Ignite Creation Date:
2024-05-05 @ 11:46 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00126048
Status:
COMPLETED
Last Update Posted:
2010-03-18
First Post:
2005-06-30
Brief Title:
Trial to Evaluate the Effect of Statins on Asthma Control of Patients With Chronic Asthma
Sponsor:
University of Glasgow
Organization:
University of Glasgow
Study Overview
Official Title:
Randomised Controlled Trial to Evaluate the Effect of Statins on Asthma Control of Patients With Chronic Asthma
Status:
COMPLETED
Status Verified Date:
2008-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Statins are the most common type of cholesterol-lowering drugs used in clinical practice Recent research suggests that they may also have anti-inflammatory properties in particular by inhibition of an important inflammatory cell called a T lymphocyte Asthma is characterised by chronic inflammation in the airways which is thought to be regulated by the activity of T lymphocytes The investigators have found the anti-inflammatory activity of a statin drug in an experimental model of allergic asthma and they have recently shown the beneficial effects of a statin atorvastatin in patients with rheumatoid arthritis These findings demonstrate the therapeutic potential of statin-sensitive pathways in allergic airways disease The investigators plan to perform a proof of concept study to determine the effectiveness of statin therapy in asthma This randomised controlled trial will test the hypothesis that statins improve asthma control of patients with chronic asthma The study will be a 22-week randomised controlled trial comparing the effect on asthma control of oral atorvastatin with that of a matched placebo Each treatment will be administered for 8 weeks separated by a 6-week washout period A total of 52 allergic asthmatic patients will be recruited to ensure that 44 patients complete the study The investigators will examine the effect of statin therapy on lung function symptom scores exacerbation rates as well as on the measurement of airway inflammation in sputum and in the blood This study will determine the benefit of atorvastatin as an add-on therapy in asthma and establish if statins might have a role in asthma management
Detailed Description:
Study Design
The study will be a 24-week randomised double blind crossover study comparing the effect on asthma control of oral atorvastatin therapy 40 mg daily with that of a matched placebo Each treatment will be administered for 8 weeks separated by a 6-week washout period and a 2-week run-in period prior to randomisation Randomisation will be performed in sequential blocks
Patients will be assessed on 9 visits 13 occasions as some visits are performed over 2 days -
Visit 1 Screening visit
Obtain written informed consent
General medical history physical examination
Complete asthma control questionnaire
Spirometry and reversibility testing
Blood sampling 35 ml for IgE serology lipids liver function tests creatinine kinase and immunological tests including sVCAM-1 Sicam-1 Spcam E-selectin CRP MCP-1 IL-6 IL-10 and TNF-alpha
Eligibility check
Issue diary card and peak flow meter
Adjustment of asthma medication to BTS guidelines if required
Visit 2 Baseline clinical measurements-2weeks after visit 1or 4 weeks if any change made to baseline asthma medication randomisation visit
Complete asthma control questionnaire
Asthma Quality of life questionnaire
ATS score to assess severity of asthma
Spirometry and reversibility testing
Induced sputum
Exhaled NO
Airway responsiveness to methacholine
Randomise patient if all criteria met
Issue diary card
Visits 3-9 at 2 4 8 14 16 18 22 weeks after randomisation
At each study visit the peak expiratory flow PEF diary will be retained and spirometry performed Patients will record morning and evening PEF measurements and daily symptoms throughout the study Airway responsiveness to methacholine asthma control score asthma quality of life questionnaire induced sputum exhaled NO and blood samples for immunological tests lipids and liver functions will be performed at visits 5 6 and 9 Pregnancy tests will be performed in all women of child-bearing age at visits 2 and 6 and subjects will be informed about adequate contraception during and for one month after the study
If a subject is found to have elevated lipids at baseline the study would be continued and the person referred to the appropriate specialist for further management after the study
If a subject has an exacerbation during the wash-out phase of the study visit 6 will be delayed until the patient has been stable for 4 weeks
