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Tiotropium Respimat efficacy and safety in asthmaDoherty, Dennis E; Bleecker, Eugene R; Moroni-Zentgraf, Petra; Zaremba-Pechmann,Liliana; Kerstjens, Huib A MPublished in:Journal of Allergy and Clinical Immunology: In Practice

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Tiotropium Respimat efficacy and safety in asthma: Relationship to age

Dennis E. Doherty, MD, Eugene R. Bleecker, MD, Petra Moroni-Zentgraf, MD, LilianaZaremba-Pechmann, PhD, Huib A.M. Kerstjens, MD

PII: S2213-2198(20)30364-0

DOI: https://doi.org/10.1016/j.jaip.2020.04.013

Reference: JAIP 2801

To appear in: The Journal of Allergy and Clinical Immunology: In Practice

Received Date: 11 December 2019

Revised Date: 2 April 2020

Accepted Date: 3 April 2020

Please cite this article as: Doherty DE, Bleecker ER, Moroni-Zentgraf P, Zaremba-Pechmann L,Kerstjens HAM, Tiotropium Respimat efficacy and safety in asthma: Relationship to age, The Journal ofAllergy and Clinical Immunology: In Practice (2020), doi: https://doi.org/10.1016/j.jaip.2020.04.013.

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2 Apr 2020 Tiotropium Respimat age analyses in asthma 1

Title 1

Tiotropium Respimat efficacy and safety in asthma: Relationship to age 2

Authors 3

Dennis E. Doherty MD ([email protected]),1 Eugene R. Bleecker MD 4

([email protected]),2 Petra Moroni-Zentgraf MD (petra.moroni-5

[email protected]),3 Liliana Zaremba-Pechmann PhD (liliana.zaremba-6

[email protected]),4 Huib A. M. Kerstjens MD 7

([email protected])5 8

1University of Kentucky, Lexington, KY; 2University of Arizona, Tucson, AZ; 3Boehringer 9

Ingelheim Pty. Ltd., Sydney, Australia; 4Boehringer Ingelheim, Biberach an der Riss, 10

Germany; 5University of Groningen, University Medical Center Groningen, and Groningen 11

Research Institute for Asthma and COPD, Groningen, The Netherlands 12

Corresponding author 13

Dennis E. Doherty 14

Address: 4852 Waterside Drive, Lexington, KY 40513 15

Email: [email protected] 16

Telephone : +1 859-576-2432 17

Funding information 18

The studies were funded by Boehringer Ingelheim, as were these pooled analyses. 19

Word counts 20

Abstract: 250; Manuscript: 2427 21


Conflict of interest 22

Dr. Doherty reports receiving a grant from NIH:NHLBI during the conduct of the studies 23

presented in this manuscript. Outside the submitted work he also reports receiving fees for 24

consultancy services from Boehringer Ingelheim, and speaker fees from Boehringer 25

Ingelheim and AstraZeneca. 26

Dr. Bleecker has undertaken clinical trials through his previous employer, Wake Forest 27

School of Medicine and currently by the University of Arizona, for AstraZeneca, MedImmune, 28

Boehringer Ingelheim, Cephalon/Teva, Genentech, Novartis, Regeneron, and Sanofi 29

Genzyme. He has also served as a paid consultant for AstraZeneca, MedImmune, 30

Boehringer Ingelheim, GlaxoSmithKline, Novartis, Regeneron, and Sanofi Genzyme. All of 31

these were outside the submitted work. 32

Dr. Moroni-Zentgraf is an employee of Boehringer Ingelheim, the sponsor of the studies 33

presented in this manuscript. 34

Dr. Zaremba-Pechmann is a contractor of Boehringer Ingelheim, the sponsor of the studies 35

presented in this manuscript. 36

Dr. Kerstjens has participated in part of the trials reported on this manuscript. He has 37

received fees for participation in advisory boards from Boehringer Ingelheim. Outside the 38

submitted work he reports fees for advisory board membership from GlaxoSmithKline, 39

Novartis, and Chiesi, consultancy fees from GlaxoSmithKline, Novartis, Chiesi, and 40

AstraZeneca. All above was paid to his institution. His institution has also received 41

unrestricted research and educational grants from Boehringer Ingelheim, Novartis, 42

GlaxoSmithKline. 43

44


Abstract 45

Background 46

Data are limited on the differential response to long-acting bronchodilators in older versus 47

younger adults with asthma. 48

Objective 49

To determine whether the response to tiotropium Respimat differed in older versus younger 50

patients with asthma. 51

Methods 52

Post-hoc analyses of four randomized, double-blind, placebo-controlled studies in adults with 53

asthma. Two studies compared tiotropium Respimat 5μg once-daily (QD) with placebo, both 54

added to high-dose inhaled corticosteroid (ICS) plus long-acting β2-agonist (LABA) (i.e., 55

severe asthma). The other two evaluated tiotropium 2.5 or 5μg QD, salmeterol 50μg twice-56

daily, or placebo, all added to medium-dose ICS (moderate asthma). Data were analyzed in 57

two pools: 1) severe and 2) moderate asthma. Efficacy endpoints: trough and peak forced 58

expiratory volume in 1 second (FEV1); trough forced vital capacity; Asthma Control 59

