Clinical Trial Results:
A single centre, randomised, double-blind, double-dummy, 2-way cross over study to compare safety assessed by knemometry and urinary cortisol measurements of CHF1535 50/6 pMDI (fixed combination of beclomethasone dipropionate and formoterol fumarate) and the free combination of licensed beclomethasone dipropionate and formoterol fumarate in asthmatic children already treated with inhaled corticosteroids.
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Summary
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EudraCT number |
2010-023637-29 |
Trial protocol |
DK |
Global end of trial date |
18 Nov 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Jul 2016
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First version publication date |
29 Jul 2016
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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 |
CCD-1012-PR-0051
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01450774 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Chiesi Farmaceutici S.p.A
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Sponsor organisation address |
Via Palermo, 26/A, Parma, Italy, 43126
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Public contact |
Chiesi Clinical Trials, Chiesi Farmaceutici S.p.A, clinicaltrials_info@chiesi.com
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Scientific contact |
Chiesi Clinical Trials, Chiesi Farmaceutici S.p.A, clinicaltrials_info@chiesi.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-000548-PIP01-09 | ||
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 |
18 Nov 2013
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
18 Nov 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Nov 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 that the fixed combination CHF 1535 50/6μg (CHF 1535) pMDI, 2 inhalations twice a day (bid), using AeroChamber Plus™ spacer device is non-inferior to a corresponding free combination (CHF 1535+FF) of BDP 50μg pMDI, 2 inhalations bid plus FF 6μg pMDI, 2 inhalations bid, using AeroChamber Plus™ spacer device in terms of lower leg growth rate (LLGR), measured by knemometry, over a 2-week treatment period.
Cross-over part of the study: 2 treatments (each part 2 weeks), wash-out (2 weeks); follow-up (2 weeks).
Study visits: V0 (pre-screening), V1 (screening), V2 (randomization, start treatment 1), V3 (end treatment 1), V4 (start treatment 2) , V5 (end treatment 2), follow-up.
BDP: beclomethasone dipropionate
bid: twice daily
CHF 1535: CHF 1535 50/6μg; fixed combination of BDP and FF
CHF 1535+FF: free combination of BDP and FF
FF: formoterol fumarate
LLGR: lower leg growth rate
pMDI: pressurised metered dose inhaler
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Protection of trial subjects |
The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practices (GCP) guidelines and local law requirements. Other than routine care, no other specific measures for protection of trial subjects were implemented.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
19 Sep 2011
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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: 62
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Worldwide total number of subjects |
62
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EEA total number of subjects |
62
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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) |
62
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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 |
Overall, 72 patients were screened; of these 62 patients were randomized. | |||||||||||||||||||||
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Pre-assignment
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Screening details |
Following a pre-screening and screening visit, eligible patients entered a 2-week placebo run-in period and training. | |||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial by sequence (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 | |||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Sequence A -- B | |||||||||||||||||||||
Arm description |
Treatment A: CHF 1535 50/6 μg pMDI with AeroChamber Plus™ spacer device = fixed dose combination. CHF 1535 50/6 μg pMDI (fixed combination of extrafine BDP 50 μg + FF 6 μg / metered dose) with AeroChamber Plus™ spacer device. Double dummy administration: 2 puffs every morning and evening from each inhaler with the spacer device for 2 weeks: # 2 inhalations b.i.d. of CHF 1535 50/6 μg pMDI # 2 inhalations b.i.d of placebo pMDI THEN CROSSOVER Treatment B: Free combination of extrafine BDP 50 μg pMDI with AeroChamber Plus™ spacer device plus FF 6 μg pMDI with AeroChamber Plus™ spacer device. Total daily dose: BDP 200 μg + FF 24 μg Double dummy administration: two puffs every morning and evening from each inhaler with the spacer device for 2 weeks: # 2 inhalations b.i.d. of extrafine BDP 50 μg pMDI # 2 inhalations b.i.d. of FF 6 μg pMDI | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
CHF 1535 50μg/6μg pMDI with AeroChamber Plus™ spacer device
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Investigational medicinal product code |
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Other name |
Treatment A, fixed dose combination
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Respiratory use
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Dosage and administration details |
Treatment A: CHF 1535 50μg/6 μg pMDI with AeroChamber Plus™ spacer device = fixed dose combination.
CHF 1535 50μg/6 μg pMDI (fixed combination of extrafine BDP 50 μg with FF 6 μg / metered dose) with AeroChamber Plus™ spacer device; double dummy administration.
Total daily dose: BDP 200 μg/FF 24 μg
2 puffs every morning and evening via inhaler with the spacer device for 2 weeks
- 2 inhalations b.i.d. of CHF 1535 50μg/6 μg pMDI
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Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Respiratory use
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Dosage and administration details |
2 puffs of placebo pMDI every morning and evening via inhaler with the spacer device for 2 weeks.
