-related complications. Results were stratified by age group; select characteristics were summarized by percent predicted FEV1 (ppFEV1) and ethnicity. Results 5348 people met inclusion criteria. Rates of positive bacterial cultures, pulmonary exacerbations, and hospitalizations were generally higher in older age groups. Prevalence of prescribed symptomatic CF therapies was substantial and also generally higher in older age groups. ppFEV1 was lower in older age groups. A greater percentage of adolescents and adults reported complications, including cirrhosis, osteoporosis, osteopenia, and sinus disease, than younger age groups. Increased prevalence of cultured Pseudomonas aeruginosa and prescribed chronic therapy was seen with decreasing ppFEV1. In each age group, ppFEV1 was slightly higher in the non-Hispanic cohort than in the Hispanic cohort. Conclusions People with F/MF genotypes have substantial disease burden that worsened in older age groups consistent with the progressive nature of CF, indicating need for additional treatment options in this subpopulation.
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- 2022
4. Effect of Subcutaneous Furosemide (Furoscix) On Natriuretic Peptides, Quality of Life and Patient/Caregiver Satisfaction in Heart Failure Patients: Secondary Outcomes of the Freedom-HF Trial
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Daniel Bensimhon, Tamas Alexy, Kathleen L. Deering, Matthew M. Goodwin, Donald Haas, Dalton McLean, Stefanie J. Millar, John F. Mohr, Frank Peacock, and William S. Weintraub
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Pulmonary and Respiratory Medicine ,Cardiology and Cardiovascular Medicine ,Critical Care and Intensive Care Medicine - Published
- 2022
5. Rapid lung function decline in adults with early-stage cystic fibrosis lung disease
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Elliott C. Dasenbrook, Stefanie J. Millar, Aliza K. Fink, David J. Pasta, Michael S. Schechter, Nicole Mayer-Hamblett, and Don B. Sanders
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Adult ,Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Time Factors ,Cystic Fibrosis ,Severity of Illness Index ,Cystic fibrosis ,03 medical and health sciences ,FEV1/FVC ratio ,0302 clinical medicine ,Predictive Value of Tests ,Risk Factors ,Forced Expiratory Volume ,Internal medicine ,Prevalence ,medicine ,Humans ,Longitudinal Studies ,Lung ,business.industry ,Confounding ,Retrospective cohort study ,respiratory system ,Airway obstruction ,Prognosis ,medicine.disease ,United States ,Respiratory Function Tests ,respiratory tract diseases ,Airway Obstruction ,030104 developmental biology ,Pulmonology ,030228 respiratory system ,Pediatrics, Perinatology and Child Health ,Cohort ,Disease Progression ,Female ,business ,Cohort study - Abstract
Rationale The prevalence of adults living with cystic fibrosis (CF) who have early-stage lung disease is increasing. Objectives Describe the prevalence and evaluate spirometric risk factors associated with the subgroup of patients with early-stage lung disease and FEV1 decline of ≥5% predicted/year. Methods Retrospective cohort study of patients ≥18 years with FEV1% predicted ≥80% included in the US CF Foundation Patient Registry from 2010–2013. Regression models were developed to estimate FEV1 rate of decline. Multivariable logistic analysis was used to assess if spirometric risk factors were associated with FEV1 decline. Measurements and main results 3,029 subjects were in the study cohort. Approximately 15% of the cohort had a substantial decline in lung function ≥5% predicted/year. In multivariable models adjusted for confounders, FEV1/FVC ratio Conclusions Even among adults with early-stage lung disease, approximately 15% are shown to progress and experience a large decline in lung function. This reinforces the concept that lung function in early-stage CF is not normal or mild. Rather, lung function decline may be delayed, but not avoided, in these individuals. Variability in FEV1% predicted and airway obstruction as measured by FEV1/FVC ratio may identify individuals at increased risk of decline. Adults with early-stage lung disease should be followed in clinic to monitor for onset of decline.
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- 2020
6. EFFECT OF ELEXACAFTOR/TEZACAFTOR/IVACAFTOR ON ANNUAL RATE OF LUNG FUNCTION DECLINE IN PEOPLE WITH CYSTIC FIBROSIS
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Tim Lee, Gregory S. Sawicki, Josje Altenburg, Stefanie J. Millar, Jessica Morlando Geiger, Mark T. Jennings, Yiyue Lou, Lisa J. McGarry, Kate Van Brunt, Rachel W. Linnemann, Pulmonology, and Pulmonary medicine
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Pulmonary and Respiratory Medicine ,Pediatrics, Perinatology and Child Health - Abstract
Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) with ? 1 F508del-CFTR allele in Phase 3 clinical trials. ELX/TEZ/IVA treatment led to improved lung function, with increases in percent predicted forced expiratory volume in 1 second (ppFEV1) and Cystic Fibrosis Questionnaire-Revised respiratory domain score. Here, we evaluated the impact of ELX/TEZ/IVA on the rate of lung function decline over time by comparing changes in ppFEV1 in participants from the Phase 3 trials with a matched group of people with CF from the US Cystic Fibrosis Foundation Patient Registry not eligible for cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Participants treated with ELX/TEZ/IVA had on average no loss of pulmonary function over a 2-year period (mean annualized rate of change in ppFEV1, +0.39 percentage points [95% CI, ?0.06 to 0.85]) compared with a 1.92 percentage point annual decline (95% CI, ?2.16 to ?1.69) in ppFEV1 in untreated controls. ELX/TEZ/IVA is the first CFTR modulator therapy shown to halt lung function decline over an extended time period.
