Clinical Trial Results:
Does a low exhaled Nitric Oxide level exclude a clinical benefit from inhaled corticosteroids in suspected asthma; a double-blind, randomised, placebo controlled trial.
Summary
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EudraCT number |
2016-000338-23 |
Trial protocol |
GB |
Global end of trial date |
22 Jun 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
17 Nov 2019
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First version publication date |
17 Nov 2019
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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 |
16013
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02771717 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
University of Nottingham
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Sponsor organisation address |
Jubilee Campus, Triumph Road, Nottingham, United Kingdom, NG8 1DH
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Public contact |
Angela Shone, University of Nottingham, +44 1158467906, sponsor@nottingham.ac.uk
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Scientific contact |
Angela Shone, University of Nottingham, +44 1158467906, sponsor@nottingham.ac.uk
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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 |
25 Oct 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
22 Jun 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Jun 2018
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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 purpose of the study is to determine if a low exhaled nitric oxide level (<27ppb) is a good predictor of a negative clinical benefit from inhaled corticosteroids in patients with suspected asthma?
The primary objective is to determine if asthma symptoms, using the 7 point ACQ (Asthma Control Questionnaire), differ between the low dose inhaled steroid and placebo groups.
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Protection of trial subjects |
None applicable
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Background therapy |
None | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
22 Feb 2016
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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 |
United Kingdom: 180
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Worldwide total number of subjects |
180
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EEA total number of subjects |
180
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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) |
0
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Adults (18-64 years) |
156
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From 65 to 84 years |
24
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were recruited from 47 primary care practices across Nottinghamshire, Leicestershire and Derbyshire as well as from the Nottingham Respiratory Research database and from advertisements in the University of Nottingham and Nottingham University Hospitals between May 2016 and March 2018. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
236 patients were screened for entry, 180 were randomised. 56 participants failed screening; 45 patients were denied entry into the study due to FeNO levels greater than 27, 4 due to FEV1 less than 70%, 1 due to insufficient short-acting bronchodilator use,2 due to spirometry contraindications and 4 who withdrew consent prior to randomisation. | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Baseline
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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, Data analyst | ||||||||||||||||||||||||
Blinding implementation details |
Patients were randomized to treatment groups in blocks of eight with stratification according to their smoking status; current (or smoked within 12 months) or never/ex (never or quit more than one year ago). Allocation sequences were generated using a pseudo-random number generator (sealedenvelop.com). This sequence was linked to an electronic case report form (eCRF) where the participants’ study data was recorded. If the participants' study data was recorded.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Budesonide | ||||||||||||||||||||||||
Arm description |
Participants received200 mcg Budesonide (Pulmicort) via a Turbuhaler or placebo one puff twice daily. The total daily dose of budesonide was therefore 400 mcg per day. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Budesonide (Pulmicort)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Pressurised inhalation
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Routes of administration |
Inhalation use
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Dosage and administration details |
200 micrograms per inhalation
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Arm title
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Placebo | ||||||||||||||||||||||||
Arm description |
Placebo 200 mcg via a Turbuhaler or placebo one puff twice daily. | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
na
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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 |
200mcg per inhalation one puff twice daily
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Period 2
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Period 2 title |
End of Trial (12 weeks)
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Is this the baseline period? |
No | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Data analyst | ||||||||||||||||||||||||
Blinding implementation details |
Patients were randomized to treatment groups in blocks of eight with stratification according to their smoking status; current (or smoked within 12 months) or never/ex (never or quit more than one year ago). Allocation sequences were generated by the Respiratory Research Unit’s database manager using a pseudo-random number generator (sealedenvelop.com). This sequence was linked to an electronic case report form (eCRF) where the participants’ study data was recorded.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Budesonide | ||||||||||||||||||||||||
Arm description |
Participants received200 mcg Budesonide (Pulmicort) via a Turbuhaler or placebo one puff twice daily. The total daily dose of budesonide was therefore 400 mcg per day. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Budesonide (Pulmicort)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Pressurised inhalation
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Routes of administration |
Inhalation use
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Dosage and administration details |
200 micrograms per inhalation
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Arm title
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Placebo | ||||||||||||||||||||||||
Arm description |
Placebo 200 mcg via a Turbuhaler or placebo one puff twice daily. | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Budesonide (Pulmicort)
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Investigational medicinal product code |
19162
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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 |
200 mcg per inhalation one puff twice daily
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Baseline characteristics reporting groups
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Reporting group title |
Budesonide
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Reporting group description |
Participants received200 mcg Budesonide (Pulmicort) via a Turbuhaler or placebo one puff twice daily. The total daily dose of budesonide was therefore 400 mcg per day. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Placebo 200 mcg via a Turbuhaler or placebo one puff twice daily. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Budesonide
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Reporting group description |
Participants received200 mcg Budesonide (Pulmicort) via a Turbuhaler or placebo one puff twice daily. The total daily dose of budesonide was therefore 400 mcg per day. | ||
Reporting group title |
Placebo
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Reporting group description |
Placebo 200 mcg via a Turbuhaler or placebo one puff twice daily. | ||
Reporting group title |
Budesonide
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Reporting group description |
Participants received200 mcg Budesonide (Pulmicort) via a Turbuhaler or placebo one puff twice daily. The total daily dose of budesonide was therefore 400 mcg per day. | ||
Reporting group title |
Placebo
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Reporting group description |
Placebo 200 mcg via a Turbuhaler or placebo one puff twice daily. |
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End point title |
ACQ7 | ||||||||||||||||||||
End point description |
Statistical analysis of the primary outcome was assessed using a two one-sided equivalence test (TOST) conducted with a delta of 0.5, the widely validated minimal clinical difference in ACQ score, and a type 1 error rate of 0.05 (5 %).