- 2 inhalations b.i.d of placebo pMDI
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Investigational medicinal product name |
Beclomethasone Dipropionate (BDP)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Respiratory use
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Dosage and administration details |
Double dummy administration: two puffs every morning and evening from each inhaler with the spacer device for two weeks.
2 inhalations b.i.d. of BDP 50 μg pMDI
BDP=Beclomethasone Dipropionate
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Investigational medicinal product name |
Formoterol Fumarate (FF)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Respiratory use
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Dosage and administration details |
Double dummy administration: two puffs every morning and evening from each inhaler with the spacer device for two weeks.
2 inhalations b.i.d. of FF 6 μg pMDI
FF=Formoterol Fumarate
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Arm title
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Sequence B -- A | |||||||||||||||||||||
Arm description |
Treatment B: Free combination of extrafine BDP 50 μg pMDI with AeroChamber Plus™ spacer device plus FF 6 μg pMDI with AeroChamber Plus™ spacer device. Total daily dose: BDP 200 μg + FF 24 μg Double dummy administration: two puffs every morning and evening from each inhaler with the spacer device for 2 weeks: # 2 inhalations b.i.d. of extrafine BDP 50 μg pMDI # 2 inhalations b.i.d. of FF 6 μg pMDI THEN CROSSOVER Treatment A: CHF 1535 50/6 μg pMDI with AeroChamber Plus™ spacer device = fixed dose combination. CHF 1535 50/6 μg pMDI (fixed combination of extrafine BDP 50 μg + FF 6 μg / metered dose) with AeroChamber Plus™ spacer device. Double dummy administration: 2 puffs every morning and evening from each inhaler with the spacer device for 2 weeks: # 2 inhalations b.i.d. of CHF 1535 50/6 μg pMDI # 2 inhalations b.i.d of placebo pMDI | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Beclomethasone Dipropionate (BDP)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Respiratory use
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Dosage and administration details |
Double dummy administration: two puffs every morning and evening from each inhaler with the spacer device for two weeks.
2 inhalations b.i.d. of BDP 50 μg pMDI
BDP=Beclomethasone Dipropionate
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Investigational medicinal product name |
Formoterol Fumarate (FF)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Respiratory use
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Dosage and administration details |
Double dummy administration: two puffs every morning and evening from each inhaler with the spacer device for two weeks.
2 inhalations b.i.d. of FF 6 μg pMDI
FF=Formoterol Fumarate
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Investigational medicinal product name |
CHF 1535 50/6 μg pMDI with AeroChamber Plus™ spacer device
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Investigational medicinal product code |
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Other name |
CHF 1535 50/6 μg pMDI with AeroChamber Plus™ spacer device = fixed dose combination
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Respiratory use
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Dosage and administration details |
Treatment A: CHF 1535 50/6 μg pMDI with AeroChamber Plus™ spacer device = fixed dose combination.
CHF 1535 50/6 μg pMDI (fixed combination of extrafine BDP 50 μg + FF 6 μg / metered dose) with AeroChamber Plus™ spacer device.
Total daily dose: BDP 200 μg/FF 24 μg
Double dummy administration: 2 puffs every morning and evening from each inhaler with the spacer device for two weeks.
- 2 inhalations b.i.d of BDP placebo pMDI
- 2 inhalations b.i.d. of CHF 1535 50/6 μg pMDI
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Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Respiratory use
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Dosage and administration details |
2 puffs of placebo pMDI every morning and evening via inhaler with the spacer device for 2 weeks.
