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.

RCT Entities:   Population Interventions Outcomes

Key Summary Points

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 (FEV1) 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 (FEF25–75%) is potentially a more sensitive parameter than FEV1 for assessing changes in peripheral airway function in pediatric patients [2, 3]. Indeed, Vilozni et al. reported that FEF25–75% was a more numerically sensitive index than FEV1 in detecting airway obstruction and response to bronchodilators [4]. However, current data on the value of FEF25–75% compared with FEV1 are limited. FEF25–75% has been described as less effort-dependent than FEV1 and is a measurement of small airway dysfunction [2, 3]. In a study comparing children aged 10–18 years with normal FEV1 (> 80% predicted) and FEF25–75% (> 60% predicted) with those who had normal FEV1 (> 80% predicted) and low FEF25–75%, reduced FEF25–75% in the presence of normal FEV1 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 FEF25–75% in children, therefore the authors defined normal FEF25–75% as > 60% predicted, using a value corresponding to 1 standard deviation from the mean FEF25–75% obtained from the initial cohort [3]. A separate study supported this finding proposing FEF25–75% > 65% predicted as normal [5].

Since FEF25–75% correlates well with bronchodilator responsiveness in children with asthma and may reflect peripheral airway obstruction in the presence of a normal FEV1 [2, 3], this prompted the evaluation of this parameter in relation to the long-acting muscarinic antagonist bronchodilator tiotropium.

Tiotropium Respimat® (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 FEF25–75% [6-9]. 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 β2-agonist ± leukotriene receptor antagonist, Table 1). We compare the change in trough FEF25–75% and trough FEV1 (defined as the pre-dose FEF25–75% or FEV1, 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 μg or 2.5 μg) or placebo Respimat.

Table 1

Baseline patient demographics and disease characteristics (treated set)

Demographic/characteristic	Symptomatic severe asthma		Symptomatic moderate asthma
	VivaTinA-asthma® (N = 400)	PensieTinA-asthma® (N = 392)	CanoTinA-asthma® (N = 401)	RubaTinA-asthma® (N = 397)
Male, n (%)	279 (69.8)	242 (61.7)	264 (65.8)	258 (65.0)
Age, years, median (range)	9.0 (6–11)	14.2 (12–17)	8.9 (6–11)	14.3 (11–17)
Race, n (%)
White	358 (89.5)	371 (94.6)	339 (84.5)	368 (92.7)
Asian	2 (0.5)	10 (2.6)	10 (2.5)	13 (3.3)
Black/African American	5 (1.3)	8 (2.0)	7 (1.7)	14 (3.5)
American Indian/Alaska Native	35 (8.8)	3 (0.8)	45 (11.2)	2 (0.5)
Hawaiian/Pacific Islander	0	0	0	0
Ethnicity, n (%)
Hispanic/Latino	72 (18.0)	68 (17.3)	55 (13.7)	42 (10.6)
Never smoked, n (%)	–	392 (100)	–	396 (99.7)
No exposure to second-hand smoke, n (%)	369 (92.3)	367 (93.6)	372 (92.8)	353 (88.9)
Age at onset of asthma, years, mean ± SD	4.1 ± 2.4	6.5 ± 3.9	4.7 ± 2.4	6.5 ± 4.1
Duration of asthma, years, median (range)	4.9 (0.6–11.0)	7.8 (0.3–16.5)	4.2 (0.5–11.0)	7.9 (0.3–16.3)
Concomitant diagnoses, n (%)
Allergic rhinitis	238 (59.5)	225 (57.4)	230 (57.4)	219 (55.2)
Atopic dermatitis	38 (9.5)	38 (9.7)	55 (13.7)	37 (9.3)
FEV1, l, mean ± SDa,b	1.57 ± 0.35	2.53 ± 0.62	1.63 ± 0.39	2.75 ± 0.66
FEV1, % predicted, mean ± SDa,b	81.64 ± 11.45	79.52 ± 11.49	84.06 ± 10.79	82.79 ± 10.56
FEV1% reversibility, median (Q1–Q3)c,d	24.03 (17.44–34.10)	26.01 (18.31–36.60)	23.19 (16.94–33.60)	23.29 (17.46–33.76)
FVC, l, mean ± SDa,b	2.05 ± 0.48	3.32 ± 0.81	2.12 ± 0.56	3.56 ± 0.86
FVC, % predicted, mean ± SDa,b	92.34 ± 13.60	91.62 ± 14.69	94.70 ± 14.71	93.70 ± 13.34
FVC, % reversibility, median (Q1–Q4)c,d	12.92 (7.00–22.90)	14.15 (7.35–25.62)	13.62 (6.15–26.35)	12.76 (5.03–25.81)
FEV1/FVC ratio, %, mean ± SDc	77.36 ± 10.12	76.87 ± 11.26	77.90 ± 10.08	77.89 ± 10.44
FEF25–75%, l/second, mean ± SDa,b	1.39 ± 0.57	2.23 ± 0.96	1.43 ± 0.58	2.48 ± 0.97
FEF25–75%, % predicted, mean ± SDa,b	61.30 ± 23.18	61.55 ± 23.06	62.44 ± 22.53	66.09 ± 20.93
FEF25–75%, % reversibility, median (Q1–Q4)c,d	51.45 (30.60–79.56)	52.61 (29.38–88.79)	48.00 (28.99–79.78)	46.48 (27.12–71.58)
ACQ score, mean ± SDb,e	1.966 ± 0.359	2.13 ± 0.43	1.868 ± 0.309	2.03 ± 0.43
Concomitant therapies at baseline, n (%)
LTRAs	339 (84.8)	315 (80.4)	107 (26.7)	33 (8.3)
LABAs	314 (78.5)	324 (82.7)	1 (0.2)	1 (0.3)
ICS dose of stable maintenance treatment (μg; budesonide or equivalent dose), mean ± SD	457.4 ± 236.0	747.0 ± 357.7	310.0 ± 112.0	539.4 ± 292.7