Questionnaire total score and responder percentage, all at Week 24. One set of analyses 60

was performed with age as a continuous covariate; the second was conducted in categories 61

<40, 40–60, and >60 years, with treatment-by-age subgroup interaction p-values obtained. 62

Safety was analyzed in age categories. 63

Results 64

Across the age categories, treatment-by-age subgroup interaction p-values for trough FEV1 65

were 0.13 and 0.77 for patients with severe and moderate asthma, respectively, not 66

indicating significant impact of age on overall treatment effect, with this observation 67

replicated in the two continuum analyses. The other endpoints (including safety) were also 68

not impacted by age. 69


Conclusions 70

Once-daily tiotropium Respimat add-on to ICS or ICS/LABA therapy was effective and well 71

tolerated in patients with asthma independent of age. 72

ClinicalTrials.gov: NCT00776984, NCT00772538, NCT01172808, NCT01172821. 73

74

Highlights 75

• What is already known about this topic? There is a perception that there is a 76

differential response to bronchodilators in older compared to younger patients with 77

asthma, yet this perception is based on limited data. 78

• What does this article add to our knowledge? The current analyses demonstrate that 79

the bronchodilator efficacy and safety of tiotropium Respimat is not impacted by age 80

in patients with symptomatic moderate or severe asthma. 81

• How does this impact current management guidelines? These results have important 82

therapeutic implications, since there is an increase in the aging population worldwide 83

as well as increased prevalence of asthma in older individuals. 84

Keywords 85

Asthma; pharmacotherapy; aging; long-acting β2-agonists; long-acting muscarinic 86

antagonists. 87

List of abbreviations 88

ACQ, Asthma Control Questionnaire 89

BID, twice daily 90

CI, confidence interval 91

COPD, chronic obstructive pulmonary disease 92


FEV1, forced expiratory volume in 1 second 93

FVC, forced vital capacity 94

GINA, Global Initiative for Asthma 95

ICS, inhaled corticosteroid 96

LABA, long-acting β2-agonist 97

QD, once daily 98

Sal, salmeterol 99

Tio, tiotropium 100

US, United States 101


Introduction 102

Inhaled corticosteroids (ICSs) are the primary controller therapy recommended for the 103

management of persistent asthma in adults.1 For patients with more than just occasional 104

symptoms, the current Global Initiative for Asthma (GINA) report recommends daily low-105

dose ICS alone, or as-needed use of low-dose ICS plus the long-acting β2-agonist (LABA) 106

formoterol.1 If this is insufficient to control a patient’s asthma, GINA recommends regular use 107

of an ICS-LABA combination, with the ICS dose gradually increased, and the long-acting 108

muscarinic antagonist tiotropium an add-on option for patients with asthma that is 109

uncontrolled with medium- or high-dose ICS plus LABA. Indeed, tiotropium Respimat has 110

been shown to be an effective add-on therapy to ICS plus LABA or to ICS alone in patients 111

with symptomatic asthma,2–4 and is now approved for use as asthma maintenance treatment 112

for patients from six years of age in many countries, including the United States (US) and 113

throughout the European Union (see local label for further details). 114

There is a perception that there is a differential response to bronchodilators in older 115

compared to younger patients with asthma. This perception is perhaps based on an early 116

study evaluating the short-acting β2-agonist albuterol and the short-acting muscarinic 117

antagonist ipratropium;5 to our knowledge, no studies have evaluated the effect of age on 118

the effectiveness of long-acting bronchodilators. Since asthma impacts individuals of all ages 119

with, for example, the US prevalence of asthma in those ≥65 years (7.8%) being similar to 120

that in children (7.5%),6 the current post-hoc analyses were therefore conducted to evaluate 121

the response to tiotropium Respimat across the 18–75 years age range of adults with 122

symptomatic moderate or severe asthma, when added-on to ICS or ICS/LABA maintenance 123

therapy. 124

125


Methods 126

These are analyses of data from four Phase III, randomized, double-blind, placebo-127

controlled studies. The first two studies were PrimoTinA-asthma (NCT00776984 and 128

NCT00772538), which compared tiotropium Respimat 5 μg once daily (QD) with placebo, 129

both added to high-dose ICS (≥800 μg budesonide or equivalent) plus LABA over 130

48 weeks.2 The other two studies were MezzoTinA-asthma (NCT01172808 and 131

NCT01172821), which evaluated tiotropium Respimat 2.5 μg or 5 μg QD, salmeterol 50 μg 132

twice daily (BID) via hydrofluoroalkane pressurized metered-dose inhaler, or placebo, 133

individually added to medium-dose ICS (400–800 μg budesonide or equivalent) over 24 134

weeks.3 Data were analyzed in two pools – one including the two PrimoTinA-asthma (severe 135

asthma) studies, and the other including the two MezzoTinA-asthma (moderate asthma) 136

studies. 137

Participants 138

Full inclusion and exclusion criteria for the four studies have been published previously.2,3 In 139

brief, all patients were aged 18–75 years, symptomatic (Asthma Control Questionnaire 140