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- 2022
7. Reduced HF Related Healthcare Costs with Furoscix Versus In-Hospital IV Diuresis in Hf Patients: The FREEDOM-HF Study
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Daniel Bensimhon, William S. Weintraub, W. Frank Peacock, Tamas Alexy, Dalton McLean, Donald Haas, Kathleen L. Deering, Stefanie J. Millar, Matthew M. Goodwin, and John F. Mohr
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- 2022
8. Lung function changes before and after pulmonary exacerbation antimicrobial treatment in cystic fibrosis
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David J. Pasta, Stefanie J. Millar, Wayne J. Morgan, Donald R. VanDevanter, Jeffrey S. Wagener, and Michael W. Konstan
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Adult ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Treatment response ,Adolescent ,Cystic Fibrosis ,Logistic regression ,Gastroenterology ,Cystic fibrosis ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Anti-Infective Agents ,Forced Expiratory Volume ,030225 pediatrics ,Internal medicine ,Regression toward the mean ,Humans ,Medicine ,Child ,Lung ,Lung function ,Pulmonary exacerbation ,business.industry ,Odds ratio ,Antimicrobial ,medicine.disease ,030228 respiratory system ,Pediatrics, Perinatology and Child Health ,Disease Progression ,Female ,business - Abstract
BACKGROUND In cystic fibrosis, observation of a lung function drop (as percent predicted forced expiratory volume in 1 s [FEV1 ]; ppFEV1 ) frequently precedes pulmonary exacerbation (PEx) diagnosis. Recovery of ppFEV1 to a previous "baseline" is commonly used to assess antimicrobial treatment response. However, not all diagnosed PEx are associated with a ppFEV1 drop, and it is unclear whether these are a different type of PEx from those associated with a ppFEV1 drop. METHODS We analyzed pre- and posttreatment ppFEV1 for PEx recorded in the Epidemiologic Study of Cystic Fibrosis from 2003 through 2005. Baseline, pretreatment, and follow-up ppFEV1 were the best recorded within 12-months pre-PEx, the lowest recorded -30 to +3 days of treatment, and the best recorded during 6-month follow-up, respectively. Logistic regression models for return of ppFEV1 to baseline during follow-up were developed separately for PEx with ≥10%
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- 2019
9. Long-term safety and efficacy of tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study
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Patrick A Flume, Reta Fischer Biner, Damian G Downey, Cynthia Brown, Manu Jain, Rainald Fischer, Kris De Boeck, Gregory S Sawicki, Philip Chang, Hildegarde Paz-Diaz, Jaime L Rubin, Yoojung Yang, Xingdi Hu, David J Pasta, Stefanie J Millar, Daniel Campbell, Xin Wang, Neil Ahluwalia, Caroline A Owen, Claire E Wainwright, Ronald L. Gibson, Steven M. Rowe, Noah Lechtzin, Richard C. Ahrens, Karen S. McCoy, Moira Aitken, Scott H. Donaldson, Kimberly Ann McBennett, Joseph M. Pilewski, Joanne Billings, Carlos Milla, Ronald Rubenstein, Daniel Brian Rosenbluth, Rachel Linnemann, Michael R. Powers, Christopher Fortner, Carla Anne Frederick, Theodore G. Liou, Philip Black, Janice Wang, John L. Colombo, Maria Berdella, Maria Veronica Indihar, Cynthia D. Brown, Michael Anstead, Lara Bilodeau, Leonard Sicilian, James Jerome Tolle, Kathryn Moffett, Samya Nasr, Jennifer Taylor-Cousar, Tara Lynn Barto, Nicholas Antos, John S. Rogers, Bryon Quick, Henry R. Thompson, Gregory Sawicki, Bruce Barnett, Robert L. Zanni, Thomas C. Smith, Karen D. Schultz, Claire Keating, Patrick Flume, Gregory J. Omlor, Alix Ashare, Karen Voter, Nighat Mehdi, Maria Gabriela Tupayachi Ortiz, Tonia E. Gardner, Steven R. Boas, Barbara Messore, Edith Zemanick, Raksha Jain, Michael McCarthy, Dana G. Kissner, Kapilkumar Patel, John McNamara, Julie Philley, Ariel Berlinski, Francisco J. Calimano, Terry Chin, Douglas Conrad, Cori Daines, Hengameh H. Raissy, Thomas G. Keens, Jorge E. Lascano, Bennie McWilliams, Brian Morrissey, Santiago Reyes, Subramanyam Chittivelu, Sabiha Hussain, Arvey Stone, James Wallace, Ross Klingsberg, Julie A. Biller, Stephanie Bui, Olaf Sommerburg, Elisabetta Bignamini, Mirella Collura, Alexander Moller, Donatello Salvatore, Chantal Belleguic, Lea Bentur, Ori Efrati, Eitan Kerem, Dario Prais, Esther Quintana Gallego, Peter Barry, Galit Livnat-Levanon, Jose Ramon Villa Asensi, David Stuart Armstrong, Oscar Asensio de la Cruz, Francis Gilchrist, Diana Elizabeth Tullis, Bradley Quon, Larry C. Lands, Nancy Morrison, Annick Lavoie, Barry Linnane, Okan Elidemir, Felix Ringshausen, Matthias Kappler, Helge Hebestreit, Jochen Mainz, Alexander Kiefer, Cordula Koerner-Rettberg, Doris Staab, Wolfgang Gleiber, Tacjana Pressler, Florian Stehling, Andreas Hector, Sivagurunathan Sutharsan, Lutz Naehrlich, Damian Downey, Jane Carolyn Davies, Robert Ian Ketchell, Mary Patricia Carroll, Simon Doe, Gordon MacGregor, Edward Fairbairn Nash, Nicholas Withers, Daniel Gavin Peckham, Martin James Ledson, Sonal Kansra, Timothy William Rayner Lee, Bertrand Delaisi, Gilles Rault, Jean Le Bihan, Dominique Hubert, Isabelle Fajac, Isabelle Sermet-Gaudelus, Marleen Bakker, Bert Arets, Christiane De Boeck, Raphael Chiron, Philippe Reix, Catherine Mainguy, Eva van Braeckel, Anne Malfroot, Isabelle Durieu, Nadine Desmazes Dufeu, Anne Prevotat, Renske van der Meer, Petrus Merkus, E.J.M. Weersink, Isabel Barrio Gomez-Aguero, Silvia Gartner, Amparo Sole Jover, Antonio Alvarez Fernandez, Desmond William Cox, Edward F. McKone, Barry James Plant, Hiranjan Selvadurai, Simon David Bowler, Claire Elizabeth Wainwright, Daniel Smith, Peter Gordon Middleton, John William Wilson, Sonia Volpi, Carla Colombo, Benedetta Fabrizzi, Vincenzina Lucidi, Federico Cresta, Salvatore Cucchiara, Ernst Eber, Helmut Ellemunter, Isidor Huttegger, Lena Hjelte, Christina Krantz, Marita Gilljam, and Pulmonology
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Adult ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Indoles ,Cystic Fibrosis ,Cystic Fibrosis Transmembrane Conductance Regulator ,Quinolones ,Aminophenols ,Cystic fibrosis ,Time ,Ivacaftor ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Benzodioxoles ,030212 general & internal medicine ,Israel ,biology ,business.industry ,Australia ,medicine.disease ,Cystic fibrosis transmembrane conductance regulator ,Discontinuation ,Europe ,Drug Combinations ,Treatment Outcome ,Clinical research ,030228 respiratory system ,Tolerability ,Mutation ,North America ,biology.protein ,Female ,business ,medicine.drug - Abstract
Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.
