Exercise-induced Bronchoconstriction (EIB)
Conditions
Brief summary
This study will see if there is a change in breathing after exercising when the child receives study drug ( montelukast or placebo). Breathing will be measured by a spirometer before exercising and measured again several times after exercising.
Interventions
DRUGComparator: montelukast sodium
Patients 4-5 years: 4 mg Montelukast chewable tablet daily Patients 6-14 years: 5 mg chewable tablet daily
Patients 4-5 years: 4 mg Pbo chewable tablet daily Patients 6-14 years: 5 mg Pbo chewable tablet daily
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
4 Years to 14 Years
Healthy volunteers
No
Inclusion criteria
* The child is 4 years to 14 years of age * The child is a non smoker * The child has exercise-induced bronchoconstriction (EIB)
Exclusion criteria
* The child has active or chronic breathing disease, other than asthma * The child has required insertion of a breathing tube for asthma * The child had major surgery within the last 4 weeks * The child is currently in the hospital * The child has or had an upper respiratory tract infection within the last 2 weeks * The child has been hospitalized or visited the emergency room or had a change in their medication for asthma within the last 4 weeks * The child has been in a research study in the last 4 weeks * The child has stomach, brain, heart, kidney or liver disease * The child drinks more that 4 caffeinated drinks a day
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Percent Fall in Forced Expiratory Volume in 1 Second (FEV1) After Exercise Challenge at 2 Hours Postdose | Pre-exercise baseline and 0-60 minutes after the exercise challenge performed 2 hours post-dose | Maximum Percent Fall in FEV1 was defined as the % change from pre-exercise baseline FEV1 to the lowest FEV1 within 60 mins (minutes) after exercise. Spirometry measurements were taken 5 mins prior to each exercise challenge and immediately, 5, 10, 15, 30, 45, & 60 mins after each exercise challenge. The 2-hour exercise challenges occurred 2 hours after the witnessed dose of study medication. The calculation used to produce the results was \[100\*(1-(X/Y))\] where X= the lowest FEV1 within 60 mins after exercise & Y= pre-exercise baseline FEV1. Smaller values mean greater response to therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve for FEV1 Percent Fall From Pre-exercise Baseline to 60 Minutes Following Exercise Challenge (AUC0-60 Min) at 2 Hours Post-dose | Pre-exercise baseline to 60 minutes after the exercise challenge performed 2 hours post-dose | AUC0-60min was defined as the Area Under the Curve for FEV1 percent change from pre-exercise baseline to the 60 mins following exercise challenge. The area was computed by applying the trapezoidal rule, and including only the area below the pre-exercise baseline. If a participant received β-agonist during the 60 mins after the exercise challenge, the FEV1 measurements obtained after β-agonist administration were excluded and the last pre-rescue FEV1 measurement was carried forward to the 60 mins time point in the calculation of the AUC0-60 min. Smaller values mean greater response to therapy. |
| Area Under the Curve for FEV1 Percent Fall From Pre-exercise Baseline to 60 Minutes Following Exercise Challenge (AUC0-60 Min) at 24 Hours Post-dose | Pre-exercise baseline to 60 minutes after the exercise challenge performed 24 hours post-dose | AUC0-60min was defined as the Area Under the Curve for FEV1 percent change from pre-exercise baseline to the 60 mins following exercise challenge. The area was computed by applying the trapezoidal rule, and including only the area below the pre-exercise baseline. If a participant received β-agonist during the 60 mins after the exercise challenge, the FEV1 measurements obtained after β-agonist administration were excluded and the last pre-rescue FEV1 measurement was carried forward to the 60 mins time point in the calculation of the AUC0-60 min. Smaller values mean greater response to therapy. |
| Time to Recovery From Maximum Percent Fall in FEV1 at 2 Hours Post-dose | 0-60 minutes and 0-90 minutes after the exercise challenge at 2 hours postdose | This endpoint was defined as the duration between the time at which the maximum percent fall in FEV1 occurred & the time when the percent fall in FEV1 returned to within 5% of the pre-exercise baseline for the first time. Spirometry measurements were taken 5 mins prior to each exercise challenge & immediately, 5, 10, 15, 30, 45, & 60 mins after each exercise challenge. If participant had not returned to within 5% of the pre-exercise FEV1 value by 60 mins, then measurements were obtained at 75 & 90 mins. The 2-hour exercise challenges occurred 2 hours after the witnessed dose of medication. |
