Outcome measures for clinical trials assessing treatment of cystic fibrosis lung disease

Background In 2010, aztreonam for inhalation solution joined aminoglycosides and colistimethate as a new cystic fibrosis (CF) chronic inhaled antimicrobial therapy. We studied how introduction of this new inhaled antibiotic class changed management of US CF patients. Methods Use of inhaled aminoglycosides, colistimethate, and aztreonam among patients followed in the CF Foundation Patient Registry was analyzed by age group, lung disease stage, and microbiologic status both annually, and at individual visits between 2009 and 2012. Results The overall prevalence of inhaled antibiotic use did not change during the period, but the prevalence of annual and any visit treatment with >1 inhaled antibiotic class more than doubled. Adults, those with advanced lung disease, and those with >1 Pseudomonas aeruginosa respiratory culture were more likely to receive >1 antibiotic class. Conclusions Inhaled antibiotic management of US CF patients has dramatically changed in association with the introduction of a third inhaled antibiotic class.

Section: Discussionmentioning

confidence: 99%

Association between the introduction of a new cystic fibrosis inhaled antibiotic class and change in prevalence of patients receiving multiple inhaled antibiotic classes

Dasenbrook¹,

Konstan²,

VanDevanter³

2015

“…FEV 1 has also been an important primary endpoint in pivotal clinical trials assessing the efficacy of new therapies (5) (6). Historically, researchers have used varied approaches to analyze FEV 1 , which has limited comparisons across studies and universal interpretation of findings.…”

Section: Introductionmentioning

confidence: 99%

Use of FEV1 in cystic fibrosis epidemiologic studies and clinical trials: A statistical perspective for the clinical researcher

Szczesniak

Heltshe

Stanojevic

et al. 2017

106

Background Forced expiratory volume in 1 second (FEV1) is an established marker of cystic fibrosis (CF) disease progression that is used to capture clinical course and evaluate therapeutic efficacy. The research community has established FEV1 surveillance data through a variety of observational data sources such as patient registries, and there is a growing pipeline of new CF therapies demonstrated to be efficacious in clinical trials by establishing improvements in FEV1. Results In this review, we summarize from a statistical perspective the clinical relevance of FEV1 based on its association with morbidity and mortality in CF, its role in epidemiologic studies of disease progression and comparative effectiveness, and its utility in clinical trials. In addition, we identify opportunities to advance epidemiologic research and the clinical development pipeline through further statistical considerations. Conclusions Our understanding of CF disease course, therapeutics, and clinical care has evolved immensely in the past decades, in large part due to the thoughtful application of rigorous research methods and meaningful clinical endpoints such as FEV1. A continued commitment to conduct research that minimizes the potential for bias, maximizes the limited patient population, and harmonizes approaches to FEV1 analysis while maintaining clinical relevance, will facilitate further opportunities to advance CF care.

“…The clinical significance attached to PEx has justified use of reduced risk of future PEx and increased median time to next PEx as efficacy outcomes in the comparison of PEx treatments (12). In addition, randomized controlled trials of chronic CF respiratory therapies commonly include risk of future PEx and time to next PEx as efficacy outcomes (13). We conducted analyses of time to next PEx on a cohort of CF patients followed at the Cleveland Ohio CF Care Center (pediatric and adult programs) to identify patient phenotypic and treatment covariates associated with differences in hazard rates of experiencing a subsequent PEx.…”

Section: Introductionmentioning

confidence: 99%

Treatment and demographic factors affecting time to next pulmonary exacerbation in cystic fibrosis

VanDevanter

Pasta

Konstan

2015

Background Pulmonary exacerbations (PEx) are important CF clinical events. Methods We studied time to next PEx following intravenous (IV) antibiotic PEx treatment among Cleveland Ohio CF center patients occurring between January 2010 and September 2014. Patient demographics, clinical presentations, and treatments were modeled by Cox proportional hazards regression to identify covariates associated with time to next PEx. Results 193 patients were treated for PEx; 155 had a subsequent IV-treated PEx. Six covariates were associated with future PEx hazard: number of PEx in the prior year (hazard ratio 25.1 for ≥3 and 4.4 for 1-2 prior-year PEx versus none; P<.0001), IV treatment duration in weeks (1.2; P=.0004), percent hospital treatment (1.1; P=.0018), and chronic inhaled aminoglycosides (2.5; P<.0001), leukotriene modifiers (1.8; P=.0031), and high dose ibuprofen (0.52; P=.0006). Conclusions Time to next PEx was profoundly associated with prior-year PEx, suggestive of high-risk PEx phenotypes that warrant recognition and further study.