We report the results of the first study to evaluate the utility of infant PFTs as potential clinical trial endpoints in the multicenter setting. Our results reinforce that PFTs (FEF75, FRC, RV, RV:TLC, and FRC:TLC) are, on average, abnormal in infants with CF compared with healthy historical control subjects. We also found that prior site experience with the infant lung function testing device and procedures used in this study significantly affected the ability to generate acceptable measurements.
Based on our results, measures of infant lung function do not yet appear appropriate as the primary efficacy endpoint for a multicenter clinical trial, particularly involving relatively inexperienced sites. However, they may be useful as safety endpoints (27
). In addition, infant PFTs may serve as useful endpoints to evaluate the short-term response to an intervention, given the fact that acute treatment effects may be larger than those sustained over longer time periods.
We identified two issues that must be addressed before using infant PFTs as a primary endpoint in multicenter trials, particularly involving inexperienced sites. First, acceptable measurements could not be obtained in a substantial proportion of participants. FRC was acceptable in 89% of attempts (range, 58–97% across individual sites), and RVRTC measurements in 72% (site range, 40–95%). Second, although the adverse event rate was as expected for chloral hydrate sedation (29
), 12% of participants withdrew due to side effects of sedation.
Because lung function has never been used as a primary endpoint in a clinical trial in infants, it is unknown whether the detectable treatment effects () are achievable. In clinical trials using conventional spirometry in older patients with CF with established lung disease, tobramycin solution for inhalation improved mean FEV1
by 10% at Week 20 compared with enrollment (30
), but it is unknown whether this magnitude of effect size could be achieved in infants with relatively mild lung disease. FRC:TLC may be able to detect a relatively small percent improvement in lung function (), but has never been tested as a clinical trial endpoint.
It should be noted that the treatment effect estimates from our multicenter study conducted at mostly relatively inexperienced centers might not apply to specialized, experienced centers. Indeed, collaborations between a limited number of experienced centers can be very effective, as demonstrated from the reports from the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST-CF) study in Australia (4
) and the Extracorporeal Membrane Oxygenation (ECMO) study in the United Kingdom (31
). Sample size estimates for specific future trials should be based on lung function data from the anticipated participating centers.
We acknowledge that prospectively collected data from a greater number of control subjects would have substantially strengthened our findings. However, ethical concerns precluded sedating healthy infants for lung function testing at all participating sites. We therefore were limited to historical control data obtained with similar equipment and techniques. These data are, in fact, the basis for the only published or available reference equations for the nSpire device, which is in relatively widespread use in clinical laboratories across the United States (15
Reference values from a large cohort of healthy infants obtained with the nSpire device are critically needed for clinical as well as research purposes. The current reference equations are based on measurements in a limited number of children, with a preponderance of very young infants, conducted at one or two specialized centers, and lack serial measurements. Limitations of these data may explain some of our apparent findings, such as the magnitude of elevation of FRC and RV in some subjects, the apparent rate of decline in FEFs over the observation period, and the better-than-expected FVC, FEV0.5, and TLC in the subjects with CF in the first year of life. Fortunately, the ongoing Canadian Healthy Infant Longitudinal Development Study (principle investigators, M. Sears, P. Subbarao, A. Becker, P. Mandhane, and S. Turvey) is currently enrolling 750 normal infants who will have serial lung function testing with the nSpire device from 3 to 18 months of age. Results from this study will provide much-needed robust reference data for infant lung function with the nSpire device.
In a prior, large, multicenter study with infant PFTs (partial FEFs) to evaluate lung disease in infants born to mothers with human immunodeficiency virus infection, uniformity of equipment and training was implemented; however, significant variability in results from individual centers was found, and was ascribed, in part, to insufficient central supervision. The conclusion from that study was to conduct site visits as a form of centralized supervision to secure uniformity (33
). In the current study, despite rigorous training and certification, standard operating procedures, and ongoing centralized quality control and feedback, our average rates of acceptable measurements were substantially lower than those reported from specialized, single or two-center studies (2
). It should be emphasized that this study was performed at sites relatively naive to infant lung function testing: of the 10 participating centers, only 3 had prior experience with the infant PFT device and procedures used in this study. The sites with prior experience performed the highest percentage of acceptable maneuvers. Thus, it appears that using sites with prior experience will yield the highest proportion of acceptable data in future studies.
Infant PFTs are now used routinely in clinical care at most of the participating sites, so these sites are significantly more experienced with these procedures than was true at the initiation of this study. For future trials using infant lung function testing as outcome measures, we suggest that the participating sites should have performed a minimum number of infant lung function tests, have a dedicated physician and team with at least 2 years of expertise in the procedures, and demonstrate the ability to perform acceptable maneuvers as criteria for study participation. A core infant lung function coordinating center that provides training, independently reads all site data, and provides ongoing quality control will help to ensure that only data with acceptable quality are analyzed. To further assess the ability of infant PFTs to serve as clinical trial endpoints, they are currently serving as an exploratory endpoint in a multicenter trial of an inhaled agent in infants with CF. The results of this trial will contribute valuable information regarding detectable treatment effects and feasibility of infant PFTs in the current era.
