TNF-alpha Directed Therapy in Asthma
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 2

Summary: 
      This trial is a randomised, single-center, placebo-controlled, double blind, parallel group
      study in patients with asthma symptomatic on inhaled steroids.

      This trial will examine the efficacy and safety of 5 mg/kg doses of infliximab in patients
      with inhaled corticosteroid-dependent asthma. The primary objective of this study is to
      obtain pharmacological evidence for a role of the pro-inflammatory cytokine TNF-alpha in
      patients with asthma symptomatic on inhaled steroids and to evaluate the safety and
      tolerability of repeated intravenous administration of infliximab.
    

Detailed description: 
      Study Overview This trial is a randomised, single-center, placebo-controlled, double blind,
      parallel group study in patients with asthma symptomatic on inhaled steroids.

      Patient Population Patients eligible for this study will have a diagnosis of moderate asthma
      defined by the American Thoracic Society criteria for > 1 year. These patients should be
      taking inhaled steroids at doses equivalent to </= 400µg and </= 2000µg per day
      beclomethasone diproprionate but not oral steroid medication. Patients taking additional oral
      steroids are required to stop oral medication at least one month prior to pre-screening.

      Many of these patients will be receiving long-acting beta2-agonists and this therapy will be
      discontinued for 48h before starting the run-in. In addition, the following therapies are not
      allowed: 1) anticholinergics; 2) theophylline; 3) oral beta2-agonists; 4) antihistamines; 5)
      inhaled cromolyn sodium or nedocromil; 6) leukotriene antagonists.

      Patients using these prohibited medications will be asked to discontinue use 2 weeks prior to
      the screening examination. During this washout period, patients will keep a clinical diary
      and will remain in contact with the clinical research center.

      Eligible patients for screening will maintain stable doses of their normal inhaled steroids
      in doses equivalent to >/= 400 µg and </= 2000µg per day beclomethasone diproprionate and
      will be able to use short-acting beta2-agonists for symptom relief.

      Screening At screening, eligible patients will have a baseline screening FEV1 of >/= 60 to
      </= 90% of predicted at least 4 hours after the last usage of a short-acting beta2-agonist.
      Patients will have reversible airway obstruction: a >/= 12% increase in FEV1 in comparison to
      baseline should be shown within 30 minutes after taking 200 µg salbutamol. If airway
      reversibility cannot be demonstrated during this visit, patients are eligible for re-testing.
      Reversible airway disease may be demonstrated at any time between screening and start of
      run-in period. The 2 to 4 week run-in period will start immediately after demonstration of
      reversible lung disease.

      Patients will also have skin tests to a standard battery of bronchial allergens performed at
      screening. Patients should have both a purified protein derivative (PPD) skin test and a
      chest radiograph prior to their first infusion. Patients with evidence of either latent or
      active tuberculosis (TB) will not be enrolled.

      Run-in Period Following acceptable screening tests patients will complete a baseline run-in
      of 2 to 4 weeks duration prior to the study start. During this period patients will be
      required to keep a symptom diary and to record baseline lung function parameters using an
      electronic spirometer. As before, patients will be maintained on their normal inhaled
      steroids in doses equivalent to >/= 400 µg and </= 2000µg per day beclomethasone
      diproprionate and will be able to use short-acting beta2-agonists for symptom relief. No
      other asthma medications will be allowed during this period and the rest of the study. Use of
      all other, non-asthma, medication will be reviewed by the Investigator and allowed at his/her
      discretion provided a stable dose regimen is maintained where possible throughout the study.

      Baseline Visit (day -1) The day before the first drug administration, patients will attend
      the clinical research unit and diary cards will be reviewed. In order to enter the study the
      patients must have a mean total daily symptom score >/= 4 measured during the last 7 days of
      the baseline run-in period [A symptom scale with scores ranging from 0 (=symptom free) to 3
      (=severe symptoms) is used, with 6 questions, and a total maximum daily symptom score of 18,
      see appendix D)] and/or have a >/= 10% and < 30% diurnal variation in PEFR measured on at
      least 2 of 7 days during the same period.

      Diurnal variation in PEFR is defined from morning and evening PEFR values; in the morning and
      evening the PEFR is determined on 3 immediately consecutive occasions and the highest value
      taken. The calculation of diurnal variation is based on:

      [(higher (am or pm) PEFR- lower (am or pm) PEFR) / higher (am or pm) PEFR x 100].

      In eligible patients, the following pharmacodynamic assessments will be made: breath NO
      levels (non-nasal) and breath condensates, pulmonary function testing (FEV1, FVC and PEFR),
      sputum induction for markers of inflammation, and a blood sample collection for the
      measurement of markers of inflammation.

      Study Treatments Patients will be randomised in a 1:1 ratio to treatment with infliximab or
      placebo, respectively. PRI will provide the randomisation list. At t=0 weeks, patients will
      either receive 5 mg/kg infliximab (Group I, n=20) or placebo (Group II, n=20). Subsequently,
      infliximab or placebo will be infused at weeks 2 and 6. Throughout the study period up to
      week 12, patients will be allowed to use inhaled corticosteroids at a stable dose regimen.
      Salbutamol, a short-acting beta2-agonist, will be allowed as necessary to relieve symptoms.

      During the study, the two treatment groups are defined as:

      Group I: Infliximab 5 mg/kg + short-acting beta2-agonist (as needed) + inhaled
      corticosteroids (equivalent to >/= 400 µg and </= 2000µg per day beclomethasone
      diproprionate).

      Group II: Placebo + short-acting beta2-agonist (as needed) + inhaled corticosteroids
      (equivalent to >/= 400 µg and </= 2000µg per day beclomethasone diproprionate).

      Study Evaluations Throughout the study, starting with the baseline run-in period, patients
      will be required to daily record their PEFR and FEV1 (morning and evening), short-acting
      beta2-agonist use and clinical symptoms using a diary card. Mean weekly scores will be
      calculated for each parameter starting at week -1 up to week 12. Prior to administration of
      study drug at week 0 and, in addition, at weeks 1, 8 and 12, the following pharmacodynamic
      assessments will be made: breath NO levels, breath condensate leukotriene B4 & C4, pulmonary
      function testing (FEV1, FVC and PEFR), sputum induction for markers of inflammation (weeks 0,
      1 and 8 only) and levels of markers of inflammation in peripheral blood. In addition, at
      weeks 2 and 6, breath NO levels will be measured and pulmonary function testing will be
      performed.

      Safety Safety evaluations will include measurement of vital signs during and immediately
      after (for 2 hours) the infusion of study medications and assessment of adverse events (AEs)
      at each of the evaluation visits. Additional vital signs and lung function measurements will
      be performed immediately after each infusion and at t = 1 and 2 hours post dose. Routine
      laboratory tests will be performed at screening, at day -1 and at weeks 2, 6, 8 and 12.
      During the study, the medical monitor will regularly review safety data.

      Follow-up During the last visit in week 12 to the clinical research center, a follow-up
      examination, including a physical examination and blood and urine chemistry will be
      performed.
    

Intervention name(s): Study drug administration; Tuberculin intradermal skin test; Lung function test for FEV1; Asthma symptom scores diary; Quality of life diary; Breath nitric oxide; Breath condensate; Sputum induction; Blood sampling; Urinalysis
Intervention type(s): Drug; Procedure; Procedure; Procedure; Procedure; Procedure; Procedure; Procedure; Procedure; Procedure
Intervention MeSH terms: Nitric Oxide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Pharmacology; Asthma; TNF-alpha