Asthmatic Smokers, Non-asthmatic Smokers
Conditions
Keywords
asthmatics, smokers, inhaled corticosteroids, leukotriene receptor antagonists
Brief summary
The purpose of this study is: 1. To compare neutrophilia, eosinophilic inflammatory markers and asthma symptom indices between smokers and non-smokers. 2. To elucidate the mechanism by which cigarette smokers are resistant to corticosteroids.
Detailed description
Many smokers have insufficient control of their symptoms due to inefficacy of ICS in this subpopulation of asthmatics. Cigarette smoking has been shown to stimulate production of cysLTs. CysLTs could activate production of IL-8 for neutrophilia as well as cause eosinophilia in the airway of asthmatics. LTRAs are felt to be less efficacious than ICS in smokers with asthma. However, LTRA's unique mechanism of action could be particularly efficacious in preventing worsening symptoms and lung function for smokers with asthma. Given this, along with the fact that ICS are less effective in smokers, targeting cysLT could lead to significant clinical benefits for asthmatic smokers. Data from this study may possibly serve as crucial data for the significant clinical benefits for asthmatic smokers and determination of the mechanism of corticosteroid resistance in smokers with asthma.
Interventions
DRUGFluticasone Propionate
DPI 250 mcg BID for 3 weeks
DRUGMontelukast
PO 10 mg QHS for 3 weeks
DRUGSalmeterol
DPI 50mg BID for 3 weeks
Sponsors
Inje University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
Asthmatics: * clinical history of asthma for at least 1 year * with evidence of reversible airway obstruction, * two documented FEV1 between 60-85%, * PC20 \< 4mg/ml by methacholine challenge test * and average baseline β-agonist use of 2 puffs/day Smokers: * smoke 1/2 to 2 packs a day * with a smoking history of 5-30 pack years Non-smokers: * Non-smokers will have either never smoked or have stopped smoking cigarettes over 5 years ago
Exclusion criteria
* positive HCG (for females) * have a respiratory tract infection or need oral corticosteroids within the preceding 6 weeks * history of COPD or respiratory disorder other than asthma * history of psychiatric illness * allergy to fluticasone propionate, salmeterol, montelukast or any of their components * significant, unstable medical condition other than asthma * history of life-threatening asthma exacerbation requiring intubation and mechanical ventilation in the last ten years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sputum Neutrophil Percentages | 24 weeks | Week 24 sputum neutrophil percentages were measured in active treatment groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sputum IL-8 Levels | 24 weeks | Week 24 sputum IL-8 levels in active treatment groups |
| Sputum GM-CSF Levels | 24 weeks | Week 24 sputum GM-CSF levels in active treatment groups were measured. |
| Sputum Eosinophil Percentages | 24 weeks | Secondary endpoints of inflammatory markers (sputum eosinophil percentages at 24 weeks) were measured in active treatment groups |
| Sputum Eotaxin Levels | 24 weeks | Week 24 sputum eotaxin levels in active treatment groups were measured. |
| Sputum RANTES Levels | 24 weeks | Week 24 sputum RANTES levels in active treatment groups were measured. |
| Sputum IFN-gamma/IL-5 Ratios | 24 weeks | Week 24 sputum IFN-gamma/IL-5 ratios were determined in active treatment groups. |
Countries
South Korea
Participant flow
Recruitment details
Recruitment period: January 2008-April 2011 Recruitment location: Asthma and Allergy Center, Inje University Sanggye Paik Hospital
Pre-assignment details
After randomization, a 10-day washout period followed in which subjects were taken off all medications except albuterol metered dose inhaler as needed. After the washout period, baseline induced sputum was obtained in each group along with primary and secondary endpoints. This was followed by a 3-week run in period.