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- 2021
10. Burden of cystic fibrosis in children12 years of age prior to the introduction of CFTR modulator therapies
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Cecile LeCamus, Glen Laird, Kathryn Bresnick, Emilio Arteaga-Solis, and Stefanie J Millar
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Cystic Fibrosis ,Cystic Fibrosis Transmembrane Conductance Regulator ,Disease ,Quinolones ,Aminophenols ,Cystic fibrosis ,Internal medicine ,Genotype ,Medicine ,Humans ,Allele ,Respiratory system ,Child ,Disease burden ,Retrospective Studies ,Lung ,business.industry ,medicine.disease ,medicine.anatomical_structure ,Cross-Sectional Studies ,Child, Preschool ,business ,Complication - Abstract
BackgroundCystic fibrosis (CF) is a genetic, multisystemic, progressive and life-shortening disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Different genotypes have been linked to variations in disease progression among people with CF. The burden of illness (BOI) in children with CF is incompletely characterised, particularly as it relates to CFTR genotypes prior to the availability of the first CFTR modulators. This retrospective, cross-sectional, descriptive study evaluated the BOI in US children with CF MethodsData from the US Cystic Fibrosis Foundation Patient Registry from 2011 were used to summarise key patient and disease characteristics using descriptive statistics, overall and grouped by age (0 to F508del/F508del, F508del/minimal function (MF), MF/MF, gating mutation on ≥1 allele, residual function mutation on ≥1 allele and R117H on ≥1 allele) group.ResultsThe analysis included 9185 children. Among 6-year-olds to 1 in 1 s was 92.6% (17.5%). Among all children ConclusionsPrior to the approval of the first CFTR modulator therapies in children
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- 2021
11. Lung function decline is delayed but not decreased in patients with cystic fibrosis and the R117H gene mutation
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Nicole Mayer-Hamblett, Gregory S. Sawicki, Richard B. Moss, Wayne J. Morgan, Michael W. Konstan, David J. Pasta, Jeffrey S. Wagener, Edward F. McKone, Stefanie J. Millar, and Christopher H. Goss
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Adult ,Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Pathology ,Adolescent ,Cystic Fibrosis ,Cystic Fibrosis Transmembrane Conductance Regulator ,Gene mutation ,Gastroenterology ,Cystic fibrosis ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,In patient ,Registries ,Age of Onset ,Child ,Lung ,Lung function ,Patient registry ,business.industry ,Homozygote ,Age Factors ,Delayed onset ,medicine.disease ,United States ,Respiratory Function Tests ,Airway Obstruction ,030104 developmental biology ,030228 respiratory system ,Lung disease ,Mutation ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,Disease Progression ,Female ,business - Abstract
BACKGROUND: Patients with cystic fibrosis (CF) experience variable lung disease phenotypes. The R117H mutation is often associated with preserved lung function. Our objective was to compare the rate of lung function decline in patients with the R117H mutation and patients homozygous for the F508del mutation. METHODS: Rate of decline in percentage-of-predicted FEV(1) (ppFEV(1)) was analyzed using the 2006-2010 US CF Foundation Patient Registry. RESULTS: 4-year rate of decline was slower in 156 R117H patients compared with 6251 F508del patients (−0.61 vs −2.03 ppFEV(1)/year, P
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- 2018
12. Pulmonary exacerbations and acute declines in lung function in patients with cystic fibrosis
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David J. Pasta, Stefanie J. Millar, Michael J. Williams, Michael W. Konstan, Jeffrey S. Wagener, and Wayne J. Morgan
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Adult ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Epidemiologic study ,Adolescent ,Cystic Fibrosis ,medicine.drug_class ,Clinical Decision-Making ,Antibiotics ,Cystic fibrosis ,Time-to-Treatment ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,In patient ,Longitudinal Studies ,030212 general & internal medicine ,Child ,Lung ,Lung function ,business.industry ,Patient Acuity ,medicine.disease ,United States ,Anti-Bacterial Agents ,Respiratory Function Tests ,Early Diagnosis ,030228 respiratory system ,Intravenous antibiotics ,Pediatrics, Perinatology and Child Health ,Cohort ,Disease Progression ,Female ,business - Abstract
Background Patients with cystic fibrosis (CF) who experience acute declines in percent predicted FEV 1 (ppFEV 1 decreased ≥10% relative to baseline) are often not treated with antibiotics for pulmonary exacerbations (PEx), whereas other patients are treated even when they have not experienced a decline in lung function. Methods We analyzed 2 patient cohorts using 3 years of Epidemiologic Study of CF data. Cohort 1 (12,837 patients) experienced a ≥10% acute decline in ppFEV 1 (n = 22,898) and Cohort 2 (10,416 patients) had a clinician-diagnosed PEx (n = 20,731). Results 70.7% of ≥10% decline events were treated with antibiotics; with intravenous antibiotics used 67.1% of the time. 32.0% of clinician-diagnosed PEx declined Conclusions A clinician's decision to diagnose a PEx and treat with antibiotics often is not defined by measured lung function: a ≥10% FEV 1 decline is not considered an absolute indication of a PEx and the lack of a decline does not contraindicate a PEx. Clinicians appear to use the history of prior PEx plus other variables as factors for diagnosing PEx.
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- 2018
13. Comparison of FEV1 reference equations for evaluating a cystic fibrosis therapeutic intervention
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Stefanie J. Millar, Wayne J. Morgan, Michael W. Konstan, Donald R. VanDevanter, Jeffrey S. Wagener, and David J. Pasta
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Future studies ,Epidemiologic study ,business.industry ,030503 health policy & services ,Dornase alfa ,medicine.disease ,Intervention studies ,Cystic fibrosis ,Pulmonary function testing ,Surgery ,03 medical and health sciences ,Percent predicted FEV1 ,0302 clinical medicine ,030228 respiratory system ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,0305 other medical science ,business ,Lung function ,medicine.drug - Abstract
Objectives The Global Lung Function Initiative (GLI, 2012) developed reference equations for forced expiratory volume in 1 s (FEV1). Previous equations were developed by groups led by Knudson (1983), Wang (1993), Hankinson (1999), and Stanojevic (2008).1,2,4,6 We assessed how different prediction equations affect the conclusions from a therapeutic intervention study that evaluated the rate of percent predicted FEV1 (ppFEV1) decline. Methodology Using data from the Epidemiologic Study of cystic fibrosis (CF), we re-analyzed our previous study evaluating the relationship of dornase alfa (DA) use with ppFEV1 using the Knudson, Wang & Hankinson, Stanojevic, and GLI equations. The change in intercept and change in slope of ppFEV1 from a 2-year pre-index period and 2-year post-index period were compared between the treated (N = 2483) and comparator groups (N = 6992, from 4110 unique patients). Results Change in intercept for the comparator group was similar across equations except that Wang & Hankinson values were more negative. The difference in change in intercept between the DA and comparator groups ranged from 3.38 to 4.02% predicted. The change in slope for the comparator group ranged from −0.58 to +0.30 ppFEV1/year, but the difference in change in slope between the DA and comparator groups was in a narrower range from +0.53 to +0.89 ppFEV1/year. Conclusions Although individual patient results are impacted by the choice of reference equations, the study conclusions from this evaluation of a therapeutic intervention were minimally affected. GLI equations are recommended for future studies, but prior results based on other equations should be accepted as reliable.
