Rationalizing endpoints for prospective studies of pulmonary exacerbation treatment response in cystic fibrosis

VanDevanter, Donald R.; Heltshe, Sonya L.; Spahr, Jonathan E.; Beckett, Valeria; Daines, Cori; Dasenbrook, Elliott C.; Gibson, Ronald L.; Jain, Raksha; Sanders, Don B.; Goss, Christopher H.; Flume, Patrick A.

doi:10.1016/j.jcf.2017.04.004

Cited by 46 publications

(44 citation statements)

References 29 publications

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“…In the current analysis, we have asked how risk factors associated with failure to return to baseline lung function differ by magnitude of ppFEV 1 drop before PEx diagnosis and treatment. Our observation of one in ten PEx having no pretreatment ppFEV 1 drop is similar to the 12.1% incidence of such events reported in the prospective STOP study (NCT02109822) when a 1‐year baseline calculation was employed . Interestingly, more than one‐third of these events in our study had a ppFEV 1 below baseline at follow‐up.…”

Section: Discussionsupporting

confidence: 87%

“…Evaluations of PEx treatment response using baseline ppFEV 1 recovery at follow‐up have often emphasized ppFEV 1 relative drops of more than 10% and excluded those PEx where an individual's ppFEV 1 at diagnosis is not less than their baseline value, because for those patients ppFEV 1 “recovery” has apparently occurred before treatment. Interestingly, these types of PEx are not particularly rare: a prospective observational study reported that 12.1% of patients were admitted to hospital for PEx with a ppFEV 1 exceeding their best recorded in the prior year and 19.6% exceeding their best in the prior 6 months . In this study, we examined the factors associated with a return to baseline ppFEV 1 not only in those PEx with a ≥10% pretreatment ppFEV 1 drop but also those with <10% and no ppFEV 1 drop.…”

Section: Introductionmentioning

confidence: 99%

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Lung function changes before and after pulmonary exacerbation antimicrobial treatment in cystic fibrosis

Wagener

VanDevanter

Konstan

et al. 2019

Pediatric Pulmonology

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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%, <10%, and no ppFEV1 drop before treatment. Results Of 15 147 PEx, 10 166 (67.1%), 3479 (23.0%), and 1502 (9.9%) presented with a ≥10%, <10%, or no ppFEV1 drop at diagnosis, respectively. 19.5%, 35.2%, and 65.6% of PEx, respectively, had follow‐up ppFEV1 equal to or exceeding baseline; overall 27.7% of all PEx treatments resulted in complete recovery of baseline ppFEV1. Significant predictors of ppFEV1 recovery at follow‐up were younger patient age, absence of Aspergillus, lower baseline ppFEV1, fewer visits during the baseline, lower frequency of prior‐year PEx, shorter elapsed time from baseline measure to treatment, smaller relative ppFEV1 drop before treatment, and non intravenous (ie, oral or inhaled antibiotic) treatment. PEx with ≥10%, <10%, and no ppFEV1 drop before treatment had only modest differences in covariate odds ratios associated with complete ppFEV1 recovery. Conclusions Among the 10% of PEx presenting with no apparent ppFEV1 drop, more than one‐third resulted in a decreased ppFEV1 during follow‐up. Risk factors for this outcome were the same as those associated with lack of ppFEV1 recovery among PEx with pretreatment ppFEV1 drops. These results suggest that inherent FEV1 variability, baseline and follow‐up sampling methodologies, ppFEV1 regression to the mean, and underlying lung disease progression complicate this approach for assessing effects of PEx and treatment response.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Lung function changes before and after pulmonary exacerbation antimicrobial treatment in cystic fibrosis

Wagener

VanDevanter

Konstan

et al. 2019

Pediatric Pulmonology

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“…84 Clinicians and patients seem to assign different priorities to resolution of symptoms, improvement in quality of life, and time to relapse as outcomes of interest. 82,84,85 The choice of primary outcome is important-for example, length of treatment is often driven by return of ppFEV1 or symptoms to baseline, so a rapid response could lead to a shorter treatment regimen, but a study of predictors of IV retreatment within 30 days following treatment for a PEx found treatment duration <9 days to be a risk factor. 80 Despite the unknowns, it is clear that antibiotic treatment of PEx is more likely to lead to recovery and preservation of lung function.…”

