Clinical Trial Results:
A double-blind, double dummy, randomised, parallel group, multicentre study to compare the efficacy and safety of Flutiform pMDI with fluticasone pMDI and with Seretide pMDI in paediatric subjects aged 5 to less than 12 years with moderate to severe persistent reversible asthma.
Summary
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EudraCT number |
2010-024635-16 |
Trial protocol |
HU CZ PL BG |
Global end of trial date |
04 Sep 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Jun 2016
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First version publication date |
30 Jul 2015
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Other versions |
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 |
FLT3506
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01511367 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Mundipharma Research Ltd.
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Sponsor organisation address |
Cambridge Science Park, Milton Road, Cambridge, United Kingdom, CB4 0GW
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Public contact |
European Medical Operations, Mundipharma Research Limited, +44 1223424900, info@contact-clinical-trials.com
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Scientific contact |
European Medical Operations, Mundipharma Research Limited, +44 1223424900, info@contact-clinical-trials.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000127-PIP01-07 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
04 Sep 2013
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
04 Sep 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
04 Sep 2013
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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 of the study is to show superiority in the efficacy of Flutiform pMDI 50/5μg (2 puffs bid) versus fluticasone pMDI 50 μg (2 puffs bid).
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Protection of trial subjects |
All subjects and their guardians/legally authorised representatives were provided with oral and written information describing the nature and duration of the study, its purpose, the procedures to be performed, the potential risks and benefits involved, and any potential discomfort. Each subject was given a copy of the PIS and ICF. The subject’s guardian /legally authorised representative was asked to sign an informed consent form and, according to local country requirements and where appropriate, the subject was asked to sign/mark (e,g. drawing if subject was very young) an informed assent form (IAF) prior to any study-specific procedures being performed. No subject could enter the study before his/her guardian’s/legally authorised representative’s informed consent had been obtained.
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Background therapy |
Salbutamol 100 µg was used as rescue medication in the run-in and treatment period. | ||
Evidence for comparator |
Seretide was chosen as a comparator product because it is a marketed asthma medication consisting of an ICS and a LABA within a pMDI. The choice of Seretide (in some countries known as Viani® or Advair®) also maintains consistency across the treatment for the steroid part of the combinations (fluticasone). Seretide is a market leader within the field of asthma and is licensed for use in children aged 4 years or older. | ||
Actual start date of recruitment |
26 Mar 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Bulgaria: 90
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Country: Number of subjects enrolled |
Poland: 187
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Country: Number of subjects enrolled |
Czech Republic: 6
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Country: Number of subjects enrolled |
Hungary: 107
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Country: Number of subjects enrolled |
India: 10
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Country: Number of subjects enrolled |
Romania: 11
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Country: Number of subjects enrolled |
Russian Federation: 72
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Country: Number of subjects enrolled |
Ukraine: 29
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Worldwide total number of subjects |
512
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EEA total number of subjects |
401
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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) |
512
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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 |
- | ||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 713 subjects provided written informed consent and were screened; 512 subjects were randomised and 509 subjects were treated. 150 subjects failed screening; 136 subjects due to failing the inclusion/exclusion criteria, 11 subjects chose not to continue, 2 subjects due to adverse event, and 1 subject due to administrative reasons. | ||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall trial (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, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
The subject and all personnel involved with the study, excluding those involved in processing and regulatory reporting of SUSARs, were blinded to the medication codes. The randomisation schedule was filed securely by the interactive response technology (IRT) provider in a manner such that blinding was properly maintained throughout the study. To maintain the blinded nature of this study, each subject received 2 inhalers.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Flutiform | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Flutiform | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Flutiform
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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 |
50/5µg, 2 puffs, Q12h
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Arm title
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Fluticasone | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Fluticasone | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fluticasone
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Investigational medicinal product code |
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Other name |
Fluticasone propionate
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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 |
50 µg, 2 puffs, Q12h
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Arm title
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Seretide | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Seretide | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Seretide
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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 |
50/25 µg, 2 puffs, Q12h
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Baseline characteristics reporting groups
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Reporting group title |
Flutiform
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Reporting group description |
Flutiform | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fluticasone
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Reporting group description |
Fluticasone | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Seretide
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Reporting group description |
Seretide | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Safety Population
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The safety population (SP) was defined as all randomised subjects who received at least one dose of study medication (IMP). Subjects were analysed according to actual treatment received.
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Subject analysis set title |
Full Analysis Population
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The full analysis population (FAP) was defined as all randomised subjects who received at least one dose of study medication (IMP) and had at least one valid efficacy (FEV1) assessment. Subjects will be analysed according to their randomised treatment.
