Bronchoprotective tolerance with indacaterol is not modified by concomitant tiotropium in persistent asthma

Clin Exp Allergy. 2017 Oct;47(10):1239-1245. doi: 10.1111/cea.12972. Epub 2017 Aug 1.


Background: Tiotropium is a long acting muscarinic antagonist (LAMA), licensed 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 downregulation and associated tolerance induced by LABA.

Objective: We hypothesize 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 first 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 ICS/IND (P<.005) or ICS/IND/TIO (P<.05).

Conclusion and clinical relevance: Our data suggest 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 as NCT02039011.

Keywords: airway; hyperresponsiveness; long acting beta 2 agonist; long acting muscarinic antagonist.

MeSH terms

  • Adult
  • Aged
  • Asthma / diagnosis
  • Asthma / drug therapy*
  • Asthma / immunology*
  • Biomarkers
  • Bronchial Hyperreactivity / drug therapy*
  • Bronchial Hyperreactivity / immunology*
  • Drug Therapy, Combination
  • Female
  • Humans
  • Indans / administration & dosage
  • Indans / therapeutic use*
  • Male
  • Middle Aged
  • Muscarinic Antagonists / administration & dosage
  • Muscarinic Antagonists / therapeutic use*
  • Quinolones / administration & dosage
  • Quinolones / therapeutic use*
  • Respiratory Function Tests
  • Tiotropium Bromide / administration & dosage
  • Tiotropium Bromide / therapeutic use*
  • Treatment Outcome


  • Biomarkers
  • Indans
  • Muscarinic Antagonists
  • Quinolones
  • indacaterol
  • Tiotropium Bromide

Associated data