Dataset Information

Evaluating assumptions of definition-based pulmonary exacerbation endpoints in cystic fibrosis clinical trials.

ABSTRACT:

Background

Cystic fibrosis (CF) pulmonary exacerbations can be serious respiratory events and reduction in exacerbation rate or risk are important efficacy endpoints for CF therapeutic trials. Variability in exacerbation diagnoses and treatment have led drug developers to employ "objective" exacerbation definitions combining antimicrobial treatment (AT) and the presence of ?4 of 12 respiratory criteria (first published by Fuchs et al. [NEJM 1994;331(10):637-42]). Assumptions underlying this approach have yet to be formally evaluated.

Methods

Respiratory events (RE) observed during a 48-week trial of ataluren (NCT02139306), a read-through agent for premature nonsense codons, were compared across six exacerbation definitions: any AT, intravenous AT (IVAT), ?4 Fuchs criteria present, AT plus ?4 Fuchs criteria, IVAT plus ?4 Fuchs criteria, and investigator assessment. Fuchs definitions were evaluated by assessing missingness of individual criteria and associations between criteria presence and clinician exacerbation assessment.

Results

Among 751 RE, more than one third had ?4 Fuchs criteria present but were not assessed as exacerbations by investigators. Data for ?1 and for 4 Fuchs criteria, respectively, were missing for ~ 90% and >30% of RE. Only 6/12 Fuchs criteria were present more often when investigators assessed RE as exacerbations than when they did not.

Conclusions

"Objective" definitions have shortcomings inconsistent with their purpose of optimizing exacerbation capture in clinical trials : 1) they capture events clinicians do not consider exacerbations, 2) are prone to data missingness which can bias the likelihood of meeting the definition, and 3) employ criteria that are not associated with investigator assessment of exacerbation.

SUBMITTER: VanDevanter DR

PROVIDER: S-EPMC7362840 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Evaluating assumptions of definition-based pulmonary exacerbation endpoints in cystic fibrosis clinical trials.

VanDevanter Donald R DR Hamblett Nicole Mayer NM Simon Noah N McIntosh Joseph J Konstan Michael W MW

Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 20200715 1

<h4>Background</h4>Cystic fibrosis (CF) pulmonary exacerbations can be serious respiratory events and reduction in exacerbation rate or risk are important efficacy endpoints for CF therapeutic trials. Variability in exacerbation diagnoses and treatment have led drug developers to employ "objective" exacerbation definitions combining antimicrobial treatment (AT) and the presence of ≥4 of 12 respiratory criteria (first published by Fuchs et al. [NEJM 1994;331(10):637-42]). Assumptions underlying t ...[more]

PMID: 32682670

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Project description:BackgroundGiven the variability in pulmonary exacerbation (PEx) management within and between Cystic Fibrosis (CF) Care Centers, it is possible that some approaches may be superior to others. A challenge with comparing different PEx management approaches is lack of a community consensus with respect to treatment-response metrics. In this analysis, we assess the feasibility of using different response metrics in prospective randomized studies comparing PEx treatment protocols.MethodsResponse parameters were compiled from the recent STOP (Standardized Treatment of PEx) feasibility study. Pulmonary function responses (recovery of best prior 6-month and 12-month FEV1% predicted and absolute and relative FEV1% predicted improvement from treatment initiation) and sign and symptom recovery from treatment initiation (measured by the Chronic Respiratory Infection Symptom Score [CRISS]) were studied as categorical and continuous variables. The proportion of patients retreated within 30days after the end of initial treatment was studied as a categorical variable. Sample sizes required to adequately power prospective 1:1 randomized superiority and non-inferiority studies employing candidate endpoints were explored.ResultsThe most sensitive endpoint was mean change in CRISS from treatment initiation, followed by mean absolute FEV1% predicted change from initiation, with the two responses only modestly correlated (R2=.157; P<0.0001). Recovery of previous best FEV1 was a problematic endpoint due to missing data and a substantial proportion of patients beginning PEx treatment with FEV1 exceeding their previous best measures (12.1% >12-month best, 19.6% >6-month best). Although mean outcome measures deteriorated approximately 2-weeks post-treatment follow-up, the effect was non-uniform: 62.7% of patients experienced an FEV1 worsening versus 49.0% who experienced a CRISS worsening.ConclusionsResults from randomized prospective superiority and non-inferiority studies employing mean CRISS and FEV1 change from treatment initiation should prove compelling to the community. They will need to be large, but appear feasible.

Project description:Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n?=?18) admitted for exacerbations received 3 doses of telavancin 7.5?mg/kg of body weight (first 6 patients) or 10?mg/kg (final 12 patients) every 24?h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc ) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (V ?) normalized by the median observed value (Vc ?=?V ??×?TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL?=?CLNR?+?CL??×?CRCL), where CLNR represents nonrenal clearance and CL? represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: V ?, 4.92? ± 0.76 liters?·?kg-1; CLNR, 0.59? ± 0.30 liters?·?h-1; CL?, 5.97?×?10-3 ± 1.24?×?10-3; Vp (volume of the peripheral compartment), 3.77? ± 1.41 liters; Q (intercompartmental clearance), 4.08? ± 2.17 liters?·?h-1 The free area under the concentration-time curve (fAUC) values for 7.5 and 10?mg/kg were 30? ± 4.6 and 52? ± 12?mg?·?h/liter, respectively. Doses of 7.5?mg/kg and 10?mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ?0.12?mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763?mg?·?h?·?liter-1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10?mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.).

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Dataset Information

Evaluating assumptions of definition-based pulmonary exacerbation endpoints in cystic fibrosis clinical trials.

Background

Methods

Results

Conclusions

Publications

Evaluating assumptions of definition-based pulmonary exacerbation endpoints in cystic fibrosis clinical trials.

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