Anti-asthma drug treatment Patients will be asked to continue on their usual anti-asthma drug therapy throughout the study
Measurements
Diary card recordings asthma symptoms PEF recordings and inhaled beta2-agonist use PEF measurements will be undertaken by patients at home using a mini-Wright peak flow meter Clement Clarke Harlow UK The best of three measurements will be recorded twice daily pre-treatment in the diary Peak flow variability will be calculated from the difference between the highest and lowest daily reading divided by the mean PEF reading multiplied by 100 amplitude mean The average of 3 of the last 7 days PEF measurements before each visit will be used for analysis
Exacerbations of asthma Mild exacerbation defined as one of the following for 2 consecutive days a drop in peak flow 20 below baseline value use of more than 3 additional puffs of reliever bronchodilator over 24 hours excluding prophylactic puffs for exercise as compared with baseline value or night awakening due to asthma A severe exacerbation will be defined as any worsening of asthma control considered by the investigator or general practitioner GP to require a short course of oral corticosteroidshospitalisation or decrease in morning peak flow to more than 30 below the baseline value on 2 consecutive days
Other indices of disease severity relating to asthma Emergencyout of hours visit of patients to the GP GP visit to patient at home GP or investigator prescribing extra treatment Accident and emergency A E department hospital attendance hospital admission and length of stay
Spirometry FEV1 FVC reversibility testing Baseline pre-bronchodilator spirometric measurements will be recorded from the best of three attempts using a dry wedge spirometer Vitalograph Buckingham UK with measurements not varying by more than 5 or 02ml Spirometric measurements will be made before and after nebulised salbutamol 25mg Measurements will be performed at the same time of day am or pm for each patient
Total and specific IgE Total serum IgE and IgE to common allergens house dust mites grass pollen and cat dander will be measured by enzyme immunoassay Unicap System Pharmacia UK Ltd Milton Keynes UK Total IgE 120 IUL and specific IgE 035 IUL are considered positive Atopy will be defined as the presence of positive specific IgE to common allergens
Airway responsiveness Bronchial challenge testing with methacholine will be undertaken using Cockcrofts technique with concentrations of methacholine from 003 to 16 mg A value of methacholine hyperreactivity 16 mgml will be read as 16 mgml Bronchial hyper-reactivity is defined as a PC20 FEV1 of 8 mgml Methacholine challenge testing will only be performed in subjects who have a baseline FEV1 of greater than 60 predicted
Induced sputum An ultrasonic nebuliser is filled with 3 saline and subjects inhale the nebulised solution for 7 minutes following pre-treatment with inhaled salbutamol After this the nebuliser is filled with 4 saline and the nebulised solution is inhaled for 7 minutes Finally the nebuliser is filled with 5 saline and the nebulised solution is inhaled for 7 minutes At 5-minute intervals the inhalation is stopped to allow expectoration into a polypropylene container The sample is kept on ice until processed for cell counts and ultra centrifugation to harvest the soluble phase of sputum Cell counts will be performed and the supernatant stored for analysis of inflammatory mediators The test will not be performed on subjects with an FEV1 1 L
Measurement of exhaled NO Exhaled NO will be measured on a chemiluminescence analyser LR2149 Logan Research Ltd Rochester Kent The methods used to measure exhaled NO will comply with the ATS guidelines
Allergen-driven lymphocyte proliferative response in the blood Peripheral blood mononuclear cells 106 cellsml will be cultured with autologous plasma for 3 days mitogen or anti-CD328 or 7 days recombinant Der p1 allergen in a humidified atmosphere at 37C5 CO2 Proliferation will be measured by incorporation of tritiated thymidine 05uCi for 16hr before harvest onto glass fibre filters and counting in a beta counter
Other immunological tests in blood
Luminex methodology for cytokine release FACS technology for co-stimulator molecule expression will be employed to estimate altered cellular immune function in whole blood cultures over time
Measurement of lipids in blood
Cholesterol triglycerides and HDL-cholesterol will be measured at screening and visits 5 6 and 9
Serum biochemistry safety checks Blood for renal function urea and electrolytes and liver function tests LFTs will be performed before and after each treatment period and creatinine kinase will be performed at baseline