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End points reporting groups
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Reporting group title |
Flutiform
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Reporting group description |
Flutiform | ||
Reporting group title |
Fluticasone
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Reporting group description |
Fluticasone | ||
Reporting group title |
Seretide
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Reporting group description |
Seretide | ||
Subject analysis set title |
Safety Population
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The safety population (SP) was defined as all randomised subjects who received at least one dose of study medication (IMP). Subjects were analysed according to actual treatment received.
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Subject analysis set title |
Full Analysis Population
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The full analysis population (FAP) was defined as all randomised subjects who received at least one dose of study medication (IMP) and had at least one valid efficacy (FEV1) assessment. Subjects will be analysed according to their randomised treatment.
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End point title |
Change from pre-dose FEV1 at baseline to the 2-hour post-dose FEV1 over the 12 week treatment period | ||||||||||||||||
End point description |
The primary endpoint, which was tested in a hierarchical (gate keeping) manner for the two study comparisons (Flutiform to Fluticasone, then Flutiform to Seretide), was the change from pre-dose Forced Expiratory Volume in 1 second (FEV1) at baseline to 2 hours post-dose FEV1 over the 12 week treatment period.
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End point type |
Primary
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End point timeframe |
From baseline to the 2-hour post-dose values over the 12 weeks.
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Statistical analysis title |
Superiority of Flutiform versus Fluticasone | ||||||||||||||||
Statistical analysis description |
Null hypothesis (H0): μ Flutiform = μ Fluticasone
Alternative (H1): μ Flutiform ≠ μ Fluticasone
The change from pre-dose FEV1 values at baseline to the 2-hour post dose FEV1 values at each post baseline visit were analysed using a repeated measures Analysis of Covariance (ANCOVA) with fixed terms for treatment, age group, pre-dose FEV1 at baseline, visit and treatment by visit interaction, and centre as a random effect.
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Comparison groups |
Flutiform v Fluticasone
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Number of subjects included in analysis |
330
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||||||
P-value |
< 0.001 [2] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Confidence interval |
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Notes [1] - Superiority was demonstrated if the primary comparison of Flutiform versus Fluticasone was significant at the 0.05 alpha level. [2] - Based on the null hypothesis that there is no difference in treatment means. |
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Statistical analysis title |
Non-inferiority of Flutiform versus Seretide | ||||||||||||||||
Statistical analysis description |
Null hypothesis (H0): μ Flutiform - μ Seretide < - 0.1
Alternative (H1): μ Flutiform - μ Seretide ≥ - 0.1
The change from pre-dose FEV1 values was analysed using a repeated measures ANCOVA with fixed terms for treatment, age group, pre-dose FEV1 at baseline, visit and treatment by visit interaction and centre as a random effect. The statistical model
was used to calculate the overall treatment difference and 95% CI.
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Comparison groups |
Flutiform v Seretide
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Number of subjects included in analysis |
330
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [3] | ||||||||||||||||
P-value |
< 0.001 [4] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Confidence interval |
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Notes [3] - Non-inferiority was concluded if the lower limit of the 95% (confidence interval) CI was greater than or equal to -0.1L and the p-value for the non-inferiority comparison was based on a treatment difference of -0.1L. [4] - P-value of the pairwise treatment comparisons (based on the null hypothesis that the difference in treatment means is -0.1L). |
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End point title |
FEV1 AUC0-4h at Week 12 | ||||||||||||||||
End point description |
Normalised four hour FEV1 area under the curve values at Week 12.
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End point type |
Secondary
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End point timeframe |
Week 12
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Statistical analysis title |
Superiority of Flutiform versus Fluticasone | ||||||||||||||||
Statistical analysis description |
Null hypothesis (H0): μ Flutiform = μ Fluticasone
Alternative (H1): μ Flutiform ≠ μ Fluticasone
The normalised 4-hour FEV1 AUC0-4h values at Week 12 were analysed using an ANCOVA with fixed terms for treatment, age group, pre-dose FEV1 at baseline, and centre as a random effect.
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Comparison groups |
Flutiform v Fluticasone
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Number of subjects included in analysis |
296
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Analysis specification |
Pre-specified
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Analysis type |
superiority [5] | ||||||||||||||||
P-value |
< 0.001 [6] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Confidence interval |
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Notes [5] - Superiority was demonstrated if the primary comparison of Flutiform versus Fluticasone was significant at the 0.05 alpha level. [6] - P-value of the pairwise treatment comparisons (based on the null hypothesis that there is no difference in treatment means). |
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Statistical analysis title |
Non-inferiority of Flutiform versus Seretide | ||||||||||||||||
Statistical analysis description |
Null hypothesis (H0): μ Flutiform - μ Seretide < - 0.1
Alternative (H1): μ Flutiform - μ Seretide ≥ - 0.1
The change from pre-dose FEV1 values from baseline to each post baseline visit over the 12 weeks was analysed using a repeated measures ANCOVA with fixed terms for treatment, age group, pre-dose FEV1 at baseline, visit and treatment by visit interaction and centre as a random effect.
