Effects of p38 Inhibitor AZD7624 in Corticosteroid Resistant Asthma
Condition: Corticosteroid Resistant (CR) Asthmatics
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a double-blind, placebo controlled 4 week crossover study to investigate the efficacy
      and safety of AZD7624 (an inhaled p38 inhibitor) in corticosteroid resistant (CR) asthmatics.
      For the purpose of this study 10 symptomatic CR asthma patients with a FEV1% predicted <80%
      and normal bronchodilator response, 10 CS asthmatics and 10 healthy controls will be
      recruited.
    

Detailed description: 
      In Part A of the study, p38 MAPK activation will be measured in CR asthmatics and compared to
      CS asthmatics. Assessment of p38 MAPK activation in whole blood samples from 5 CR and 5 CS
      asthma patients will be performed. After fulfilling all enrollment criteria blood samples
      will be collected from asthma patients at Visit 1 for the whole blood evaluation of MAPK
      activation by flow cytometry.

      After the initial visit, asthmatics will be given oral prednisone for 1 week and patients
      will return for the spirometry assessment. Patients will be defined as CR if <10% improvement
      in FEV1 % predicted is observed and as CS if >12% improvement in FEV1 % predicted is
      observed. If at least 2 fold increase in p-p38 MAPK expression in CD14+ cells of CR asthma
      patients is demonstrated when compared to CS asthmatics, Part B will be triggered. If no
      difference in p38 MAPK phosphorylation will be observed in monocytes of CR and CS asthmatics
      by flow cytometry assessment, the study will be terminated.

      In Part B of the study, CR asthmatics will be randomized for treatment with AZD7624 or
      placebo for one month in a cross over design; the ability of AZD7624 to inhibit p38 MAPK
      activity will be assessed in CR patients. Five CR asthma patients from Part A may also take
      part in Part B. Additional CR (n=10 total patients required) and CS asthmatics (n=5) will be
      recruited in part B.

      Baseline levels of p38 MAPK and other biomarkers will also be assessed in CR asthmatics and
      compared to both CS asthmatics and healthy volunteers. Patients will be enrolled and assessed
      for baseline p38 MAPK activation as above in peripheral blood. Patients will be re-defined as
      CR or CS as above based on changes in the lung function after 1 week of oral prednisone burst
      as above. Levels of p38 MAPK activity and other biomarkers will be compared between CR and CS
      patients (n=10 in each group based on recruitment for Part A and Part B) and also compared to
      healthy volunteers (n=10). After 1 week following oral prednisone burst, CR patients will
      return to undergo bronchoscopy with the collection of BAL and bronchial epithelial brushes.
      Blood samples will be collected for evaluation of p38 MAPK activation. CS patients will not
      undergo bronchoscopy, but will give a blood sample one week after oral prednisone burst for
      the analysis of p38 MAPK activation. Blood samples will also be collected from healthy
      controls during the initial visit to assess p38 MAPK activation. CR patients will be
      randomized for treatment with p38 inhibitor AZD7624 or placebo (5 patients per group). After
      4 weeks of treatment with AZD7624 or placebo, CR patients will undergo additional
      bronchoscopy with the collection of BAL, brushes and blood. Patients will be monitored for
      adverse events during the trial. After completion of first block of cross over treatment, CR
      patients will undergo a 1 month wash-out period, after which, they will return for induced
      sputum and blood collection, and then undergo the second crossover period with AZD7624 or
      placebo. After the second 4 week treatment block, patients will come for sputum induction and
      blood collection. In CR asthma patients assessment of lung function, asthma control, airway
      hyperreactivity, p38 MAPK activation in peripheral blood, BAL, induced sputum samples and
      cellular responsiveness to corticosteroids before and after treatment with AZD7624 will be
      performed.
    

Intervention name(s): AZD7624; prednisone; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): oral prednisone 20 mg bid for one week
Intervention MeSH terms: Prednisone; AZD7624
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment