1. Once-daily tiotropium add-on to at least ICS improves control and reduces exacerbation risk in symptomatic asthma, independent of serum IgE or blood eosinophils
Presented by Alberto de la Hoz4 on behalf of:
Michael Thomas,1 J Christian Virchow,2 Mark Vandewalker,3 Michael Engel,4 Petra Moroni-Zentgraf,4 Reinhold Lühmann,5 Thomas Casale6
1Aldermoor Health Centre, University of Southampton, Southampton, UK; 2Department of Pneumology, Intensive Care Medicine, Zentrum für Innere Medizin, Klinik I, University Clinic Rostock, Rostock, Germany; 3Clinical Research of the Ozarks, Columbia, MO, USA; 4TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany; 5Global Biometrics and Data Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany; 6Division of Allergy and Immunology, University of South Florida Morsani College of Medicine, Tampa, FL, USA

2. Disclosures
Dr Alberto de la Hoz is an employee of the Global Medical Team at Boehringer Ingelheim

3. Introduction and aim Introduction
Over 40% of patients with asthma have symptomatic or uncontrolled disease1–3
Elevated TH2 biomarkers are often found in patients whose disease remains symptomatic despite treatment with ICS ± LABA4
Tiotropium Respimat® reduces the risk of severe exacerbations and worsening and improves asthma symptom control5,6
These effects have also been observed in subgroups of patients with serum IgE ≤ or >430 µg/La or blood eosinophil counts ≤ or >0.6 × 109b in conventional subgroup analyses7,8
Aim
To investigate whether the beneficial effects of tiotropium Respimat® add-on to ICS ± LABA on exacerbations and asthma control can be observed across the continuous range of IgE levels and eosinophil counts
1. Bateman et al. Am J Respir Crit Care Med 2004; 2. Partridge et al. Prim Care Respir J 2011; 3. Demoly et al. Eur Respir Rev 2009; 4. Price. Prim Care Respir J 2008; 5. Kerstjens et al. N Engl J Med 2012;
6. Kerstjens et al. Lancet Respir Med 2015; 7. Dahl et al. Allergy 2013; 8. Dahl et al. Thorax 2014
aEquivalent to IU/L; bEquivalent to 600 µL
ICS, inhaled corticosteroids; IgE, immunoglobulin E; LABA, long-acting β2-agonist; TH2, T helper 2

4. PrimoTinA-asthma® study design and end points
Treatment: add-on therapy
to ICS (≥800 μg budesonide or equivalent) + LABA
Follow- up
Screening
Tiotropium Respimat® 5 µga
Placebo Respimat®
Visit 1 2 3 4 5 6 9 10
Week −4 4 12 24 36 48 52
Randomisation
Co-primary end points: peak FEV1(0–3h) and trough FEV1 responses at Week 24; time to first severe exacerbation during 48 weeks (pooled)
Secondary end points included: time to first episode of asthma worsening during 48 weeks (pooled) and ACQ-7
aTwo puffs of 2.5 µg once daily
ACQ-7, seven-question Asthma Control Questionnaire; FEV1, forced expiratory volume in 1 second; peak FEV1(0−3h), peak FEV1 within 3 hours post-dose
Kerstjens et al. N Engl J Med 2012

5. MezzoTinA-asthma® study design and endpoints
Treatment: add-on therapy to ICS (400–800 μg budesonide or equivalent)
Follow- up
Screening
Tiotropium Respimat® 2.5 µga
Tiotropium Respimat® 5 µgb
Salmeterol HFA-MDI 50 µg
Placebo Respimat®
Visit 1 2 3 4 5 6 7
Week −4 4 8 12 24 27
Randomisation
Co-primary end points: peak FEV1(0–3h) and trough FEV1 responses, and ACQ-7 responder rate (pooled), at Week 24
Secondary end points included: time to first severe exacerbation and time to first episode of asthma worsening during 24 weeks (pooled)
aTwo puffs of 1.25 µg; bTwo puffs of 2.5 µg
Kerstjens et al. Lancet Respir Med 2015;