- Published
- 2017
14. Patients with Cystic Fibrosis and a G551D or Homozygous F508del Mutation: Similar Lung Function Decline
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Jeffrey S. Wagener, David J. Pasta, Stefanie J. Millar, Barry Lubarsky, Michael W. Konstan, Edward F. McKone, and Gregory S. Sawicki
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Adult ,Male ,Pulmonary and Respiratory Medicine ,Adolescent ,Cystic Fibrosis ,MEDLINE ,Cystic Fibrosis Transmembrane Conductance Regulator ,Critical Care and Intensive Care Medicine ,Bioinformatics ,Cystic fibrosis ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Forced Expiratory Volume ,Humans ,Medicine ,Registries ,030212 general & internal medicine ,Young adult ,Child ,Lung function ,business.industry ,Homozygote ,Disease progression ,medicine.disease ,030228 respiratory system ,Mutation ,Mutation (genetic algorithm) ,Disease Progression ,Female ,business - Published
- 2017
15. Relationship of Antibiotic Treatment to Recovery after Acute FEV1 Decline in Children with Cystic Fibrosis
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Stefanie J. Millar, David J. Pasta, Michael W. Konstan, Wayne J. Morgan, Donald R Van Devanter, and Jeffrey S. Wagener
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Pulmonary and Respiratory Medicine ,Spirometry ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.drug_class ,Antibiotics ,Odds ratio ,medicine.disease ,Logistic regression ,Cystic fibrosis ,Confidence interval ,03 medical and health sciences ,0302 clinical medicine ,030228 respiratory system ,Internal medicine ,Epidemiology ,Medicine ,030212 general & internal medicine ,business ,Prospective cohort study ,Intensive care medicine - Abstract
Rationale: Children with cystic fibrosis often experience acute declines in lung function. We previously showed that such declines are not always treated with antibiotics, but we did not assess whether treatment improves the likelihood of recovery.Objectives: To determine whether new antibiotic treatment was associated with recovery from acute FEV1 decline.Methods: We studied episodes of FEV1 decline (≥10% from baseline) in the Epidemiologic Study of Cystic Fibrosis. Treatments were hospitalization, home intravenous antibiotic, new inhaled oral quinolone, or other oral antibiotic. We used logistic regression to evaluate whether treatment was associated with recovery to baseline or near baseline.Results: Logistic regression of 9,875 patients showed that new antibiotic treatment was associated with an increased likelihood of recovery to 90% of baseline (P
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- 2017
16. P255 Rate of lung function decline in patients with cystic fibrosis (cf) having a residual function gene mutation
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Edward F. McKone, E Suthoff, Wayne J. Morgan, David J. Pasta, Richard B. Moss, Stefanie J. Millar, Nicole Mayer-Hamblett, Barry Lubarsky, Christopher H. Goss, Michael W. Konstan, and Gregory S. Sawicki
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medicine.medical_specialty ,Patient registry ,business.industry ,Gene mutation ,medicine.disease ,Cystic fibrosis ,Gastroenterology ,Internal medicine ,Mutation (genetic algorithm) ,Cohort ,medicine ,In patient ,Young adult ,business ,Lung function - Abstract
Objective Patients with cystic fibrosis (CF) and mutations associated with residual CFTR chloride transport have improved survival rates compared with those homozygous for the F508del-CFTR mutation. Since little is known about rate of lung function decline in patients with CF and residual function (RF) mutations, we evaluated differences in rates of percent predicted FEV1 (ppFEV1) decline between patients with an RF mutation who were heterozygous for F508del and those who were homozygous for F508del, and whether rates of ppFEV1 decline differed across age groups. Methods Patients in the US CF Foundation Patient Registry from 2006 to 2014 with an RF mutation heterozygous for F508del were compared with F508del-homozygous patients. Mutations were identified based on clinical or in vitro evidence of residual ion transport. Annual rates of ppFEV1 decline were estimated for patients 6 to 45 years of age with ≥3 ppFEV1 values spanning ≥0.5 years in a randomly chosen 2 year period that began at the first ppFEV1 measurement in the calendar year. Results A total of 1242 RF and 11,916 F508del-homozygous patients were included. At the first visit, the RF cohort was older (mean [SD], 23.0 [12.1] vs 18.0 [9.6] years) and had better nutritional status (mean [SD] BMI z score, 0.36 [1.09] vs −0.29 [1.08]). Mean (SD) ppFEV1 differed at the first visit between cohorts (80.4 [24.8] vs 73.4 [26.5]; p Conclusion Patients with CF and an RF mutation have lower rates of lung function decline compared with F508del-homozygous patients. However, patients with an RF mutation still demonstrate progressive lung disease, particularly during young adulthood. Please refer to page A259 for declarations of interest in relation to abstract P255.
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- 2017
17. Sustained Benefit from Ivacaftor Demonstrated by Combining Clinical Trial and Cystic Fibrosis Patient Registry Data
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Michael W. Konstan, Gregory S. Sawicki, Edward F. McKone, Jeffrey S. Wagener, David J. Pasta, Charles A. Johnson, and Stefanie J. Millar
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Pulmonary and Respiratory Medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Cystic Fibrosis ,Cystic Fibrosis Transmembrane Conductance Regulator ,Nutritional Status ,Quinolones ,Aminophenols ,Critical Care and Intensive Care Medicine ,Cystic fibrosis ,Body Mass Index ,Pulmonary function testing ,Ivacaftor ,Internal medicine ,Weight for Age ,medicine ,Humans ,Registries ,Propensity Score ,Intensive care medicine ,Lung ,Clinical Trials as Topic ,business.industry ,medicine.disease ,Respiratory Function Tests ,Clinical trial ,Mutation (genetic algorithm) ,Propensity score matching ,business ,Body mass index ,medicine.drug - Abstract
In clinical trials, patients with cystic fibrosis and a G551D mutation who received ivacaftor experienced improvements in pulmonary and nutritional outcomes. However, whether these improvements reflect a change in disease trajectory cannot be determined without longer-term analyses with an appropriate comparator population.To examine, over a 3-year period, whether ivacaftor therapy affects pulmonary function and nutritional measures in patients with CF with a G551D mutation compared with patients with CF who are homozygous for the F508del mutation.A propensity score was used to match patients with CF greater than or equal to 6 years of age who have a G551D mutation and received ivacaftor in clinical trials for up to 144 weeks with data from patients in the U.S. Cystic Fibrosis Foundation Patient Registry who are homozygous for the F508del mutation. Matching was based on variables including age, sex, weight for age, height for age, body mass index for age, % predicted FEV1, and chronic therapies (dornase alfa, inhaled antibiotics, inhaled and oral corticosteroids).By calculating the annual estimated rate of decline in lung function for G551D patients receiving ivacaftor and comparing it with the rate of decline in lung function for matched F508del control patients, we show that the rate of lung function decline in G551D ivacaftor-treated patients was slower by nearly half. Moreover, treatment with ivacaftor is shown to improve body mass index and weight-for-age z scores for G551D patients over the 3-year analysis period.These findings suggest that ivacaftor is a disease-modifying therapy for the treatment of cystic fibrosis.
