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

INTERVENTION: 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 FeNO, Asthma questionnaire and methacholine 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 methacholine. This follows a strict protocol which administers incerasing doses of nebulised merthacholine until a 20% 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 and a fractional exhaled nitric oxide (FeNO) measurement will be done. All three of these end of arm measures will be compared to measurements done at baseline on screening visits. CONDITION: Asthma PRIMARY OUTCOME: Graph drawn of time against FEV1 measured. Points plotted for 0, 5, 10, 15 minutes (each being after 0, 100micrograms, 100micrograms, 200micrograms salbutamol respectively). Area under curve measured to compare recovery with beta agonist following methacholine challenge. FEV1 will be assessed using hand held spirometry. ; SECONDARY OUTCOME: Adverse events ‐ such as injury, loss of consciousness (patient diary) Asthma symptoms questionnaire ‐ using ACQ 5 questionnaire Cardiovascular response – blood pressure and pulse measured with sphygmomanometer and pulse oximeter . Dose of salbutamol required to reach 80% recovery of FEV1. This information will be available as part of the primary outcome data using the FEV1 against time recovery graph. ; FEV1 will be assessed using hand held spirometry. Fractional exhaled nitric oxide (FeNO) PC20methacholine – Concentration of methacholine required to cause 20% drop in FEV1 as per standardised methacholine challenge protocol. FEV1 will be assessed using hand held spirometry. Patient reported symptoms: e.g. lightheadedness, shortness of breath, lethargy (patient diary) as a composite outcome INCLUSION CRITERIA: • Physician diagnosis of asthma • Airway hyper responsiveness. Demonstrated with post methacholine ( a 20 percent decrease in FEV1 at a methacholine concentration of 8 mg/mL, PC20 <8mg/ml) • Over 18 years of age ; Time to 80% recovery of FEV1 which will be assessed by plotting the recovery time graph (FEV1 against time) which is required for measuring the primary endpoint of area under the curve. The FEV1 is assessed using hand held spirometry.