[ACQ] mean score ≥1.5), with the diagnosis of asthma having been made prior to the age of 141

40 years, and either lifelong non-smokers or ex-smokers (<10 pack-years, with no smoking 142

in the year before enrollment). Patients with a diagnosis of chronic obstructive pulmonary 143

disease (COPD) were excluded. All patients provided written informed consent prior to any 144

study-related procedure. The studies were approved by the independent ethics committees 145

or research boards at each institution, and were performed in accordance with the principles 146

of the Declaration of Helsinki, and the International Conference on Harmonization notes for 147

guidance on Good Clinical Practice (ICH/CPMP/135/95). 148

Outcomes 149

Co-primary endpoints of all four studies were trough forced expiratory volume in 1 second 150

(FEV1) response (assessed within 10 min prior to study medication), and peak FEV1 within 151


3 hours post-dose, both at Week 24. Secondary endpoints included trough forced vital 152

capacity (FVC), mean ACQ total score and the percentage of ACQ responders (defined as 153

an improvement in ACQ from baseline of at least 0.5 points; this was a co-primary endpoint 154

in the two MezzoTinA-asthma studies) at Week 24. The data reported in this manuscript are 155

from post-hoc analyses of these endpoints, with one set of analyses performed with age as a 156

continuous covariate (“continuum analyses”), and the second set of analyses conducted in 157

patients subgrouped in the categories <40, 40–60, and >60 years of age (“subgroup 158

analyses”). Safety data by age category were also analyzed. Some of the tiotropium vs 159

placebo data from the subgroup analyses have previously been published,7,8 but none of the 160

salmeterol data or the continuum analyses have been published. 161

Sample size and statistical methods 162

The analyses presented in this manuscript were not formally powered, and are post-hoc and 163

exploratory in nature. 164

Three different sets of models were run – one set for the continuum analyses and two for the 165

subgroup analyses. In all three sets, trough and peak FEV1, trough FVC, and ACQ total 166

score were analyzed using mixed effects models that included “treatment”, “study”, “visit”, 167

and “treatment-by-visit” as fixed, categorical effects, and “baseline” and “baseline-by-visit” as 168

fixed, continuous covariates (where “baseline” is the value of the respective variable 169

assessed pre-dose on Day 1); ACQ responder rate was analyzed using logistic regression 170

models that included “treatment” and “study”. The first set of models, run for the continuum 171

analyses, were performed across the full age range and included age as a continuous 172

covariate. The second set of models were used to obtain the results within the age 173

subgroups. The third set of models were performed across the age subgroups to derive the 174

interaction p-value, and included “age subgroup” and “age_subgroup-by-treatment” 175

interaction. 176


Results 177

Participants 178

The current analyses included data from 912 patients in PrimoTinA-asthma and 2100 179

patients in MezzoTinA-asthma. Their baseline demographics and disease characteristics are 180

shown in Table 1. The mean age of patients in PrimoTinA-asthma was 53.0 years, and in 181

MezzoTinA-asthma 43.1 years.2,3 Other than age, the only consistent differences between 182

the three age groups were asthma duration on entry to the studies and bronchodilator 183

reversibility in liters, but not in percent. 184

Outcomes 185

In the continuum analyses, bronchodilator efficacy vs placebo in terms of trough FEV1 was 186

consistently in favor of tiotropium and not influenced by age (Figure 1a shows the results for 187

patients with severe asthma, with the results for patients with moderate asthma shown in 188

Figure 1b). This was also demonstrated in the subgroup analyses, in which the treatment-by-189

age subgroup interaction p values were both non-significant (p=0.13 for patients with severe 190

asthma [Figure 1c], and p=0.77 for patients with moderate asthma [Figure 1d]). 191

The analyses of peak FEV1 were similar to trough FEV1, with no clear influence of age on 192

bronchodilator efficacy in either the patients with severe (Figure 2a and Figure E1a in the 193

online repository) or moderate asthma (Figure 2b and Figure E1b), and non-significant 194

treatment-by-age subgroup interactions (p=0.57 and 0.97 for patients with severe and 195

moderate asthma, respectively). Further, age did not impact trough FVC in patients with 196

severe (Figure 3a and Figure E2a) or moderate asthma (Figure 3b and Figure E2b); the 197

interaction p values were 0.052 and 0.47, respectively. 198

In patients with severe asthma, the effect of the addition of tiotropium Respimat 5 µg QD on 199

mean ACQ total score was not influenced by age, either in the continuum (Figure 4a) or 200

subgroup analysis (Table E1 in the online repository), with a non-significant treatment-by-201

age subgroup interaction (p=0.13). Similarly, in patients with moderate asthma, age did not 202


influence the effect of tiotropium Respimat on mean ACQ total score (Figure 4b and Table 203

