Forced Expiratory Flow (FEF25–75%) as a Clinical Endpoint in Children and Adolescents with Symptomatic Asthma Receiving Tiotropium: A Post Hoc Analysis

Introduction In pediatric patients with asthma, measurements of forced expiratory volume in 1 s (FEV1) may be normal or may not correlate with symptom severity. Forced expiratory flow at 25–75% of the vital capacity (FEF25–75%) is a potentially more sensitive parameter for assessing peripheral airway function. This post hoc analysis compared FEF25–75% with FEV1 as an endpoint to assess bronchodilator responsiveness in children with asthma. Methods Change from baseline in trough FEF25–75% and trough FEV1 following treatment with either tiotropium (5 µg or 2.5 µg) or placebo Respimat® was analyzed in four phase III trials in children (aged 6–11 years) and adolescents (aged 12–17 years) with symptomatic moderate (VivaTinA-asthma® and PensieTinA-asthma®) and mild (CanoTinA-asthma® and RubaTinA-asthma®) asthma. Data from all treatment arms were pooled and correlations between FEF25–75% and FEV1 were calculated and analyzed. Results A total of 1590 patients were included in the analysis. Tiotropium Respimat® consistently improved FEF25–75% and FEV1 versus placebo, although in adolescents with severe asthma, the observed improvements were not statistically significant. Improvements in FEF25–75% response with tiotropium versus placebo were largely more pronounced than improvements in FEV1. Statistical assessment of the correlation of FEV1 and FEF25–75% showed moderate-to-high correlations (Pearson’s correlation coefficients 0.73–0.80). Conclusions In pediatric patients, FEF25–75% may be a more sensitive measure to detect treatment response, certainly to tiotropium, than FEV1 and should be evaluated as an additional lung function measurement. Electronic Supplementary Material The online version of this article (10.1007/s41030-020-00117-6) contains supplementary material, which is available to authorized users.

between FEF 25-75% and FEV 1 were calculated and analyzed. Results: A total of 1590 patients were included in the analysis. Tiotropium Respimat Ò consistently improved FEF 25-75% and FEV 1 versus placebo, although in adolescents with severe asthma, the observed improvements were not statistically significant. Improvements in FEF 25-75% response with tiotropium versus placebo were largely more pronounced than improvements in FEV 1 . Statistical assessment of the correlation of FEV 1 and FEF 25-75% showed moderate-to-high correlations (Pearson's correlation coefficients 0.73-0.80). Conclusions: In pediatric patients, FEF 25-75% may be a more sensitive measure to detect treatment response, certainly to tiotropium, than FEV 1 and should be evaluated as an additional lung function measurement.

Key Summary Points
Interpretation of lung function data from children and adolescents can be challenging because standard measures such as forced expiratory volume in 1 s (FEV 1 ) do not always correlate with symptom severity.
Forced expiratory flow at 25-75% of the vital capacity (FEF 25-75% ) could be a more sensitive measure of peripheral airway function than FEV 1 in these patients.
Using pooled data from four phase III trials in patients with asthma aged 6-17 years, we investigated change from baseline in trough FEF 25-75% and FEV 1 following treatment with either tiotropium (5 lg or 2.5 lg) or placebo Respimat Ò . Trough was defined as the predose FEF 25-75% or FEV 1 , respectively, measured 24 h post previous drug administration, 10 min prior to the evening dose of usual asthma medication and daily dose of randomized treatment.
Tiotropium Respimat Ò consistently improved FEF 25-75% and FEV 1 versus placebo, with improvements in FEF 25-75% largely more pronounced than those seen in FEV 1 . Improvements were statistically significant versus placebo except in adolescents with severe asthma.
FEF 25-75% may be a more sensitive measure to detect treatment response, certainly to tiotropium, than FEV 1 and should be evaluated as an additional lung function measurement in pediatric patients.

COMMENTARY
Assessment of standard measures of lung function can be more challenging in children and adolescents compared with adults. Whilst forced expiratory volume in 1 s (FEV 1 ) is accepted as a standard measure of lung function in adults with asthma, it is often found to be normal in pediatric patients, and measurements may not always correlate with symptom severity [1].