Statistical Analysis
Power calculations A sample size of 44 will have 90 power to detect a difference in means of 20Lmin in peak expiratory flow PEF primary endpoint assuming a standard deviation of differences of 40Lmin using a paired t-test with a 005 two-sided significance level A total of 52 patients will be recruited to ensure that 44 patients complete the study
Data processing and analysis The primary analysis is a comparison between treatments of morning PEF Secondary endpoints include symptom scores exacerbation rates spirometry airway responsiveness to methacholine sputum cell counts eNO and immunological tests in blood The main analyses will be carried out by Normal Linear Models that include parameters for patient period and treatment Some variables may be unsuitable for this in which case the within-patient treatment differences will be calculated and then analysed by either t-tests or Wilcoxon tests as appropriate
The study will be a 24-week randomised double blind crossover study comparing the effect on asthma control of oral atorvastatin therapy 40 mg daily with that of a matched placebo Each treatment will be administered for 8 weeks separated by a 6-week washout period and a 2-week run-in period prior to randomisation Randomisation will be performed in sequential blocks
Patients will be assessed on 9 visits 13 occasions as some visits are performed over 2 days -
Visit 1 Screening visit
Obtain written informed consent
General medical history physical examination
Complete asthma control questionnaire
Spirometry and reversibility testing
Blood sampling 35 ml for IgE serology lipids liver function tests creatinine kinase and immunological tests including sVCAM-1 Sicam-1 Spcam E-selectin CRP MCP-1 IL-6 IL-10 and TNF-alpha
Eligibility check
Issue diary card and peak flow meter
Adjustment of asthma medication to BTS guidelines if required
Visit 2 Baseline clinical measurements-2weeks after visit 1or 4 weeks if any change made to baseline asthma medication randomisation visit
Complete asthma control questionnaire
Asthma Quality of life questionnaire
ATS score to assess severity of asthma
Spirometry and reversibility testing
Induced sputum
Exhaled NO
Airway responsiveness to methacholine
Randomise patient if all criteria met
Issue diary card
Visits 3-9 at 2 4 8 14 16 18 22 weeks after randomisation
At each study visit the peak expiratory flow PEF diary will be retained and spirometry performed Patients will record morning and evening PEF measurements and daily symptoms throughout the study Airway responsiveness to methacholine asthma control score asthma quality of life questionnaire induced sputum exhaled NO and blood samples for immunological tests lipids and liver functions will be performed at visits 5 6 and 9 Pregnancy tests will be performed in all women of child-bearing age at visits 2 and 6 and subjects will be informed about adequate contraception during and for one month after the study
If a subject is found to have elevated lipids at baseline the study would be continued and the person referred to the appropriate specialist for further management after the study
If a subject has an exacerbation during the wash-out phase of the study visit 6 will be delayed until the patient has been stable for 4 weeks
Anti-asthma drug treatment Patients will be asked to continue on their usual anti-asthma drug therapy throughout the study
Measurements
Diary card recordings asthma symptoms PEF recordings and inhaled beta2-agonist use PEF measurements will be undertaken by patients at home using a mini-Wright peak flow meter Clement Clarke Harlow UK The best of three measurements will be recorded twice daily pre-treatment in the diary Peak flow variability will be calculated from the difference between the highest and lowest daily reading divided by the mean PEF reading multiplied by 100 amplitude mean The average of 3 of the last 7 days PEF measurements before each visit will be used for analysis
Exacerbations of asthma Mild exacerbation defined as one of the following for 2 consecutive days a drop in peak flow 20 below baseline value use of more than 3 additional puffs of reliever bronchodilator over 24 hours excluding prophylactic puffs for exercise as compared with baseline value or night awakening due to asthma A severe exacerbation will be defined as any worsening of asthma control considered by the investigator or general practitioner GP to require a short course of oral corticosteroidshospitalisation or decrease in morning peak flow to more than 30 below the baseline value on 2 consecutive days
