University of Groningen Tiotropium Respimat efficacy and safety in asthma Doherty, Dennis E; Bleecker, Eugene R; Moroni-Zentgraf, Petra; Zaremba-Pechmann, Liliana; Kerstjens, Huib A M Published in: Journal of Allergy and Clinical Immunology: In Practice DOI: 10.1016/j.jaip.2020.04.013 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2020 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Doherty, D. E., Bleecker, E. R., Moroni-Zentgraf, P., Zaremba-Pechmann, L., & Kerstjens, H. A. M. (2020). Tiotropium Respimat efficacy and safety in asthma: Relationship to age. Journal of Allergy and Clinical Immunology: In Practice. https://doi.org/10.1016/j.jaip.2020.04.013 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 27-06-2020
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University of Groningen
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
DOI:10.1016/j.jaip.2020.04.013
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.
Document VersionPublisher's PDF, also known as Version of record
Publication date:2020
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):Doherty, D. E., Bleecker, E. R., Moroni-Zentgraf, P., Zaremba-Pechmann, L., & Kerstjens, H. A. M. (2020).Tiotropium Respimat efficacy and safety in asthma: Relationship to age. Journal of Allergy and ClinicalImmunology: In Practice. https://doi.org/10.1016/j.jaip.2020.04.013
CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.
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.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the additionof a cover page and metadata, and formatting for readability, but it is not yet the definitive version ofrecord. This version will undergo additional copyediting, typesetting and review before it is publishedin its final form, but we are providing this version to give early visibility of the article. Please note that,during the production process, errors may be discovered which could affect the content, and all legaldisclaimers that apply to the journal pertain.
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
2 Apr 2020 Tiotropium Respimat age analyses in asthma 13
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
2 Apr 2020 Tiotropium Respimat age analyses in asthma 14
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
2 Apr 2020 Tiotropium Respimat age analyses in asthma 15
References 326
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2. Kerstjens HAM, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, et al. 331 Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J 332 Med. 2012;367:1198–207. 333
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4. Paggiaro P, Halpin DMG, Buhl R, Engel M, Zubek VB, Blahova Z, et al. The effect of 339 tiotropium in symptomatic asthma despite low- to medium-dose inhaled 340 corticosteroids: A randomized controlled trial. J Allergy Clin Immunol Pract. 341 2016;4:104-113.e2. 342
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7. Kerstjens HAM, Moroni-Zentgraf P, Tashkin DP, Dahl R, Paggiaro P, Vandewalker M, 349 et al. Tiotropium improves lung function, exacerbation rate, and asthma control, 350 independent of baseline characteristics including age, degree of airway obstruction, 351 and allergic status. Respir Med. 2016;117:198–206. 352
8. Casale TB, Aalbers R, Bleecker ER, Meltzer EO, Zaremba-Pechmann L, de la Hoz A, 353 et al. Tiotropium Respimat® add-on therapy to inhaled corticosteroids in patients with 354 symptomatic asthma improves clinical outcomes regardless of baseline 355 characteristics. Respir Med. 2019;158:97–109. 356
9. Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, et al. 357 Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J 358 Med. 2010;363:1715–26. 359
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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
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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
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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
2 Apr 2020 Tiotropium Respimat age analyses in asthma 17
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
2 Apr 2020 Tiotropium Respimat age analyses in asthma 18
Tables
Table 1. Baseline demographics and disease characteristics.
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.
2 Apr 2020 Tiotropium Respimat age analyses in asthma 20
Table 2. Overall summary of adverse events.
% PrimoTinA -asthma a,b MezzoTinA -asthma a,c
Tiotropium Respimat 5 μg QD
(n=456)
Placebo
(n=456)
Tiotropium Respimat 2.5 μg QD
(n=519)
Tiotropium Respimat 5 μg QD
(n=517)
Salmeterol 50 μg BID (n=541)
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
2 Apr 2020 Tiotropium Respimat age analyses in asthma – supplementary tables 2
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
Adjusted mean ± SE 2.038±0.046
(N=241)
2.156±0.048
(N=224)
Active-placebo difference, adjusted
mean (95% CI; p value)a
–0.118
(–0.250, 0.013; 0.0766)
Patients with a clinically relevant
improvement,b n/N (%)
137/256 (53.5) 114/238 (47.9)
>60 years
Adjusted mean ± SE 1.991±0.059
(N=121)
2.153±0.055
(N=141)
Active-placebo difference, adjusted
mean (95% CI; p value)a
–0.163
(–0.321, –0.004; 0.0444)
Patients with a clinically relevant
improvement,b n/N (%)
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.
2 Apr 2020 Tiotropium Respimat age analyses in asthma – supplementary tables 3
Table E2. ACQ total score and responders at Week 24 in patients with moderate asthma (MezzoTinA-asthma). Tiotropium
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.