Participants by arm
| Arm | Count |
|---|---|
| Asthmatic Smokers Treated With Combination Therapy Asthmatic smokers treated with combination therapy:
Fluticasone propionate dosage - DPI 250 mcg BID for 3 months Salmeterol dosage - DPI 50 mcg BID for 3 months | 8 |
| Asthmatic Smoker Treated With Montelukast Only Asthmatic smoker treated with Montelukast only:
Montelukast dosage - PO 10 mg QHS for 3 months | 32 |
| Non-smoking Asthmatic Treated With Combination Therapy Non-smoking asthmatic treated with combination therapy:
Fluticasone propionate dosage - DPI 250 mcg BID for 3 months Salmeterol dosage - DPI 50 mcg BID for 3 months | 11 |
| Non-smoking Asthmatic Treated With Montelukast Only Non-smoking asthmatic treated with Montelukast only:
Montelukast dosage - PO 10 mg QHS for 3 months | 24 |
| Normal Controls Normal controls did not receive any treatment. | 30 |
| Total | 105 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 5 | 0 | 1 | 0 |
| Overall Study | Other Reason | 0 | 3 | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 2 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 7 | 2 | 3 | 0 |
Baseline characteristics
| Characteristic | Asthmatic Smoker Treated With Montelukast Only | Non-smoking Asthmatic Treated With Combination Therapy | Non-smoking Asthmatic Treated With Montelukast Only | Asthmatic Smokers Treated With Combination Therapy | Normal Controls | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants | 11 Participants | 24 Participants | 8 Participants | 30 Participants | 105 Participants |
| Age Continuous | 36.03 years STANDARD_DEVIATION 8.52 | 45.64 years STANDARD_DEVIATION 17.46 | 39.00 years STANDARD_DEVIATION 14.79 | 51.38 years STANDARD_DEVIATION 11.41 | 40.55 years STANDARD_DEVIATION 11.35 | 40.09 years STANDARD_DEVIATION 4.24 |
| Region of Enrollment Korea, Republic of | 32 participants | 11 participants | 24 participants | 8 participants | 30 participants | 105 participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 22 Participants | 3 Participants | 22 Participants | 56 Participants |
| Sex: Female, Male Male | 27 Participants | 7 Participants | 2 Participants | 5 Participants | 8 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 8 | 0 / 32 | 0 / 11 | 0 / 24 | 0 / 0 |
| serious Total, serious adverse events | 0 / 8 | 0 / 32 | 0 / 11 | 0 / 24 | 0 / 0 |
Outcome results
Primary
Sputum Neutrophil Percentages
Week 24 sputum neutrophil percentages were measured in active treatment groups.
Time frame: 24 weeks
Population: We will be using intention-to-treat and per protocol for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Asthmatic Smokers Treated With Combination Therapy | Sputum Neutrophil Percentages | 86.00 percentage of neutrophils | Standard Deviation 8.22 |
| Asthmatic Smoker Treated With Montelukast Only | Sputum Neutrophil Percentages | 72.53 percentage of neutrophils | Standard Deviation 24.14 |
| Non-smoking Asthmatic Treated With Combination Therapy | Sputum Neutrophil Percentages | 89.33 percentage of neutrophils | Standard Deviation 6.41 |
| Non-smoking Asthmatic Treated With Montelukast Only | Sputum Neutrophil Percentages | 79.84 percentage of neutrophils | Standard Deviation 17.07 |
Secondary
Sputum Eosinophil Percentages
Secondary endpoints of inflammatory markers (sputum eosinophil percentages at 24 weeks) were measured in active treatment groups
Time frame: 24 weeks
Population: We will use ITT and PP protocols for analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Asthmatic Smokers Treated With Combination Therapy | Sputum Eosinophil Percentages | 2.33 percentage of eosinophils | Standard Deviation 3.01 |
| Asthmatic Smoker Treated With Montelukast Only | Sputum Eosinophil Percentages | 3.60 percentage of eosinophils | Standard Deviation 6.43 |
| Non-smoking Asthmatic Treated With Combination Therapy | Sputum Eosinophil Percentages | 1.60 percentage of eosinophils | Standard Deviation 1.34 |
| Non-smoking Asthmatic Treated With Montelukast Only | Sputum Eosinophil Percentages | 3.26 percentage of eosinophils | Standard Deviation 6.1 |
Secondary
Sputum Eotaxin Levels
Week 24 sputum eotaxin levels in active treatment groups were measured.
