Clinical Trial Results:
A 6-month, open label, randomised, efficacy study to evaluate fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) Inhalation Powder delivered once daily via the Dry Powder Inhaler Ellipta™ compared with usual ICS/LABA maintenance therapy delivered by Dry Powder Inhaler in subjects with Persistent Asthma
Summary
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EudraCT number |
2014-000551-81 |
Trial protocol |
DE |
Global end of trial date |
20 Jul 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Jul 2018
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First version publication date |
20 Jul 2018
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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 |
116492
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
GlaxoSmithKline
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Sponsor organisation address |
980 Great West Road, Brentford, Middlesex, United Kingdom,
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Public contact |
GSK Response Center, GlaxoSmithKline, 1 8664357343,
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Scientific contact |
GSK Response Center, GlaxoSmithKline, 1 8664357343,
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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? |
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 Dec 2017
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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 |
20 Jul 2017
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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 compare the efficacy of fluticasone furoate (FF)/vilanterol (VI) 100 mcg/ 25 mcg or FF/VI 200 mcg/25 mcg with usual fixed combinations inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) for asthma maintenance therapy at Week 12 (Visit 4).
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Protection of trial subjects |
Eligibility criteria have been incorporated into the protocol to exclude participants for whom any of the study treatments are contraindicated e.g. participants with historical or current evidence of uncontrolled or clinically significant cardiovascular disease, chronic users of systemic corticosteroids, participants with a history of life-threatening asthma, including severe and unstable asthma, and/or history of repeated severe exacerbations (3/year) and/or exacerbation in the previous 6 weeks.
The protocol requires that spirometry procedures are stopped if participants experience shortness of breath, coughing, light-headedness and/or chest tightness.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
09 Jul 2015
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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 |
France: 226
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Country: Number of subjects enrolled |
Germany: 213
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Worldwide total number of subjects |
439
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EEA total number of subjects |
439
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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) |
0
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Adolescents (12-17 years) |
1
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Adults (18-64 years) |
368
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From 65 to 84 years |
70
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 439 participants with persistent asthma were screened. The study was conducted at 63 centers in 2 countries: 43 in France and 20 in Germany from 09 July 2015 to 20 July 2017. Age value being reported for all participants is an approximate age accurate to within + or -1 year. | |||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 439 participants were screened for this study and 423 participants were randomized to treatment. Three of the randomized participants did not receive study treatment and were not included in the Intent-To-Treat (ITT) population. | |||||||||||||||||||||||||||||||||
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 |
Not blinded | |||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Usual ICS/LABA | |||||||||||||||||||||||||||||||||
Arm description |
Eligible participants received fixed combination inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) (Fluticasone propionate [FP]/ Salmeterol [S] 250/50 micrograms [mcg] or 500/50 mcg, 1 inhalation twice daily; or Budesonide [BUD]/ Formoterol [F] 200/6 mcg or 400/12 mcg, 1 or 2 inhalations twice daily) for 24 weeks. | |||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fluticasone propionate (FP)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder, pre-dispensed
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Routes of administration |
Inhalation use
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Dosage and administration details |
FP 250 mcg or 500 mcg blended with lactose administered twice daily via DISKUS DPI.
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Investigational medicinal product name |
Salmeterol (S)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder, pre-dispensed
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Routes of administration |
Inhalation use
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Dosage and administration details |
Salmeterol 50 mcg blended with lactose administered twice daily via DISKUS DPI.
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Investigational medicinal product name |
Budesonide (BUD)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder, pre-dispensed
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Routes of administration |
Inhalation use
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Dosage and administration details |
BUD 200 mcg or 400 mcg blended with lactose administered twice daily via TURBUHALER DPI.
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Investigational medicinal product name |
Formoterol (F)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder, pre-dispensed
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Routes of administration |
Inhalation use
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Dosage and administration details |
Formoterol 6 mcg or 12 mcg blended with lactose administered twice daily via TURBUHALER DPI.
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Arm title
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FF/VI | |||||||||||||||||||||||||||||||||
Arm description |
Eligible participants received Fluticasone Furoate (FF)/ Vilanterol (VI) 100 mcg/22 mcg or FF/VI 200 mcg/25 mcg 1 inhalation once daily for 24 weeks. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fluticasone Furoate (FF)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder, pre-dispensed
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Routes of administration |
Inhalation use
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Dosage and administration details |
FF 100 mcg or 200 mcg blended with lactose administered once daily via ELLIPTA dry powder inhaler (DPI).