| Maximum Percent Fall in FEV1 After Exercise Challenge at 24 Hours Post-dose | Pre-exercise baseline and 0-60 minutes after the exercise challenge performed 24 hours post-dose | Maximum Percent Fall in FEV1 was defined as the % change from pre-exercise baseline FEV1 to the lowest FEV1 within 60 mins after exercise. Spirometry measurements were taken 5 mins prior to each exercise challenge and immediately, 5, 10, 15, 30, 45, & 60 mins after each exercise challenge. The 24-hour exercise challenges occurred 20-24 hours after the witnessed dose of study medication. The calculation used to produce the resulted results was \[100\*(1-(X/Y))\] where X= the lowest FEV1 within 60 mins after exercise & Y= pre-exercise baseline FEV1. Smaller values mean greater response to therapy. |
| Number of Participants Requiring Rescue Medication at 2 Hours Postdose | 0-90 minutes after the exercise challenge at 2 hours postdose | This endpoint was defined as the number of participants requiring rescue medication with β-agonist within the 90 mins following exercise challenge. The 2-hour exercise challenges occurred 2 hours after the witnessed dose of study medication. |
| Number of Participants Requiring Rescue Medication at 24 Hours Postdose | 0-90 minutes after the exercise challenge at 24 hours postdose | This endpoint was defined as the number of participants requiring rescue medication with β-agonist within the 90 mins following exercise challenge. The 24-hour exercise challenges occurred 20-24 hours after the witnessed dose of study medication. |
| Time to Recovery From Maximum Percent Fall in FEV1 at 24 Hours Post-dose | 0-60 minutes and 0-90 minutes after the exercise challenge at 24 hours postdose | This endpoint was defined as the duration between the time at which the maximum percent fall in FEV1 occurred & the time when the percent fall in FEV1 returned to within 5% of the pre-exercise baseline for the first time. Spirometry measurements were taken 5 mins prior to each exercise challenge & immediately, 5, 10, 15, 30, 45 & 60 mins after each exercise challenge. If participant had not returned to within 5% of the pre-exercise FEV1 value by 60 mins, then measurements were obtained at 75 & 90 mins. The 24-hour exercise challenges occurred 20-24 hours after the witnessed dose of medication. |
Participant flow
Pre-assignment details
Of the 364 participants screened for inclusion, 298 participants were excluded during screening and were not randomized. The remaining 66 participants met inclusion criteria and were randomly allocated to one of the two treatment sequences.
Participants by arm
| Arm | Count |
|---|---|
| Montelukast/ Placebo In Period I (screening period/ placebo run-in) participants received a single-blind dose of matching-image placebo. In Period II, participants 4-5 years of age were randomized to receive one Montelukast 4-mg chewable tablet (single dose). Period III was the crossover to one matching placebo 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one Montelukast 5-mg chewable tablet (single dose) in Period II, crossing over to one matching placebo 5-mg chewable tablet (single dose) in Period III after a 3- to 7-day washout period. | 33 |
| Placebo/ Montelukast In Period I (screening period/ placebo run-in) participants received a single-blind dose of matching-image placebo. In Period II, participants 4-5 years of age were randomized to receive one placebo 4-mg chewable tablet (single dose). Period III was the crossover to one Montelukast 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one placebo 5-mg chewable tablet (single dose) in Period II, crossing over to one Montelukast 5-mg chewable tablet (single dose) in Period III after a 3- to 7-day washout period. | 33 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 2: Treatment Montelukast/ Placebo | Protocol Violation | 0 | 1 |
| Period 3: Crossover Placebo/ Montelukast | Physician Decision | 1 | 0 |
| Period 3: Crossover Placebo/ Montelukast | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Montelukast/ Placebo | Placebo/ Montelukast | Total |
|---|---|---|---|
| Age, Continuous | 10.9 years STANDARD_DEVIATION 2.3 | 11.5 years STANDARD_DEVIATION 1.8 | 11.2 years STANDARD_DEVIATION 2.1 |
| Sex: Female, Male Female | 14 Participants | 15 Participants | 29 Participants |
| Sex: Female, Male Male | 19 Participants | 18 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 65 | 0 / 66 |
| serious Total, serious adverse events | 0 / 65 | 0 / 66 |
Outcome results
Primary
Maximum Percent Fall in Forced Expiratory Volume in 1 Second (FEV1) After Exercise Challenge at 2 Hours Postdose
Maximum Percent Fall in FEV1 was defined as the % change from pre-exercise baseline FEV1 to the lowest FEV1 within 60 mins (minutes) after exercise. Spirometry measurements were taken 5 mins prior to each exercise challenge and immediately, 5, 10, 15, 30, 45, & 60 mins after each exercise challenge. The 2-hour exercise challenges occurred 2 hours after the witnessed dose of study medication. The calculation used to produce the results was \[100\*(1-(X/Y))\] where X= the lowest FEV1 within 60 mins after exercise & Y= pre-exercise baseline FEV1. Smaller values mean greater response to therapy.
