Clinical Trial Results:
A Double-Blind, Double-Dummy, Randomised, Placebo- And Active-Controlled, Three-Way Crossover Study to Evaluate the Effect of Budesonide/Formoterol Spiromax® 80/4.5 mcg Inhalation Powder and Symbicort® Turbohaler® 100/6 mcg on the Short-Term Lower Leg Growth Rate in Prepubescent Children With Persistent Asthma
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Summary
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EudraCT number |
2010-019082-29 |
Trial protocol |
DK |
Global end of trial date |
26 Jan 2011
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Mar 2019
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First version publication date |
23 Mar 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
BFS-AS-305
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Teva Branded Pharmaceutical Products R&D, Inc.
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Sponsor organisation address |
74 NW, 176th Street, Miami, FL, United States, 33169
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Public contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc., 001 215-591-3000, info.eraclinical@teva.de
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Scientific contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc., 001 215-591-3000, info.eraclinical@teva.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
26 Jan 2011
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
26 Jan 2011
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective was to demonstrate the non-inferiority of Budesonide/Formoterol Spiromax® 80/4.5 micrograms (mcg) Inhalation Powder (Budesonide Formoterol [BF] Spiromax) relative to Symbicort® Turbohaler® 100/6 mcg (Symbicort Turbohaler) on short-term growth rate of the right lower leg as measured by knemometry in prepubescent children with persistent asthma.
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Protection of trial subjects |
This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, clinical research guidelines established by the US Code of Federal Regulations (Title 21, CFR Parts 50, 56 and 312), European Union (EU) Directives (where applicable), with Good Clinical Practice (GCP) requirements described in the current revision of International Conference on Harmonization (ICH) of Technical Requirements of Pharmaceuticals for Human Use guidelines, and in accordance with local regulations and legal requirements.
The study was conducted with due attention to the rights of children. The interest of the
children always prevailed over those of science and society.
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Background therapy |
Participants were allowed to take short-acting beta agonist (SABA) therapy throughout the study (during 2-week run-in period, 2-week wash-out periods, and 3 treatment periods [2 weeks each]). | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Sep 2010
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Denmark: 77
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Worldwide total number of subjects |
77
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EEA total number of subjects |
77
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
77
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||
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Pre-assignment
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Screening details |
A total of 81 participants were screened, of which 4 participants were screen failures. A total of 77 participants were randomized and treated in 1 of the 6 different treatment sequences, after the 14-day run-in period. | ||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||
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Arms
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Arm title
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All Participants | ||||||||||||||||
Arm description |
All participants were randomized to 1 of 6 treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA), each of which was comprised of the same 3 interventions (A, B, and C). Treatment A consisted of 2 oral inhalations of Budesonide 80 mcg/Formoterol 4.5 mcg (BF SPIROMAX®) (active treatment) in morning (AM) and 2 oral inhalations in evening (PM) along with 2 oral inhalations of Turbohaler placebo both in AM and PM. Treatment B consisted of 2 oral inhalations of Budesonide 100 mcg/Formoterol 6 mcg (Symbicort® Turbohaler®) (comparator) in AM and 2 oral inhalations in PM along with 2 oral inhalations of Spiromax placebo both in AM and PM. Treatment C consisted of 2 oral inhalations of Spiromax placebo in AM and 2 oral inhalations in PM along with 2 oral inhalations of Turbohaler placebo both in AM and PM. The study included 3 treatment periods which were 14 days (+/-4 days) each. Treatment Periods 1 and 2 were followed by a 14-day Washout Period (+/-4 days). | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
BF SPIROMAX®
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder
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Routes of administration |
Inhalation use
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Dosage and administration details |
Budesonide 80 mcg and formoterol fumarate dihydrate 4.5 mcg; administered as oral inhalations.
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Investigational medicinal product name |
Symbicort® Turbohaler®
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder
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Routes of administration |
Inhalation use
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Dosage and administration details |
Budesonide 100 mcg and formoterol fumarate dihydrate 6 mcg; administered as oral inhalations.
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Investigational medicinal product name |
Spiromax Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder
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Routes of administration |
Inhalation use
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Dosage and administration details |
Spiromax placebo administered as oral inhalations.
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Investigational medicinal product name |
Turbohaler Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder
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Routes of administration |
Inhalation use
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Dosage and administration details |
Turbohaler placebo administered as oral inhalations.
