Página de ensayos clínicos Nct

Clinical Trial Results:
A Multicenter, Randomised, Double Blind Study Comparing the Clinical Effects of Intravenous Montelukast With Placebo in Patients With Acute Asthma

Summary
EudraCT number
 2004-000614-39
Trial protocol
 IT   DK  
Global end of trial date
12 Mar 2007

Results information
Results version number
 v2(current)
This version publication date
20 May 2016
First version publication date
10 Apr 2015
Other versions
 v1
Version creation reason

Trial information

 Close Top of page
Trial identification
Sponsor protocol code
0476-288
Additional study identifiers
ISRCTN number
 -
US NCT number
 NCT00092989
WHO universal trial number (UTN)
 -
Sponsors
Sponsor organisation name
Merck Sharpe & Dohme Corp.
Sponsor organisation address
2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
Public contact
Clinical Trials Disclosure, Merck Sharpe & Dohme Corp., ClinicalTrialsDisclosure@merck.com
Scientific contact
Clinical Trials Disclosure, Merck Sharpe & Dohme Corp., ClinicalTrialsDisclosure@merck.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)
No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
Yes
Results analysis stage
Analysis stage
Final
Date of interim/final analysis
12 Mar 2007
Is this the analysis of the primary completion data?
Yes
Primary completion date
12 Mar 2007
Global end of trial reached?
Yes
Global end of trial date
12 Mar 2007
Was the trial ended prematurely?
No
General information about the trial
Main objective of the trial
The purpose of this study was to evaluate the safety and efficacy of montelukast (Singulair™) 7 mg, a leukotriene receptor antagonist, in the treatment of acute exacerbations of asthma when given as an intravenous (IV) bolus dose in addition to a standard care regimen consistent with the Global Initiative for Asthma (GINA) guideline recommendations. During a 60 minute screening period, change from baseline (BL) in lung function was quantified as forced expiratory volume in 1 second (FEV1) before and after the administration of standard care for acute asthma in an emergency department. The primary hypothesis was that in adult patients with acute asthma, the addition of montelukast IV 7 mg to standard therapy will cause a significant improvement in FEV1 within the first 60 minutes after administration (i.e., average change in FEV1 from preallocation baseline over the first 60 minutes after study drug administration) compared with placebo.
Protection of trial subjects
This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. The following additional measures for this study were in place for the protection of trial participants: Rescue medication was available for participants that required rescue therapy within 3 hours following the end of study drug administration. Rescue therapy was defined as the administration of any of the following treatments within 30 minutes prior to end of study drug administration, or at least 10 minutes after end of study drug administration and within 3 hours following the end of study drug administration: systemic corticosteroids (prednisone/prednisolone), short-acting β-agonists (albuterol/salbutamol), short-acting anti-cholinergic drugs (ipratropium), magnesium.
Background therapy
 Upon entering the Screening Period (Period 1), standardized treatment for an acute severe asthma episode was initiated and continued throughout the Treatment Period (Period 2) for all participants. Standardized treatment could consist of: (1) β-agonist, (2) oxygen therapy, (3) inhaled ipratropium (optional), and 4) systemic corticosteroids (only administered following completion of study drug in Period 2).
Evidence for comparator
 -
Actual start date of recruitment
06 Jul 2004
Long term follow-up planned
No
Independent data monitoring committee (IDMC) involvement?
No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled
South Africa: 22
Country: Number of subjects enrolled
United States: 318
Country: Number of subjects enrolled
Australia: 5
Country: Number of subjects enrolled
Brazil: 4
Country: Number of subjects enrolled
Chile: 6
Country: Number of subjects enrolled
Colombia: 24
Country: Number of subjects enrolled
Denmark: 1
Country: Number of subjects enrolled
France: 28
Country: Number of subjects enrolled
Guatemala: 10
Country: Number of subjects enrolled
India: 19
Country: Number of subjects enrolled
Israel: 14
Country: Number of subjects enrolled
Italy: 28
Country: Number of subjects enrolled
Mexico: 40
Country: Number of subjects enrolled
New Zealand: 5
Country: Number of subjects enrolled
Peru: 59
Worldwide total number of subjects
583
EEA total number of subjects
57
Number of subjects enrolled per age group
In utero
0
Preterm newborn - gestational age
0
Newborns (0-27 days)
0
Infants and toddlers (28 days-23 months)
0
Children (2-11 years)
0
Adolescents (12-17 years)
9
Adults (18-64 years)
529
From 65 to 84 years
45
85 years and over
0

Subject disposition

 Close Top of page
Recruitment
Recruitment details
 Participants were recruited from 34 sites in the United States and 28 sites in 15 countries.