Time frame: Pre-exercise baseline and 0-60 minutes after the exercise challenge performed 2 hours post-dose
Population: The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized patients who received the witnessed dose of study drug in both active treatment periods and had at least one post-exercise FEV1 measurement in both active treatment periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Maximum Percent Fall in Forced Expiratory Volume in 1 Second (FEV1) After Exercise Challenge at 2 Hours Postdose | 15.35 Percent fall in FEV1 | Standard Deviation 9.47 |
| Placebo | Maximum Percent Fall in Forced Expiratory Volume in 1 Second (FEV1) After Exercise Challenge at 2 Hours Postdose | 20.00 Percent fall in FEV1 | Standard Deviation 15.75 |
p-value: 0.02ANOVA
Secondary
Area Under the Curve for FEV1 Percent Fall From Pre-exercise Baseline to 60 Minutes Following Exercise Challenge (AUC0-60 Min) at 24 Hours Post-dose
AUC0-60min was defined as the Area Under the Curve for FEV1 percent change from pre-exercise baseline to the 60 mins following exercise challenge. The area was computed by applying the trapezoidal rule, and including only the area below the pre-exercise baseline. If a participant received β-agonist during the 60 mins after the exercise challenge, the FEV1 measurements obtained after β-agonist administration were excluded and the last pre-rescue FEV1 measurement was carried forward to the 60 mins time point in the calculation of the AUC0-60 min. Smaller values mean greater response to therapy.
Time frame: Pre-exercise baseline to 60 minutes after the exercise challenge performed 24 hours post-dose
Population: The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized patients who received the witnessed dose of study drug in both active treatment periods and had at least one post-exercise FEV1 measurement in both active treatment periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Area Under the Curve for FEV1 Percent Fall From Pre-exercise Baseline to 60 Minutes Following Exercise Challenge (AUC0-60 Min) at 24 Hours Post-dose | 229.19 percent fall * minute | Standard Deviation 233.93 |
| Placebo | Area Under the Curve for FEV1 Percent Fall From Pre-exercise Baseline to 60 Minutes Following Exercise Challenge (AUC0-60 Min) at 24 Hours Post-dose | 349.59 percent fall * minute | Standard Deviation 315.29 |
p-value: 0.013ANOVA
Secondary
Area Under the Curve for FEV1 Percent Fall From Pre-exercise Baseline to 60 Minutes Following Exercise Challenge (AUC0-60 Min) at 2 Hours Post-dose
AUC0-60min was defined as the Area Under the Curve for FEV1 percent change from pre-exercise baseline to the 60 mins following exercise challenge. The area was computed by applying the trapezoidal rule, and including only the area below the pre-exercise baseline. If a participant received β-agonist during the 60 mins after the exercise challenge, the FEV1 measurements obtained after β-agonist administration were excluded and the last pre-rescue FEV1 measurement was carried forward to the 60 mins time point in the calculation of the AUC0-60 min. Smaller values mean greater response to therapy.
Time frame: Pre-exercise baseline to 60 minutes after the exercise challenge performed 2 hours post-dose
Population: The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized patients who received the witnessed dose of study drug in both active treatment periods and had at least one post-exercise FEV1 measurement in both active treatment periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Area Under the Curve for FEV1 Percent Fall From Pre-exercise Baseline to 60 Minutes Following Exercise Challenge (AUC0-60 Min) at 2 Hours Post-dose | 294.50 percent fall * minute | Standard Deviation 278.46 |
| Placebo | Area Under the Curve for FEV1 Percent Fall From Pre-exercise Baseline to 60 Minutes Following Exercise Challenge (AUC0-60 Min) at 2 Hours Post-dose | 415.37 percent fall * minute | Standard Deviation 375.94 |
p-value: 0.022ANOVA
Secondary
Maximum Percent Fall in FEV1 After Exercise Challenge at 24 Hours Post-dose
Maximum Percent Fall in FEV1 was defined as the % change from pre-exercise baseline FEV1 to the lowest FEV1 within 60 mins after exercise. Spirometry measurements were taken 5 mins prior to each exercise challenge and immediately, 5, 10, 15, 30, 45, & 60 mins after each exercise challenge. The 24-hour exercise challenges occurred 20-24 hours after the witnessed dose of study medication. The calculation used to produce the resulted results was \[100\*(1-(X/Y))\] where X= the lowest FEV1 within 60 mins after exercise & Y= pre-exercise baseline FEV1. Smaller values mean greater response to therapy.