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Baseline characteristics reporting groups
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Reporting group title |
All Participants
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Reporting group description |
All participants were randomized to 1 of 6 treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA), each of which was comprised of the same 3 interventions (A, B, and C). Treatment A consisted of 2 oral inhalations of Budesonide 80 mcg/Formoterol 4.5 mcg (BF SPIROMAX®) (active treatment) in morning (AM) and 2 oral inhalations in evening (PM) along with 2 oral inhalations of Turbohaler placebo both in AM and PM. Treatment B consisted of 2 oral inhalations of Budesonide 100 mcg/Formoterol 6 mcg (Symbicort® Turbohaler®) (comparator) in AM and 2 oral inhalations in PM along with 2 oral inhalations of Spiromax placebo both in AM and PM. Treatment C consisted of 2 oral inhalations of Spiromax placebo in AM and 2 oral inhalations in PM along with 2 oral inhalations of Turbohaler placebo both in AM and PM. The study included 3 treatment periods which were 14 days (+/-4 days) each. Treatment Periods 1 and 2 were followed by a 14-day Washout Period (+/-4 days). | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
All Participants
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Reporting group description |
All participants were randomized to 1 of 6 treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA), each of which was comprised of the same 3 interventions (A, B, and C). Treatment A consisted of 2 oral inhalations of Budesonide 80 mcg/Formoterol 4.5 mcg (BF SPIROMAX®) (active treatment) in morning (AM) and 2 oral inhalations in evening (PM) along with 2 oral inhalations of Turbohaler placebo both in AM and PM. Treatment B consisted of 2 oral inhalations of Budesonide 100 mcg/Formoterol 6 mcg (Symbicort® Turbohaler®) (comparator) in AM and 2 oral inhalations in PM along with 2 oral inhalations of Spiromax placebo both in AM and PM. Treatment C consisted of 2 oral inhalations of Spiromax placebo in AM and 2 oral inhalations in PM along with 2 oral inhalations of Turbohaler placebo both in AM and PM. The study included 3 treatment periods which were 14 days (+/-4 days) each. Treatment Periods 1 and 2 were followed by a 14-day Washout Period (+/-4 days). | ||
Subject analysis set title |
BF Spiromax
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Budesonide 80 mcg/Formoterol 4.5 mcg, two oral inhalations in morning and two oral inhalations in evening in each treatment period.
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Subject analysis set title |
Symbicort Turbohaler
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Budesonide 100 mcg/Formoterol 6 mcg, two oral inhalations in morning and two oral inhalations in evening in each treatment period.
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Subject analysis set title |
Placebo
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Spiromax placebo or Turbohaler placebo, two oral inhalations in morning and two oral inhalations in evening in each treatment period.
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End point title |
Short-Term Lower Leg Growth Rate (LLGR) of The Right Lower Leg | ||||||||||||||||
End point description |
Short-term LLGR was measured by knemometry of the right lower leg after 2 weeks of treatment, and was calculated for each participant and for each treatment period in millimeters per week (mm/week). Four measurements were taken at each visit, with summaries and analysis based on the mean of the last three results. The LLGR was then determined from the change in growth measurement and number of days in each period; that is, LLGR (mm/week) = ([length in mm (end) - length in mm (start)]/[date (end) - date (start)] + 1) * 7. Per-protocol (PP) population included all data from the ITT population (included all randomised participants who received at least one dose of randomised study medication and had at least one post-baseline assessment.) obtained prior to experiencing major protocol violations.
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End point type |
Primary
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End point timeframe |
Treatments periods 1, 2, and 3 (each treatment period = 2 weeks)
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Statistical analysis title |
BF Spiromax vs. Symicort Turbohaler | ||||||||||||||||
Statistical analysis description |
Actual number of participants analysed=70. Analysis was performed using ANOVA model with fixed effects of treatment, sequence, and period, a random effect of participant within sequence. Non-inferiority was demonstrated if the lower limit of the 95% two-sided confidence interval for the treatment difference in the short-term LLGR (BF Spiromax minus Symbicort Turbohaler) was greater than -0.200 mm/week.
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Comparison groups |
BF Spiromax v Symbicort Turbohaler
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Number of subjects included in analysis |
140
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||
Method |
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Parameter type |
Least square (LS) mean difference | ||||||||||||||||
Point estimate |
-0.086
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.203 | ||||||||||||||||
upper limit |
0.032 | ||||||||||||||||
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End point title |
Change From Period-Specific Baseline in Daily Trough Morning (AM) and Evening (PM) Peak Expiratory Flow (PEF) Rate at End of Each Treatment Period | ||||||||||||||||||||||||||||||||||||||||
End point description |
PEF was determined twice daily, in AM and in PM, before administration of study medications or rescue bronchodilator during run-in period and throughout study. AM PEF was calculated as daily average of AM PEF over the previous 7 days prior to beginning of each treatment period with at least 4 days of non-missing values. The period-specific baseline trough AM PEF was calculated as daily average of AM PEF over each 2-week treatment period with at least 4 days of non-missing values. If non-missing days in each period was less than 4 days, the values were treated as missing. PM PEF and period-specific baseline trough PM PEF was calculated in a manner similar to AM PEF. PP population included all data from ITT population (included all randomised participants who received at least 1 dose of randomised study medication and had at least 1 post-baseline assessment.) obtained prior to experiencing major protocol violations. Here, "n" = number of participants evaluable for specified categories.