Pre-assignment
Screening details
 Screening began at participant arrival at the study site and consisted of the time between the start of urgent treatment (oxygen, short-acting β-agonist) and IV montelukast or placebo, not to exceed 60 minutes

Pre-assignment period milestones
Number of subjects started
 1147 [1]
Number of subjects completed
 583

Pre-assignment subject non-completion reasons
Reason: Number of subjects
 Participant ineligible: 545
Reason: Number of subjects
 Consent withdrawn by subject: 14
Reason: Number of subjects
 Protocol deviation: 5
Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The worldwide number represents the number of eligible enrolled participants that were treated on study. 1147 participants were screened for inclusion.
Period 1
Period 1 title
Pre-allocation Evaluation and Treatment
Is this the baseline period?
 No
Allocation method
Not applicable
Blinding used
 Not blinded

Arms
Arm title
 Pre-allocation Evaluation and Treatment
Arm description
 Participants admitted to the study site because of an acute exacerbation of asthma entered the screening period (Period 1) and received standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium).
Arm type
 Pre-study Evaluation and Treatment

Investigational medicinal product name
No investigational medicinal product assigned in this arm
Number of subjects in period 1
Pre-allocation Evaluation and Treatment
Started
583
Completed
583
Period 2
Period 2 title
Active Treatment
Is this the baseline period?
 Yes [2]
Allocation method
Randomised - controlled
Blinding used
 Double blind
Roles blinded
 Investigator, Subject

Arms
Are arms mutually exclusive
Yes

Arm title
 Montelukast 7 mg + Standard Treatment
Arm description
 During Period 2, randomised participants received IV montelukast 7 mg in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of montelukast.
Arm type
 Experimental

Investigational medicinal product name
Montelukast sodium
Investigational medicinal product code
Other name
Singulair™
Pharmaceutical forms
Powder for solution for injection/infusion
Routes of administration
Intravenous bolus use
Dosage and administration details
Participants received IV montelukast administered in one 7 mg dose after reconstitution of a vial containing montelukast sodium in a lypophilised powder form dissolved in 20 mL of a solution of 3.3% dextrose/0.3% sodium chloride and given as a manual bolus over a period of 2 to 5 minutes.

Arm title
 Placebo + Standard Treatment
Arm description
 During Period 2, randomised participants received IV placebo for montelukast in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of IV placebo.
Arm type
 Placebo

Investigational medicinal product name
Placebo for montelukast
Investigational medicinal product code
Other name
Singulair™
Pharmaceutical forms
Powder for solution for injection/infusion
Routes of administration
Intravenous bolus use
Dosage and administration details
Participants received matching placebo for montelukast supplied as a lyophilised powder in light-protected vials. Placebo powder was reconstituted in 20 mL of a solution of 3.3% dextrose/0.3% sodium chloride and given as a manual bolus infusion over 2 to 5 minutes.

Notes
[2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: Period 1 was a screening period to determine eligible participants and to randomize participants. For the purpose of reporting baseline characteristics by reporting arm, Period 2 has been designated the baseline period.
Number of subjects in period 2
Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
Started
291
292
Completed
288
285
Not completed
3
7
     Protocol deviation
-
1
     Lack of efficacy
-
3
     Unable to complete spirometry
1
-
     Discontinued due to chest xray findings
1
-
     Adverse event, non-fatal
-
1
     Consent withdrawn by subject
-
1
     Randomization error
1
-
     Unable to do spirometry due to AEs
-
1
Period 3
Period 3 title
Post-study (14 Days)
Is this the baseline period?
 No
Allocation method
Randomised - controlled
Blinding used
 Double blind
Roles blinded
 Subject, Investigator

