The Effect of Prasugrel on Bronchial Hyperreactivity and on Markers of Inflammation in Patients With Chronic Asthma
Status:
Completed
Trial end date:
2011-12-01
Target enrollment:
Participant gender:
Summary
Cysteinyl leukotrienes (cys-LTs) are lipid inflammatory mediators that abound in mucosal
inflammation and play a validated role in the pathogenesis of human asthma. It has recently
been demonstrated that the platelet adenosine diphosphate (ADP) receptor, P2Y12, is required
for LT4-mediated pulmonary inflammation and could be a novel potential therapeutic target for
asthma. Thienopyridines (such as ticlopidine and clopidogrel) are pro-drugs, with proven
antithrombotic efficacy, whose active metabolites selectively inhibit the platelet P2Y12
receptors. One of the drawbacks of thienopyridines is the high inter-individual variability
in pharmacological response, mostly due to the high inter-individual variability in the
capacity of transforming the pro-drug in its active metabolite. Prasugrel is a new member of
the class of thienopyridines, with faster onset of action and a more uniform inhibition of
platelet function compared to the other thienopyridines. Primary objective of our study will
be to test whether or not the inhibition of the platelet P2Y12 receptor by prasugrel reduces
the bronchial hyper-reactivity in patients with chronic asthma. The investigators designed a
randomized, double blind (Subject, Caregiver, Investigator, Outcomes Assessor), crossover,
placebo-controlled, prospective study, which will enroll 26 patients. Randomization will be
performed in sequential blocks. Patients will be blindly and randomly allocated to treatment
A (prasugrel 10 mg daily) or B (placebo) for 15 days. After a 15-day wash-out period,
patients who had initially been allocated to treatment "A" will be allocated to treatment
"B", and vice versa. Measurements will be done at baseline and on day 15 after each
treatment, at the same time (+/- 1 h) of the day. Primary efficacy measure will be changes in
airway hyper-responsiveness, recorded as reduction of FEV1 using the mannitol test induction.
Secondary efficacy measures will be changes in markers of airway inflammation in sputum,
changes in measurement of nitric oxide expiration (as surrogate marker of airway lung
inflammation), count of eosinophil granulocytes in peripheral blood smear, changes in asthma
exacerbation rates and symptom scores. Changes in phosphorylation of platelet VASP
(Vasodilator-stimulated phosphoprotein) by ADP, measured with a flow cytometric technique,
will be used as markers of the degree of inhibition of platelet P2Y12 receptors attained in
each subjects by treatment with prasugrel.