Data from each study includes from all treatment arms

aPre-bronchodilator

bMeasured at randomization (Visit 2)

cMeasured at screening (Visit 1)

dReversibility was calculated using measurements of lung function before and 15–30 min after patients inhaled 400 µg salbutamol

eACQ-IA in CanoTinA-asthma® and VivaTinA-asthma®

ACQ Asthma Control Questionnaire, ACQ-IA interviewer-administered ACQ, FEF forced expiratory flow at 25–75% of the pulmonary volume, FEV forced expiratory volume in 1 s, FVC forced vital capacity, ICS inhaled corticosteroid, LABA long-acting β2-agonist, LTRA leukotriene receptor antagonist, SD standard deviation

We analyzed data from four double-blind, parallel-group, randomized, placebo-controlled phase III trials: VivaTinA-asthma® (NCT01634152; a 12-week trial in 6 to 11-year-old patients with symptomatic severe asthma) [7], PensieTinA-asthma® (NCT01277523; a 12-week trial in 12 to 17-year-old patients with symptomatic severe asthma) [6], CanoTinA-asthma® (NCT01634139; a 48-week trial in 6 to 11-year-old patients with symptomatic moderate asthma) [8] and RubaTinA-asthma® (NCT01257230; a 48-week trial in 12 to 17-year-old patients with symptomatic moderate asthma) [9]. Details for each study have been published previously [6-9]. Each study was conducted in accordance with the amended Declaration of Helsinki. The ethics research boards of the respective institutions approved the protocols, and signed, informed consent was obtained from all patients and/or their parents [6-9].

We compared change from baseline in trough FEV1 and trough FEF25–75% at the time of the primary endpoint (PensieTinA- and VivaTinA-asthma at week 12; RubaTinA- and CanoTinA-asthma at week 24), and analyzed correlations between FEF25–75% response and FEV1 response at these time points. Pearson’s correlation coefficients were calculated between trough FEV1 and trough FEF25–75%, pooling data from all treatment arms. As measurement of FEF25–75% relies on accurate measurement of forced vital capacity (FVC), mean FEF25–75% was calculated from the maneuver (≥ 3 and ≤ 8 maneuvers per time point) with the largest total sum of FEV1 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 11- and 12 to 17-year-old patients with moderate/severe asthma, tiotropium Respimat consistently improved trough FEV1 (Fig. 1a) and trough FEF25–75% (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].

