Data from phase 3 studies of Tiotropium ( Spiriva ) delivered via the Respimat inhaler in mild, moderate and severe asthma patients were presented at the 2014 American Academy of Allergy, Asthma & Immunology ( AAAAI ) annual meeting in San Diego.
Tiotropium is being studied to determine its efficacy and safety in treating asthma patients and is not currently approved for this indication.
The first results from the phase 3 GraziaTinA-asthma study showed that Tiotropium delivered via the Respimat inhaler improved lung function response, as measured by forced expiratory volume in one second ( FEV1 ), in patients with mild asthma who remained symptomatic while receiving low-dose inhaled corticosteroid ( ICS ) treatment.
A pre-specified subset of data from the phase 3 MezzoTinA-asthma trials showed that, in patients with moderate asthma who remained symptomatic while receiving medium-dose inhaled corticosteroid therapy, the addition of once-daily Tiotropium reduced airflow obstruction independently of allergic status, as measured by the TH2 phenotype biomarkers.
Another subset of data found the addition of once-daily Tiotropium in the phase 3 PrimoTinA-asthma trials improved lung function responses independently of concomitant use of a leukotriene receptor antagonist ( LTRA ) in patients with severe asthma.
The GraziaTinA-asthma trial is a phase 3, randomized, double-blind, parallel-group trial designed to evaluate Tiotropium delivered via the Respimat inhaler as an add-on treatment in patients with persistent asthma who remain symptomatic while receiving at least low-dose maintenance inhaled corticosteroid treatment ( 200-400 mcg Budesonide equivalent ).
The primary endpoint was FEV1 peak(0-3h) response ( change from baseline ) at 12 weeks. The key secondary endpoint was trough FEV1. Additional secondary endpoints included FEV1 area under the curve ( AUC(0-3h) ), peak expiratory flow ( PEF ) responses ( measured with the AM2+ device ) and Asthma Control Questionnaire ( ACQ-7 ) score. Of 464 treated patients, 155 received Tiotropium 5 mcg, 154 received Tiotropium 2.5 mcg, and 155 received placebo.
Both Tiotropium doses were superior to placebo in FEV1 peak(0-3h) response ( adjusted mean difference: 5 mcg, 128 mL; 2.5 mcg, 159 mL; both p less than 0.001 ) and trough FEV1 response ( adjusted mean difference: 5 mcg, 122 mL, p=0.001; 2.5 mcg, 110 mL, p=0.003 ).
FEV1 AUC(0-3h) response at each visit, versus placebo, significantly favored Tiotropium 5 mcg ( p=0.009 to p less than 0.001 ) and Tiotropium 2.5 mcg ( all p less than 0.001, except Day 1 ).
Adjusted mean PEFAM and PEFPM responses, versus placebo, each week, all favored Tiotropium 5 mcg ( all p less than 0.001 ) and 2.5 mcg ( all p less than 0.003 ).
Adjusted mean ACQ-7 score was similar across all arms ( 5 mcg, 1.391; 2.5 mcg, 1.438; placebo, 1.377 ).
The incidence of reported adverse events was similar across treatment groups: Tiotropium 5 mcg, 32.3%; Tiotropium 2.5 mcg, 31.2%; placebo, 29.0%.
Using the accepted serum IgE and eosinophil counts as biomarkers for TH2 inflammatory status, TH2-low and TH2-high subgroups were pre-defined in the MezzoTinA-asthma trials at baseline as total serum IgE less than or equal to or greater than 430 mcg/L, or blood eosinophils less than or equal to or greater than 0.6×109/L.
Of 2081 patients in the full analysis who received tiotropium or placebo, 1221/1961 were reported with IgE greater than 430 mcg/L and 404/1969 with an eosinophil count of greater than 0.6×109/L.
Both doses of Tiotropium had a similar effect on peak and trough FEV1 versus placebo, independent of IgE and eosinophil count.
Trough FEV1 also improved with both doses of Tiotropium versus placebo, independently of IgE and eosinophil count.
In all subgroups, peak FEV1(0–3h) and trough FEV1 responses among patients who received Tiotropium were within the same magnitude as responses in the active comparator Salmeterol group.
The most frequently reported treatment-emergent adverse events in both MezzoTinA-asthma phase 3 studies included asthma, PEF rate decrease and nasopharyngitis.
Of the 912 patients in the PrimoTinA-asthma trials randomized to receive either Tiotropium ( n=456 ) or placebo ( n=456 ) for 48 weeks, 205 reported pre-screening LTRA use, 200 received LTRA at baseline, and 187 had efficacy data at week 24.
Use of LTRAs was permitted during run-in and treatment. Subgroups were defined by pre-screening LTRA use: Yes/No.
Mean percent predicted FEV1 at baseline was 55% in both groups.
Lung function responses improved independent of LTRA use: peak FEV1 was 99±50 mL ( p=0.049 ) in the LTRA Yes group, and 113±28 mL ( p less than 0.001 ) in the LTRA No group ( peak FEV1 improvements independent of concomitant LTRA use [ interaction p-value=0.6742 ] ).
Trough FEV1 ( difference from placebo ) was 90±46 mL ( p=0.052 ) in the LTRA Yes group and 93±25 mL ( p less 0.001 ) in the LTRA No group ( trough FEV1 improvements independent of concomitant LTRA use [ interaction p-value=0.5218 ] ).
The most frequently reported treatment-emergent adverse events in both PrimoTinA-asthma phase 3 studies included asthma, PEF rate decrease and nasopharyngitis. ( Xagena )
Source: Boehringer-Ingelheim, 2014