E2); the overall treatment-by-age subgroup interaction was non-significant (p=0.49). In both 204

the subgroup analysis and the continuum analysis, there was a slight decrease in salmeterol 205

efficacy with increasing age in patients with moderate asthma. 206

In the ACQ responder analyses with continuous age there was a slight influence of age in 207

both moderate and severe asthma, with a trend towards decreasing efficacy with increasing 208

age, although the low number of patients in the lowest and highest age groups resulted in 209

wide CIs (Figures 5a and 5b). In the subgroup analyses there was no consistent effect of 210

age on the efficacy of tiotropium Respimat, either for patients with severe (Table E1) or 211

moderate asthma (Table E2), with more than 50% of patients in all age groups receiving 212

tiotropium Respimat showing clinically relevant improvements from baseline. For salmeterol, 213

there was a trend to decreasing efficacy with increasing age in both the continuum (Figure 214

5b) and the subgroup (Table E2) analysis. 215

Safety 216

The overall frequencies of adverse events and serious adverse events with tiotropium 217

Respimat were unaffected by age, with the percentage of adverse events similar to those 218

observed with placebo (Table 2). Asthma serious adverse events (i.e., a flare/exacerbation 219

of asthma, based on the preferred term ‘asthma’, Medical Dictionary for Regulatory Activities 220

version 16.1), were reported by 38 patients in PrimoTinA-asthma (17 [3.7%] with tiotropium 221

Respimat 5 µg and 21 [4.6%] with placebo) and 8 patients in MezzoTinA-asthma (2 [0.4%], 1 222

[0.2%], 2 [0.4%] and 3 [0.6%] with tiotropium Respimat 2.5 and 5 µg, salmeterol and 223

placebo, respectively).2,3 There was no consistent relationship between age and occurrence 224

of this event (Table 2). 225

226


Discussion 227

Although the studies were not specifically designed to evaluate the effect of age on 228

bronchodilator efficacy or safety in patients with asthma, these post-hoc analyses were 229

designed to provide useful information about the use of tiotropium in clinical settings. The 230

analyses show that there is no differential age-based response to tiotropium in patients with 231

moderate asthma who were symptomatic on medium-dose ICS alone, or in those with 232

severe asthma not well controlled on combination therapy with high-dose ICS plus LABA. 233

The lack of an influence of age on tiotropium efficacy was especially evident for the lung 234

function endpoints. Any differences between age groups were small and not clinically 235

meaningful either in patients with moderate or severe asthma. Furthermore, the continuum 236

analyses demonstrated no clear or consistent influence of age on lung function. Similarly, for 237

asthma control, age did not influence the overall treatment effect of tiotropium in terms of 238

ACQ total score, either in the continuum or subgroup analyses. In the responder continuum 239

analyses, there appeared to be a slight fall with increasing age in the odds ratio for response 240

to tiotropium, both in patients with severe asthma and in those with moderate disease. 241

However, the percentages of patients with a clinically relevant improvement in the tiotropium 242

treatment groups was consistently above 50% in all age categories, with no indication of an 243

effect of age. In contrast, the percentage of responders on placebo increased with increasing 244

age in both disease severities, suggesting that the fall in the odds ratio for response 245

observed in the continuum analysis was due to an increasing placebo effect, and not a 246

decrease in tiotropium efficacy. 247

As with tiotropium, age did not influence the efficacy of salmeterol in terms of the 248

bronchodilator responsiveness endpoints. With increasing age there was a gradual (although 249

small) fall in the effect of salmeterol on ACQ total score and ACQ responders, both in the 250

continuum and the subgroup analyses. However, the patient numbers were not balanced 251

across age groups (with relatively few patients with moderate asthma aged over 60 years), 252

and all interaction p values were non-significant, indicating that overall there was no impact 253


of age on treatment effect, and so these results should be interpreted with caution. Indeed, 254

in a previous study in adults with asthma (mean age 42.2 years), tiotropium and salmeterol 255

had similar effects on ACQ mean score, although tiotropium had a significantly greater effect 256

on FEV1.9 257

There is a perception that β2-agonists are more effective in younger patients, whereas 258

muscarinic antagonists may be more effective in older patients. Some early preclinical 259

studies suggested that age had an impact on the activity or function of β2 or muscarinic 260

receptors,10–14 although this was not found in other preclinical studies.15,16 The perception of 261

differential efficacy is perhaps based on a clinical trial conducted nearly 30 years ago in 262

patients with mild or moderate airflow limitation, in which those below 60 years of age tended 263

to have a greater response to albuterol, whereas individuals over 60 years tended to have a 264

greater response to ipratropium.5 However, the study recruited both patients with asthma 265

and those with COPD from general medical practice settings. In the subgroup of patients 266

with asthma, although there was a slight trend to decreasing efficacy with age for albuterol, 267

age had no significant influence on the efficacy of ipratropium.5 Similarly, in a study that only 268

evaluated patients with asthma, although the efficacy of both albuterol and ipratropium was 269

lower in older than younger patients, within each age group responses to albuterol and 270

ipratropium were similar.17 Likewise, in a study that recruited patients with stable asthma, 271

both albuterol and ipratropium were effective in younger (18–25 years) and older (>65 years) 272

patients, and age was not a predictor of response to either drug.18 These studies 273

demonstrate the importance of recruiting appropriate patient populations; all of the 274

