Background: Tiotropium is a long acting antimuscarinic (LAMA), licenced as triple therapy with inhaled corticosteroid and long acting beta-agonist (ICS/LABA). There may be a synergistic benefit between LAMA and LABA as a consequence of receptor cross-talk, which in turn could modify beta-2 receptor down-regulation and associated tolerance induced by LABA.Objective: We hypothesise this mechanism may result in a reduction of airway hyperresponsiveness (AHR) when using triple therapy.Methods: We evaluated 14 non-smoking asthmatics using an open-label, randomized crossover design. ICS with Indacaterol and Tiotropium (IND/TIO) vs ICS with Indacaterol (IND) over 4 weeks with challenge performed after 1st and last doses at trough.Results: We found no significant difference in mannitol sensitivity, expressed as the provocative dose of mannitol required to reach a 15% drop in FEV1, or mannitol reactivity, expressed as the response dose ratio (RDR: max % fall in FEV1 / cumulative dose ) , when comparing ICS/IND/TIO to ICS/IND. Geometric mean fold differences for RDR comparing single and chronic dosing were 3.26 fold (95%CI 1.46-7.29) and 2.51 fold (95%CI 1.32-4.79) for IND and IND/TIO respectively. Furthermore, salbutamol recovery post challenge was significantly blunted after chronic compared to single dosing with either IND (P<0.005) or IND/TIO (P<0.05).Conclusion & Clinical Relevance: Our data suggests that concomitant tiotropium does not modify the bronchoprotective tolerance induced by Indacaterol, in turn suggesting that cross-talk may not be clinically relevant when using triple therapy. This study was registered on clinicaltrials.gov as NCT02039011