- 2 inhalations b.i.d of placebo pMDI
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Baseline characteristics reporting groups
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Reporting group title |
Sequence A -- B
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Reporting group description |
Treatment A: CHF 1535 50/6 μg pMDI with AeroChamber Plus™ spacer device = fixed dose combination. CHF 1535 50/6 μg pMDI (fixed combination of extrafine BDP 50 μg + FF 6 μg / metered dose) with AeroChamber Plus™ spacer device. Double dummy administration: 2 puffs every morning and evening from each inhaler with the spacer device for 2 weeks: # 2 inhalations b.i.d. of CHF 1535 50/6 μg pMDI # 2 inhalations b.i.d of placebo pMDI THEN CROSSOVER Treatment B: Free combination of extrafine BDP 50 μg pMDI with AeroChamber Plus™ spacer device plus FF 6 μg pMDI with AeroChamber Plus™ spacer device. Total daily dose: BDP 200 μg + FF 24 μg Double dummy administration: two puffs every morning and evening from each inhaler with the spacer device for 2 weeks: # 2 inhalations b.i.d. of extrafine BDP 50 μg pMDI # 2 inhalations b.i.d. of FF 6 μg pMDI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sequence B -- A
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Reporting group description |
Treatment B: Free combination of extrafine BDP 50 μg pMDI with AeroChamber Plus™ spacer device plus FF 6 μg pMDI with AeroChamber Plus™ spacer device. Total daily dose: BDP 200 μg + FF 24 μg Double dummy administration: two puffs every morning and evening from each inhaler with the spacer device for 2 weeks: # 2 inhalations b.i.d. of extrafine BDP 50 μg pMDI # 2 inhalations b.i.d. of FF 6 μg pMDI THEN CROSSOVER Treatment A: CHF 1535 50/6 μg pMDI with AeroChamber Plus™ spacer device = fixed dose combination. CHF 1535 50/6 μg pMDI (fixed combination of extrafine BDP 50 μg + FF 6 μg / metered dose) with AeroChamber Plus™ spacer device. Double dummy administration: 2 puffs every morning and evening from each inhaler with the spacer device for 2 weeks: # 2 inhalations b.i.d. of CHF 1535 50/6 μg pMDI # 2 inhalations b.i.d of placebo pMDI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Sequence A -- B
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Reporting group description |
Treatment A: CHF 1535 50/6 μg pMDI with AeroChamber Plus™ spacer device = fixed dose combination. CHF 1535 50/6 μg pMDI (fixed combination of extrafine BDP 50 μg + FF 6 μg / metered dose) with AeroChamber Plus™ spacer device. Double dummy administration: 2 puffs every morning and evening from each inhaler with the spacer device for 2 weeks: # 2 inhalations b.i.d. of CHF 1535 50/6 μg pMDI # 2 inhalations b.i.d of placebo pMDI THEN CROSSOVER Treatment B: Free combination of extrafine BDP 50 μg pMDI with AeroChamber Plus™ spacer device plus FF 6 μg pMDI with AeroChamber Plus™ spacer device. Total daily dose: BDP 200 μg + FF 24 μg Double dummy administration: two puffs every morning and evening from each inhaler with the spacer device for 2 weeks: # 2 inhalations b.i.d. of extrafine BDP 50 μg pMDI # 2 inhalations b.i.d. of FF 6 μg pMDI | ||
Reporting group title |
Sequence B -- A
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Reporting group description |
Treatment B: Free combination of extrafine BDP 50 μg pMDI with AeroChamber Plus™ spacer device plus FF 6 μg pMDI with AeroChamber Plus™ spacer device. Total daily dose: BDP 200 μg + FF 24 μg Double dummy administration: two puffs every morning and evening from each inhaler with the spacer device for 2 weeks: # 2 inhalations b.i.d. of extrafine BDP 50 μg pMDI # 2 inhalations b.i.d. of FF 6 μg pMDI THEN CROSSOVER Treatment A: CHF 1535 50/6 μg pMDI with AeroChamber Plus™ spacer device = fixed dose combination. CHF 1535 50/6 μg pMDI (fixed combination of extrafine BDP 50 μg + FF 6 μg / metered dose) with AeroChamber Plus™ spacer device. Double dummy administration: 2 puffs every morning and evening from each inhaler with the spacer device for 2 weeks: # 2 inhalations b.i.d. of CHF 1535 50/6 μg pMDI # 2 inhalations b.i.d of placebo pMDI | ||
Subject analysis set title |
Subjects who received CHF 1535 50/6 µg treatment
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All randomized subjects who received at least one administration of the treatment (CHF 1535).
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Subject analysis set title |
Subjects who received BDP+FF treatment
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All randomized subjects who received at least one administration of the treatment (BDP+FF).
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Subject analysis set title |
Subjects who received placebo during the run-in phase
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All randomized subjects who received at least one administration of the placebo during the run-in phase.
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End point title |
1_Lower Leg Growth Rate (LLGR) comparison of active treatments | ||||||||||||||||
End point description |
The primary safety endpoint was the Lower Leg Growth Rate (LLGR) after 2-week treatment with active drug. Comparison was made between the active treatments i.e. fixed combination (CHF 1535 50/6 µg) and the free combination (BDP+FF).
LLGR = Lower Leg Growth Rate
BDP = Beclomethasone dipropionate
FF=Formoterol fumarate
CHF 1535 50/6 µg=Fixed combination of BDP and FF
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End point type |
Primary
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End point timeframe |
After treatment with CHF 1535 50/6 µg (fixed dose combination ) and BDP+FF (free dose combination); each treatment was for 2 weeks.
