Multicenter evaluation of infant lung function tests as cystic fibrosis clinical trial endpoints

Abstract

Rationale: The conducting of clinical trials in infants with cystic fibrosis (CF) has been hindered by lack of sensitive outcome measures.

Objectives: To evaluate safety, feasibility, and ability to detect abnormalities in lung function of serial pulmonary function tests (PFTs) in infants with CF.

Methods: Multicenter observational study using a commercial device, rigorous training, ongoing quality control, and over-reading of data by an independent panel. Raised volume rapid thoracoabdominal compression technique and plethysmography were performed at enrollment and at 6 and 12 months, with an additional 1-month reproducibility visit.

Measurements and main results: A total of 342 procedures were performed in 100 infants with CF at 10 centers. FRC measurements were acceptable at a higher proportion of study visits (89%) than raised volume (72%) or fractional lung volume (68%) measurements. Average Z scores for many parameters differed significantly from historical control values. Mean (95% confidence interval) Z scores were: -0.52 (-0.78 to -0.25) for forced expiratory flow at 75% (FEF₇₅) for FVC; 1.92 (1.39-2.45) for FRC; 1.22 (0.68-1.76) for residual volume; 0.87 (0.60-1.13) for FRC/total lung capacity; and 0.66 (0.27-1.06) for residual volume/total lung capacity. For future multicenter clinical trials using infant PFTs as primary endpoints, minimum detectable treatment effects are presented for several sample sizes.

Conclusions: In this 10-center study, key PFT measures were significantly different in infants with CF than in historical control subjects. However, infant PFTs do not yet appear ready as primary efficacy endpoints for multicenter clinical trials, particularly at inexperienced sites, based on acceptability rates, variability, and potentially large sample sizes required to detect reasonable treatment effects.

Figure 1.

Plots of the observed values of the infant pulmonary function test measures versus length. Measurements for historical control data are in blue. The measurements for the infants with cystic fibrosis are in red, and repeated measures are connected by the red segments. FEF_25–75 = 25–75% of forced expiratory flow; FEF₇₅, 75% of FEF; RV = residual volume; TLC = total lung capacity.

Figure 2.

Plots of infant pulmonary function test Z scores versus age for the cystic fibrosis (CF) participants and the historical control subjects, with the average trend in Z scores by age among the participants with CF superimposed (thick, solid lines). Measurements for historical control data are in blue. The measurements for the infants with CF are in red, and repeated measures are connected by the red segments. Dashed lines indicate a z score of zero. FEF_25–75 = 25–75% of forced expiratory flow; FEF₇₅, 75% of FEF; RV = residual volume; TLC = total lung capacity.

Figure 3.

Plots of FRC Z score (top) and residual volume (RV) Z score (bottom) against forced expiratory flow at the 75th percent of vital capacity (FEF₇₅) z score at enrollment. Dotted lines are drawn at 1.64 and −1.64, the upper and lower limits of normal for FRC or RV, and FEF₇₅, respectively.