Other indices of disease severity relating to asthma Emergencyout of hours visit of patients to the GP GP visit to patient at home GP or investigator prescribing extra treatment Accident and emergency A E department hospital attendance hospital admission and length of stay
Spirometry FEV1 FVC reversibility testing Baseline pre-bronchodilator spirometric measurements will be recorded from the best of three attempts using a dry wedge spirometer Vitalograph Buckingham UK with measurements not varying by more than 5 or 02ml Spirometric measurements will be made before and after nebulised salbutamol 25mg Measurements will be performed at the same time of day am or pm for each patient
Total and specific IgE Total serum IgE and IgE to common allergens house dust mites grass pollen and cat dander will be measured by enzyme immunoassay Unicap System Pharmacia UK Ltd Milton Keynes UK Total IgE 120 IUL and specific IgE 035 IUL are considered positive Atopy will be defined as the presence of positive specific IgE to common allergens
Airway responsiveness Bronchial challenge testing with methacholine will be undertaken using Cockcrofts technique with concentrations of methacholine from 003 to 16 mg A value of methacholine hyperreactivity 16 mgml will be read as 16 mgml Bronchial hyper-reactivity is defined as a PC20 FEV1 of 8 mgml Methacholine challenge testing will only be performed in subjects who have a baseline FEV1 of greater than 60 predicted
Induced sputum An ultrasonic nebuliser is filled with 3 saline and subjects inhale the nebulised solution for 7 minutes following pre-treatment with inhaled salbutamol After this the nebuliser is filled with 4 saline and the nebulised solution is inhaled for 7 minutes Finally the nebuliser is filled with 5 saline and the nebulised solution is inhaled for 7 minutes At 5-minute intervals the inhalation is stopped to allow expectoration into a polypropylene container The sample is kept on ice until processed for cell counts and ultra centrifugation to harvest the soluble phase of sputum Cell counts will be performed and the supernatant stored for analysis of inflammatory mediators The test will not be performed on subjects with an FEV1 1 L
Measurement of exhaled NO Exhaled NO will be measured on a chemiluminescence analyser LR2149 Logan Research Ltd Rochester Kent The methods used to measure exhaled NO will comply with the ATS guidelines
Allergen-driven lymphocyte proliferative response in the blood Peripheral blood mononuclear cells 106 cellsml will be cultured with autologous plasma for 3 days mitogen or anti-CD328 or 7 days recombinant Der p1 allergen in a humidified atmosphere at 37C5 CO2 Proliferation will be measured by incorporation of tritiated thymidine 05uCi for 16hr before harvest onto glass fibre filters and counting in a beta counter
Other immunological tests in blood
Luminex methodology for cytokine release FACS technology for co-stimulator molecule expression will be employed to estimate altered cellular immune function in whole blood cultures over time
Measurement of lipids in blood
Cholesterol triglycerides and HDL-cholesterol will be measured at screening and visits 5 6 and 9
Serum biochemistry safety checks Blood for renal function urea and electrolytes and liver function tests LFTs will be performed before and after each treatment period and creatinine kinase will be performed at baseline
Statistical Analysis
Power calculations A sample size of 44 will have 90 power to detect a difference in means of 20Lmin in peak expiratory flow PEF primary endpoint assuming a standard deviation of differences of 40Lmin using a paired t-test with a 005 two-sided significance level A total of 52 patients will be recruited to ensure that 44 patients complete the study
Data processing and analysis The primary analysis is a comparison between treatments of morning PEF Secondary endpoints include symptom scores exacerbation rates spirometry airway responsiveness to methacholine sputum cell counts eNO and immunological tests in blood The main analyses will be carried out by Normal Linear Models that include parameters for patient period and treatment Some variables may be unsuitable for this in which case the within-patient treatment differences will be calculated and then analysed by either t-tests or Wilcoxon tests as appropriate
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| Ethics committee04SO70986 | None | None | None |
| Grant number04015 | None | None | None |
| RDWN04RM024 | None | None | None |