Fig. 1

a Trough FEV1 response; b trough FEF25–75% response. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. FEF forced expiratory flow at 25–75% of the pulmonary volume, FEV forced expiratory volume in 1 s, PBO placebo, SE standard error, Tio tiotropium

Improvements in trough FEF25–75% response with tiotropium add-on therapy versus placebo were largely more pronounced than improvements in trough FEV1, as evidenced both by the numerical changes and the percentage difference, suggesting that trough FEF25–75% may be a more sensitive measure to detect treatment response, certainly to tiotropium, than trough FEV1. Statistical assessment of the correlation between changes in trough FEF25–75% and changes in trough FEV1 showed moderate-to-high correlations (0.73–0.80; Supplementary Fig. 1).

Even though assessment of FEF25–75% is not currently recommended in asthma guidelines, there are good arguments for its use to supplement FEV1 measurements, particularly in children with asthma. During the early stages of asthma, higher, near-normal FEV1 and FEV1/ FVC values may obscure airway involvement caused by an inflammatory process, whereas FEF25–75% may signify early functional airway impairment, especially of peripheral airways [11]. FEF25–75% may also better reflect small airways disease due to peripheral positioning of the airflow choke point in patients with mid-to-low lung volumes [2]. Compared with FEV1, low FEF25–75% may be a more sensitive indicator of childhood symptomatic asthma, whereas FEV1 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 FEV1 percent predicted at baseline was predominantly in or just under the normal range (≥ 80%). It has been suggested that FEF25–75% may be a functional marker of asthma severity, whereby low FEF25–75% alongside normal FEV1 is associated with increased asthma severity, systemic steroid use, and asthma exacerbations in children [3].

Furthermore, FEF25–75% has been shown to correlate well with bronchodilator (short-acting β2-agonist) responsiveness in children with asthma who have normal FEV1 [2], and it may therefore be a helpful measure to predict which patients might benefit from further bronchodilation [2]. Certainly, in our study, FEF25–75% 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 FEF25–75% as a more sensitive measure of airway response to bronchodilators than FEV1 in children and adolescents with asthma, irrespective of delivery device [4].

FEF25–75% has certain limitations, including a larger variability than FEV1, 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, FEF25–75% 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 FEF25–75% by itself may have limited diagnostic value. Quanjer et al. previously challenged both the usefulness of FEF25–75% 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 FEF25–75% may help in the identification of children and adolescents who may have a normal FEV1 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 FEF25–75% in children and adolescents with asthma, the suggestion that FEF25–75% should be used as an additional lung function measurement is appropriate.

In conclusion, our results strengthen the evidence that FEF25–75% should be evaluated as an additional lung function measurement in pediatric patients. Moreover, FEF25–75% may contribute as a measure to detect response to treatment.

Below is the link to the electronic supplementary material.

Supplementary Figure 1. Correlation between trough FEV1 and trough FEF25–75% response. A. VivaTinA-asthma®; B. PensieTinA asthma®; C. CanoTinA-asthma®; D. RubaTinA-asthma®. PCC: <0.2, very weak correlation; 0.2–0.4, low correlation; 0.4–0.75, moderate correlation; 0.75–0.9, high and substantial correlation; 0.9–1.0, very high/certain correlation. Abbreviations: FEF25–75%, forced expiratory flow at 25–75% of the pulmonary volume; FEV1, forced expiratory volume in 1 second; PCC, Pearson’s correlation coefficient (PDF 317 kb)

Interpretation of lung function data from children and adolescents can be challenging because standard measures such as forced expiratory volume in 1 s (FEV1) do not always correlate with symptom severity.

Forced expiratory flow at 25–75% of the vital capacity (FEF25–75%) could be a more sensitive measure of peripheral airway function than FEV1 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 FEF25–75% and FEV1 following treatment with either tiotropium (5 µg or 2.5 µg) or placebo Respimat®. Trough was defined as the pre-dose FEF25–75% or FEV1, 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® consistently improved FEF25–75% and FEV1 versus placebo, with improvements in FEF25–75% largely more pronounced than those seen in FEV1. Improvements were statistically significant versus placebo except in adolescents with severe asthma.

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 in pediatric patients.