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End point type |
Primary
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End point timeframe |
Baseline to end of study (12 weeks)
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Statistical analysis title |
Equivalence | ||||||||||||||||||||
Statistical analysis description |
Two One Sided Equivalence Test (TOST)
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Comparison groups |
Budesonide v Placebo v Budesonide v Placebo
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Number of subjects included in analysis |
314
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [1] | ||||||||||||||||||||
P-value |
< 0.0001 [2] | ||||||||||||||||||||
Method |
TOST | ||||||||||||||||||||
Parameter type |
TOST | ||||||||||||||||||||
Confidence interval |
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Notes [1] - Difference baseline to 12 weeks between active and placebo [2] - P values : <0.001, 0.0462 CI: -0.004 to 0.49 around the equivalence margin of -0.5 to 0.5 |
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End point title |
FEV1 | ||||||||||||||||||||
End point description |
Lung function as assessed by forced expiratory volume over one second where the minimum clinically significant improvement was 02 L from baseline to 12 weeks.
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End point type |
Secondary
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End point timeframe |
Baseline to end of study (12 weeks)
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Statistical analysis title |
TOST | ||||||||||||||||||||
Statistical analysis description |
Two One-Sided T-Test (TOST)
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Comparison groups |
Budesonide v Budesonide v Placebo v Placebo
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Number of subjects included in analysis |
314
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [3] | ||||||||||||||||||||
P-value |
< 0.001 [4] | ||||||||||||||||||||
Method |
TOST | ||||||||||||||||||||
Confidence interval |
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level |
90% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.06 | ||||||||||||||||||||
upper limit |
0.06 | ||||||||||||||||||||
Notes [3] - TOST for equivalence -0.2 to 0.2 [4] - P values: <0.0001, <0.0001 CI: -.0.6 to 0.06 |
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End point title |
LCQ | ||||||||||||||||||||
End point description |
LCQ possible scores ranged from 3-21 where 3 represented the worst cough and 21 was no cough. An increase of ≥ 1.3 was required for the difference to be considered clinically significant
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End point type |
Secondary
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End point timeframe |
Baseline to end of study ( 12 weeks)
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Statistical analysis title |
TOST | ||||||||||||||||||||
Statistical analysis description |
two one-sides t-test (TOST)
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Comparison groups |
Budesonide v Placebo v Budesonide v Placebo
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Number of subjects included in analysis |
314
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [5] | ||||||||||||||||||||
P-value |
= 0.0501 [6] | ||||||||||||||||||||
Method |
TOST | ||||||||||||||||||||
Confidence interval |
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level |
90% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-1.06 | ||||||||||||||||||||
upper limit |
1.31 | ||||||||||||||||||||
Notes [5] - equivalnce with delta -1.3 to 1.3 [6] - P values: =0.0235, =0.0501 CI: -1.06 to 1.31 |
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End point title |
MRC | ||||||||||||||||||||
End point description |
MRC assessed the level of perceived breathlessness on a 1-5 stage scale where any decrease in points was considered a clinically significant improvement.
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End point type |
Secondary
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End point timeframe |
Baseline to end of study ( 12 weeks)
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No statistical analyses for this end point |
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Adverse events information [1]
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Timeframe for reporting adverse events |
Regular monitoring took place throughout the trial by the CI.
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Adverse event reporting additional description |
The stopping rules and discontinuation from the study were an increase in ACQ7 of > 0.5 points or a fall in FEV1 of 20% from baseline. Discontinuation was assessed on an individual basis by the CI
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Assessment type |
Systematic | |||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
no dictionary used | |||||||||||||||
Dictionary version |
0
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Control treatment with placebo | |||||||||||||||
Reporting group title |
Budesonide
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Reporting group description |
Active treatment with budesonide | |||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||
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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: Budesonide is routinely prescribed with a high safety profile and within the short time frame of the study, no new unexpected adverse events were expected. |
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
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 |