Forced expiratory flow at 25-75% of the vital capacity (FEF 25-75% ) is potentially a more sensitive parameter than FEV 1 for assessing changes in peripheral airway function in pediatric patients [2,3]. Indeed, Vilozni et al. reported that FEF 25-75% was a more numerically sensitive index than FEV 1 in detecting airway obstruction and response to bronchodilators [4]. However, current data on the value of FEF 25-75% compared with FEV 1 are limited. FEF 25-75% has been described as less effort-dependent than FEV 1 and is a measurement of small airway dysfunction [2,3]. In a study comparing children aged 10-18 years with normal FEV 1 ([ 80% predicted) and FEF 25-75% ([ 60% predicted) with those who had normal FEV 1 ([ 80% predicted) and low FEF 25-75% , reduced FEF 25-75% in the presence of normal FEV 1 was associated with increased asthma severity and reversible airflow obstruction [2,3]. However, it was noted that there is no guideline regarding normal values for FEF 25-75% in children, therefore the authors defined normal FEF 25-75% as [ 60% predicted, using a value corresponding to 1 standard deviation from the mean FEF 25-75% obtained from the initial cohort [3]. A separate study supported this finding proposing FEF 25-75%-[ 65% predicted as normal [5].
Since FEF 25-75% correlates well with bronchodilator responsiveness in children with asthma and may reflect peripheral airway obstruction in the presence of a normal FEV 1 [2,3], this prompted the evaluation of this parameter in relation to the long-acting muscarinic antagonist bronchodilator tiotropium.
Tiotropium Respimat Ò (Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany) has been shown to improve different measures of lung function in clinical studies with both children and adolescents, including FEF 25-75% [6][7][8][9]. This is a post hoc analysis of four placebo-controlled trials in children and adolescents with symptomatic asthma who remained uncontrolled despite maintenance therapy (inhaled corticosteroids ± long-acting b 2 -agonist ± leukotriene receptor antagonist, Table 1). We compare the change in trough FEF 25-75% and trough FEV 1 (defined as the pre-dose FEF 25-75% or FEV 1 , respectively, measured 24 h post previous drug administration, 10 min prior to the evening dose of usual asthma medication and daily dose of randomized treatment) following treatment with either tiotropium Respimat (5 lg or 2.5 lg) or placebo Respimat.
We compared change from baseline in trough FEV 1 and trough FEF 25-75% at the time of the primary endpoint (PensieTinA-and Viva-TinA-asthma at week 12; RubaTinA-and Cano-TinA-asthma at week 24), and analyzed correlations between FEF 25-75% response and FEV 1 response at these time points. Pearson's correlation coefficients were calculated between trough FEV 1 and trough FEF 25-75% , pooling data from all treatment arms. As measurement of FEF 25-75% relies on accurate measurement of forced vital capacity (FVC), mean FEF 25-75% was calculated from the maneuver (C 3 and B 8 maneuvers per time point) with the largest total sum of FEV 1 and FVC. Use and daily calibration of all spirometers used in the four pediatric trials discussed in this analysis met American Thoracic Society/European Respiratory Society criteria [10].
A total of 1590 patients were included in the analysis (Table 1). Across the trials in 6 to 11and 12 to 17-year-old patients with moderate/severe asthma, tiotropium Respimat consistently improved trough FEV 1 (Fig. 1a) and trough FEF 25-75% (Fig. 1b) versus placebo; although in the PensieTinA-asthma study in adolescents with severe asthma, the observed improvements were not statistically significant, possibly due to a pronounced placebo response, which left little room for differentiation between the treatment groups [6].
Improvements in trough FEF 25-75% response with tiotropium add-on therapy versus placebo were largely more pronounced than improvements in trough FEV 1 , as evidenced both by the numerical changes and the percentage difference, suggesting that trough FEF 25-75% may be a more sensitive measure to detect treatment response, certainly to tiotropium, than trough FEV 1 . Statistical assessment of the correlation between changes in trough FEF 25-75% and changes in trough FEV 1 showed moderate-tohigh correlations (0.73-0.80; Supplementary  Fig. 1).