Time frame: Pre-exercise baseline and 0-60 minutes after the exercise challenge performed 24 hours post-dose
Population: The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized patients who received the witnessed dose of study drug in both active treatment periods and had at least one post-exercise FEV1 measurement in both active treatment periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Maximum Percent Fall in FEV1 After Exercise Challenge at 24 Hours Post-dose | 12.96 percent fall in FEV1 | Standard Deviation 10.38 |
| Placebo | Maximum Percent Fall in FEV1 After Exercise Challenge at 24 Hours Post-dose | 17.22 percent fall in FEV1 | Standard Deviation 12.06 |
p-value: 0.005ANOVA
Secondary
Number of Participants Requiring Rescue Medication at 24 Hours Postdose
This endpoint was defined as the number of participants requiring rescue medication with β-agonist within the 90 mins following exercise challenge. The 24-hour exercise challenges occurred 20-24 hours after the witnessed dose of study medication.
Time frame: 0-90 minutes after the exercise challenge at 24 hours postdose
Population: The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized patients who received the witnessed dose of study drug in both active treatment periods and had at least one post-exercise FEV1 measurement in both active treatment periods.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Montelukast | Number of Participants Requiring Rescue Medication at 24 Hours Postdose | 0 Participants |
| Placebo | Number of Participants Requiring Rescue Medication at 24 Hours Postdose | 2 Participants |
Secondary
Number of Participants Requiring Rescue Medication at 2 Hours Postdose
This endpoint was defined as the number of participants requiring rescue medication with β-agonist within the 90 mins following exercise challenge. The 2-hour exercise challenges occurred 2 hours after the witnessed dose of study medication.
Time frame: 0-90 minutes after the exercise challenge at 2 hours postdose
Population: The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized patients who received the witnessed dose of study drug in both active treatment periods and had at least one post-exercise FEV1 measurement in both active treatment periods.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Montelukast | Number of Participants Requiring Rescue Medication at 2 Hours Postdose | 1 participants |
| Placebo | Number of Participants Requiring Rescue Medication at 2 Hours Postdose | 2 participants |
p-value: 1McNemar
Secondary
Time to Recovery From Maximum Percent Fall in FEV1 at 24 Hours Post-dose
This endpoint was defined as the duration between the time at which the maximum percent fall in FEV1 occurred & the time when the percent fall in FEV1 returned to within 5% of the pre-exercise baseline for the first time. Spirometry measurements were taken 5 mins prior to each exercise challenge & immediately, 5, 10, 15, 30, 45 & 60 mins after each exercise challenge. If participant had not returned to within 5% of the pre-exercise FEV1 value by 60 mins, then measurements were obtained at 75 & 90 mins. The 24-hour exercise challenges occurred 20-24 hours after the witnessed dose of medication.
Time frame: 0-60 minutes and 0-90 minutes after the exercise challenge at 24 hours postdose
Population: The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized patients who received the witnessed dose of study drug in both active treatment periods and had at least one post-exercise FEV1 measurement in both active treatment periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Time to Recovery From Maximum Percent Fall in FEV1 at 24 Hours Post-dose | 11.58 Minutes | Standard Deviation 16.51 |
| Placebo | Time to Recovery From Maximum Percent Fall in FEV1 at 24 Hours Post-dose | 18.46 Minutes | Standard Deviation 22.66 |
p-value: 0.054ANOVA
Secondary
Time to Recovery From Maximum Percent Fall in FEV1 at 2 Hours Post-dose
This endpoint was defined as the duration between the time at which the maximum percent fall in FEV1 occurred & the time when the percent fall in FEV1 returned to within 5% of the pre-exercise baseline for the first time. Spirometry measurements were taken 5 mins prior to each exercise challenge & immediately, 5, 10, 15, 30, 45, & 60 mins after each exercise challenge. If participant had not returned to within 5% of the pre-exercise FEV1 value by 60 mins, then measurements were obtained at 75 & 90 mins. The 2-hour exercise challenges occurred 2 hours after the witnessed dose of medication.
Time frame: 0-60 minutes and 0-90 minutes after the exercise challenge at 2 hours postdose
Population: The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized patients who received the witnessed dose of study drug in both active treatment periods and had at least one post-exercise FEV1 measurement in both active treatment periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Time to Recovery From Maximum Percent Fall in FEV1 at 2 Hours Post-dose | 16.21 Minutes | Standard Deviation 22.01 |
| Placebo | Time to Recovery From Maximum Percent Fall in FEV1 at 2 Hours Post-dose | 24.48 Minutes | Standard Deviation 27.91 |
p-value: 0.064ANOVA