Similar to our findings, an elevated FRC measured by plethysmography or gas dilution has been reported in infants with CF in several small studies (18
). Only one small prior study has evaluated fractional lung volumes in infants with CF; our findings are consistent with that study (18
). Of note, the majority of those infants with elevated RV or FRC values had diminished FEF75
, consistent with airways obstruction occurring concomitantly with gas trapping.
Our results for FVC, FEV0.5
, and FEF75
agree well, qualitatively, with prior studies (2
). Among 37 infants with CF evaluated by the London CF Collaborative (2
), the average FVC, FEV0.5
, and FEF75
was significantly lower than in concurrent control subjects at two measurements 6 months apart (median age at first measurement, 28 wk). A recent Australian study in 68 infants identified through newborn screening demonstrated that the average FVC, FEV0.5
, and FEF75
were similar in CF and control infants younger than 6 months of age, but significantly lower in the infants with CF older than 6 months of age (4
). In our study, the average FEF75
was lower among our infants with CF than the historical control subjects for all sampled ages. Although, across all ages, the average FVC and FEV0.5
Z scores among our infants with CF were not significantly different from zero, there was a significant decline in FVC and FEV0.5
Z scores with advancing age, similar to the Australian study. Our apparent finding of better average FVC and FEV0.5
among infants with CF than in the control subjects during the first 18 months of life may, in part, be explained by the small sample of historical control subjects, and the fact that the historical control subjects were, on average, younger than our infants with CF (Jones and colleagues : mean age, 48 wk; range 3–149 wk; Castile and colleagues : mean age, 45 wk; range 3–120 wk).
The magnitude of the differences between CF and control measurements in our study was not as dramatic as in these previous publications. In the London Collaborative Study (2
), at a median age of 59 weeks, the mean Z score among the infants with CF for FVC, FEV0.5
, and FEF75
were −1.5, −2.0, and −1.0, respectively. In the Australian infants identified by newborn screening, the corresponding mean Z scores at study visits after 6 months of age were −0.58, −1.13, and −1.07, respectively (4
). In our study, between 1 and 2 years of age, the corresponding mean Z scores were 0.14, 0.04, and −0.56 (). The difference in our findings compared with these prior studies may be due to measurement techniques, differences between the control infants from which the Z score equations were derived, or true differences in respiratory health among the participants with CF at the time of testing, perhaps due to different treatment practices or exposures. There is some indication that the infants enrolled in our study were healthier than those in the London CF Collaborative study. For example, in the London study (2
), the mean weight Z score at the first visit was −1.8 (equivalent to fourth percentile ), whereas the mean weight percentile (39
) at enrollment in our study was 27.7. Infants in the London study also had a higher rate of Pseudomonas aeruginosa
isolation and more chest exam abnormalities than the infants in our study.
Similar to the observations of Linnane and colleagues (4
), we found FEFs and volumes to decline in infants at an apparently greater rate than those observed in older patients with CF who can cooperate with standard spirometry. Several explanations are possible for the apparent steeper decline in lung function in infancy. First, there may truly be loss of lung function in infancy not appreciated during later childhood. Second, the measurement of FEFs is performed differently in these two age ranges; therefore, they may not be directly comparable. We are completing a follow-up study of the majority of participants in this cohort, in which preschool spirometry measurements and clinical characteristics were obtained serially between 3 and 5 years of age. Future studies with the same measurement across all age ranges, such as the lung clearance index, may also help to elucidate age-related trends in lung function. Alternatively, the observed magnitude of the decline in lung function in the patients with CF may, in part, be attributed to the fact that the cohort of control infants to which they were compared was, on average, younger, and lacked serial measurements. Longitudinal changes in lung function in healthy control subjects deserves further study to better understand comparable changes in infants with chronic respiratory conditions.
There is rapidly growing interest in conducting clinical trials of established and novel therapies in infants with CF, in an attempt to delay or prevent irreversible structural airway damage. Therapies aimed at correcting the basic defect, such as CF transmembrane conductance regulator potentiators and correctors, may be most effective if initiated soon after diagnosis. CF newborn screening now affords the opportunity to intervene in the presymptomatic period. However, clinical trials in very youngest patients with CF are still hindered by the lack of appropriate outcome measures in this age range. Potential endpoints include infant PFTs, lung clearance assessed by multiple breath washout (5
), controlled ventilation computed tomography scans (6
), as well as parental reports of infant respiratory symptoms, pulmonary exacerbations, resting respiratory rate, oximetry, and objective monitoring of cough. All these measures have pros and cons, and are in varying stages of development. It is likely that no single endpoint will be the “holy grail” or fit the needs of all clinical trials. With appropriate site training and experience, infant PFTs may come to play a role in the armamentarium of infant clinical trial endpoints.