Even though assessment of FEF 25-75% is not currently recommended in asthma guidelines, there are good arguments for its use to supplement FEV 1 measurements, particularly in children with asthma. During the early stages of asthma, higher, near-normal FEV 1 and FEV 1 / FVC values may obscure airway involvement caused by an inflammatory process, whereas FEF 25-75% may signify early functional airway impairment, especially of peripheral airways [11]. FEF 25-75% may also better reflect small airways disease due to peripheral positioning of the airflow choke point in patients with mid-tolow lung volumes [2]. Compared with FEV 1 , low FEF 25-75% may be a more sensitive indicator of childhood symptomatic asthma, whereas FEV 1 in children can be normal, even in the presence of symptoms of uncontrolled asthma [3]. Indeed, in our study of children with symptomatic moderate or severe asthma, mean FEV 1 percent predicted at baseline was predominantly in or just under the normal range (C 80%). It has been suggested that FEF 25-75% may be a functional marker of asthma severity, whereby low FEF 25-75% alongside normal FEV 1 is associated with increased asthma severity, systemic steroid use, and asthma exacerbations in children [3]. Furthermore, FEF 25-75% has been shown to correlate well with bronchodilator (short-acting *P \ 0.05; **P \ 0.01; ***P \ 0.001; ****P \ 0.0001. FEF 25-75% forced expiratory flow at 25-75% of the pulmonary volume, FEV 1 forced expiratory volume in 1 s, PBO placebo, SE standard error, Tio tiotropium b 2 -agonist) responsiveness in children with asthma who have normal FEV 1 [2], and it may therefore be a helpful measure to predict which patients might benefit from further bronchodilation [2]. Certainly, in our study, FEF 25-75% was useful in detecting treatment response to tiotropium. However, it should be noted that tiotropium, as a bronchodilator, may have other mechanisms of action affecting small as well as large airways, although there is currently no evidence of this. A previous study using a different bronchodilator, albuterol, with an alternative delivery device (pressurized metered dose inhaler), provided results in accordance with those reported here, further supporting the utility of FEF 25-75% as a more sensitive measure of airway response to bronchodilators than FEV 1 in children and adolescents with asthma, irrespective of delivery device [4].
FEF 25-75% has certain limitations, including a larger variability than FEV 1 , particularly in adults, and its reliance on the valid measurement of FVC [12,13]. As FVC and total lung capacity can be affected by disease progression or therapeutic interventions, FEF 25-75% pre-and post-interventions may be not be comparable [13]. Ideally, measurements should be standardized for total lung capacity, but this is not usually feasible and the vital capacity is used as a proxy for lung size [13], and was not possible within this post hoc analysis. The potential lack of specificity means that FEF 25-75% by itself may have limited diagnostic value. Quanjer et al. previously challenged both the usefulness of FEF 25-75% as a clinical marker and the hypothesis that reduced mid-expiratory flows are specific for small airways disease [13]. Yet, this analysis provides further support to the literature that suggests the use of FEF 25-75% may help in the identification of children and adolescents who may have a normal FEV 1 but significant asthma symptoms, or who may require further evaluation from a healthcare professional or adjustments to their treatment regimen [14]. In addition, since this analysis of four studies is probably the largest to investigate the effect of a bronchodilator on FEF 25-75% in children and adolescents with asthma, the suggestion that FEF 25-75% should be used as an additional lung function measurement is appropriate.
In conclusion, our results strengthen the evidence that FEF 25-75% should be evaluated as an additional lung function measurement in pediatric patients. Moreover, FEF 25-75% may contribute as a measure to detect response to treatment.
Regeneron, fees for lectures from Genentech, GlaxoSmithKline and Teva, and consulting fees from Novartis and Genentech. Christian Vogelberg reports study-related payments to their institution from Boehringer Ingelheim during the conduct of the study, and personal fees for advisory boards and lectures from Boehringer Ingelheim and Novartis outside the submitted work. Eckard H. Hamelmann, George W. Bensch, and John Given have nothing to disclose. Branko Jugovic, Michael Engel, Petra M. Moroni-Zentgraf, and Ralf Sigmund are employees of Boehringer Ingelheim.
Compliance with Ethics Guidelines. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Data Availability. The data sets analyzed during the current study are available from the corresponding author on reasonable request.
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