- Published
- 2015
18. Cystic fibrosis clinical characteristics associated with dornase alfa treatment regimen change
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Michael W. Konstan, Wayne J. Morgan, David J. Pasta, Marcia L. Craib, Donald R. VanDevanter, and Stefanie J. Millar
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Pulmonary and Respiratory Medicine ,Adult ,medicine.medical_specialty ,Respiratory Therapy ,Cystic Fibrosis ,Population ,Cystic fibrosis ,Drug Administration Schedule ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,Administration, Inhalation ,medicine ,Deoxyribonuclease I ,Humans ,030212 general & internal medicine ,education ,Lung ,Pulmonary exacerbation ,education.field_of_study ,business.industry ,Treatment regimen ,Incidence (epidemiology) ,Clinical course ,Dornase alfa ,medicine.disease ,Recombinant Proteins ,Surgery ,Anti-Bacterial Agents ,Regimen ,030228 respiratory system ,Pediatrics, Perinatology and Child Health ,Administration, Intravenous ,business ,medicine.drug - Abstract
Background When the chronic respiratory therapy dornase alfa was made commercially available for cystic fibrosis (CF) more than 20 years ago, two regimens were approved: 2.5 mg inhaled once daily (QD) or twice daily (BID). In the intervening years, there has been little guidance as to when to use each regimen. We have studied clinical practice patterns captured in the Epidemiologic Study of CF (ESCF) during the decade following dornase alfa approval (1994-2005) to better understand clinical characteristics associated with QD versus BID dornase alfa use. Methods We studied the characteristics of ESCF patients who received either dornase alfa regimen for at least 12 months and who were then switched to the alternate regimen for at least 6 months and who had adequate data available around the time of the switch. Average lung function and weight-for-age (WFA) z-scores, numbers of intravenous (IV) antibiotic-treated pulmonary exacerbations, and prevalence of signs and symptoms were determined for 6-month periods capturing the beginning (FIRST) and the end (LAST) of the initial regimen, the 6 months preceding the final 6 months of the initial regimen (PRIOR), and the beginning of the second regimen (POST). Changes in values from FIRST to LAST, PRIOR to LAST, and LAST to POST were studied to better understand clinical scenarios associated with decisions to change regimens. Results A total of 1342 QD and 574 BID regimens were studied with median durations of 3.19 and 2.09 years, respectively. On average, patients beginning BID regimens had worse lung function and a greater number of pulmonary exacerbations treated with IV antibiotics than those beginning QD regimens. However, by the time of regimen switch, patients switching from QD to BID dornase alfa had experienced substantial deterioration with respect to pulmonary exacerbations and signs and symptoms, whereas patients switching from BID to QD had not. Interestingly, incidence of IV-treated pulmonary exacerbations and signs and symptom prevalence decreased for both populations after regimen switch. Conclusions We have studied populations of patients with CF receiving dornase alfa who were switched between regimens to characterize clinical course. Our results suggest that the most common clinical attribute associated with switching from QD to BID dornase alfa was a marked deterioration in stability characterized by increased incidence and frequency of pulmonary exacerbation. For this population, deterioration in lung function did not appear to be a driver for this switch. In contrast, patients receiving BID dornase alfa who were ultimately switched to QD appeared to be clinically stable, on average, suggesting that treatment burden and cost may have been drivers of the decision to switch regimens.
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- 2017
19. Relationship of Antibiotic Treatment to Recovery after Acute FEV
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Wayne J, Morgan, Jeffrey S, Wagener, David J, Pasta, Stefanie J, Millar, Donald R, VanDevanter, and Michael W, Konstan
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Male ,Adolescent ,Cystic Fibrosis ,Quinolones ,Anti-Bacterial Agents ,Logistic Models ,Forced Expiratory Volume ,North America ,Ambulatory Care ,Disease Progression ,Humans ,Female ,Pseudomonas Infections ,Prospective Studies ,Child ,Lung - Abstract
Children with cystic fibrosis often experience acute declines in lung function. We previously showed that such declines are not always treated with antibiotics, but we did not assess whether treatment improves the likelihood of recovery.To determine whether new antibiotic treatment was associated with recovery from acute FEVWe studied episodes of FEVLogistic regression of 9,875 patients showed that new antibiotic treatment was associated with an increased likelihood of recovery to 90% of baseline (P 0.001), especially for hospitalization compared with no new antibiotic (odds ratio [OR], 2.79; 95% confidence interval, 2.41-3.23). All four outpatient treatments were associated with greater likelihood of recovery compared with no treatment (OR, 1.27-1.64). Inpatient treatment was better than outpatient treatment (OR, 1.94; 95% confidence interval, 1.68-2.23). Treatment-type ORs were similar across recovery criteria and levels of baseline lung function.New antibiotic therapy, and especially inpatient treatment, is associated with greater likelihood of recovery after acute decline in FEV
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- 2017
20. Comparison of FEV
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Michael W, Konstan, Jeffrey S, Wagener, Donald R, VanDevanter, David J, Pasta, Stefanie J, Millar, and Wayne J, Morgan
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Adult ,Male ,Young Adult ,Adolescent ,Cystic Fibrosis ,Forced Expiratory Volume ,Deoxyribonuclease I ,Humans ,Female ,Child ,Algorithms ,Recombinant Proteins - Abstract
The Global Lung Function Initiative (GLI, 2012) developed reference equations for forced expiratory volume in 1 s (FEVUsing data from the Epidemiologic Study of cystic fibrosis (CF), we re-analyzed our previous study evaluating the relationship of dornase alfa (DA) use with ppFEVChange in intercept for the comparator group was similar across equations except that WangHankinson values were more negative. The difference in change in intercept between the DA and comparator groups ranged from 3.38 to 4.02% predicted. The change in slope for the comparator group ranged from -0.58 to +0.30 ppFEVAlthough individual patient results are impacted by the choice of reference equations, the study conclusions from this evaluation of a therapeutic intervention were minimally affected. GLI equations are recommended for future studies, but prior results based on other equations should be accepted as reliable.
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- 2017
21. Early childhood wheezing is associated with lower lung function in cystic fibrosis
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Wayne J. Morgan, Stefanie J. Millar, Margaret Rosenfeld, David J. Pasta, Michael W. Konstan, and Clement L. Ren
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Pulmonary and Respiratory Medicine ,Spirometry ,medicine.medical_specialty ,Pediatrics ,medicine.diagnostic_test ,business.industry ,Wheeze ,Pediatrics, Perinatology and Child Health ,Epidemiology ,Cohort ,medicine ,Respiratory sounds ,medicine.symptom ,Age of onset ,Prospective cohort study ,business ,Cohort study - Abstract
SummaryObjective To study the association between wheezing in children with cystic fibrosis (CF) and lung function in later life. Methods We used data from the Epidemiologic Study of CF, a longitudinal observational study from 1994 to 2005. Wheezing phenotypes were defined as: no wheezing in the first 6 years of life (NW), transient wheezing (TW; wheezing
- Published
- 2013
22. Clinical use of tobramycin inhalation solution (TOBI®) shows sustained improvement in FEV1 in cystic fibrosis
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Wayne J. Morgan, Michael W. Konstan, David J. Pasta, Stefanie J. Millar, and Jeffrey S. Wagener
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Epidemiologic study ,business.industry ,Confounding ,medicine.disease ,Cystic fibrosis ,Surgery ,Pulmonary function testing ,Internal medicine ,Pediatrics, Perinatology and Child Health ,Epidemiology ,medicine ,Tobramycin ,Young adult ,business ,Inhalation Solution ,medicine.drug - Abstract
SummaryObjectives Tobramycin inhalation solution (TIS; TOBI®) has improved forced expiratory volume in 1 sec (FEV1) in cystic fibrosis (CF) trials. Using data from the Epidemiologic Study of CF (ESCF), we assessed the change in level and trend of FEV1 % predicted (pred) over a 2-year period associated with initiation of TIS during routine clinical practice. Methods Patients age 8–38 years and in ESCF for ≥2 years before treatment with TIS as a chronic therapy were selected if they remained on therapy for 2 years, defined as being on TIS for at least 3 months per year (C-TIS group). Comparator intervals age 8–38 years used TIS
- Published
- 2013
23. 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
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Wayne J. Morgan, Gautham Marigowda, Michael W. Konstan, Stefanie J. Millar, Barry Lubarsky, Jaime L. Rubin, David J. Pasta, Christopher H. Goss, David Waltz, Gregory S. Sawicki, Richard B. Moss, Xiaohong Huang, S. Tian, Edward F. McKone, and Nicole Mayer-Hamblett
- Subjects
Pulmonary and Respiratory Medicine ,Male ,Pediatrics ,medicine.medical_specialty ,Combination therapy ,Adolescent ,Cystic Fibrosis ,Drug intolerance ,Aminopyridines ,Cystic Fibrosis Transmembrane Conductance Regulator ,Quinolones ,Placebo ,Aminophenols ,Drug Administration Schedule ,law.invention ,Time ,Ivacaftor ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Randomized controlled trial ,Double-Blind Method ,law ,Forced Expiratory Volume ,medicine ,Humans ,030212 general & internal medicine ,Benzodioxoles ,Adverse effect ,Child ,Lung ,business.industry ,Lumacaftor ,Homozygote ,Clinical trial ,Drug Combinations ,Treatment Outcome ,030228 respiratory system ,chemistry ,Cough ,Mutation ,Disease Progression ,Female ,business ,medicine.drug - Abstract
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.
