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Original Research: ASTHMA |

Single-Dose Montelukast or Salmeterol as Protection Against Exercise-Induced Bronchoconstriction* FREE TO VIEW

George Philip, MD; David S. Pearlman, MD; César Villarán, MD; Catherine Legrand, PhD; Tom Loeys, PhD; Ronald B. Langdon, PhD; Theodore F. Reiss, MD
Author and Funding Information

*From the Merck Research Laboratories (Drs. Philip, Legrand, Loeys, Langdon, and Reiss), Rahway, NJ; the Colorado Allergy and Asthma Centers, PC (Dr. Pearlman), Denver, CO; and the Clinica Ricardo Palma (Dr. Villarán), Lima, Peru.

Correspondence to: George Philip, MD, Merck Research Laboratories, Respiratory & Allergy Department, Mail code RY34B-348, 126 East Lincoln Ave, Rahway, NJ 07065; e-mail: george_philip@merck.com



Chest. 2007;132(3):875-883. doi:10.1378/chest.07-0550
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Background and objective: It has been previously established that montelukast provides protection against exercise-induced bronchoconstriction (EIB) after a single dose. The present objective was to assess the onset and duration of this protective action in a trial that included both positive and negative controls.

Methods: A randomized, active-controlled and placebo-controlled, double-blind, double-dummy, three-way crossover study was conducted in 47 patients (age range, 15 to 44 years) in whom there was a 20 to 40% fall in FEV1 following exercise (ΔFEV1). In randomized sequence, patients received oral montelukast (10 mg), placebo, or inhaled salmeterol (50 μg) as a positive control. Dosing was followed by exercise challenges at 2, 8.5, and 24 h. The primary end point was maximum ΔFEV1 at 2 h postdose. Secondary end points included maximum ΔFEV1 at the two later time points, and other measures (including recovery time and need for β-agonist rescue) at all time points.

Results: The maximum ΔFEV1 magnitudes at 2, 8.5, and 24 h were significantly smaller after montelukast administration than after placebo administration (least squares mean [± SE], 13.2 ± 1.2%, 11.7 ± 1.2%, and 10.0 ± 1.1% vs 21.8 ± 1.2%, 16.8 ± 1.3%, and 14.0 ± 1.1%, respectively; p ≤ 0.001, < 0.01, and < 0.05). All secondary end point results supported the primary end point. Montelukast and salmeterol had similar efficacy at 2 and 8.5 h, but only montelukast was effective at 24 h.

Conclusion: Montelukast provided significant protection against EIB having an onset within 2 h following a single oral dose and lasting for at least 24 h.

Figures in this Article

Exercise-induced bronchoconstriction (EIB) is an episodic respiratory syndrome that limits physical activity in many individuals with airway hyperreactivity.1Its prevalence is estimated as 50 to 90% in patients with asthma, 11 to 50% in athletes overall (whether or not they also have overt asthma), and 10 to 15% in the general population.24 EIB is commonly managed through the treatment of the underlying asthma (when present) and the as-needed use of preventive agents that are inhaled prior to planned exercise or other physical exertion.5 Notable among the latter are cromolyn and the β-adrenergic receptor agonists albuterol, formoterol, and salmeterol. These agents are all capable of reducing the severity of EIB episodes significantly, and the choice between them is largely based on differences in their speed of onset and duration of action. As a β-agonist that is often effective for ≥ 8 h,58 salmeterol has been regarded as a standard of care since the 1990s.

Leukotrienes are endogenous mediators of inflammation that are known to play a significant role in the pathogenesis of bronchoconstriction,910 and evidence suggests that antileukotrienes are protective against EIB as a class of drugs.5,1017 Montelukast is an orally active leukotriene receptor antagonist that is widely used as an asthma controller agent, and studies of its long-term administration have demonstrated protection against EIB exceeding that provided by the long-term administration of salmeterol.1820 Oral montelukast has also been found to protect against EIB after a single dose,2122 and two recent studies2324 have focused on defining the onset and duration of its single-dose action. In both of these studies, montelukast provided significant protection against EIB at the initial time point, 2 h postdose; this protection continued at similar levels through 12 and 24 h postdose in one of these studies.23In the other study,24 however, the occurrence of EIB was low in both placebo-treated and montelukast-treated patients at 12 and 24 h; thus, the outcome was inconclusive regarding the duration of action. Neither study included an active control.

