Effect of cardio selective beta blockers on rescue beta agonists following controlled bronchoconstriction challenge in Asthmatics

Cross over study with two blinded arms and a third unblinded arm. Incrimental once daily oral capsule dose of cardioselective beta blocker (bisoprolol) or placebo going up after at least 48 hours at each step from 1.25mg to 2.5mg (if no symptoms of lightheadedness or fainting on a phone call assessment) then up to 5mg (if heart rate >60 and systolic blood pressure >100 on visit assessment). Minimum time at each step 48 hours, maximum 5 days. A third open label arm will be run involving any of the participants who tolerated the 5mg bisoprolol. They will be uptitrated after at least 48 hours at each dose from 2.5mg to 5mg to 7.5mg (if no symptoms of lightheadedness or fainting on a phone call assessment to advise on each dose increase) then after a further minimum of 48 hours up to 10mg (if heart rate >60 and systolic blood pressure >100 on visit assessment) which will be continued for a minimum of 48 hours up to and including the date of the final visit with Asthma questionnaire and mannitol challenge. Strategies used to monitor adherence include drug tablet return. No wash out period is required as the measure of spirometry will be at the end of each arm and therefore over 7 days since the last dose of the previous study drug was taken. As such there will have been sufficient time for the stabalisation of adrenoreceptors to demonstrate findings sufficiently. At the end of each of the three arms, on the day of the last study drug administration, controlled bronchoconstriction using mannitol. This follows a strict protocol which administers increasing doses of inhaled dry powder mannitol until a 15% fall in the forced expiratory volume in one second (FEV1) is reached. The response to inhaled salbutamol (100, 100, 200 mg at 5 min intervals) will then be measured. Dose response curves will be compared using an analysis of covariance. Also on this last day a asthma questionnaire will be done. All three of these end of arm measures will be compared to measurements done at baseline on screening visits.