- Published
- 2016
24. Design and powering of cystic fibrosis clinical trials using rate of FEV1 decline as an efficacy endpoint
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Stefanie J. Millar, Donald R. VanDevanter, Jeffrey S. Wagener, Ashley Yegin, David J. Pasta, and Michael W. Konstan
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Adult ,Research design ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Time Factors ,Adolescent ,Cystic Fibrosis ,Risk Assessment ,Cystic fibrosis ,Article ,Young Adult ,Risk Factors ,Forced Expiratory Volume ,Internal medicine ,medicine ,Humans ,Rate of decline ,Pediatrics, Perinatology, and Child Health ,Young adult ,Child ,Personnel Selection ,Intensive care medicine ,Lung ,Lung function ,business.industry ,Sample size ,Study design ,Middle Aged ,respiratory system ,medicine.disease ,respiratory tract diseases ,Clinical trial ,Treatment Outcome ,medicine.anatomical_structure ,Research Design ,Sample size determination ,Pediatrics, Perinatology and Child Health ,Feasibility Studies ,Risk assessment ,business - Abstract
BackgroundRate of lung function decline (RLFD) (as FEV1 percent predicted/yr) is a robust measure of CF therapeutic efficacy rarely used as a study endpoint, in part due to uncertainty of sample size requirements.MethodsSample size requirements for 1:1 randomizations to detect RLFD treatment effects from 20% to 80% were assessed in Epidemiologic Study of CF (ESCF) patients. Effects of measuring FEV1 1–4 times per year in studies of 1- to 4-year durations were assessed in 399 patients age ≥6years with FEV1 ≥70%. Impacts of inclusion/exclusion based on risk factors in 2369 ESCF patients were assessed over 1.5years using semi-annual FEV1 measures.ResultsIncreasing study duration and exclusion of lower risk patients (e.g., no P. aeruginosa infection) both substantially reduced requirements.ConclusionsCF RLFD studies of 1.5years in duration appear feasible provided that investigators account for the beneficial effects of subject inclusion/exclusion based on risk factors in power estimates.
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- 2010
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25. 54 Relationship between rate of percent predicted FEV1 (ppFEV1) decline and baseline and acute change in ppFEV1 in patients (pts) with cystic fibrosis (CF) treated with lumacaftor/ivacaftor (LUM/IVA)
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Richard B. Moss, Wayne J. Morgan, Edward F. McKone, Gregory S. Sawicki, Nicole Mayer-Hamblett, Stefanie J. Millar, Barry Lubarsky, Jaime L. Rubin, Michael W. Konstan, Christopher H. Goss, and David J. Pasta
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,Lumacaftor ,medicine.disease ,Cystic fibrosis ,Ivacaftor ,chemistry.chemical_compound ,Percent predicted FEV1 ,chemistry ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,In patient ,business ,Intensive care medicine ,medicine.drug - Published
- 2017
26. Long-term effects of pregnancy and motherhood on disease outcomes of women with cystic fibrosis
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Stefanie J. Millar, Alexandra L. Quittner, Michael S. Schechter, David J. Pasta, Michael W. Konstan, and Ann McMullen
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Pulmonary and Respiratory Medicine ,Adult ,medicine.medical_specialty ,Pediatrics ,Time Factors ,Cystic Fibrosis ,Disease outcome ,Mothers ,Disease ,Cystic fibrosis ,Quality of life ,Pregnancy ,Health care ,medicine ,Humans ,Prospective Studies ,business.industry ,Forced Expiratory Flow Rates ,medicine.disease ,Pregnancy Complications ,Propensity score matching ,Physical therapy ,Quality of Life ,Female ,business ,Body mass index ,Follow-Up Studies - Abstract
Studies of pregnancy in cystic fibrosis (CF) have shown no short-term harmful effects, but there are no long-term studies on the impact of motherhood.This study sought to evaluate longer-term physiologic and functional outcomes in women with CF reporting a pregnancy, with the intent of assessing how the demands of parenting impacted on disease course.Using 1994 to 2005 Epidemiologic Study of Cystic Fibrosis data, we developed a propensity score to match women reporting a pregnancy at a 1:10 ratio with never-pregnant control subjects and compared clinical outcomes, health-related quality of life, and health care use.One hundred nineteen pregnant women presumed to have become mothers were matched with 1,190 control subjects, a median of 6.0 years (range 1.8-11.1 yr) from the pregnancy. No differences were found in annualized change from baseline FEV1 and body mass index, in respiratory signs and symptoms, or in prescribed chronic therapies. Women who had been pregnant were treated for more pulmonary exacerbations and had more illness-related clinic visits but showed no increase in prescribed chronic therapies. They also reported lower health-related quality-of-life scores for Respiratory Symptoms, Physical Functioning, Vitality, and Health Perceptions.Pregnancy and motherhood do not appear to accelerate disease progression but lead to more illness-related visits, pulmonary exacerbations, and a decrease in some domains of quality of life. These differences presumably reflect the impact of the physical and emotional challenges of early motherhood on disease self-management.
- Published
- 2013
27. Early childhood wheezing is associated with lower lung function in cystic fibrosis
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Clement L, Ren, Michael W, Konstan, Margaret, Rosenfeld, David J, Pasta, Stefanie J, Millar, and Wayne J, Morgan
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Male ,Cystic Fibrosis ,Vital Capacity ,Infant ,Prognosis ,Article ,Cohort Studies ,Spirometry ,Child, Preschool ,Forced Expiratory Volume ,Humans ,Female ,Longitudinal Studies ,Prospective Studies ,Age of Onset ,Child ,Lung ,Respiratory Sounds - Abstract
To study the association between wheezing in children with cystic fibrosis (CF) and lung function in later life.We used data from the Epidemiologic Study of CF, a longitudinal observational study from 1994 to 2005. Wheezing phenotypes were defined as: no wheezing in the first 6 years of life (NW), transient wheezing (TW; wheezing3 years old, but no wheezing after 3), late wheezing (LW; wheezing only after age 3 years), and persistent wheezing (PW; wheezing both before and after age 3 years). A linear regression model was developed predicting the best forced expiratory volume in 1 sec (FEV1 ) at age 6 or 7 years (6 to8) for each wheezing phenotype.A total of 1302 children met the cohort inclusion criteria; 61% of the cohort had wheezing in the first 6 years of life. A history of any wheezing in the first 6 years of life was associated with a significantly lower FEV1 at 6 to8 years compared to children with NW. The FEV1 of children with NW at age 6 to8 years was 104% predicted, whereas the mean FEV1 in TW, LW, and PW groups was 98%, 100%, and 96% predicted, respectively (P 0.05 compared to NW).Childhood wheezing in CF is common and is associated with lower lung function at age 6 to8 years. Our results identify a clinical feature in early childhood CF associated with lower lung function in later life.