Here, we report on a montelukast crossover study with both negative and positive controls, the latter being inhaled salmeterol. Our primary hypothesis was that montelukast would provide significant protection at 2 h postdose, and secondarily we examined whether this protection continued to be significant through 8.5 and 24 h postdose. Given the previously observed variability in EIB severity after placebo administration postrandomization, salmeterol was included in the study to provide perspective on the clinical significance of the observed montelukast effects.

This was a multicenter, randomized, placebo-controlled, three-way crossover study (Merck Protocol 316) with a double-blind, double-dummy design, that was conducted between December 2005 and August 2006 at five locations in North America and South America. The conduct of this study was approved by an ethics review committee, and all patients gave their written informed consent before participating.

Patients

This study included men and women (age range, 15 to 45 years) who demonstrated a fall in FEV1 following exercise (ΔFEV1) of ≥ 20% on both of two preliminary visits (Fig 1, 2 ). Patients with ΔFEV1 of > 40% on either visit were excluded from the study, as were patients with a preexercise FEV1 of < 70% predicted. Active smokers (ie, have smoked within the past 6 months) were excluded from the study, as were past smokers with a history of > 15 pack-years of cigarette smoking. The use of short-acting β-agonists (SABAs) was permitted during the study, but exercise testing was excluded when SABA use had occurred within 8 h prior to a scheduled challenge test. The daily use of inhaled corticosteroids at low and stable doses was permitted. All other asthma treatments were excluded.

Study Design

Exercise challenges and spirometric testing were performed as previously described.23,25 For each challenge, patients ran on a treadmill for 6 min targeting a workload that increased heart rate to 80 to 90% of each individual’s age-predicted maximum heart rate. During this exertion, patients breathed dry air at room temperature supplied through a mask from a compressed air tank. Patients were asked to refrain from exercise for 72 h prior to the first visit and 18 h prior to all subsequent visits. Using a computer-generated randomization schedule, qualifying patients were assigned to one of six treatment sequences in which responses to oral montelukast (Singulair, 10 mg; Merck & Co, Inc; Whitehouse Station, NJ) plus inhaled placebo, oral placebo plus inhaled salmeterol (Serevent Diskus, 50 μg; GlaxoSmithKline; Research Triangle Park, NC), or the two placebos together were sequentially tested in three crossover periods (Fig 2, top, A). These treatments were supplied to investigators in coded containers, and investigators, monitors, patient-care personnel, and patients remained blind to the treatments until data collection had been completed for the entire study.

In each crossover period, early morning dosing was followed by exercise challenges at 2, 8.5, and 24 h postdose (Fig 2, bottom, B). The 2-h time point was chosen because oral montelukast is known to reach substantial (though not yet maximal) plasma levels by this time.26 Efficacy was examined at 8.5 h to facilitate comparison between the present findings and previously reported outcomes with our positive control7; efficacy was tested at 24 h because montelukast has previously been found to have efficacy at 24 h in long-term-dose studies.1819,25,27

End Points

The primary end point was the maximum ΔFEV1 (expressed as a positive number) observed after exercise challenge at 2 h postdose (Fig 1). Secondary end points included maximum ΔFEV1 observed after the challenges at 8.5 and 24 h postdose, and the following measures at all three postdose times: recovery time; area under the curve integrating ΔFEV1 over the 60 min interval immediately following exercise (AUC0–60min); and the percentages of patients requiring SABA rescue (with albuterol) within 90 min after exercise. When SABA rescue was required, the last observed value of ΔFEV1 was carried over to calculate recovery time and AUC0–60min.

