Corticosteroid Resistant (CR) Asthmatics Clinical Trial
Official title:
Effects of p38 Inhibitor AZD7624 in Corticosteroid Resistant Asthma
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.
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.
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