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| Notes [1] - Safety analysis population [2] - Safety analysis population [3] - Safety analysis population |
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Statistical analysis title |
Difference in LLGR between active treatments | ||||||||||||||||
Statistical analysis description |
The Lower Leg Growth Rate (LLGR) after 2 weeks of treatment was compared between the active treatments, using an analysis of co-variance (ANCOVA). The model included the treatment and period as fixed effects, subject as random effect, and baseline LLGR as co-variable.
Cross-over study, groups examined should not be added up. The number N=119 (subjects in this analysis set) is an innate error of the EudraCT database system.
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Comparison groups |
Subjects who received CHF 1535 50/6 µg treatment v Subjects who received BDP+FF treatment
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Number of subjects included in analysis |
119
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [4] | ||||||||||||||||
P-value |
= 0.073 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
Least Square Means | ||||||||||||||||
Point estimate |
-0.173
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.363 | ||||||||||||||||
upper limit |
0.017 | ||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.09
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| Notes [4] - Non-inferiority testing, comparing the lower confidence limit with greater than or equal to -0.20 mm/week. Point estimate represents Least Square (LS) adjusted mean. |
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Statistical analysis title |
Difference in LLGR CHF 1535 50/6 µg - Placebo | ||||||||||||||||
Statistical analysis description |
The Lower Leg Growth Rate (LLGR) after 2 weeks of treatment was compared between the CHF 1535 50/6 µg - Placebo. Results from ANOVA with treatment (Placebo, CHF 1535 50/6 µg, BDP+FF) as fixed effect, subject as random effect.
Cross-over study, groups examined should not be added up. The number N=122 (subjects in this analysis set) is an innate error of the EudraCT database system.
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Comparison groups |
Subjects who received CHF 1535 50/6 µg treatment v Subjects who received placebo during the run-in phase
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Number of subjects included in analysis |
122
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Analysis specification |
Pre-specified
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Analysis type |
superiority [5] | ||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Least Square Means | ||||||||||||||||
Point estimate |
-0.346
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.527 | ||||||||||||||||
upper limit |
-0.165 | ||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.09
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| Notes [5] - Point estimate represents Least Square (LS) adjusted mean. |
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Statistical analysis title |
Difference in LLGR BDP+FF - Placebo | ||||||||||||||||
Statistical analysis description |
The Lower Leg Growth Rate (LLGR) after 2 weeks of treatment was compared between the BDP+FF - Placebo. Results from ANOVA with treatment (Placebo, CHF 1535 50/6 µg, BDP+FF) as fixed effect, subject as random effect.
Cross-over study, groups examined should not be added up. The number N=121 (subjects in this analysis set) is an innate error of the EudraCT database system.
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Comparison groups |
Subjects who received placebo during the run-in phase v Subjects who received BDP+FF treatment
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Number of subjects included in analysis |
121
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Analysis specification |
Pre-specified
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Analysis type |
superiority [6] | ||||||||||||||||
P-value |
= 0.066 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Least Square Means | ||||||||||||||||
Point estimate |
-0.171
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.352 | ||||||||||||||||
upper limit |
0.011 | ||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.09
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| Notes [6] - Point estimate represents Least Square (LS) adjusted mean. |
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End point title |
2_24-h Urinary Free Cortisol (UFC) corrected for creatinine; active treatments | ||||||||||||
End point description |
Determine 24-h urinary free cortisol (UFC), corrected for creatinine (ratio cortisol/creatinine).
Comparison was made for this parameter between the active treatments, considering the change in UFC between the start and end of each treatment (2 weeks).
Patients collected urine over 24 h to measure free cortisol and creatinine on the day before and after 2 weeks of active treatment (free combination CHF 1535 and fixed combination BDP+FF). The urine collection started in the morning at the time when the patient woke up and ended in the morning of the following day, at the time when the patient woke up.
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End point type |
Secondary
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||||||||||||
End point timeframe |
After treatment with CHF 1535 50/6 µg (fixed dose combination) and BDP+FF (free dose combination); each treatment was for 2 weeks.
|
||||||||||||
|
|||||||||||||
| Notes [7] - Safety analysis population [8] - Safety analysis population |
|||||||||||||
Statistical analysis title |
24-h UFC (corrected) comparison active treatments | ||||||||||||
Statistical analysis description |
Comparison of 24-h urinary free cortisol (UFC), corrected for creatinine, between the start vs end of each active treatments after 2 weeks.
|
||||||||||||
Comparison groups |
Subjects who received CHF 1535 50/6 µg treatment v Subjects who received BDP+FF treatment
|
||||||||||||
Number of subjects included in analysis |
93
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
non-inferiority [9] | ||||||||||||
P-value |
= 0.5738 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Log ratio | ||||||||||||
Point estimate |
1.059
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.862 | ||||||||||||
upper limit |
1.302 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.11
|
||||||||||||
| Notes [9] - Comparison of data for 24-h UFC levels (corrected for creatinine); change after treatment with CHF 1535 (fixed combination) and with BDP+FF (free combination) was evaluated using an ANCOVA model with treatment and period as fixed effects, subject as a random effect, and the baseline (run-in) 24-h UFC/creatinine as covariates. Cross-over study, groups examined should not be added. The number N=93 (subjects in this analysis set) is an innate error of the EudraCT. |
|||||||||||||
|
|||||||||||||||||
End point title |
3_24-h Urinary Free Cortisol (UFC) corrected for creatinine; active treatment vs placebo | ||||||||||||||||
End point description |
24-hour urinary free cortisol (UFC) levels (corrected for creatinine), at the end of the active treatment phase, compared with UFC (corrected for creatinine), at the end of the placebo run-in, training phase.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
After treatment with CHF 1535 50/6 µg (fixed dose combination ) and BDP+FF (free dose combination); each treatment was for 2 weeks.
|
||||||||||||||||
|
|||||||||||||||||
| Notes [10] - Safety analysis population [11] - Safety analysis population [12] - Safety analysis population |
|||||||||||||||||
Statistical analysis title |
24-h UFC (cor) CHF 1535 50/6 µg vs Placebo run-in | ||||||||||||||||
Statistical analysis description |
24-h UFC levels (corrected for creatinine ), after active treatment CHF 1535 50/6 µg compared with the 24-h UFC levels (corrected for creatinine), after Placebo (run-in, training time).
Cross-over study, groups examined should not be added up. The number N=108 (subjects in this analysis set) is an innate error of the EudraCT database system.
|
||||||||||||||||
Comparison groups |
Subjects who received CHF 1535 50/6 µg treatment v Subjects who received placebo during the run-in phase
|
||||||||||||||||
Number of subjects included in analysis |
108
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [13] | ||||||||||||||||
P-value |
= 0.5307 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Log ratio | ||||||||||||||||
Point estimate |
0.943
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.785 | ||||||||||||||||
upper limit |
1.134 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
1.1
|
||||||||||||||||
| Notes [13] - The comparison of the 24-h UFC (corrected for creatinine) excretion of each of the two active treatments with placebo was done using an analysis of variance (ANOVA) with treatment (CHF 1535 and placebo run-in, training time) as fixed effect and subject as random effect. |
|||||||||||||||||
Statistical analysis title |
24-h UFC (corr) BDP+FF vs Placebo run-in | ||||||||||||||||
Statistical analysis description |
24-h UFC, corrected for creatinine ratio levels, after active treatment BDP+FF compared with the 24-h UFC corrected for creatinine ratio levels, after Placebo (run-in, training time).
Cross-over study, groups examined should not be added up. The number N=106 (subject analysis set) is an innate error of the EudraCT database system.
|
||||||||||||||||
Comparison groups |
Subjects who received BDP+FF treatment v Subjects who received placebo during the run-in phase
|
||||||||||||||||
Number of subjects included in analysis |
106
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [14] | ||||||||||||||||
P-value |
= 0.1381 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Log ratio | ||||||||||||||||
Point estimate |
0.867
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.718 | ||||||||||||||||
upper limit |
1.048 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
1.1
|
||||||||||||||||
| Notes [14] - The comparison of the 24-h UFC/creatinine ratio excretion of each of the two active treatments with placebo was done using an analysis of variance (ANOVA) with treatment (BDP+FF and run-in placebo) as fixed effect and subject as random effect. |
|||||||||||||||||
|
||||||||||
End point title |
4_Incidence of adverse events during active treatment | |||||||||
End point description |
The incidence of adverse events (AEs) was presented with descriptive statistics. Information was collected on treatment-emergent AEs (TEAEs), adverse drug reactions (ADRs), serious adverse events (SAEs) (if any), Serious adverse drug reaction (SADRs) (if any), and AEs leading to study withdrawal (if any).
A TEAE was defined as any AE with onset at or after first study drug administration. If the time of onset of AE was missing and the start date of the AE was on the day of first study drug administration, this AE was considered as treatment-emergent.