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Investigational medicinal product name |
Vilanterol (VI)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder, pre-dispensed
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Routes of administration |
Inhalation use
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Dosage and administration details |
VI 25 mcg blended with lactose and magnesium stearate administered once daily via ELLIPTA DPI.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: A total of 439 participants were screened, of which 12 participants were inclusion/exclusion criteria failures; remaining 4 were not randomized due to physician decision, withdrawal by subject and protocol deviation. There were 3 participants who were randomized but not included in the ITT Population because they did not receive study treatment. These 3 participants were withdrawn from the study due to physician decision, withdrawal by subject and protocol deviation. |
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Baseline characteristics reporting groups
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Reporting group title |
Usual ICS/LABA
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Reporting group description |
Eligible participants received fixed combination inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) (Fluticasone propionate [FP]/ Salmeterol [S] 250/50 micrograms [mcg] or 500/50 mcg, 1 inhalation twice daily; or Budesonide [BUD]/ Formoterol [F] 200/6 mcg or 400/12 mcg, 1 or 2 inhalations twice daily) for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
FF/VI
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Reporting group description |
Eligible participants received Fluticasone Furoate (FF)/ Vilanterol (VI) 100 mcg/22 mcg or FF/VI 200 mcg/25 mcg 1 inhalation once daily for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Usual ICS/LABA
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Reporting group description |
Eligible participants received fixed combination inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) (Fluticasone propionate [FP]/ Salmeterol [S] 250/50 micrograms [mcg] or 500/50 mcg, 1 inhalation twice daily; or Budesonide [BUD]/ Formoterol [F] 200/6 mcg or 400/12 mcg, 1 or 2 inhalations twice daily) for 24 weeks. | ||
Reporting group title |
FF/VI
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Reporting group description |
Eligible participants received Fluticasone Furoate (FF)/ Vilanterol (VI) 100 mcg/22 mcg or FF/VI 200 mcg/25 mcg 1 inhalation once daily for 24 weeks. |
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End point title |
Change from Baseline in asthma control test (ACT) total score at Week 12 | |||||||||||||||
End point description |
The ACT is a validated self-completed questionnaire consisting of 5 questions that evaluate asthma control during the past 4 weeks on a 5-point categorical scale. Total scores are calculated from the sum of the scores from the 5 questions and can range from 5 to 25, with higher scores indicating better control. An ACT total score of 5 to 19 suggests that the participant’s asthma is unlikely to be well controlled, whilst a score of 20 to 25 suggests that the participant’s asthma is likely to be well controlled. Baseline value was the last assessment prior to randomization (Day 0). Change from Baseline was post-dose visit value minus the Baseline value. Least square mean change is presented.
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End point type |
Primary
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End point timeframe |
Baseline and Week 12
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Notes [1] - ITT Population. Only those participants available at the specified time points were analyzed. [2] - ITT Population. Only those participants available at the specified time points were analyzed. |
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Statistical analysis title |
Statistical analysis 1 | |||||||||||||||
Statistical analysis description |
The analysis method was an MMRM adjusted for randomized treatment, visit (Week 6 and Week 12), Baseline ACT total score, randomized treatment-by-visit interaction, Baseline ACT total score-by-visit interaction, gender, age, country and participant fitted as a random factor. The Restricted Maximum Likelihood (REML) estimation approach was used with a default covariance structure of unstructured.
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Comparison groups |
Usual ICS/LABA v FF/VI
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Number of subjects included in analysis |
376
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [3] | |||||||||||||||
P-value |
= 0.033 | |||||||||||||||
Method |
Mixed model repeated measures (MMRM) | |||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||
Point estimate |
0.8
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.1 | |||||||||||||||
upper limit |
1.5 | |||||||||||||||
Notes [3] - Non-inferiority of fixed combination FF/VI to usual ICS/LABA in inhalation powder was assessed assuming a non-inferiority margin of -1.5. |
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End point title |
Change from Baseline in ACT total score at Week 24 | |||||||||||||||
End point description |
The ACT is a validated self-completed questionnaire consisting of 5 questions that evaluate asthma control on a 5-point categorical scale. Total scores are calculated from the sum of the scores from the 5 questions and can range from 5 to 25, with higher scores indicating better control. An ACT total score of 5 to 19 suggests that the participant’s asthma is unlikely to be well controlled, whilst a score of 20 to 25 suggests that the participant’s asthma is likely to be well controlled. Baseline value was the last assessment prior to randomization (Day 0). Change from Baseline was post-dose visit value minus the Baseline value. Least square mean change is presented.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 24
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Notes [4] - ITT Population. Only those participants available at the specified time points were analyzed. [5] - ITT Population. Only those participants available at the specified time points were analyzed. |
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Statistical analysis title |
Statistical analysis 1 | |||||||||||||||
Statistical analysis description |
The analysis method was an MMRM adjusted for randomized treatment, visit (Week 6, Week 12, Week 18 and Week 24), Baseline ACT total score, randomized treatment-by-visit interaction, Baseline ACT total score-by visit interaction, gender, age, country and participant fitted as a random factor. The REML estimation approach was used with a default covariance structure of unstructured.