Time frame: 24 weeks
Population: ITT and PP were used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Asthmatic Smokers Treated With Combination Therapy | Sputum Eotaxin Levels | 47.13 pg/ml | Standard Deviation 41.93 |
| Asthmatic Smoker Treated With Montelukast Only | Sputum Eotaxin Levels | 87.90 pg/ml | Standard Deviation 93.15 |
| Non-smoking Asthmatic Treated With Combination Therapy | Sputum Eotaxin Levels | 65.14 pg/ml | Standard Deviation 25.54 |
| Non-smoking Asthmatic Treated With Montelukast Only | Sputum Eotaxin Levels | 64.61 pg/ml | Standard Deviation 44.07 |
Secondary
Sputum GM-CSF Levels
Week 24 sputum GM-CSF levels in active treatment groups were measured.
Time frame: 24 weeks
Population: We will use ITT and PP for analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Asthmatic Smokers Treated With Combination Therapy | Sputum GM-CSF Levels | 17.60 pg/ml | Standard Deviation 24.67 |
| Asthmatic Smoker Treated With Montelukast Only | Sputum GM-CSF Levels | 15.18 pg/ml | Standard Deviation 16.37 |
| Non-smoking Asthmatic Treated With Combination Therapy | Sputum GM-CSF Levels | 13.92 pg/ml | Standard Deviation 10.66 |
| Non-smoking Asthmatic Treated With Montelukast Only | Sputum GM-CSF Levels | 12.16 pg/ml | Standard Deviation 18.05 |
Secondary
Sputum IFN-gamma/IL-5 Ratios
Week 24 sputum IFN-gamma/IL-5 ratios were determined in active treatment groups.
Time frame: 24 weeks
Population: ITT and PP were used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Asthmatic Smokers Treated With Combination Therapy | Sputum IFN-gamma/IL-5 Ratios | 627.4 ratio | Standard Deviation 742.1 |
| Asthmatic Smoker Treated With Montelukast Only | Sputum IFN-gamma/IL-5 Ratios | 272.4 ratio | Standard Deviation 387.1 |
| Non-smoking Asthmatic Treated With Combination Therapy | Sputum IFN-gamma/IL-5 Ratios | 183.8 ratio | Standard Deviation 82.7 |
| Non-smoking Asthmatic Treated With Montelukast Only | Sputum IFN-gamma/IL-5 Ratios | 279.0 ratio | Standard Deviation 563.3 |
Secondary
Sputum IL-8 Levels
Week 24 sputum IL-8 levels in active treatment groups
Time frame: 24 weeks
Population: We will ITT and PP protocols for analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Asthmatic Smokers Treated With Combination Therapy | Sputum IL-8 Levels | 334545 pg/ml | — |
| Asthmatic Smoker Treated With Montelukast Only | Sputum IL-8 Levels | 26,300 pg/ml | — |
| Non-smoking Asthmatic Treated With Combination Therapy | Sputum IL-8 Levels | 3602 pg/ml | Standard Deviation 2342 |
| Non-smoking Asthmatic Treated With Montelukast Only | Sputum IL-8 Levels | 317778 pg/ml | Standard Deviation 738415 |
Secondary
Sputum RANTES Levels
Week 24 sputum RANTES levels in active treatment groups were measured.
Time frame: 24 weeks
Population: ITT and PP were used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Asthmatic Smokers Treated With Combination Therapy | Sputum RANTES Levels | 42.79 pg/ml | Standard Deviation 32.47 |
| Asthmatic Smoker Treated With Montelukast Only | Sputum RANTES Levels | 44.03 pg/ml | Standard Deviation 40.41 |
| Non-smoking Asthmatic Treated With Combination Therapy | Sputum RANTES Levels | 41.78 pg/ml | Standard Deviation 19.93 |
| Non-smoking Asthmatic Treated With Montelukast Only | Sputum RANTES Levels | 36.41 pg/ml | Standard Deviation 29.93 |