MezzoTinA-asthma studies (which utilized medium-dose ICS) and PrimoTinA-asthma 275

studies (which utilized high-dose ICS plus long-acting bronchodilators) specifically recruited 276

patients with asthma, excluding those with COPD, and showed results that were consistent 277

with previous asthma studies that employed short-acting bronchodilators. The MezzoTinA-278

asthma data extend and expand these previous data using two long-acting bronchodilators: 279

tiotropium showed similar effectiveness across the age groups studied in terms of both lung 280


function and asthma control, with the effectiveness of salmeterol on lung function not 281

impacted by age. Importantly, all treatments were well tolerated, with adverse event profiles 282

similar to placebo without evidence that side effects varied with age. 283

The main limitation of the analyses in this manuscript is the variation in sizes of the patient 284

subgroups, and especially the relatively small sizes of the below 40 years category in the 285

two PrimoTinA-asthma studies and the above 60 years category in the two MezzoTinA-286

asthma studies. However, the consistency of the tiotropium data across all endpoints in the 287

two pairs of studies suggest that our findings are unlikely to be substantially impacted by the 288

sizes of these subgroups. In addition, these analyses were not formally powered, and lack of 289

statistical significance of a treatment-by-age subgroup interaction from such analyses should 290

be interpreted with caution. A prospective, suitably designed study would be required to 291

confirm the findings. Of course, care should be taken when extrapolating the data from any 292

randomized controlled trial (where inclusion and exclusion criteria were applied to select 293

patients) to real life. 294

In conclusion, once-daily tiotropium add-on to ICS or ICS/LABA therapy improved lung 295

function and was effective and well tolerated in patients with symptomatic asthma 296

independent of age. The analyses clearly show that the bronchodilator effects of anti-297

muscarinic therapy with tiotropium are similar in younger and older patients, and so provide 298

evidence that differs from the perception that there is a reduced bronchodilator response in 299

the elderly. These findings have important therapeutic implications, since there is an 300

increase in the aging population worldwide as well as increased prevalence of asthma in 301

older individuals. 302

303


Acknowledgements 304

The authors would like to thank the investigators and patients at the investigative sites for 305

their support of these studies. The authors also thank Michael Engel and Ralf Sigmund 306

(Boehringer Ingelheim, Germany) for their input into the development of this manuscript. 307

Author contributions 308

The authors meet criteria for authorship as recommended by the International Committee of 309

Medical Journal Editors (ICMJE). Specifically, DED, ERB, PMZ, LZP and HAMK 310

substantially contributed to the conception of this manuscript, and to the interpretation of the 311

data, revised the manuscript critically for important intellectual content, provided approval of 312

the version to be published, and agree to be accountable for all aspects of the work. PMZ, 313

as an employee of the sponsor, was responsible for the tiotropium Respimat asthma clinical 314

development plan and all of the core protocols. The authors received no direct compensation 315

related to the development of the manuscript. 316

Role of the sponsors 317

The studies were funded by Boehringer Ingelheim Pharma GmbH, as were these pooled 318

analyses. 319

Writing support was provided by David Young of Young Medical Communications and 320

Consulting Ltd., which was contracted and funded by Boehringer Ingelheim 321

Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the manuscript for 322

medical and scientific accuracy as well as intellectual property considerations. 323

324

325


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12. Scarpace PJ, Baresi LA. Increased beta-adrenergic receptors in the light-density 364 membrane fraction in lungs from senescent rats. J Gerontol. 1988;43:B163-7. 365

13. Feldman RD, Limbird LE, Nadeau J, Robertson D, Wood AJ. Alterations in leukocyte 366 beta-receptor affinity with aging. A potential explanation for altered beta-adrenergic 367 sensitivity in the elderly. N Engl J Med. 1984;310:815–9. 368

14. Preuss JM, Goldie RG. Age-related changes in airway responsiveness to 369 phosphodiesterase inhibitors and activators of adenyl cyclase and guanylyl cyclase. 370 Pulm Pharmacol Ther. 1999;12:237–43. 371

15. Arakawa H, Mochizuki H, Tokuyama K, Morikawa A, Lötvall J. Airway responsiveness 372


to acetylcholine or capsaicin in immature and mature guinea pigs in vivo. Allergol Int. 373 2000;49:99–104. 374

16. Abrass IB, Scarpace PJ. Human lymphocyte beta-adrenergic receptors are unaltered 375 with age. J Gerontol. 1981;36:298–301. 376

17. Moore WC, Smith R, Krings J, Li X, Peters SP, Wenzel SE, et al. Elderly subjects with 377 asthma are less responsive to albuterol and ipratropium bromide when compared to 378 younger subjects, but have similar responses to the two drugs. Am J Respir Crit Care 379 Med. 2013;187:A4215. 380

18. Kradjan WA, Driesner NK, Abuan TH, Emmick G, Schoene RB. Effect of age on 381 bronchodilator response. Chest. 1992;101:1545–51. 382