Statistical Analysis

Following a prespecified data analysis plan, efficacy outcomes were analyzed for each postdose time point on a modified intention-to-treat basis inclusive of all patients who had been tested at that specific time point in at least two of the three crossover periods. The primary analysis looked at the difference in maximum ΔFEV1 between montelukast and placebo treatments at 2 h postdose. Assuming a within-patient SD of 9% and using a two-sided test of significance with α = 0.05, it was estimated that the completion of the study by at least 36 patients would provide 95% power to detect a difference in maximum ΔFEV1 of eight percentage points or greater when comparing montelukast and placebo treatment effects at 2 h postdose. The evaluation of secondary end points and time points followed a prespecified step-down procedure.28Maximum ΔFEV1, recovery time, and AUC0–60min were analyzed using an analysis-of-variance model with terms for treatment, patient, and period effect.29 The proportion of patients requiring β-agonist rescue was compared between treatments using an exact McNemar test. As prespecified, 95% confidence intervals (CIs) were calculated for differences in outcome between montelukast and salmeterol treatment using a continuity-corrected Wilson score (Newcombe method 10).30

We also performed a post hoc analysis to evaluate spirometric end points solely in those patients who had consistent EIB, which is defined as EIB that continued, after randomization and administration of placebo, to meet the entry criterion of a maximum ΔFEV1 of ≥ 20%. This specific cutoff level was chosen because our purpose was to evaluate the treatment effects in those patients whose conditions had not improved after administration of placebo. Three consistent-EIB subgroups were created, one for each postdose time at which efficacy was assessed.

Patient Demographics and Baseline Characteristics

One hundred thirteen patients were screened for this study, and 47 of these patients were subsequently randomized (Fig 3 ). Most exclusions were for inadequate EIB severity (n = 44), unstable or overly severe asthma (n = 9), or overly severe EIB (n = 4). Demographic data and asthma statistics for our randomized patients are presented in Table 1 and prerandomization and postrandomization end-point measures in Table 2 . The level of asthma was generally mild in this group. The mean baseline FEV1 at visit 1 was 3.42 L (87.8% of predicted), and only 2 of the 47 patients were receiving inhaled corticosteroids.

Treatment Outcomes With Placebo or Salmeterol

Before randomization (when tested at 2 h following placebo treatment at visit 2), all patients responded to exercise challenge with a maximum ΔFEV1 of ≥ 20% (an entry requirement), and the mean value of maximum ΔFEV1 was 27.8%. Following randomization, however, only 53% of the patients continued to have a ΔFEV1 of ≥ 20% at 2 h after placebo treatment; at later times, even fewer did (32% and 20% of patients, respectively, at 8.5 and 24 h). The mean values of maximum ΔFEV1 after placebo administration (our negative control) fell accordingly to 21.8%, 16.8%, and 14.0%, respectively, at 2, 8.5, and 24 h postdose (Table 2). A threshold criterion of ΔFEV1 ≥ 10% or 15% is often used in the diagnosis and study of EIB.5,31 In our sample, 72%, 65%, and 61% of patients, respectively, continued to have ΔFEV1 of ≥ 10% after randomization on placebo at 2, 8.5, and 24 h.

As our positive control, salmeterol, produced results that were consistent with expectations. Compared with placebo treatment, salmeterol treatment was accompanied by higher levels of FEV1 before exercise, significant reductions in mean maximum ΔFEV1 (Fig 4, 5 ), and fewer instances of β-agonist rescue (Table 2). Also as expected, efficacy was observed at 2 and 8.5 h after treatment, but not at 24 h after treatment. Salmeterol administration reduced the mean maximum ΔFEV1 by 11.6 percentage points (from 21.8 to 10.2%) and 6.1 percentage points (from 16.8 to 10.7%) at 2 h and 8.5 h after treatment, respectively. These levels of improvement were smaller than those generally seen in previous single-dose studies of salmeterol,7,21 but were consistent with the relatively mild level of EIB among patients in the present study. In Figure 4, we show averaged EIB time course data for the entire sample, with separate traces for each respective treatment and postdose time.