6. Methods
Analyses
Severe exacerbations: post hoc Cox regression analyses were performed:
HRs and 95% CIs were calculated across continuous ranges of eosinophils (0.05–2.00×109/L) and IgE (2–2000 μg/L), adjusted for treatment and eosinophils or IgE, and treatment by eosinophils or IgE interaction
ACQ-7 responder rates:
Post hoc logistical regression analysis was performed, adjusting for ‘study’ and including the ‘treatment’ effect
ORs and 95% CIs were calculated across continuous ranges of blood eosinophils (0.05–2.00×109/L) and total serum IgE (0–2000 μg/L)
Adjusted for treatment and eosinophils or IgE, and treatment by eosinophil or IgE interaction
Eosinophil counts and IgE levels were log-transformed for modelling
Two pairs of twin studies from BI’s Tiotropium in Asthma (TinA) development programme are in scope: the PrimoTinA-asthma® studies in patients with severe asthma and the MezzoTinA-asthma® studies in patients with moderate asthma
Classical subgroup analysis focuses on analysing the treatment effect for fixed patient groups based on categorisation of continuous baseline variables, eg IgE values (threshold 430 µg/L) and eosinophil counts (threshold 0.6 Giga/L). This was also done in the TinA programme
However, choice of thresholds for subgroup analyses often remains a topic of debate. Introduction of several thresholds and subsequent analyses increase the problem of multiplicity in testing and, hence, the likelihood to observe false-positive results. Therefore, in this presentation we complement the classical subgroup analysis through exploratory regression modelling of the treatment effect across the whole spectrum of the baseline variables IgE and eosinophils
For ACQ specifically a logistical regression model was used to estimate the odds ratios for the treatment effect tiotropium/placebo including 95% confidence intervals. Treatment by IgE-baseline-value interaction was included in the model. The same applies to the analysis of eosinophil counts
This way it is possible assess the treatment effect of an efficacy variable (here: ACQ-7) over the whole range of baseline IgE and eosinophils
CI, confidence interval; HR, hazard ratio; OR, odds ratio

7. Baseline demographics and disease characteristics
MezzoTinA-asthma® (n=2100)
PrimoTinA-asthma® (n=912)
Background therapy
ICS (400–800 µg budesonide or equivalent)
ICS (≥800 µg budesonide or equivalent) + LABA
Female, %
59.0
60.4
Age, years
43.1 ± 12.9
53.0 ± 12.4
Body mass index, kg/m2
26.8 ± 6.2
28.2 ± 6.0
Never smoked, %
83.6
75.9
Ex-smoker, %
16.4
24.1
Smoking history, pack-years
4.2 ± 2.8
5.1 ± 2.7
Duration of asthma, years
21.7 ± 14.3
30.3 ± 13.9
Age at asthma onset, years
21.4 ± 12.7
22.7 ± 12.9
FEV1 % predicted
75.1 ± 11.5
56.0 ± 13.1
ACQ-7 score
2.18 ± 0.49
2.63 ± 0.69
Treated set; pooled data. All values are mean ± standard deviation except for female gender and smoking status

8. PrimoTinA-asthma®: tiotropium Respimat® 5 µg reduces the risk of severe exacerbations across IgE and blood eosinophil ranges
Risk of severe exacerbations in the overall study population:
Tiotropium 5 µg vs placebo HR = 0.79 (95% CI: 0.62, 1.00; P=0.03)1
Blood eosinophils
Total serum IgE
Tiotropium 5 µg vs placebo HR
95% Cl 4
0.125
0.25
0.5 1 2
Favours placebo HR
Favours tiotropium
0.125
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
250
500
750
1000
1250
1500
1750
2000
Eosinophils (×109/L)
IgE (µg/L)
Number of patients above threshold
Placebo
441
296
305
130
151 57 77 25 40 13 24 7 4 11 10
359
380
236
173
194
137
156 96
121 81 97 68 80 57 69 42 61
263
Tiotropium 5 µg
Post hoc Cox regression analysis
1. Kerstjens et al. N Engl J Med 2012