AEs starting in the wash-out phase or follow-up period were considered TEAEs. AEs starting during the wash-out phase were accounted to preceding phase with active treatment and AEs starting during follow-up time were accounted to preceding phase with active treatment.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
After treatment with CHF 1535 50/6 µg (fixed dose combination ) and BDP+FF (free dose combination); each treatment was for 2 weeks.
|
|||||||||
|
||||||||||
| Notes [15] - Safety analysis population [16] - Safety analysis population |
||||||||||
| No statistical analyses for this end point | ||||||||||
|
|||||||||||||
End point title |
5_Heart rate change between start and end of active treatment | ||||||||||||
End point description |
Heart rate was recorded during the treatment period and the changes within each treatment period were summarised with descriptive statistics by treatment group.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
After treatment with CHF 1535 50/6 µg (fixed dose combination) and BDP+FF (free dose combination); each treatment was for 2 weeks.
|
||||||||||||
|
|||||||||||||
| Notes [17] - Safety analysis population [18] - Safety analysis population |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||
End point title |
6_Mean expiratory flow (PEF) active treatment, change from baseline | ||||||||||||||||||
End point description |
Peak expiratory flow (PEF) in L/min was measured twice daily (in the morning and in the evening) and documented in the patient’s diary. The morning and evening mean daily PEF shown as change from baseline, during the baseline (placebo, run-in phase) and during the active treatment phase.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
After 2 weeks of baseline (placebo run-in phase), after 2 weeks of treatment phase with CHF 1535 50/6 µg, and after 2 weeks of treatment phase with BDP+FF.
INPUT needed from Chiesi stats. - please check whether OK to use only overall means;
|
||||||||||||||||||
|
|||||||||||||||||||
| Notes [19] - Intention-to-treat analysis population [20] - Intention-to-treat analysis population |
|||||||||||||||||||
Statistical analysis title |
PEF morning treatment difference | ||||||||||||||||||
Statistical analysis description |
Mean change from baseline in PEF (morning); treatment difference CHF 1535 50/6 µg - BDP+FF.
Cross-over study, groups examined should not be added. The number N=120 (subject in this analysis set) is an innate error of the EudraCT database system.
|
||||||||||||||||||
Comparison groups |
Subjects who received CHF 1535 50/6 µg treatment v Subjects who received BDP+FF treatment
|
||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
non-inferiority [21] | ||||||||||||||||||
P-value |
= 0.647 | ||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||
Parameter type |
LS adjusted mean | ||||||||||||||||||
Point estimate |
1.852
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
95% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
-6.209 | ||||||||||||||||||
upper limit |
9.913 | ||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||
Dispersion value |
4.02
|
||||||||||||||||||
| Notes [21] - Results from ANCOVA with treatment (CHF 1535 50/6 µg, BDP+FF) and period as fixed effects, subject as random effect and baseline. Change from baseline. Intention-to-treat analysis population. Cross-over study, groups examined should not be added. The number N=120 (subjects in this analysis set) is an innate error of the EudraCT database system. |
|||||||||||||||||||
Statistical analysis title |
PEF evening treatment difference | ||||||||||||||||||
Statistical analysis description |
Mean change from baseline in PEF (evening); treatment difference CHF1535 - BDP+FF.
Cross-over study, groups examined should not be added. The number N=120 (subjects in this analysis set) is an innate error of the EudraCT database system.
|
||||||||||||||||||
Comparison groups |
Subjects who received BDP+FF treatment v Subjects who received CHF 1535 50/6 µg treatment
|
||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
non-inferiority [22] | ||||||||||||||||||
P-value |
= 0.843 | ||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||
Parameter type |
LS adjusted mean | ||||||||||||||||||
Point estimate |
0.826
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
95% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
-7.483 | ||||||||||||||||||
upper limit |
9.135 | ||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||
Dispersion value |
4.15
|
||||||||||||||||||
| Notes [22] - Results from ANCOVA with treatment (CHF 1535, BDP+FF) and period as fixed effects, subject as random effect and baseline. Change from baseline. Intention-to-treat analysis population. |
|||||||||||||||||||
|
||||||||||||||||||||||
End point title |
7_Overall asthma symptom score, active treatment, change from baseline | |||||||||||||||||||||
End point description |
Change in overall asthma symptom score. Data are presented as the overall asthma symptom score, for the daytime (evening measurement), nighttime (morning measurement), and whole day. Comparison was made between active treatments CHF 1535 50/6 µg vs BDP+FF from baseline (run-in, training to the last visit of treatment period 2). The asthma scores is presented as descriptive measures.
Asthma symptoms were recorded twice daily during the run-in, active treatment , and during the wash-out. Asthma symptoms were assessed as cough, wheeze, chest tightness, breathlessness, and overall. The scores were evaluated on a scale from 0 (none) to 3 (severe).
The mean daily asthma scores for each symptom (daytime, nighttime, overall=defined as the average of the morning and evening score) averaged over all days of the run-in period and of the 2-week treatment periods (also wash out period).
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
The patient was required to complete a diary card daily from screening to the last visit of treatment 2.
|
|||||||||||||||||||||
|
||||||||||||||||||||||
| Notes [23] - Intention-to-treat-population [24] - Intention-to-treat-population |
||||||||||||||||||||||
Statistical analysis title |
Asthma score (difference btw treatments) daytime | |||||||||||||||||||||
Statistical analysis description |
Results from ANCOVA with treatment (CHF 1535 50/6 µg, BDP+FF) and period as fixed effects, subject as random effect and baseline score as covariable. The average score of the run-in period is used as baseline for active treatment phase 1 and the average score of the wash out period is used as the baseline for active treatment phase 2.