- Published
- 2013
28. ePS03.4 Improved rate of decline in percent predicted FEV 1 (ppFEV 1 ) is not associated with acute improvement in ppFEV 1 in patients with cystic fibrosis (CF) treated with ivacaftor
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Gregory S. Sawicki, Stefanie J. Millar, Michael W. Konstan, Edward F. McKone, David J. Pasta, Jeffrey S. Wagener, and Jaime L. Rubin
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,medicine.disease ,Cystic fibrosis ,Ivacaftor ,Percent predicted FEV1 ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,In patient ,Intensive care medicine ,business ,medicine.drug - Published
- 2016
29. Clinical use of tobramycin inhalation solution (TOBI®) shows sustained improvement in FEV1 in cystic fibrosis
- Author
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Michael W, Konstan, Jeffrey S, Wagener, David J, Pasta, Stefanie J, Millar, and Wayne J, Morgan
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Adult ,Male ,Adolescent ,Cystic Fibrosis ,Article ,Anti-Bacterial Agents ,Young Adult ,Treatment Outcome ,Forced Expiratory Volume ,Administration, Inhalation ,Tobramycin ,Humans ,Female ,Child - Abstract
Tobramycin inhalation solution (TIS; TOBI®) has improved forced expiratory volume in 1 sec (FEV1 ) in cystic fibrosis (CF) trials. Using data from the Epidemiologic Study of CF (ESCF), we assessed the change in level and trend of FEV1 % predicted (pred) over a 2-year period associated with initiation of TIS during routine clinical practice.Patients age 8-38 years and in ESCF for ≥2 years before treatment with TIS as a chronic therapy were selected if they remained on therapy for 2 years, defined as being on TIS for at least 3 months per year (C-TIS group). Comparator intervals age 8-38 years used TIS10% of the time. For each interval, we estimated the level and trend (rate of decline) in FEV1 % pred before and after the index using a piecewise linear mixed-effects model adjusted for potential confounders.During the 2-year pre-index period the C-TIS group (n = 2,534) had a more rapid decline in FEV1 (-2.49% vs. -1.39% pred/year) and a lower FEV1 at index (62.6% vs. 74.7% pred) than the comparator group (N = 17,656 intervals). After starting chronic TIS, the FEV1 trend line over the 2-year post-index period was higher, but the comparator group's FEV1 was essentially unchanged (difference 2.22, P 0.001). Change in slope was not different between groups (0.06, P = 0.82).Initiating chronic TIS therapy in the routine clinical care of patients with CF was associated with improvement in FEV1 % pred but no change in rate of decline, which means that this benefit was sustained over the 2 years studied.
- Published
- 2012
30. Clinical Use Of Tobramycin Inhalation Solution (TOBI®) Shows Sustained Improvement In FEV1 In Patients With Cystic Fibrosis
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Stefanie J. Millar, Michael W. Konstan, David J. Pasta, Wayne J. Morgan, and Jeffrey S. Wagener
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medicine.medical_specialty ,business.industry ,Anesthesia ,Tobramycin ,Medicine ,In patient ,business ,Intensive care medicine ,medicine.disease ,Cystic fibrosis ,Inhalation Solution ,medicine.drug - Published
- 2012
31. Clinical Use of Dornase Alfa Is Associated with a Slower Rate of FEV1 Decline in Cystic Fibrosis
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Michael W. Konstan, Stefanie J. Millar, Wayne J. Morgan, Joan R. Jacobs, David J. Pasta, Jeffrey S. Wagener, and Ashley Yegin
- Subjects
Pulmonary and Respiratory Medicine ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Cystic Fibrosis ,Cystic fibrosis ,Sensitivity and Specificity ,Article ,Pulmonary function testing ,law.invention ,Young Adult ,Randomized controlled trial ,law ,Internal medicine ,Forced Expiratory Volume ,Epidemiology ,medicine ,Deoxyribonuclease I ,Humans ,Longitudinal Studies ,Prospective Studies ,Young adult ,Prospective cohort study ,Child ,business.industry ,Dornase alfa ,medicine.disease ,Recombinant Proteins ,Surgery ,Pediatrics, Perinatology and Child Health ,Observational study ,Female ,business ,medicine.drug - Abstract
Objectives Randomized controlled trials of dornase alfa have shown forced expiratory volume in 1 sec (FEV1) to improve in patients with cystic fibrosis (CF) but have not assessed change in the rate of lung function decline. We assessed the relationship of dornase alfa use and FEV1 decline using the Epidemiologic Study of Cystic Fibrosis (ESCF). Methodology Patients aged 8–38 years who had been enrolled in ESCF for 2 years when initially treated with dornase alfa were selected if they remained on treatment during the following 2 years. A comparator group included patients aged 8–38 who were not yet reported to have received dornase alfa. For each patient we estimated the annual rate of decline in FEV1% predicted before and after the index using a mixed-effects model adjusted for age, gender, pulmonary exacerbations, respiratory therapies, and nutritional supplements. Results The dornase alfa group (n = 2,230) had a lower FEV1% predicted at index and a more rapid decline during the pre-index period. The mean rate of FEV1 decline improved for the dornase alfa group; the improvement was similar in adults and children 8–17 years old but was not statistically significant in adults. The comparator group (n = 5,970) showed no change among adults and an increased rate of decline among children 8–17 years old. Conclusions The use of dornase alfa for a 2-year period is associated with a reduction in the rate of FEV1 decline. These results also demonstrate the value of using an observational study to assess the association of instituting new therapies in the clinical setting with changes in the rate of FEV1 decline in patients with CF. Pediatr. Pulmonol. 2011; 46:545–553. © 2011 Wiley-Liss, Inc.
- Published
- 2011
32. PRM139 Including Patients in Multiple Groups and Multiple Times in the Same Group in Longitudinal Observational Research: A Cystic Fibrosis Example
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Stefanie J. Millar and David J. Pasta
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medicine.medical_specialty ,Pathology ,Group (mathematics) ,business.industry ,Health Policy ,Internal medicine ,Public Health, Environmental and Occupational Health ,Medicine ,Observational study ,business ,medicine.disease ,Cystic fibrosis - Published
- 2012
33. Probability of Treatment Following Acute Decline in Lung Function in Children with Cystic Fibrosis is Related to Baseline Pulmonary Function
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Wayne J, Morgan, Jeffrey S, Wagener, Ashley, Yegin, David J, Pasta, Stefanie J, Millar, Michael W, Konstan, and Marlyn, Woo
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Male ,medicine.medical_specialty ,Time Factors ,Epidemiologic study ,Adolescent ,Cystic Fibrosis ,Logistic regression ,Cystic fibrosis ,Article ,Pulmonary function testing ,Decile ,Forced Expiratory Volume ,Internal medicine ,Odds Ratio ,medicine ,Humans ,Pseudomonas Infections ,Longitudinal Studies ,Prospective Studies ,Respiratory system ,Child ,Lung ,Lung function ,Probability ,business.industry ,medicine.disease ,Respiratory Function Tests ,respiratory tract diseases ,Treatment Outcome ,Intravenous antibiotics ,Pediatrics, Perinatology and Child Health ,Physical therapy ,Regression Analysis ,Female ,business - Abstract
To determine whether the association between high forced expiratory volume in 1 second (FEV1) and increased rate of decline in FEV1 in children with cystic fibrosis could be due to less frequent intervention after acute declines (sudden decline events) in FEV1.Patients with cystic fibrosis aged 6-17 years enrolled in the Epidemiologic Study of Cystic Fibrosis were assessed for a sudden decline event, defined as a 10% relative decline in FEV1% predicted from an average of 3 consecutive stable baseline spirometries. The likelihood of therapeutic intervention within 14 days before and 56 days after this event was then related to their baseline FEV1% predicted age-specific decile using a logistic regression adjusting for age group (6-12 years, 13-17 years) and presence of Pseudomonas aeruginosa on respiratory culture.A total of 10 888 patients had at least 1 sudden decline event in FEV1. Patients in the highest FEV1 decile were significantly less likely than those in the lowest decile to receive intravenous antibiotics (OR, 0.14; 95% CI, 0.11-0.18; P.001) or be hospitalized (OR, 0.18; 95% CI, 0.14-0.23; P.001) following decline.Children and adolescents with high baseline lung function are less likely to receive a therapeutic intervention following an acute decline in FEV1, which may explain their greater rate of FEV1 decline.