Montelukast Treatment Effects

Montelukast treatment was associated with significant decreases in EIB severity and duration at all three of the postdose time points (Fig 4, 5). At 2, 8.5, and 24 h postdose, the least squares (LS) mean maximum ΔFEV1 was 8.7, 5.1, and 4.0 percentage points lower after montelukast treatment than after placebo (p ≤ 0.001, p = 0.005, and p = 0.014, respectively) [Fig 5, top left, A]. Recovery time was also significantly reduced at each of these same time points by 26.0, 22.1, and 13.0 min, respectively (LS mean, p ≤ 0.001, p = 0.004, and p ≤ 0.001) [Fig 5, middle left, B], and AUC0–60min was reduced significantly by 454% × min, 322% × min, and 178% × min, respectively (LS mean, p ≤ 0.001, p ≤ 0.001, and p = 0.019) [Fig 5, bottom left, C]. Montelukast treatment was also followed by substantially less use of β-agonist rescue than treatment with placebo (Table 2), and this effect was significant at 2 h postdose (p = 0.031). All 95% CIs for differences in outcome between montelukast and salmeterol were inclusive of zero at 2 and 8.5 h postdose (implying nonsignificance) and generally exclusive of zero at 24 h postdose (data not shown).

Our exploratory analysis of the consistent-EIB patients specifically evaluated treatment effects in those patients in whom placebo truly was a negative control (ie, patients who continued to have ΔFEV1 ≥ 20% in the absence of active treatment). Within our consistent-EIB subgroups, the post-placebo administration maximum ΔFEV1 had LS mean (± SE) values of 32.1 ± 1.7% (n = 26), 31.8 ± 4.7% (n = 12), and 28.1 ± 3.7% (n = 9), respectively, at 2, 8.5, and 24 h postdose. In these same patients, salmeterol improved maximum ΔFEV1 over placebo by (LS mean differences from placebo ± 95% CI) 19.2 ± 5.1 percentage points and 18.8 ± 6.2 percentage points, respectively, at 2 and 8.5 h postdose, values that are highly consistent with previous reports.7,21 Montelukast improved maximum ΔFEV1 in these same patients by mean differences over placebo of 13.9 ± 5.1 percentage points, 11.9 ± 6.6 percentage points, and 13.4 ± 10.2 percentage points, respectively, at 2, 8.5, and 24 h postdose (Fig 5, top right, D, middle right, E, and bottom right, F).

Safety

Six adverse events were observed following montelukast treatment, seven adverse events occurred after patients had received placebo, and two occurred after treatment with salmeterol. None were serious. The most common adverse event was headache (three episodes of mild-to-moderate intensity, two of which occurred after placebo treatment). One patient was discontinued from the study due to worsening respiratory allergies that were treated with mometasone nasal spray (which was an excluded medication); this occurred during the washout period following placebo treatment.

The central observation in this study was that spirometric indexes of EIB were reduced significantly when assessed from 2 to 24 h after a single oral dose of montelukast, compared with those observed after placebo administration; thus, our study hypothesis was confirmed. In the following discussion, we consider whether these statistically significant improvements were also clinically significant. There are three lines of evidence that bear on this question, as follows: (1) comparison between observed salmeterol and montelukast effects on spirometric end points; (2) SABA rescue data; and (3) our subgroup analyses in consistent-EIB patients.

Salmeterol was incorporated into this study primarily to serve as a positive control, and as such it produced treatment effects on maximum ΔFEV1 that were somewhat smaller than have previously been reported. Direct comparison with previous data are invalid, however, because the postrandomization level of EIB severity was also lower in the present study. We propose that, taking this difference into consideration, the present salmeterol results are reasonably in line with previous data.

This study was not designed as a formal comparison between montelukast and salmeterol, but, given that the latter is generally recognized as being protective against EIB, our present salmeterol data provide a benchmark for interpreting the clinical significance of the observed montelukast effects. Here, we found that efficacy outcomes were similar for montelukast and salmeterol at 2 and 8.5 h postdose, as was indicated by the large overlap of 95% CIs for spirometric end points at these two time points (Fig 5). This finding of similar montelukast and salmeterol effects was consistent with observations made previously in a smaller study21 in which protection was evaluated 1 to 12 h after single doses of either were administered. In the present study, it was further observed that rates of resort to SABA rescue were similar after montelukast and salmeterol therapy (Table 2).