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Comparison groups |
Flutiform v Seretide
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Number of subjects included in analysis |
301
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [7] | ||||||||||||||||
P-value |
< 0.001 [8] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Confidence interval |
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Notes [7] - Non-inferiority was concluded if the lower limit of the 95% (confidence interval) CI was greater than or equal to -0.1L. The statistical model was used to calculate the overall treatment difference and 95% CI. [8] - P-value of the pairwise treatment comparisons (based on the null hypothesis that the difference in treatment means is -0.1L). |
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End point title |
Change from pre-dose FEV1 at baseline over the 12 week treatment period | ||||||||||||||||
End point description |
Change from pre-dose Forced Expiratory Volume in 1 second (FEV1) from baseline over the 12 week treatment period.
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End point type |
Secondary
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End point timeframe |
From baseline to each post baseline visit over 12 weeks.
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Statistical analysis title |
Superiority of Flutiform versus Fluticasone | ||||||||||||||||
Statistical analysis description |
Null hypothesis (H0): μ Flutiform = μ Fluticasone
Alternative (H1): μ Flutiform ≠ μ Fluticasone
The change from pre-dose FEV1 values from baseline to each post baseline visit over 12 weeks was analysed using a repeated measures ANCOVA with fixed terms for treatment, age group, pre-dose FEV1 at baseline, visit and treatment by visit interaction, and centre as a random effect. The statistical model was used to calculate the overall treatment difference and 95% CI.
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Comparison groups |
Fluticasone v Flutiform
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Number of subjects included in analysis |
337
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Analysis specification |
Pre-specified
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Analysis type |
superiority [9] | ||||||||||||||||
P-value |
= 0.091 [10] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Confidence interval |
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Notes [9] - Superiority was demonstrated if the primary comparison of Flutiform versus Fluticasone was significant at the 0.05 alpha level. [10] - P-value of the pairwise treatment comparisons (based on the null hypothesis that there is no difference in treatment means). |
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Statistical analysis title |
Non-inferiority of Flutiform versus Seretide | ||||||||||||||||
Statistical analysis description |
Null hypothesis (H0): μ Flutiform - μ Seretide < - 0.1
Alternative (H1): μ Flutiform - μ Seretide ≥ - 0.1
The change from pre-dose FEV1 values from baseline to each post baseline visit over 12 weeks was analysed using a repeated measures ANCOVA with fixed terms for treatment, age group, pre-dose FEV1 at baseline, visit and treatment by visit interaction and centre as a random effect.
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Comparison groups |
Flutiform v Fluticasone v Seretide
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Number of subjects included in analysis |
502
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [11] | ||||||||||||||||
P-value |
< 0.001 [12] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Confidence interval |
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Notes [11] - Non-inferiority was concluded if the lower limit of the 95% (confidence interval) CI was greater than or equal to -0.1L and the p-value for the non-inferiority comparison was based on a treatment difference of -0.1L. [12] - P-value of the pairwise treatment comparisons (based on the null hypothesis that the difference in treatment means is -0.1L). |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse Events (AEs) were recorded from the point at which the Informed Consent was signed until 14 days after the subject left the study. This included new AEs that were reported in the 14 days following the subject’s completion/discontinuation visit.
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Adverse event reporting additional description |
Only treatment emergent AEs were summarised. A treatment emergent AE was defined as any AE with an onset date on or after the first dose of study medication if the AE was absent before the first dose of study medication, or worsened after the first dose of study medication.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
14.1
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Reporting groups
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Reporting group title |
Flutiform
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Reporting group description |
Flutiform | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fluticasone
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Reporting group description |
Fluticasone | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Seretide
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Reporting group description |
Seretide | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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16 May 2013 |
Protocol Amendment No. 3 was a substantial amendment which revised the study objectives and amended the statistical analysis accordingly following Scientific advice from the MHRA.
The approved indication for Flutiform in adults and adolescents includes a “switch” to Flutiform in patients already adequately controlled on a combination of an inhaled corticosteroid and a long-acting β2 agonist. In the light of this indication, at a scientific advice meeting on the 27th February 2013, the MHRA advised the sponsor to revise the paediatric study objectives and to designate non-inferiority versus Seretide as a key secondary objective. Although the Paediatric Development Committee (PDCO) had already endorsed the design and comparisons in the original study, in order to accommodate the MHRA’s recommendation the sponsor altered the designation of comparators accordingly and amended the original sequence of statistical tests in order to control the Type 1 error rate. Furthermore given the confirmatory nature of the comparison versus Seretide in the amended protocol the primary timepoint for this comparison was revised. |
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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 |