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

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.

Figure 1.. Changes in FEV₁ and CRISS values from admission for IV antibiotic treatment and end of IV treatment to Day 28.

Panel A: Absolute FEV₁% predicted change from admission to Day 28. Panel B: Relative FEV₁ (L or % predicted) change from admission to Day 28. Panel C: CRISS score change from admission to Day 28. Panel D: Cumulative frequency of absolute FEV₁% predicted change from end of IV treatment to Day 28. Panel E: Cumulative frequency of relative (from admission) FEV₁ change from end of IV treatment to Day 28. Panel F. Cumulative frequency of CRISS score change from end of IV treatment to Day 28. Vertical dashed lines identify zero change. Smooth gray curves represent the parametric normal distribution.

Figure 2.

Least squares regression of absolute FEV₁ and CRISS score changes from admission to Day 28.

Figure 3.. Sample size requirements for superiority and non-inferiority studies of continuous FEV₁ and CRISS endpoints.

Panels A-C: Sample size requirements for 1:1 randomized two-sided superiority studies with alpha = 0.05 using change from admission to Day 28 in absolute FEV₁ change (Panel A), relative FEV₁ change (Panel B), and CRISS Score change (Panel C) as endpoints. Horizontal dashed lines show treatment effects equivalent to 25% and 50% improvements over STOP study outcomes (Table 1). Dotted curves show sample size requirements to attain 80% power and solid curves show 90% power requirements. Panels D-F: Sample size requirements for 1:1 randomized one-sided non-inferiority studies of identically effective treatments with alpha = 0.025 as a function of pre-established non-inferiority (NI) margins for FEV₁ change (Panel D), relative FEV₁ change (Panel E) and CRISS change (Panel F) from baseline. Dashed lines show NI margins that retain 50% of the lower bound of STOP treatment effectd. Dotted curves show sample size requirements to attain 80% power and solid curves show 90% power requirements. Panels G-I: Sample size requirements for 1:1 randomized one-sided non-inferiority studies with alpha = 0.025 using absolute FEV₁ change (Panel G), relative FEV₁ change (Panel G), and CRISS Score change (Panel I) as endpoints. Non-inferiority (NI) margins were derived as half of the lower bound of the 95% confidence interval from STOP study outcomes (Table 1). Y-axes represent actual differences in treatment effects between groups, with the horizontal line placed at no difference between treatments. Dotted curves show sample size requirements to attain 80% power and solid curves show 90% power requirements.

Figure 4.. Sample size requirements for superiority studies of categorical FEV₁, CRISS, and IV retreatment endpoints.

Sample size requirements for 1:1 randomized two-sided superiority studies with alpha = 0.05. Panel A: Difference in proportion of subjects achieving a ≥9 % predicted FEV₁ increase from admission at Day 28. Panel B: Difference in proportion of subjects achieving a ≥11-point decrease in CRISS score from admission at Day 28. Panel C: Difference in proportion of subjects retreated with IV antibiotics for exacerbation between days 7 and 28 after end of IV antibiotic treatment. Dotted curves show sample size requirements to attain 80% power and solid curves show 90% power sample size requirements.