383

384

385


Figure legends 386

Figure 1. Trough FEV1 at Week 24: Adjusted mean treatment-placebo difference continuum 387 analysis in patients with (a) severe asthma (PrimoTinA-asthma), and (b) moderate asthma 388 (MezzoTinA-asthma), and adjusted mean values and treatment–placebo differences in age 389 categories in patients with (c) severe asthma (PrimoTinA-asthma), and (d) moderate asthma 390 (MezzoTinA-asthma). 391

Footnote: Full analysis set. Pooled data; panels a and c are add-on to inhaled corticosteroid plus 392 long-acting β2-agonist; panels b and d are add-on to inhaled corticosteroid. Data plotted are adjusted 393 mean treatment-placebo difference and 95% CI in panels a and b, and adjusted mean ± standard 394 error in panels c and d. QD, once daily; BID, twice daily; FEV1, forced expiratory volume in 1 second; 395 CI, confidence interval; Tio, tiotropium; Sal, salmeterol. 396

Figure 2. Adjusted mean treatment–placebo difference in peak FEV1 at Week 24 in patients 397 with (a) severe asthma (PrimoTinA-asthma), and (b) moderate asthma (MezzoTinA-asthma). 398

Footnote: Full analysis set. Pooled data; (a) add-on to inhaled corticosteroid plus long-acting β2-399 agonist; (b) add-on to inhaled corticosteroid. Data plotted are adjusted mean treatment-placebo 400 difference and 95% confidence interval. QD, once daily; BID, twice daily; FEV1, forced expiratory 401 volume in 1 second; Tio, tiotropium; Sal, salmeterol. 402

Figure 3. Adjusted mean treatment–placebo difference in trough FVC at Week 24 in patients 403 with (a) severe asthma (PrimoTinA-asthma), and (b) moderate asthma (MezzoTinA-asthma). 404

Footnote: Full analysis set. Pooled data; (a) add-on to inhaled corticosteroid plus long-acting β2-405 agonist; (b) add-on to inhaled corticosteroid. Data plotted are adjusted mean treatment-placebo 406 difference and 95% confidence interval. QD, once daily; BID, twice daily; FVC, forced vital capacity; 407 Tio, tiotropium; Sal, salmeterol. 408

Figure 4. Adjusted mean treatment–placebo difference in ACQ total score at Week 24 in 409 patients with (a) severe asthma (PrimoTinA-asthma), and (b) moderate asthma (MezzoTinA-410 asthma). 411

Footnote: Full analysis set. Pooled data; (a) add-on to inhaled corticosteroid plus long-acting β2-412 agonist; (b) add-on to inhaled corticosteroid. Data plotted are adjusted mean treatment-placebo 413 difference and 95% confidence interval. QD, once daily; BID, twice daily; ACQ, Asthma Control 414 Questionnaire; Tio, tiotropium; Sal, salmeterol. 415

Figure 5. Treatment–placebo odds ratio for ACQ response at Week 24 in patients with (a) 416 severe asthma (PrimoTinA-asthma), and (b) moderate asthma (MezzoTinA-asthma). 417

Footnote: Full analysis set. Pooled data; (a) add-on to inhaled corticosteroid plus long-acting β2-418 agonist; (b) add-on to inhaled corticosteroid. Data plotted are treatment-placebo odds ratio and 95% 419 confidence interval. QD, once daily; BID, twice daily; ACQ, Asthma Control Questionnaire; Tio, 420 tiotropium; Sal, salmeterol. 421


Tables

Table 1. Baseline demographics and disease characteristics.

<40 / 40–60 / >60 years of age

PrimoTinA -asthma MezzoTinA -asthma

Tiotropium Respimat 5 μg QD

(n=456)

Placebo

(n=456)

Tiotropium Respimat 2.5 μg QD

(n=519)


(n=517)

Salmeterol 50 μg BID (n=541)

Placebo

(n=523)

Number of patients 69 / 258 / 129 67 / 239 / 150 209 / 259 / 51 193 / 261 / 63 237 / 253 / 51 217 / 258 / 48

Female, % 59 / 59 / 63 52 / 65 / 59 56 / 66 / 59 52 / 62 / 60 50 / 64 / 63 53 / 62 / 73

Age (years) 31±6 / 51±6 / 66±4

32±6 / 52±6 / 66±4

31±6 / 49±6 / 65±4

31±6 / 49±6 / 65±4

30±6 / 49±6 / 65±3

30±6 / 49±6 / 66±4

Body mass index (kg/m2)

27±7 / 29±6 / 28±5

27±6 / 29±7 / 28±5

25±6 / 28±6 / 29±8

26±7 / 28±6 / 28±5

25±6 / 28±6 / 29±7

26±7 / 28±6 / 28±5

Smoking status, %

Never smoked 78 / 73 / 75 69 / 76 / 83 87 / 82 / 82 86 / 79 / 78 87 / 81 / 69 94 / 81 / 83

Ex-smoker 22 / 27 / 25 31 / 24 / 17 13 / 18 / 18 14 / 21 / 22 13 / 19 / 31 6 / 19 / 17