Cross-over study, groups examined should not be added up. The number N=120 (subjects in this analysis set) is an innate error of the EudraCT database system.
|
|||||||||||||||||||||
Comparison groups |
Subjects who received CHF 1535 50/6 µg treatment v Subjects who received BDP+FF treatment
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
non-inferiority [25] | |||||||||||||||||||||
P-value |
= 0.146 | |||||||||||||||||||||
Method |
ANCOVA | |||||||||||||||||||||
Parameter type |
LS adjusted mean | |||||||||||||||||||||
Point estimate |
-0.111
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.262 | |||||||||||||||||||||
upper limit |
0.04 | |||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||
Dispersion value |
0.08
|
|||||||||||||||||||||
| Notes [25] - Daytime Results from ANCOVA with treatment (CHF1535 50/6 µg, BDP+FF) and period as fixed effects, subject as random effect and baseline score as covariable. The average score of the run-in is used as baseline for period 1 and the average score of the wash out period is used as the baseline for period 2. |
||||||||||||||||||||||
Statistical analysis title |
Asthma score (difference btw treatments) nighttime | |||||||||||||||||||||
Statistical analysis description |
Results from ANCOVA with treatment (CHF 1535, BDP+FF) and period as fixed effects, subject as random effect and baseline score as covariable. The average score of the run-in period is used as baseline for active treatment phase 1 and the average score of the wash out period is used as the baseline for active treatment phase 2.
Cross-over study, groups examined should not be added up. The number N=120 (subjects in this analysis set) is an innate error of the EudraCT database system.
|
|||||||||||||||||||||
Comparison groups |
Subjects who received CHF 1535 50/6 µg treatment v Subjects who received BDP+FF treatment
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
non-inferiority [26] | |||||||||||||||||||||
P-value |
= 0.247 | |||||||||||||||||||||
Method |
ANCOVA | |||||||||||||||||||||
Parameter type |
LS mean adjusted | |||||||||||||||||||||
Point estimate |
-0.09
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.243 | |||||||||||||||||||||
upper limit |
0.064 | |||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||
Dispersion value |
0.08
|
|||||||||||||||||||||
| Notes [26] - Nighttime Results from ANCOVA with treatment (CHF1535, BDP+FF) and period as fixed effects, subject as random effect and baseline score as covariable. The average score of the run-in is used as baseline for period 1 and the average score of the wash out period is used as the baseline for period 2. |
||||||||||||||||||||||
Statistical analysis title |
Asthma score (difference btw treatments) whole day | |||||||||||||||||||||
Statistical analysis description |
Results from ANCOVA with treatment (CHF 1535, BDP+FF) and period as fixed effects, subject as random effect and baseline score as covariable. The average score of the run-in period is used as baseline for active treatment phase 1 and the average score of the wash out period is used as the baseline for active treatment phase 2.
Cross-over study, groups examined should not be added up. The number N=120 (subjects in this analysis set) is an innate error of the EudraCT database system.
|
|||||||||||||||||||||
Comparison groups |
Subjects who received CHF 1535 50/6 µg treatment v Subjects who received BDP+FF treatment
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
non-inferiority [27] | |||||||||||||||||||||
P-value |
= 0.183 | |||||||||||||||||||||
Method |
ANCOVA | |||||||||||||||||||||
Parameter type |
LS adjusted mean | |||||||||||||||||||||
Point estimate |
-0.104
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.259 | |||||||||||||||||||||
upper limit |
0.051 | |||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||
Dispersion value |
0.08
|
|||||||||||||||||||||
| Notes [27] - Whole day Results from ANCOVA with treatment (CHF1535, BDP+FF) and period as fixed effects, subject as random effect and baseline score as covariable. The average score of the run-in is used as baseline for period 1 and the average score of the wash out period is used as the baseline for period 2. |
||||||||||||||||||||||
|
|||||||||||||
End point title |
8_Change in FEV1 active treatment, change from baseline | ||||||||||||
End point description |
Measurement of forced expiratory volume in 1 second (FEV1) in liters (L) was performed at each study visit.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
After treatment with CHF 1535 50/6 µg (fixed dose combination ) and BDP+FF (free dose combination); each treatment was for 2 weeks.
|
||||||||||||
|
|||||||||||||
| Notes [28] - Intention-to-treat population [29] - Intention-to-treat population |
|||||||||||||
Statistical analysis title |
FEV1 treatment difference | ||||||||||||
Statistical analysis description |
Mean change from baseline in FEV1; treatment difference CHF 1535 50/6 µg - BDP+FF.