Arms
Are arms mutually exclusive
Yes

Arm title
 Montelukast 7 mg + Standard Treatment: Post-Study
Arm description
 During the follow-up period, montelukast-treated participants received a telephone call approximately 14 days after the participant had completed Period 2 to review information on subsequent asthma-related healthcare contacts (doctor visits, emergency visits, and/or hospitalizations), asthma-related medication usage, impact on work, concomitant therapies, adverse experiences, and procedures that may have been performed within the 14 ± 3 days.
Arm type
 Follow-up

Investigational medicinal product name
No investigational medicinal product assigned in this arm
Arm title
 Placebo + Standard Treatment: Post-Study
Arm description
 During the follow-up period, placebo-treated participants received a telephone call approximately 14 days after the participant had completed Period 2 to review information on subsequent asthma-related healthcare contacts (doctor visits, emergency visits, and/or hospitalizations), asthma-related medication usage, impact on work, concomitant therapies, adverse experiences, and procedures that may have been performed within the 14 ± 3 days.
Arm type
 Follow-up

Investigational medicinal product name
No investigational medicinal product assigned in this arm
Number of subjects in period 3
Montelukast 7 mg + Standard Treatment: Post-Study Placebo + Standard Treatment: Post-Study
Started
288
285
Completed
291
292
Joined
3
7
     Follow-up call, though did not complete Period 2
3
7

Baseline characteristics

 Close Top of page
Baseline characteristics reporting groups
Reporting group title
Montelukast 7 mg + Standard Treatment
Reporting group description
 During Period 2, randomised participants received IV montelukast 7 mg in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of montelukast.

Reporting group title
Placebo + Standard Treatment
Reporting group description
 During Period 2, randomised participants received IV placebo for montelukast in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of IV placebo.

Reporting group values
 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment Total
Number of subjects
 291 292 583
Age categorical
Units: Subjects
Age continuous
Units: years
    arithmetic mean (standard deviation)
 41.1 ± 15 41 ± 15.3 -
Gender categorical
Units: Subjects
    Female
 153 175 328
    Male
 138 117 255
Baseline FEV1
Baseline FEV1 was defined as last measurement obtained prior to the administration of study drug. Data were available for 287 in the Montelukast 7 mg group and 284 in the Placebo group.
Units: Liters
    arithmetic mean (standard deviation)
 1.3 ± 0.4 1.2 ± 0.4 -

End points

 Close Top of page
End points reporting groups
Reporting group title
Pre-allocation Evaluation and Treatment
Reporting group description
 Participants admitted to the study site because of an acute exacerbation of asthma entered the screening period (Period 1) and received standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium).
Reporting group title
Montelukast 7 mg + Standard Treatment
Reporting group description
 During Period 2, randomised participants received IV montelukast 7 mg in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of montelukast.

Reporting group title
Placebo + Standard Treatment
Reporting group description
 During Period 2, randomised participants received IV placebo for montelukast in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of IV placebo.
Reporting group title
Montelukast 7 mg + Standard Treatment: Post-Study
Reporting group description
 During the follow-up period, montelukast-treated participants received a telephone call approximately 14 days after the participant had completed Period 2 to review information on subsequent asthma-related healthcare contacts (doctor visits, emergency visits, and/or hospitalizations), asthma-related medication usage, impact on work, concomitant therapies, adverse experiences, and procedures that may have been performed within the 14 ± 3 days.

Reporting group title
Placebo + Standard Treatment: Post-Study
Reporting group description
 During the follow-up period, placebo-treated participants received a telephone call approximately 14 days after the participant had completed Period 2 to review information on subsequent asthma-related healthcare contacts (doctor visits, emergency visits, and/or hospitalizations), asthma-related medication usage, impact on work, concomitant therapies, adverse experiences, and procedures that may have been performed within the 14 ± 3 days.