Smoking history (pack-years)

4.2±3.1 / 5.0±2.6 / 6.6±2.7

4.0±2.6 / 5.1±2.5 / 4.5±3.0

2.5±2.1 / 4.8±2.8 / 4.6±3.6

4.0±2.5 / 4.6±3.3 / 4.9±2.8

3.3±2.8 / 4.5±2.7 / 4.6±2.6

3.4±2.0 / 4.0±2.5 / 6.1±2.6

Duration of asthma (years)

20±9 / 27±13 / 39±12

22±8 / 28±13 / 41±13

15±11 / 24±14 / 38±12

14±11 / 26±13 / 40±14

13±10 / 24±13 / 39±14

14±11 / 24±13 / 38±12

FEV1 % predicted pre-bronchodilationa

55±12 / 55±12 / 54±13

52±13 / 56±12 / 55±12

74±8 / 72±8 / 71±7

72±8 / 72±8 / 71±8

74±8 / 72±8 / 73±8

74±8 / 73±8 / 73±8


<40 / 40–60 / >60 years of age

PrimoTinA -asthma MezzoTinA -asthma


(n=456)

Placebo

(n=456)


(n=519)


(n=517)


Placebo

(n=523)

FEV1 % predicted post-bronchodilationa

63±12 / 62±13 / 60±13

59±13 / 63±13 / 62±13

91±10 / 88±11 / 89±14

88±10 / 87±11 / 87±16

90±11 / 89±12 / 88±10

90±10 / 89±11 / 88±11

FVC % predicted pre-bronchodilationa

78±16 / 80±16 / 80±17

77±17/ 79±16 / 80±17

93±12 / 95±14 / 97±14

92±13 / 95±14 / 97±13

92±12 / 95±14 / 97±14

93±13 / 97±14 / 98±16

FVC % predicted post-bronchodilationa

86±15 / 88±16 / 87±18

85±15 / 87±16 / 91±17

103±12 / 106±14 / 112±19

102±13 / 106±14 / 111±15

101±12 / 107±15 / 110±16

103±11 / 108±14 / 108±17

FEV1/FVC % post-bronchodilator

63±7 / 60±8 / 57±9

59±8 / 61±8 / 56±10

76±9 / 70±9 / 65±11

74±9 / 70±9 / 64±8

76±10 / 70±9 / 66±8

75±8 / 69±9 / 68±9

FEV1 reversibility (L) 0.319±0.257 / 0.219±0.201 / 0.149±0.167

0.281±0.283 / 0.223±0.240 / 0.186±0.159

0.579±0.283 / 0.456±0.208 / 0.410±0.231

0.516±0.236 / 0.431±0.204 / 0.378±0.244

0.544±0.250 / 0.471±0.264 / 0.374±0.134

0.552±0.248 / 0.445±0.194 / 0.342±0.143

FEV1 reversibility (%b) 19±19 / 15±14 / 13±14

17±18 / 16±17 / 15±14

24±12 / 23±9 / 25±14

22±9 / 21±10 / 23±15

22±10 / 23±12 / 21±7

22±10 / 22±9 / 22±9

ICS dose of stable maintenance treatment (μg)c

1224±521 / 1159±545 / 1239±485

1230±544 / 1181±540 / 1231±580

642±208 / 663±220 / 679±202

634±218 / 681±214 / 682±213

639±223 / 660±191 / 659±186

654±229 / 682±213 / 661±182

Treated set (pooled data). aMeasured at Visit 1(screening); bPercentage change from pre- to post-bronchodilator value; cBudesonide or equivalent dose. All values are mean ± standard deviation except where indicated. QD, once daily; BID, twice daily; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ICS, inhaled corticosteroid.


Table 2. Overall summary of adverse events.

% PrimoTinA -asthma a,b MezzoTinA -asthma a,c


(n=456)

Placebo

(n=456)


(n=519)


(n=517)


Placebo

(n=523)

Any adverse event

<40 years 73.9 79.1 61.2 58.5 55.3 53.9

40–60 years 73.6 79.9 57.1 59.0 52.2 62.0

>60 years 72.9 81.3 51.0 46.0 60.8 66.7

Asthmad adverse events

<40 years 44.9 50.7 15.8 23.3 20.3 20.7

40–60 years 40.7 53.1 17.8 19.5 17.0 23.6

>60 years 35.7 47.3 5.9 23.8 27.5 18.8

Serious adverse events

<40 years 10.1 6.0 2.4 1.6 1.3 1.8

40–60 years 7.4 8.8 1.9 2.3 1.6 2.7

>60 years 8.5 10.0 3.9 3.2 7.8 6.3

Asthmad serious adverse event

<40 years 8.7 4.5 0.5 0 0 0.5

40–60 years 3.1 5.0 0.4 0 0.8 0.8

>60 years 2.3 4.0 0 1.6 0 0

Treated set. aPooled data, with percentages calculated using the number of patients in the treatment group and age category as denominator; bAdd-on to inhaled corticosteroid plus long-acting β2-agonist; cAdd-on to inhaled corticosteroid; dBased on the preferred term ‘asthma’, Medical Dictionary for Regulatory Activities version 16.1. QD, once daily; BID, twice daily.