Cross-over study, groups examined should not be added. The number N=107 (subjects in this analysis set) is an innate error of the EudraCT database system.
|
||||||||||||
Comparison groups |
Subjects who received CHF 1535 50/6 µg treatment v Subjects who received BDP+FF treatment
|
||||||||||||
Number of subjects included in analysis |
107
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
non-inferiority [30] | ||||||||||||
P-value |
= 0.893 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS adjusted mean | ||||||||||||
Point estimate |
0.004
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.056 | ||||||||||||
upper limit |
0.064 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.03
|
||||||||||||
| Notes [30] - Results from ANCOVA with treatment (CHF1535 50/6 µg, BDP+FF) and period as fixed effects, subject as random effect and pre-dose FEV1 values at visit 2 for period 1 and at visit 4 for period 2 as covariable. Change from baseline. Treatment difference CHF 1535 50/6 µg - BDP+FF. Intention-to-treat analysis population. |
|||||||||||||
|
|||||||||||||
End point title |
9_Change in forced vital capacity (FVC) active treatment, change from baseline | ||||||||||||
End point description |
Measurement of Forced vital capacity (FVC) in liters (L) was performed at each study visit.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
After treatment with CHF 1535 50/6 µg (fixed dose combination ) and BDP+FF (free dose combination); each treatment was for 2 weeks.
|
||||||||||||
|
|||||||||||||
| Notes [31] - Intention-to-treat population [32] - Intention-to-treat population |
|||||||||||||
Statistical analysis title |
FVC treatment difference | ||||||||||||
Statistical analysis description |
Mean change from baseline in FVC; treatment difference CHF 1535 50/6 µg - BDP+FF.
Cross-over study, groups examined should not be added. The number N=121 (subjects in this analysis set) is an innate error of the EudraCT database system.
|
||||||||||||
Comparison groups |
Subjects who received CHF 1535 50/6 µg treatment v Subjects who received BDP+FF treatment
|
||||||||||||
Number of subjects included in analysis |
107
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
non-inferiority [33] | ||||||||||||
P-value |
= 0.275 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS mean adjusted | ||||||||||||
Point estimate |
-0.036
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.103 | ||||||||||||
upper limit |
0.03 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.03
|
||||||||||||
| Notes [33] - Results from ANCOVA with treatment (CHF1535 50/6 µg, BDP+FF) and period as fixed effects, subject as random effect and pre-dose FVC values at visit 2 for period 1 and at visit 4 for period 2 as covariable. Change from baseline. Treatment difference CHF 1535 50/6 µg - BDP+FF. Intention-to-treat analysis population. |
|||||||||||||
|
|||||||||||||
End point title |
10_Days of use of rescue medication, comparison of active treatments | ||||||||||||
End point description |
Intake of rescue medication was analysed descriptively, collecting information per treatment group.
Comparison was made for the time when active treatments were administered (2 weeks).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
After treatment with CHF 1535 50/6 μg (fixed dose combination) and BDP+FF (free dose combination);
each treatment was for 2 weeks.
|
||||||||||||
|
|||||||||||||
| Notes [34] - Safety analysis population [35] - Safety analysis population |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||||||||||||||||||||
|
Adverse events information
|
||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
For the overall duration of the study (from screening to the end of follow-up).
|
|||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Patients entered a 2-week placebo run-in period, including a training period. The cross-over part of the study was: 2 treatment periods of 2 weeks, each separated by a wash-out period of 2 weeks. Study visits were at start and end of each treatment period. A follow-up phone call was performed 2 weeks after the last visit to monitor unresolved AEs.
|
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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 |
14
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Reporting groups
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Reporting group title |
CHF 1535
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Reporting group description |
For this reporting group, the Subjects affected by non-serious adverse events is 25 instead of 23. Due to an ERROR of the system this value couldn't be entered successfully. Therefore the correct ratio: Total subjects affected by non-serious adverse events / subject exposed is 25/61 is 41% | |||||||||||||||||||||||||||||||||
Reporting group title |
BDP+FF
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Reporting group description |
- | |||||||||||||||||||||||||||||||||
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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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07 May 2012 |
The planned end date of the study was postponed from March 2012 to January 2014 due to the low recruitment.
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12 Apr 2013 |
An amendment to the Investigational Medicinal Product Dossier (approved on 07 March 2013) included an update of the placebo shelf-life according to the updated stability data of the active product BDP pMDI. The new proposed shelf-life was 36 months below 25°C instead of previously 30°C. The changes were applied to the batches used to prepare the study kits produced from March 2013. |
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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. | |||
