Multicenter evaluation of infant lung function tests as cystic fibrosis clinical trial endpoints.
BACKGROUND
The conducting of clinical trials in infants with cystic fibrosis (CF) has been hindered by lack of sensitive outcome measures.


OBJECTIVE
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.


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.
Davis
Stephanie D
SD
Department of Pediatrics, North Carolina Children’s Hospital, University of North Carolina at Chapel Hill, USA. sddavis@med.unc.edu
Rosenfeld
Margaret
M
Kerby
Gwendolyn S
GS
Brumback
Lyndia
L
Kloster
Margaret H
MH
Acton
James D
JD
Colin
Andrew A
AA
Conrad
Carol K
CK
Hart
Meeghan A
MA
Hiatt
Peter W
PW
Mogayzel
Peter J
PJ
Johnson
Robin C
RC
Wilcox
Stephanie L
SL
Castile
Robert G
RG
D002986:Clinical Trials as Topic; D003550:Cystic Fibrosis / Q000175:diagnosis*; D005240:Feasibility Studies; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007223:Infant; D008137:Longitudinal Studies; D008297:Male; D010991:Plethysmography / Q000379:methods; D011446:Prospective Studies; D015203:Reproducibility of Results; D012129:Respiratory Function Tests / Q000379:methods; D012680:Sensitivity and Specificity