We did observe, consistent with expectations, that salmeterol had a numerically greater direct effect on baseline (preexercise) FEV1 than did montelukast (the differences in the LS mean being 0.23 and 0.13 L, respectively, at 2 and 8.5 h postdose) [Table 2]. Our analyses were specifically focused, however, on measuring bronchoprotection during exercise as a drug effect separate from preexercise bronchodilation. This is the standard approach for studying EIB,3,5,78,27 and it is consistent with the rationale that single-dose, preventive therapy for EIB is most appropriately given to patients who have nearly normal basal lung function. For patients in whom this is not the case, a greater level of chronic controller therapy is recommended.32

Observed rates of postexercise SABA rescue provide a direct reflection of patients’ and physicians’ unbiased (blinded) perceptions of EIB severity. We found that significantly fewer patients needed SABA rescue at 2 h after montelukast treatment, compared with placebo, and this implies that patients felt or appeared to be less distressed by EIB after taking montelukast. Reductions in the use of rescue medication were also seen at 8.5 and 24 h postdose with montelukast treatment, although they were nonsignificant. It should be noted that this comparison had limited statistical power because the overall number of occurrences of rescue therapy was small.

Many of the patients recruited into this study had EIB that became less severe after randomization (as indicated by their responses to exercise after receiving placebo), and this has also been seen to varying extent in several previous studies of similar design.11,15,2324,33 Besides its potential relevance to the clinical management of EIB, this phenomenon is also of technical interest, in that large placebo response improvement has tended to be associated in previous studies with findings of nonsignificant montelukast efficacy (eg, at 2 and 24 h postdose,33 and at 12 h postdose24). This improvement is not easily explained, however. Some of the observed improvement may have occurred simply through “regression to the mean,” despite the study requirement for two documented episodes of EIB before randomization. The repetition of exercise may have also played a role, in that it has long been known that airways become temporarily refractory to bronchoconstriction after exercise.34 However, refractoriness to EIB has generally been brief in prior studies compared with the intervals that separated testing in this study. Hypothetically, a repetition of exercise might be capable of eliciting a long-lasting form of refractoriness, but we found no clear pattern of development of this over the course of the 11 exercise challenges in this study (data not shown).

Regardless of the underlying mechanism, it is clear that our overall cohort included patients in whom EIB improved even in the absence of active treatment, and others in whom EIB was more resistant to improvement. These latter patients were the intended focus of our post hoc subgroup analysis. Spirometric improvements were observed in these patients that suggested that they benefited substantially from either montelukast or salmeterol treatment. This subgroup analysis also had implications regarding the time course of the treatment effects. In the overall patient sample, efficacy appeared to decline with increasing postdose time (Fig 5, top left, A, middle left, B, and bottom left, C), but this may have been due in part to the decline in the average level of EIB severity (even on placebo). In the subgroup analysis, each patient cohort had nearly the same mean level of EIB severity while receiving placebo, regardless of postdose time, and comparison across these time points suggests that salmeterol efficacy persisted without loss from 2 to 8.5 h postdose and that montelukast efficacy persisted without loss throughout the entire 24-h interval studied (Fig 5, top right, D, middle right, E, and bottom right, F).

In this study of onset and duration of action, single doses of these medicines were given in isolation, whereas in real life, patients may take these as often as every day (as is done when montelukast is used for chronic asthma) or twice daily (as is commonly done when salmeterol is used as an adjunct to long-term asthma controller therapy). Montelukast has been shown to have stable efficacy against EIB when taken daily.19,27,35 Daily use of long-acting β-agonists, however, tends to reduce the magnitude and duration of their protection against EIB and elicit cross-tolerance to other β-agonists.8,3641

In conclusion, a single 10-mg oral dose of montelukast was found in this study to provide significant protection against EIB with onset of protection within 2 h following administration and a duration of at least 24 h. Its efficacy appeared to be similar in magnitude to that of a single 50-μg dose of inhaled salmeterol, but longer in duration. Present and previous data have also indicated that montelukast has a favorable safety profile. These data support a conclusion that montelukast is of clinical benefit in the short-term prophylactic treatment of EIB.

Abbreviations: AUC0–60min = area under the curve integrating fall in FEV1 following exercise over the 60 min interval immediately following exercise; CI = confidence interval; EIB = exercise-induced bronchoconstriction; ΔFEV1 = fall in FEV1 following exercise; LS = least squares; SABA = short-acting β-agonist

This study was funded by Merck Research Laboratories, Rahway, NJ.

Drs. Philip, Legrand, Loeys, Langdon, and Reiss are employees of Merck Research Laboratories. Drs. Pearlman and Villarán served as Principal Investigators in this study and in previous Merck-sponsored studies.