Primary: Time-weighted Average Change from Baseline in FEV1 (0 to 60 minutes)

 Close Top of page
End point title
 Time-weighted Average Change from Baseline in FEV1 (0 to 60 minutes)
End point description
Time-weighted average change from baseline in FEV1 over the first 60 minutes after IV montelukast or placebo administration. Changes from baseline in FEV1 were computed at 10, 20, 40 and 60 minutes post study drug administration and then used to calculate a time-weighted average for 0-60 minutes, with the time interval between any measurement and the measurement prior to it being used as the weighting factor. The Full Analysis Set (FAS), comprised of all participants who started study drug and had efficacy measurements (FEV1) both at BL and at least one time point over the time interval considered, was used for this analysis.
End point type
Primary
End point timeframe
0 minutes (baseline), 10, 20, 40, and 60 minutes after IV bolus infusion of montelukast 7 mg or placebo.
End point values
 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
Number of subjects analysed
287 [1]
284 [2]
Units: Liters
    least squares mean (confidence interval 95%)
0.32 (0.27 to 0.37)
0.22 (0.17 to 0.27)
Notes
[1] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
[2] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
Statistical analysis title
 Time-weighted Average ΔFEV1 (0-60 min)
Statistical analysis description
Time-weighted average change from baseline (BL) in FEV1, computed in the interval 0-60 minutes, was analysed using an analysis of covariance (ANCOVA) model with the baseline FEV1 as a covariate and including treatment, prior therapy with systemic corticosteroids and/or anti-leukotriene (yes or no), and region (US or non-US) as factors. The ANCOVA model was used to estimate the least squares mean (LS mean) for treatment, between-treatment difference, and 95% CI.
Comparison groups
Montelukast 7 mg + Standard Treatment v Placebo + Standard Treatment
Number of subjects included in analysis
571
Analysis specification
Pre-specified
Analysis type
 superiority
P-value
 ≤ 0.001 [3]
Method
 ANCOVA
Parameter type
 LS mean difference
Point estimate
0.1
Confidence interval
     level
 95%
     sides
2-sided
     lower limit
 0.04
     upper limit
 0.16
Notes
[3] - P-value for LS mean difference between treatments, montelukast 7 mg versus placebo.

Secondary: Percentage of Participants with Treatment Failure

 Close Top of page
End point title
 Percentage of Participants with Treatment Failure
End point description
The percentage of participants with treatment failure was summarized. Treatment failure was defined as: (1) participants that required hospitalization; or (2) participants for whom a decision to discharge home had not been reached by 3 hours following the end of study drug administration. The FAS was used for this analysis.
End point type
Secondary
End point timeframe
Up to ≥ 3 hours after IV manual bolus infusion of montelukast 7 mg or placebo.
End point values
 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
Number of subjects analysed
287 [4]
284 [5]
Units: Percentage of Participants
    number (not applicable)
26.8
29.9
Notes
[4] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
[5] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
Statistical analysis title
 Percentage of Participants With Treatment Failure
Statistical analysis description
A logistic regression model was used for analysis of the FAS population to compare the percentage of treatment failures between treatment groups. Factors in the model included treatment, prior therapy with systemic corticosteroids and/or anti-leukotriene, and baseline FEV1 was used as a covariate. Descriptive statistics by treatment group provided by definition of treatment failure: participants requiring hospitalization or participants for whom decision to discharge home not reached by 3 hours.
Comparison groups
Montelukast 7 mg + Standard Treatment v Placebo + Standard Treatment
Number of subjects included in analysis
571
Analysis specification
Pre-specified
Analysis type
 superiority [6]
P-value
 = 0.654 [7]
Method
 Regression, Logistic
Parameter type
 Odds ratio (OR)
Point estimate
0.92
Confidence interval
     level
 95%
     sides
2-sided
     lower limit
 0.63
     upper limit
 1.34
Notes
[6] - Treatment differences were summarized by the odds ratio (OR) derived from the logistic regression model and the 95% CI.
[7] - Percentage of treatment failures in the IV montelukast 7 mg group compared to the placebo treatment group.