9. MezzoTinA-asthma®: tiotropium Respimat® 5 µg reduces the risk of severe exacerbations across IgE and blood eosinophil ranges
Risk of severe exacerbations in the overall study population:
Tiotropium 5 µg vs placebo HR = 0.72 (95% CI: 0.45, 1.14; P=0.16)1
Blood eosinophils
Total serum IgE
Tiotropium 5 µg vs placebo HR
95% Cl 4
0.125
0.25
0.5 1 2
Favours placebo HR
Favours tiotropium
0.125
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
250
500
750
1000
1250
1500
1750
2000
Eosinophils (×109/L)
IgE (µg/L)
Number of patients above threshold
Placebo
517
510
353
354
165
158 60 63 30 22 20 12 13 7 6 8
514
509
395
304
303
240
237
197
208
168
172
148
155
127
134
111
123
387
Tiotropium 5 µg
Post hoc Cox regression analysis
1. Kerstjens et al. Lancet Respir Med 2015;

10. PrimoTinA-asthma®: tiotropium Respimat® 5 µg increases the ACQ-7 responder rate across IgE and blood eosinophil ranges
ACQ-7 responder rate in the overall study population:
Tiotropium 5 µg vs placebo: 53.9% vs 46.9%
OR = 1.32 (95% CI: 1.01, 1.73; P=0.04)
Blood eosinophils
Total serum IgE
Tiotropium 5 µg vs placebo OR
95% Cl 8 8 4 4
Favours tiotropium 2 2 OR 1 1
0.5
0.5
Favours placebo
0.25
0.25
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
250
500
750
1000
1250
1500
1750
2000
Eosinophils (×109/L)
IgE (µg/L)
Number of patients above threshold
Placebo
441
296
305
130
151 57 77 25 40 13 24 7 4 11 10
359
380
236
173
194
137
156 96
121 81 97 68 80 57 69 42 61
263
Tiotropium 5 µg
Post hoc logistical regression analysis

11. MezzoTinA-asthma®: tiotropium Respimat® 5 µg increases the ACQ-7 responder rate across IgE and blood eosinophil ranges
ACQ-7 responder rate in the overall study population:
Tiotropium 5 µg vs placebo: 64.3% vs 57.7%
OR = 1.32 (95% CI: 1.02, 1.71; P=0.03)1
Blood eosinophils
Total serum IgE
Tiotropium 5 µg vs placebo OR
95% Cl 8 8 4 4
Favours tiotropium 2 2 OR 1 1
0.5
0.5
Favours placebo
0.25
0.25
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
250
500
750
1000
1250
1500
1750
2000
Eosinophils (×109/L)
IgE (µg/L)
Number of patients above threshold
Placebo
517
353
165 60 30 22 12 7 6
514
395
304
240
197
168
148
127
111
Tiotropium 5 µg
510
354
158 63 30 20 13 12 8
509
387
303
237
208
172
155
134
123
Post hoc logistical regression analysis
Kerstjens et al. Lancet Respir Med 2015;

12. Conclusions
Once-daily tiotropium Respimat® add-on to ICS ± LABA in patients with moderate or severe symptomatic asthma:
improves asthma symptom control
reduces risk of severe exacerbations
These two effects were largely independent of IgE levels or blood eosinophil counts
These findings support the findings of previous subgroup analyses using binary cut-offs of serum IgE ≤ or >430 µg/L and blood eosinophils ≤ or >0.6×109/L
Tiotropium Respimat® add-on therapy may therefore be beneficial in symptomatic patients independent of TH2 status, avoiding the need for phenotyping before treatment