Figure Jump LinkFigure 1. An example of EIB timecourse as observed in an individual patient on prerandomization visit 2, with superimposed illustration of the derivation of the three spirometric end points, maximum ΔFEV1, recovery time (ie, the time between maximum ΔFEV1 and return to within 5% of the preexercise baseline, as determined by interpolation), and AUC0–60min. Prior to exercise challenge (hatched bar), FEV1 in this patient was 4.30 L (94.7% predicted).Grahic Jump Location
Figure Jump LinkFigure 2. Top, A: overall study design. Bottom, B: a timeline of the sequence of drug dosing, exercise challenges, and associated assessments of FEV1 followed during each of the three randomized treatment periods.Grahic Jump Location
Table Graphic Jump Location
Table 1. Demographic Characteristics and Asthma Severity in the Study Cohort (n = 47)*
* 

Values are given as the mean ± SD (range) or No. (%). ICS = inhaled corticosteroid.

Table Graphic Jump Location
Table 2. End Points Recorded During the Study and in the Study Cohort Prior to Randomization*
* 

Values are given as the mean ± SE or No. (%). NA = not applicable.

 

There was no dosing during visit 1.

 

During visit 2, all patients received the oral and inhaled placebos (single blind) 2 h prior to exercise testing.

§ 

Fewer patients were tested at 8.5 h postdose because of exclusion for having needed SABA rescue following challenge at 2 h postdose.

 

All tests of statistical significance were evaluations of montelukast vs placebo.

Figure Jump LinkFigure 4. Mean (± SE) changes in FEV1 over time in the montelukast, salmeterol, and placebo treatment groups following exercise challenges given at (top, A) 2 h postdose, (middle, B) 8.5 h postdose, and (bottom, C) 24 h postdose.Grahic Jump Location
Figure Jump LinkFigure 5. Net montelukast (MNK) and salmeterol (SAL) treatment effects at 2, 8.5, and 24 h postdose calculated by subtracting the respective placebo responses (differences in LS mean ± 95% CI). Top left, A, middle left, B, and bottom left, C: the results of prespecified analysis of the entire patient sample (the respective sample sizes are given in Table 2). Top right, D, middle right, E, and bottom right, F: the results of post hoc analysis of subgroups composed of patients with consistent EIB. Negative differences (plotted upward) favor the active treatment over placebo. As prespecified, p values were calculated only for differences of montelukast vs placebo observed in the full patient sample. * = p ≤ 0.05; ** = p ≤ 0.01; *** = p ≤ 0.001.Grahic Jump Location

We wish to thank Sima Gaile, RN/BSN (Rahway, NJ), for her technical assistance in the organization and conduct of this study. In addition to Drs. Pearlman and Villarán, other participating investigators included Mark H. Moss, MD (Madison, WI), Aaron Deykin, MD (Boston, MA), and Ashley J. Tatum, MD (Seattle, WA).

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Edmunds, AT, Tooley, M, Godfrey, S The refractory period after exercise-induced asthma: its duration and relation to the severity of exercise.Am Rev Respir Dis1978;117,247-254. [PubMed]
 
de Benedictis, FM, Del Giudice, MM, Forenza, N, et al Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children.Eur Respir J2006;28,291-295. [PubMed]
 
Ramage, L, Lipworth, BJ, Ingram, CG, et al Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol.Respir Med1994;88,363-368. [PubMed]
 
Garcia, R, Guerra, P, Feo, F, et al Tachyphylaxis following regular use of formoterol in exercise-induced bronchospasm.J Investig Allergol Clin Immunol2001;11,176-182. [PubMed]
 
Hancox, RJ, Subbarao, P, Kamada, D, et al β2-agonist tolerance and exercise-induced bronchospasm.Am J Respir Crit Care Med2002;165,1068-1070. [PubMed]
 
Storms, W, Chervinsky, P, Ghannam, AF, et al A comparison of the effects of oral montelukast and inhaled salmeterol on response to rescue bronchodilation after challenge.Respir Med2004;98,1051-1062. [PubMed]
 