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End point type |
Secondary
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End point timeframe |
Baseline, at end of treatment period 1, 2 and 3 (each treatment period = 2 weeks)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
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End point title |
Change From Period-Specific Baseline in Percentage of Rescue-Free Days at End of Each Treatment Period | ||||||||||||||||||||||||||||
End point description |
Participants recorded their use of rescue medication twice daily (AM and PM) before intake of study medications. For the purpose of this study, a "day" was the combination of AM and PM in a 24-hour period. Percentage of days rescue medication taken was calculated as: (Number of days with puffs = 0 / Number of non-missing days (>=4 days)*100. Period-specific baseline was defined as percentage of rescue-free days over the last 7 days prior to the beginning of each treatment period with at least 4 days of non-missing values. A non-missing day was defined as a day in which rescue medication records were non-missing in either the AM or PM or both. PP population included all data from the ITT population (included all randomised participants who received at least one dose of randomised study medication and had at least one post-baseline assessment.) obtained prior to experiencing major protocol violations. Here, "n" signifies number of participants evaluable at specified treatment period.
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End point type |
Secondary
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End point timeframe |
Baseline, at end of treatment period 1, 2 and 3 (each treatment period = 2 weeks)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Change From Period-Specific Baseline in Inspiratory Flow Rate at End of Each Treatment Period | ||||||||||||||||||||||||||||
End point description |
Period-specific baseline was defined as the average of the 3 inspiratory flow rate obtained at the beginning of each treatment period. PP population included all data from the ITT population (included all randomised participants who received at least one dose of randomised study medication and had at least one post-baseline assessment.) obtained prior to experiencing major protocol violations. Since this was a crossover study, a participant could be excluded from one treatment period, but still be included in the PP population for the other treatment periods. Here, "n" signifies number of participants evaluable at specified treatment period.
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End point type |
Secondary
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End point timeframe |
Baseline, at end of treatment period 1, 2 and 3 (each treatment period =2 weeks)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
24-Hour Urinary Cortisol (UC) Excretion | ||||||||||||||||||||||||||||
End point description |
UC population included all randomised participants who received at least one dose of randomised study medication, and whose urine samples did not have confounding factors that would affect the interpretation of the results. Here, "n" signifies number of participants evaluable at specified treatment period.
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End point type |
Other pre-specified
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End point timeframe |
Treatment periods 1, 2, and 3 (each treatment period = 2 weeks)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
24-Hour Urinary Cortisol/Creatinine Ratio | ||||||||||||||||||||||||||||
End point description |
UC population included all randomised participants who received at least one dose of randomised study medication, and whose urine samples did not have confounding factors that would affect the interpretation of the results. Here, "n" signifies number of participants evaluable at specified treatment period.
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End point type |
Other pre-specified
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End point timeframe |
Treatment periods 1, 2, and 3 (each treatment period = 2 weeks)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From randomization until end of third treatment period (in total up to approximately 10 weeks)
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Adverse event reporting additional description |
Safety population included all randomised participants who received at least one dose of randomised study medication.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
13.0
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Reporting groups
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Reporting group title |
BF Spiromax
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Reporting group description |
Budesonide 80 mcg/Formoterol 4.5 mcg, two oral inhalations in morning and two oral inhalations in evening in each treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Spiromax placebo or Turbohaler placebo, two oral inhalations in morning and two oral inhalations in evening in each treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Symbicort Turbohaler
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Reporting group description |
Budesonide 100 mcg/Formoterol 6 mcg, two oral inhalations in morning and two oral inhalations in evening in each treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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02 Nov 2010 |
The purpose of amendment was to remove blood pressure (BP) as a study assessment. BP was included as a study assessment as it was a non-invasive measure and was not anticipated to be problematic to obtain. However, in attempting to obtain BP measurements, the Principal Investigator noted that the study participants were not used to having their BP measured. This caused high levels of anxiety about the BP measurements by many of the study participants with the result that BP measurements may have been artificially elevated in many participants. Anxiety about the BP measurements by many of the study participants was particularly evident during the baseline BP measurements. However, by the time Protocol Amendment 1 had been submitted to the Danish Medicines Agency, the Principal Investigator confirmed that study participants had become accustomed to the BP assessment process and that study participants were no longer anxious about their BP measurements. The Principal Investigator also confirmed that all study participants and their parents were agreeable to have BP assessments for the remainder of the study. Therefore, the request to the Danish Medicines Agency to authorise Protocol Amendment 1 was withdrawn and was not implemented. The study continued using the Final Version, Revision 1 of the Protocol which was dated 21 Sep 2010. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