Secondary: Time-weighted Average Change from Baseline in FEV1 (0 to 40 minutes)

 Close Top of page
End point title
 Time-weighted Average Change from Baseline in FEV1 (0 to 40 minutes)
End point description
Time-weighted average change from baseline in FEV1 over the first 40 minutes after IV montelukast or placebo administration. Changes from baseline in FEV1 were computed at 10, 20, and 40 minutes post study drug administration and then used to calculate a time-weighted average for 0-40 minutes, with the time interval between any measurement and the measurement prior to it being used as the weighting factor. The FAS was used for this analysis.
End point type
Secondary
End point timeframe
0 minutes (BL), 10, 20, and 40 minutes after IV bolus infusion of montelukast 7 mg or placebo.
End point values
 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
Number of subjects analysed
287 [8]
283 [9]
Units: Liters
    least squares mean (confidence interval 95%)
0.28 (0.23 to 0.33)
0.18 (0.13 to 0.23)
Notes
[8] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
[9] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
Statistical analysis title
 Time-weighted Average ΔFEV1 (0-40 min)
Statistical analysis description
The time weighted average change from baseline in FEV1, computed in the interval 0-40 minutes, was analysed with an ANCOVA model using the baseline FEV1 as a covariate and including treatment, prior therapy with systemic corticosteroids and/or anti-leukotriene (yes/no), and region (US/Non-US) as factors. This ANCOVA model was used to estimate the least squares mean (LS-mean) for each treatment, between-treatment difference, and 95% CI.
Comparison groups
Montelukast 7 mg + Standard Treatment v Placebo + Standard Treatment
Number of subjects included in analysis
570
Analysis specification
Pre-specified
Analysis type
 superiority
P-value
 ≤ 0.001 [10]
Method
 ANCOVA
Parameter type
 LS mean difference
Point estimate
0.09
Confidence interval
     level
 95%
     sides
2-sided
     lower limit
 0.04
     upper limit
 0.15
Notes
[10] - P-value for LS mean difference between treatments, montelukast 7 mg versus placebo.

Secondary: Time-weighted Average Change From Baseline in FEV1 (0 to 20 minutes)

 Close Top of page
End point title
 Time-weighted Average Change From Baseline in FEV1 (0 to 20 minutes)
End point description
Time-weighted average change from baseline in FEV1 over the first 20 minutes after IV montelukast or placebo administration. Changes from baseline in FEV1 were computed at 10 and 20 minutes post study drug administration and then used to calculate a time-weighted average for 0-20 minutes, with the time interval between any measurement and the measurement prior to it being used as the weighting factor. The FAS was used for this analysis.
End point type
Secondary
End point timeframe
0 minutes (BL), 10, and 20 minutes after IV bolus infusion of montelukast 7 mg or placebo.
End point values
 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
Number of subjects analysed
287 [11]
282 [12]
Units: Liters
    least squares mean (confidence interval 95%)
0.23 (0.19 to 0.28)
0.15 (0.1 to 0.2)
Notes
[11] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
[12] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
Statistical analysis title
 Time-weighted Average ΔFEV1 (0-20 min)
Statistical analysis description
The time weighted average change from baseline in FEV1, computed in the interval 0-20 minutes, was analysed with an ANCOVA model using the baseline FEV1 as a covariate and including treatment, prior therapy with systemic corticosteroids and/or anti-leukotriene (yes/no), and region (US/Non-US) as factors. This ANCOVA model was used to estimate the least squares mean (LS-mean) for each treatment, between-treatment difference, and 95% CI.
Comparison groups
Montelukast 7 mg + Standard Treatment v Placebo + Standard Treatment
Number of subjects included in analysis
569
Analysis specification
Pre-specified
Analysis type
 superiority
P-value
 = 0.002 [13]
Method
 ANCOVA
Parameter type
 LS mean difference
Point estimate
0.09
Confidence interval
     level
 95%
     sides
2-sided
     lower limit
 0.03
     upper limit
 0.14
Notes
[13] - P-value for LS mean difference between treatments, i.e., montelukast 7 mg versus placebo.