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- 2013
34. Socioeconomic Status and the Likelihood of Antibiotic Treatment for Signs and Symptoms of Pulmonary Exacerbation in Children with Cystic Fibrosis
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Michael S, Schechter, Susanna A, McColley, Warren, Regelmann, Stefanie J, Millar, David J, Pasta, Jeffrey S, Wagener, Michael W, Konstan, Wayne J, Morgan, and Marlyn, Woo
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Male ,Canada ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Cystic Fibrosis ,medicine.drug_class ,Antibiotics ,Signs and symptoms ,medicine.disease_cause ,Cystic fibrosis ,Article ,Disease severity ,Humans ,Medicine ,Pseudomonas Infections ,In patient ,Longitudinal Studies ,Child ,Infusions, Intravenous ,Socioeconomic status ,Pulmonary exacerbation ,business.industry ,Pseudomonas aeruginosa ,medicine.disease ,Drug Utilization ,United States ,Anti-Bacterial Agents ,Social Class ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Female ,business - Abstract
To determine whether socioeconomic status (SES) influences the likelihood of antibiotic treatment of pulmonary exacerbations in patients with cystic fibrosis (CF).We used data on 9895 patients ≤ 18 years old from the Epidemiologic Study of CF. After establishing an individual baseline of clinical signs and symptoms, we ascertained whether antibiotics were prescribed when new signs/symptoms suggested a pulmonary exacerbation, adjusting for sex, presence of Pseudomonas aeruginosa, the number of new signs/symptoms, and baseline disease severity.In a 12-month period, 20.0% of patients6 years of age, 33.8% of patients 6 to 12 years of age, and 41.4% of patients 13 to 18 years of age were treated with any (oral, intravenous (IV), or inhaled) antibiotics; the percentage receiving IV antibiotics was 7.3%, 15.2%, and 20.9%, respectively. SES had little effect on treatment for pulmonary exacerbation with any antibiotics, but IV antibiotics were prescribed more frequently for patients with lower SES.SES-related disparities in CF health outcomes do not appear to be explained by differential treatment of pulmonary exacerbations.
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- 2011
35. Design and powering of cystic fibrosis clinical trials using pulmonary exacerbation as an efficacy endpoint
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Wayne J. Morgan, Michael W. Konstan, Donald R. VanDevanter, David J. Pasta, Ashley Yegin, and Stefanie J. Millar
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Adult ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Microbiological culture ,Exacerbation ,Adolescent ,Cystic Fibrosis ,medicine.drug_class ,Antibiotics ,Population ,medicine.disease_cause ,Cystic fibrosis ,Article ,Young Adult ,Internal medicine ,Forced Expiratory Volume ,medicine ,Humans ,Pulmonary exacerbation ,Pediatrics, Perinatology, and Child Health ,Intensive care medicine ,education ,Child ,Lung ,education.field_of_study ,Clinical Trials as Topic ,Pseudomonas aeruginosa ,business.industry ,Sample size ,Incidence (epidemiology) ,Study design ,medicine.disease ,Clinical trial ,Treatment Outcome ,Research Design ,Pediatrics, Perinatology and Child Health ,Disease Progression ,Female ,business - Abstract
Background Reduction in pulmonary exacerbations is an important efficacy endpoint for CF clinical studies. Powering exacerbation endpoints requires estimation of the future exacerbation incidence in CF study populations, but rates differ across the population. Methods We have estimated exacerbation rates for Epidemiologic Study of CF subpopulations stratified by age, FEV 1 % predicted, sex, weight-for-age percentile, respiratory signs and symptoms, and history of exacerbation and bacterial culture. Sample sizes required to attain 80% power to detect exacerbation reductions of 20% to 80% in 1:1 randomized studies of 3 to 12month duration were determined. Exacerbation treatments with "any" antibiotic (new oral quinolone, new inhaled antibiotic, or intravenous (IV) antibiotic) and with IV antibiotics were studied. Results At all ages, decreased FEV 1 , female sex, exacerbation history, and Pseudomonas aeruginosa culture history were associated with increased treatment for exacerbation. Conclusions These data should assist investigators in the design of future CF exacerbation studies.
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36. Treatment complexity in cystic fibrosis: Trends over time and associations with site-specific outcomes
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David J. Pasta, Clement L. Ren, Gregory S. Sawicki, Stefanie J. Millar, Alexandra L. Quittner, and Michael W. Konstan
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Male ,Pulmonary and Respiratory Medicine ,Pediatrics ,medicine.medical_specialty ,Time Factors ,Adolescent ,Cystic Fibrosis ,business.industry ,Treatment burden ,Treatment outcome ,fungi ,MEDLINE ,medicine.disease ,Health outcomes ,Cystic fibrosis ,Article ,Treatment Outcome ,Multicenter study ,Pediatrics, Perinatology and Child Health ,medicine ,Humans ,Female ,Pediatrics, Perinatology, and Child Health ,business ,Child - Abstract
BackgroundPatients with cystic fibrosis (CF) have increasing treatment complexity and high treatment burden. We describe trends in treatment complexity and evaluate its relationship with health outcomes.MethodsUsing Epidemiologic Study of Cystic Fibrosis (ESCF) data, we developed a treatment complexity score (TCS) from 37 chronic therapies and assessed change by age group (6–13, 14–17, and 18+ years) over a three year period. Differences in average site TCS were evaluated by quartiles based on FEV1, BMI, or Treatment Burden score on the Cystic Fibrosis Questionnaire-Revised (CFQ-R).ResultsTCS scores were calculated for 7252 individual patients (42% child, 16% adolescent, 43% adult) across 153 sites. In 2003, mean TCS was 11.1 for children, 11.8 for adolescents, and 12.1 for adults. In all 3 age groups, TCS increased over 3years; the increase in TCS from 2003–2005 for children was 1.25 (95% CI 1.16–1.34), for adolescents 0.77 (0.62–0.93), and for adults 1.20 (1.08–1.31) (all P
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