2 Apr 2020 Tiotropium Respimat age analyses in asthma – supplementary figure legends 1

Tiotropium Respimat efficacy and safety in asthma:

Relationship to age

Dennis E. Doherty MD, Eugene R. Bleecker MD, Petra Moroni-Zentgraf MD, Liliana

Zaremba-Pechmann PhD, Huib A. M. Kerstjens MD

Supplementary figure legends

Figure E1. Adjusted mean peak FEV1 and treatment–placebo differences at Week 24 in patients with (a) severe asthma (PrimoTinA-asthma), and (b) moderate asthma (MezzoTinA-asthma).

Full analysis set. Pooled data; (a) add-on to inhaled corticosteroid plus long-acting β2-agonist; (b) add-on to inhaled corticosteroid. Data plotted are adjusted mean ± standard error. QD, once daily; BID, twice daily; FEV1, forced expiratory volume in 1 second; CI, confidence interval.

Figure E2. Adjusted mean trough FVC and treatment–placebo differences at Week 24 in patients with (a) severe asthma (PrimoTinA-asthma), and (b) moderate asthma (MezzoTinA-asthma).

Full analysis set. Pooled data; (a) add-on to inhaled corticosteroid plus long-acting β2-agonist; (b) add-on to inhaled corticosteroid. Data plotted are adjusted mean ± standard error. QD, once daily; BID, twice daily; FVC, forced vital capacity; CI, confidence interval.

2 Apr 2020 Tiotropium Respimat age analyses in asthma – supplementary tables 1

Tiotropium Respimat efficacy and safety in asthma:

Relationship to age

Dennis E. Doherty MD, Eugene R. Bleecker MD, Petra Moroni-Zentgraf MD, Liliana

Zaremba-Pechmann PhD, Huib A. M. Kerstjens MD

Supplementary tables


Table E1. ACQ total score and responders at Week 24 in patients with severe asthma (PrimoTinA-asthma).

Tiotropium

Respimat 5 μg QD

Placebo

<40 years

Adjusted mean ± SE 1.934±0.093

(N=61)

2.214±0.094

(N=60)

Active-placebo difference, adjusted

mean (95% CI; p value)a

–0.280

(–0.540, –0.021; 0.0341)

Patients with a clinically relevant

improvement,b n/N (%)

36/69 (52.2) 26/67 (38.8)

40–60 years


(N=241)

2.156±0.048

(N=224)



–0.118

(–0.250, 0.013; 0.0766)



137/256 (53.5) 114/238 (47.9)

>60 years


(N=121)

2.153±0.055

(N=141)



–0.163

(–0.321, –0.004; 0.0444)



71/128 (55.5) 73/149 (49.0)

aInteraction p value 0.13. bDefined as an improvement in ACQ from baseline of at least 0.5 points. Full analysis set. Pooled data; add-on to inhaled corticosteroid plus long-acting β2-agonist. N = number of patients with measurements at the respective timepoint. ACQ, Asthma Control Questionnaire; QD, once daily; SE, standard error; CI, confidence interval.


Table E2. ACQ total score and responders at Week 24 in patients with moderate asthma (MezzoTinA-asthma). Tiotropium

Respimat 2.5 μg QD

Tiotropium

Respimat 5 μg QD

Salmeterol

50 µg BID

Placebo

<40 years


(N=193)

1.347±0.050

(N=178)

1.197±0.045

(N=219)

1.483±0.047

(N=196)



–0.169

(–0.301, –0.037; 0.0121)

–0.136

(–0.271, –0.001; 0.0482)

–0.286

(–0.414, –0.158; <0.0001)



132/208 (63.5) 127/192 (66.1) 162/234 (69.2) 120/216 (55.6)

40–60 years


(N=252)

1.439±0.044

(N=245)

1.407±0.044

(N=242)

1.534±0.044

(N=246)



–0.167

(–0.287, –0.046; 0.0067)

–0.095

(–0.216, 0.026; 0.1219)

–0.127

(–0.248, –0.006; 0.0405)



168/257 (65.4) 160/258 (62.0) 162/250 (64.8) 150/254 (59.1)

>60 years


(N=47)

1.463±0.088

(N=59)

1.458±0.098

(N=48)

1.568±0.101

(N=45)



–0.095

(–0.372, 0.182; 0.4997)

–0.106

(–0.369, 0.158; 0.4308)

–0.110

(–0.387, 0.167; 0.4362)



32/50 (64.0) 43/63 (68.3) 32/51 (62.7) 29/48 (60.4)

aInteraction p value 0.49. bDefined as an improvement in ACQ from baseline of at least 0.5 points. Full analysis set. Pooled data; add-on to inhaled corticosteroid. N = number of patients with measurements at the respective timepoint. ACQ, Asthma Control Questionnaire; QD, once daily; BID, twice daily; SE, standard error; CI, confidence interval.

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