Secondary: Average Change from Baseline in FEV1 at 10 minutes

 Close Top of page
End point title
 Average Change from Baseline in FEV1 at 10 minutes
End point description
Average change from baseline in FEV1 at 10 minutes after IV montelukast or placebo. The FAS was used for this analysis.
End point type
Secondary
End point timeframe
0 minutes (baseline), 10 minutes after IV manual bolus infusion of montelukast 7 mg or placebo.
End point values
 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
Number of subjects analysed
269 [14]
260 [15]
Units: Liters
    least squares mean (confidence interval 95%)
0.2 (0.15 to 0.26)
0.12 (0.06 to 0.17)
Notes
[14] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
[15] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
Statistical analysis title
 Average ΔFEV1 at 10 min
Statistical analysis description
The average change from baseline in FEV1, computed at 10 minutes, was analysed with an ANCOVA model using the baseline FEV1 as a covariate and including treatment, prior therapy with systemic corticosteroids and/or anti-leukotriene (yes/no), and region (US/Non-US) as factors. This ANCOVA model was used to estimate the least squares mean (LS-mean) for each treatment, between treatment difference, and 95% CI.
Comparison groups
Montelukast 7 mg + Standard Treatment v Placebo + Standard Treatment
Number of subjects included in analysis
529
Analysis specification
Pre-specified
Analysis type
 superiority
P-value
 = 0.008 [16]
Method
 ANCOVA
Parameter type
 LS mean difference
Point estimate
0.08
Confidence interval
     level
 95%
     sides
2-sided
     lower limit
 0.02
     upper limit
 0.15
Notes
[16] - P-value for LS mean difference between treatments, i.e., montelukast 7 mg versus placebo.

Secondary: Total Dose of β-agonist Administered Within 3 Hours

 Close Top of page
End point title
 Total Dose of β-agonist Administered Within 3 Hours
End point description
Total dose of β-agonist in mg administered per participant within 3 hours following end of study drug administration or placebo. Participants hospitalised prior to 3 hours post IV montelukast or placebo administration were assigned the largest total dose of β-agonist observed over all randomised participants plus 1 mg, or 5 mg plus 1 mg, whichever is larger.
End point type
Secondary
End point timeframe
Up to 3 hours following end of IV manual bolus infusion of montelukast 7 mg or placebo.
End point values
 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
Number of subjects analysed
287 [17]
284 [18]
Units: mg
    median (inter-quartile range (Q1-Q3))
5 (1 to 10)
5 (0.9 to 10)
Notes
[17] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
[18] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
Statistical analysis title
 Total Dose of β-Agonist
Statistical analysis description
A non-parametric ANCOVA model based on Tukey’s normalised ranks was used with factors for treatment, prior therapy with systemic corticosteroids and/or anti-leukotriene, region, and rank of BL FEV1 as covariate. Total dose of β-agonist administered per participant over a period of 3 hours following end of study drug administration was compared between treatment groups. Within-treatment effect was described using medians. Difference between medians were computed by the Hodges-Lehmann estimation.
Comparison groups
Montelukast 7 mg + Standard Treatment v Placebo + Standard Treatment
Number of subjects included in analysis
571
Analysis specification
Pre-specified
Analysis type
 other [19]
P-value
 = 0.952 [20]
Method
 ANCOVA
Parameter type
 Median difference (final values)
Point estimate
0
Confidence interval
     level
 95%
     sides
2-sided
     lower limit
 0
     upper limit
 0
Notes
[19] - Distribution-free confidence interval was based on the rank-sum test.
[20] - P-value for comparison between treatment groups, IV montelukast 7 mg versus placebo treatment.

Secondary: Number of Doses of β-agonist Administered Within 3 Hours

 Close Top of page
End point title
 Number of Doses of β-agonist Administered Within 3 Hours
End point description
Number of times a dose of a β-agonist was administered per participant within 3 hours following end of study drug or placebo administration. Participants hospitalised prior to 3 hours post study drug or placebo administration were assigned the largest number of β-agonist doses administered as observed over all randomised patients.
End point type
Secondary
End point timeframe
Up to 3 hours after IV manual bolus infusion of montelukast 7 mg or placebo.
End point values
 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
Number of subjects analysed
287
284
Units: Doses
    median (inter-quartile range (Q1-Q3))
2 (1 to 3)
2 (1 to 4)
Statistical analysis title
 Number of Doses of β-agonist
Statistical analysis description
A non-parametric ANCOVA model based on Tukey’s normalised ranks was used with factors for treatment, prior therapy with systemic corticosteroids and/or anti-leukotriene, region, and rank of BL FEV1 as covariate. Number of doses of β-agonist administered per participant over a period of 3 hours following end of study drug administration was compared between treatment groups. Within-treatment effect was described using medians. Difference of medians was computed by the Hodges-Lehmann estimation.
Comparison groups
Montelukast 7 mg + Standard Treatment v Placebo + Standard Treatment
Number of subjects included in analysis
571
Analysis specification
Pre-specified
Analysis type
 other [21]
P-value
 = 0.265 [22]
Method
 ANCOVA
Parameter type
 Median difference (final values)
Point estimate
0
Confidence interval
     level
 95%
     sides
2-sided
     lower limit
 0
     upper limit
 0
Notes
[21] - Distribution-free confidence interval was based on the rank-sum test.
[22] - P-value for comparison between treatment groups, IV montelukast 7 mg versus placebo treatment.

