Trial to Evaluate the Effect of Statins on Asthma Control of Patients With Chronic Asthma
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 2/Phase 3

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 1(or 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 corticosteroids/hospitalisation 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: Emergency/'out 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 0.2ml.
      Spirometric measurements will be made before and after nebulised salbutamol (2.5mg).
      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 IU/L and specific IgE >0.35 IU/L 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
      Cockcroft's technique with concentrations of methacholine from 0.03 to 16 mg. A value of
      methacholine hyperreactivity > 16 mg/ml will be read as 16 mg/ml. Bronchial hyper-reactivity
      is defined as a PC20 FEV1 of < 8 mg/ml. 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 cells/ml) will be cultured with autologous plasma for 3 days (mitogen or
      anti-CD3/28) or 7 days (recombinant Der p1 allergen) in a humidified atmosphere at 37°C/5%
      CO2. Proliferation will be measured by incorporation of tritiated thymidine (0.5uCi) 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 (LFT's) 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 20L/min in peak expiratory flow [PEF] (primary endpoint), assuming a standard deviation of
      differences of 40L/min, using a paired t-test with a 0.05 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.
    

Intervention name(s): Atorvastatin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 40mg tablet; Placebo tablet
Other intervention name(s): Lipitor
Intervention MeSH terms: Atorvastatin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Atopy; Statin; Asthma; methacholine; FEV1