Section: Treatment Of Pulmonary Exacerbationsmentioning

confidence: 99%

Reevaluating approaches to cystic fibrosis pulmonary exacerbations

Schechter

2018

Pediatric Pulmonology

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Cystic Fibrosis (CF) lung disease is characterized by intermittent acute episodes of worsening signs, symptoms, and pulmonary function; these so-called pulmonary exacerbations (PEx) appear to be important drivers of long-term declines in lung function, quality of life, and life expectancy. Surveillance for development of PEx and their treatment is a fundamental component of chronic CF management, and the merits of novel CF therapies are often judged based on their ability to reduce the frequency of PEx. Given the central role that they play, it is surprising how poorly PEx are understood, how thin is the evidence base for their treatment and how often they are left unrecognized and untreated in clinical practice. This paper reviews what is known and what is unknown regarding the nature of PEx, and discusses the impact of missed recognition and treatment of these episodes as well as the apparent variation in practice across CF care centers. The arguments supporting a liberal, highly sensitive approach to the diagnosis of PEx are presented, as well as recommendation for how care programs can achieve consistency in their early recognition and treatment. A stepwise approach to personalized treatment supported by close follow-up to ensure the successful resolution of all signs and symptoms will lead to the stabilization of patients' lung function and quality of life. Recommendations are made regarding important priorities for research into evidence-based approaches to improving the care of PEx.

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“…However, there is evidence that such an approach may be misleading: exacerbating patients treated with intravenous (IV) antibiotics for less than 9 days (presumably because of an observation of rapid response) are at about double the risk of being retreated within 30 days as their peers treated longer with IV antibiotics, irrespective of other risk factors [7]. Further, it has been demonstrated that some patients continue to recover pulmonary function and experience reduced signs and symptoms of exacerbations for weeks after treatment stops (and unfortunately, the health of others degrades shortly after treatment cessation) [7,9,10]. Thus, clinical presentation immediately at the end of treatment may not accurately reflect clinical status even weeks after treatment.…”

Section: Comparisons Of Acute Treatments For Pulmonary Exacerbationsmentioning

confidence: 99%

“…This initial study was completed in 2016 [11,12]. Surveys of clinician and patient treatment goals were also collected and, in combination with treatment responses, sample size requirements and relative strengths and weaknesses of different possible efficacy endpoints for prospective randomized comparative trials of exacerbation treatments were delineated [10]. Currently, a larger, innovative multicenter study (STOP2; NCT02781610), in which IV antibiotic treatments of 10, 14, and 21 days in adults with CF will be compared is in active enrollment [13].…”

Section: Comparisons Of Acute Treatments For Pulmonary Exacerbationsmentioning

confidence: 99%

Innovating cystic fibrosis clinical trial designs in an era of successful standard of care therapies

VanDevanter

Mayer-Hamblett

2017

Current Opinion in Pulmonary Medicine

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Purpose of review Evolving cystic fibrosis (CF) ‘standards of care’ have influenced recent CF clinical trial designs for new therapies; care additions/improvements will require innovative trial designs to maximize feasibility and efficacy detection. Recent findings Three CF therapeutic areas (pulmonary exacerbations, Pseudomonas aeruginosa airway infections, and reduced CF Transmembrane Conductance Regulator [CFTR] protein function) differ with respect to the duration for which recognized ‘standards of care’ have been available. However, developers of new therapies in all three areas are affected by similar challenge: standards of care have become so strongly entrenched that traditional placebo-controlled studies in CF populations likely to benefit from newer therapies have become less and less feasible. Today, patients/clinicians are more likely to entertain participation in active comparator trial designs, which have substantial challenges of their own. Foremost among these are the selection of ‘valid’ active comparator(s), estimation of a comparator’s current clinical efficacy (required for testing non-inferiority hypotheses), and effective blinding of commercially available comparators. Summary Recent and future CF clinical trial designs will have to creatively address this collateral result of successful past development of effective CF therapies: patients and clinicians are much less likely to accept simple, placebo-controlled studies to evaluate future therapies.

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Rationalizing endpoints for prospective studies of pulmonary exacerbation treatment response in cystic fibrosis

Abstract: Results from randomized prospective superiority and non-inferiority studies employing mean CRISS and FEV change from treatment initiation should prove compelling to the community. They will need to be large, but appear feasible.

Cited by 46 publications

References 29 publications

Lung function changes before and after pulmonary exacerbation antimicrobial treatment in cystic fibrosis

Lung function changes before and after pulmonary exacerbation antimicrobial treatment in cystic fibrosis

Reevaluating approaches to cystic fibrosis pulmonary exacerbations

Innovating cystic fibrosis clinical trial designs in an era of successful standard of care therapies

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