Adverse events

 Close Top of page
Adverse events information [1]
Timeframe for reporting adverse events
During the treatment period after IV montelukast or placebo administration until permanent discontinuation (end of Period 2) plus 14 days (Post-study, Period 3).
Adverse event reporting additional description
All randomised patients who started study drug were included in the All-Participants-as-Treated (APaT) set for the safety analyses. The participant’s treatment group was determined by the actual treatment received.
Assessment type
 Systematic
Dictionary used for adverse event reporting
Dictionary name
 MedDRA
Dictionary version
10.0
Reporting groups
Reporting group title
Placebo + Standard Treatment
Reporting group description
 During Period 2, randomised participants received IV placebo for montelukast in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of IV placebo.

Reporting group title
Montelukast 7 mg + Standard Treatment
Reporting group description
 During Period 2, randomised participants received IV montelukast 7 mg in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of montelukast.

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: No nonserious adverse events reaching the cut-off of >5% on at least one treatment arm were reported.
Serious adverse events
 Placebo + Standard Treatment Montelukast 7 mg + Standard Treatment
Total subjects affected by serious adverse events
     subjects affected / exposed
26 / 292 (8.90%)
28 / 291 (9.62%)
     number of deaths (all causes)
1
0
     number of deaths resulting from adverse events
0
0
Injury, poisoning and procedural complications
Drug Toxicity
     subjects affected / exposed
1 / 292 (0.34%)
0 / 291 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 1
0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
     subjects affected / exposed
23 / 292 (7.88%)
23 / 291 (7.90%)
     occurrences causally related to treatment / all
1 / 24
0 / 24
     deaths causally related to treatment / all
0 / 0
0 / 0
Chronic obstructive pulmonary disease
     subjects affected / exposed
0 / 292 (0.00%)
2 / 291 (0.69%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Dyspnoea
     subjects affected / exposed
0 / 292 (0.00%)
1 / 291 (0.34%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Status asthmaticus
     subjects affected / exposed
1 / 292 (0.34%)
0 / 291 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Nervous system disorders
Transient ischaemic attack
     subjects affected / exposed
0 / 292 (0.00%)
1 / 291 (0.34%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Hepatobiliary disorders
Cholecystitis
     subjects affected / exposed
1 / 292 (0.34%)
0 / 291 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Metabolism and nutrition disorders
Hyperglycaemia
     subjects affected / exposed
0 / 292 (0.00%)
1 / 291 (0.34%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Infections and infestations
Varicella
     subjects affected / exposed
1 / 292 (0.34%)
0 / 291 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Frequency threshold for reporting non-serious adverse events: 0%
Non-serious adverse events
 Placebo + Standard Treatment Montelukast 7 mg + Standard Treatment
Total subjects affected by non serious adverse events
     subjects affected / exposed
0 / 292 (0.00%)
0 / 291 (0.00%)

More information

 Close Top of page

Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date
Amendment
22 Mar 2005
Amendment 01: Primary reasons for the amendment were to incorporate revisions to the inclusion and exclusion criteria, add language that removes the requirement to report hospitalisation due to worsening asthma (which is also a study endpoint) as a serious adverse experience, and include an updated montelukast sodium product circular that includes new in vitro data regarding CYP2C8.

Interruptions (globally)
Were there any global interruptions to the trial? No

Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir