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Abstract
Background Phase III studies have demonstrated reduced exacerbation rates with tiotropium Respimat® (tioR) add-on to ICS + LABA in patients with symptomatic asthma (Kerstjens et al. NEJM 2012;367:1198–207). There are currently no reported specific treatments for asthma that work equally well in both TH2-low and TH2-high phenotypes. We explored, in patients with moderate or severe symptomatic asthma, whether TH2 status influenced tioR responses, assessed by time to first exacerbation.
Methods In two 48-week trials (PrimoTinA-asthma®: NCT00776984/NCT00772538), patients on ICS + LABA (≥800 µg budesonide or equivalent) received once-daily tioR 5 µg or placebo Respimat®. In two 24-week trials (MezzoTinA-asthma®: NCT01172808/NCT01172821), patients on ICS (400–800 µg budesonide or equivalent) received once-daily tioR 5 µg or 2.5 µg, twice-daily salmeterol 50 µg via hydrofluoroalkane metered-dose inhaler (active comparator) or placebo (identical devices in a double-dummy protocol). Pre-planned analyses (pooled data) of time to first severe exacerbation and time to first episode of asthma worsening were performed in TH2-low and TH2-high subgroups: total serum immunoglobulin (IgE) ≤ or >430 µg/L (179.2 IU/L); blood eosinophils ≤ or >0.6 × 109/L (600/μL).
Results 912 patients with severe asthma received tioR 5 µg or placebo Respimat®: 205/182 were reported with IgE >430 µg/L and 99/87 with an eosinophil count of >0.6 × 109/L. 2100 patients with moderate asthma received tioR 5 µg or 2.5 µg, salmeterol or placebo: 319/320/319/326 were reported with IgE >430 µg/L and 104/103/111/107 with an eosinophil count of >0.6 × 109/L. Time to first severe exacerbation was longer with tioR versus placebo (Table 1) in patients with severe or moderate asthma, independent of IgE and eosinophils (interaction p values [Cox regression] 0.169 and 0.754, respectively, for PrimoTinA-asthma®; analyses not performed for MezzoTinA-asthma® because of low incidence of severe exacerbations). Time to first asthma worsening was longer with tioR versus placebo (Table 1) in patients with moderate or severe asthma, independent of IgE (interaction p values 0.998 [PrimoTinA-asthma®] and 0.041 [MezzoTinA-asthma®]) and eosinophils (interaction p values 0.251 [PrimoTinA-asthma®] and 0.125 [MezzoTinA-asthma®]).
Risk of severe asthma exacerbation and asthma worsening in PrimoTinA-asthma® and MezzoTinA-asthma®
Conclusion Once-daily tiotropium Respimat® add-on to at least ICS reduced the risk of severe exacerbation and asthma worsening in patients with moderate or severe symptomatic asthma, independent of TH2 phenotype.