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

J Cyst Fibros. 2017 Sep;16(5):607-615. doi: 10.1016/j.jcf.2017.04.004. Epub 2017 Apr 21.

Abstract

Background: Given 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.

Methods: Response 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.

Results: The 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.

Conclusions: Results 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.

Keywords: Clinical trial; Endpoints; Exacerbation; Sample size.

MeSH terms

  • Adult
  • Anti-Bacterial Agents / therapeutic use*
  • Clinical Protocols / standards
  • Cystic Fibrosis* / complications
  • Cystic Fibrosis* / diagnosis
  • Cystic Fibrosis* / drug therapy
  • Endpoint Determination* / methods
  • Endpoint Determination* / standards
  • Feasibility Studies
  • Female
  • Forced Expiratory Volume / drug effects
  • Humans
  • Male
  • Outcome Assessment, Health Care* / methods
  • Outcome Assessment, Health Care* / standards
  • Randomized Controlled Trials as Topic / methods*
  • Respiratory Tract Infections* / drug therapy
  • Respiratory Tract Infections* / etiology
  • Sample Size
  • Surveys and Questionnaires / standards
  • Symptom Flare Up

Substances

  • Anti-Bacterial Agents