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Comparison groups |
Usual ICS/LABA v FF/VI
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Number of subjects included in analysis |
364
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [6] | |||||||||||||||
P-value |
= 0.224 | |||||||||||||||
Method |
Mixed model repeated measures (MMRM) | |||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||
Point estimate |
0.4
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-0.3 | |||||||||||||||
upper limit |
1.1 | |||||||||||||||
Notes [6] - Non-inferiority of fixed combination FF/VI to usual ICS/LABA in inhalation powder was assessed assuming a non-inferiority margin of -1.5. |
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End point title |
Percentage of participants with correct use of device, defined as not making any critical or non-critical errors, at Week 12, and at Week 24 independently of the use at Week 12 | |||||||||||||||
End point description |
Participants were asked to read the appropriate package insert for their prescribed inhaler and then the investigator (or suitably qualified designee) demonstrated the proper use of the inhaler. The participant was then asked to self-administer their first dose of study treatment under the supervision of the investigator and any critical and non-critical errors were recorded. Individual instruments for assessing correct inhaler use were provided for each of the three devices used in this study.
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End point type |
Secondary
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End point timeframe |
Week 12 and Week 24
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Notes [7] - ITT Population. Only those participants available at the specified time points were analyzed. [8] - ITT Population. Only those participants available at the specified time points were analyzed. |
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Statistical analysis title |
Statistical analysis 1 | |||||||||||||||
Statistical analysis description |
The analysis method was logistic regression adjusted for randomized treatment, correct use of inhaler device at Baseline, gender, age and country.
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Comparison groups |
FF/VI v Usual ICS/LABA
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Number of subjects included in analysis |
420
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.82 [9] | |||||||||||||||
Method |
Regression, Logistic | |||||||||||||||
Parameter type |
Adjusted Odds Ratio | |||||||||||||||
Point estimate |
1.11
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.47 | |||||||||||||||
upper limit |
2.62 | |||||||||||||||
Notes [9] - Week 12 |
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Statistical analysis title |
Statistical analysis 2 | |||||||||||||||
Statistical analysis description |
The analysis method was logistic regression adjusted for randomized treatment, correct use of inhaler device at Baseline, gender, age and country.
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Comparison groups |
FF/VI v Usual ICS/LABA
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Number of subjects included in analysis |
420
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.566 [10] | |||||||||||||||
Method |
Regression, Logistic | |||||||||||||||
Parameter type |
Adjusted Odds Ratio | |||||||||||||||
Point estimate |
1.41
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.43 | |||||||||||||||
upper limit |
4.6 | |||||||||||||||
Notes [10] - Week 24 |
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Adverse events information [1]
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Timeframe for reporting adverse events |
On-treatment serious adverse events (SAEs) and non-serious adverse drug reactions were collected from start of study treatment up to Week 24
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Adverse event reporting additional description |
On-treatment SAEs and non-serious adverse drug reactions were collected for the Safety Population comprised of all enrolled participants who received at least one dose of study medication (either FF/VI or usual ICS/LABA) and considered as-treated.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
FF/VI
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Reporting group description |
Eligible participants received Fluticasone FF/Vilanterol VI 100 mcg/22 mcg or FF/VI 200 mcg/25 mcg 1 inhalation once daily for 24 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Usual ICS/LABA
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Reporting group description |
Eligible participants received fixed combination ICS/LABA (FP/S 250/50 mcg or 500/50 mcg, 1 inhalation twice daily; or BUD/F 200/6 mcg or 400/12 mcg, 1 or 2 inhalations twice daily) for 24 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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: There were no non-serious adverse events above 5% threshold. |
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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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14 Aug 2015 |
This protocol amendment has been created to correct mistakes in the wording of the inhaler errors questionnaires for the Ellipta®, Diskus® and Turbuhaler inhalers, which are included in Section 7.3.1 of the protocol. All references to ‘Type A errors’ and ‘overall errors’ within the protocol, have been changed to ‘critical’ and ‘non-critical’ errors, respectively, for consistency with the inhaler errors questionnaire worksheets.
Storage condition instructions for Seretide® (fluticasone propionate/salmeterol) in Section 6.7 have been amended.
The wording for the recommended number of spirometry efforts has been revised.
New text has been included with regards to investigational product malfunction in Section 6.8.
The secondary medical monitor contact information has been revised to include a new study physician.
Other minor corrections and edits have been made. |
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28 Apr 2016 |
This amendment has been written primarily to allow the addition of a new country/countries to the study. This includes:
• Removing reference to France unless specifically required
• Amending text to make language more applicable to participating countries
• Updating the number of sites
• Defining permitted ‘usual ICS/LABA combinations’
The endpoint associated with Inhaler Correct Use has been further defined.
The objective and associated endpoint of adherence with study medication has been amended to compliance with study medication.
Mepolizumab (Nucala®) has been added as a prohibited medication at screening and during the study.
The option to rescreen a participant following approval by the medical monitor has been added.
The section describing planned dose adjustments has been updated to clarify that dose increases are permitted but switching between treatments is not permitted, in accordance with the intention of the protocol.
It has been clarified that GSK will not provide treatment following the study.
The T&E table has been updated to reflect that Screening, Visit 6 and Withdrawal Visit should be logged on RAMOS NG. This was previously omitted in error.
The description of the Per Protocol Population has been updated to reflect terminology now used as standard at GSK.
Other minor corrections and edits have been made. |
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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 |