Salpeter, SR, Buckley, NS, Ormiston, TM, et al Meta-analysis: effect of long-acting β-agonists on severe asthma exacerbations and asthma-related deaths.Ann Intern Med2006;144,904-912. [PubMed]
 
Anderson, SD, Caillaud, C, Brannan, JD β2-agonists and exercise-induced asthma.Clin Rev Allergy Immunol2006;31,163-180. [PubMed]
 

Figures

Figure Jump LinkFigure 1. An example of EIB timecourse as observed in an individual patient on prerandomization visit 2, with superimposed illustration of the derivation of the three spirometric end points, maximum ΔFEV1, recovery time (ie, the time between maximum ΔFEV1 and return to within 5% of the preexercise baseline, as determined by interpolation), and AUC0–60min. Prior to exercise challenge (hatched bar), FEV1 in this patient was 4.30 L (94.7% predicted).Grahic Jump Location
Figure Jump LinkFigure 2. Top, A: overall study design. Bottom, B: a timeline of the sequence of drug dosing, exercise challenges, and associated assessments of FEV1 followed during each of the three randomized treatment periods.Grahic Jump Location
Figure Jump LinkFigure 4. Mean (± SE) changes in FEV1 over time in the montelukast, salmeterol, and placebo treatment groups following exercise challenges given at (top, A) 2 h postdose, (middle, B) 8.5 h postdose, and (bottom, C) 24 h postdose.Grahic Jump Location
Figure Jump LinkFigure 5. Net montelukast (MNK) and salmeterol (SAL) treatment effects at 2, 8.5, and 24 h postdose calculated by subtracting the respective placebo responses (differences in LS mean ± 95% CI). Top left, A, middle left, B, and bottom left, C: the results of prespecified analysis of the entire patient sample (the respective sample sizes are given in Table 2). Top right, D, middle right, E, and bottom right, F: the results of post hoc analysis of subgroups composed of patients with consistent EIB. Negative differences (plotted upward) favor the active treatment over placebo. As prespecified, p values were calculated only for differences of montelukast vs placebo observed in the full patient sample. * = p ≤ 0.05; ** = p ≤ 0.01; *** = p ≤ 0.001.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Demographic Characteristics and Asthma Severity in the Study Cohort (n = 47)*
* 

Values are given as the mean ± SD (range) or No. (%). ICS = inhaled corticosteroid.

Table Graphic Jump Location
Table 2. End Points Recorded During the Study and in the Study Cohort Prior to Randomization*
* 

Values are given as the mean ± SE or No. (%). NA = not applicable.

 

There was no dosing during visit 1.

 

During visit 2, all patients received the oral and inhaled placebos (single blind) 2 h prior to exercise testing.

§ 

Fewer patients were tested at 8.5 h postdose because of exclusion for having needed SABA rescue following challenge at 2 h postdose.

 

All tests of statistical significance were evaluations of montelukast vs placebo.

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de Benedictis, FM, Del Giudice, MM, Forenza, N, et al Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children.Eur Respir J2006;28,291-295. [PubMed]
 
Ramage, L, Lipworth, BJ, Ingram, CG, et al Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol.Respir Med1994;88,363-368. [PubMed]
 
Garcia, R, Guerra, P, Feo, F, et al Tachyphylaxis following regular use of formoterol in exercise-induced bronchospasm.J Investig Allergol Clin Immunol2001;11,176-182. [PubMed]
 
Hancox, RJ, Subbarao, P, Kamada, D, et al β2-agonist tolerance and exercise-induced bronchospasm.Am J Respir Crit Care Med2002;165,1068-1070. [PubMed]
 
Storms, W, Chervinsky, P, Ghannam, AF, et al A comparison of the effects of oral montelukast and inhaled salmeterol on response to rescue bronchodilation after challenge.Respir Med2004;98,1051-1062. [PubMed]
 
Salpeter, SR, Buckley, NS, Ormiston, TM, et al Meta-analysis: effect of long-acting β-agonists on severe asthma exacerbations and asthma-related deaths.Ann Intern Med2006;144,904-912. [PubMed]
 
Anderson, SD, Caillaud, C, Brannan, JD β2-agonists and exercise-induced asthma.Clin Rev Allergy Immunol2006;31,163-180. [PubMed]
 
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