Accepted Manuscript

A phase III randomized controlled trial of tiotropium add-on therapy in children with
severe symptomatic asthma

Stanley J. Szefler, MD, Kevin Murphy, MD, Thomas Harper, III, MD, Attilio Boner, MD,
István Laki, MD, Michael Engel, MD, Georges El Azzi, MD, Petra Moroni-Zentgraf,
MD, Helen Finnigan, MSc, Eckard Hamelmann, MD
PII: S0091-6749(17)30218-X
DOI: 10.1016/j.jaci.2017.01.014
Reference: YMAI 12627

To appear in: Journal of Allergy and Clinical Immunology

Received Date: 7 June 2016

Revised Date: 13 December 2016
Accepted Date: 30 January 2017

Please cite this article as: Szefler SJ, Murphy K, Harper III T, Boner A, Laki I, Engel M, El Azzi G,
Moroni-Zentgraf P, Finnigan H, Hamelmann E, A phase III randomized controlled trial of tiotropium add-
on therapy in children with severe symptomatic asthma, Journal of Allergy and Clinical Immunology
(2017), doi: 10.1016/j.jaci.2017.01.014.

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 ACCEPTED MANUSCRIPT
A phase III randomized controlled trial of tiotropium add-on therapy in

children with severe symptomatic asthma

Stanley J. Szefler, MD,a Kevin Murphy, MD,b Thomas Harper, III, MD,c Attilio Boner,

MD,d István Laki, MD,e Michael Engel, MD,f Georges El Azzi, MD,f Petra Moroni-

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Zentgraf, MD,g Helen Finnigan, MSc,h and Eckard Hamelmann, MDi

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a
Department of Pediatrics, Children’s Hospital of Colorado and the University of Colorado

School of Medicine, The Breathing Institute, 13123 E. 16th Avenue, Aurora, CO 80045, USA;

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b
Boys Town National Research Hospital, 14080 Boys Town, Hospital Rd, Boys Town, NE

68010, USA; cCharleston Allergy and Asthma, 2090 Charlie Hall Blvd, Suite 301,

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Charleston, SC 29414, USA; dU.O. di Pediatria, S.S.O. Dipartimento Sperimentale di
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Pediatria, Policlinico “G. Rossi”, Piazzale L.A. Scuro, 10, 37134, Verona, Italy;
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Department of Paediatric Pulmonology, Munkacsy u. 70, Törökbálint, 2045 Hungary;
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TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Straße
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173, 55216 Ingelheim am Rhein, Germany; gBoehringer Ingelheim Pty Limited, Sydney,
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Australia; hBiostatistics and Data Sciences, Boehringer Ingelheim Ltd, Ellesfield Avenue,

Bracknell, West Berkshire, RG12 8YS, UK; iEvangelisches Krankenhaus Bielefeld, Grenzweg
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10, 33617 Bielefeld, and Allergy Center of the Ruhr University, Universitätsstraße 150,
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44801 Bochum, Germany

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Authors’ email addresses:

Stanley J. Szefler: Stanley.Szefler@childrenscolorado.org

Kevin Murphy: kevin.murphy@boystown.org

Thomas Harper, III: Thomas.harper@charlestonallergy.com

Attilio Boner: attilio.boner@univr.it

István Laki: gyermektudo@gmail.com

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Michael Engel: michael.engel@boehringer-ingelheim.com

Georges El Azzi: georges.el_azzi@boehringer-ingelheim.com

Petra Moroni-Zentgraf: petra.moroni-zentgraf@boehringer-ingelheim.com

Helen Finnigan: helen.finnigan.ext@boehringer-ingelheim.com

Eckard Hamelmann: eckard.hamelmann@evkb.de

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Corresponding author: Stanley J. Szefler, MD, Department of Pediatrics, Children’s Hospital

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of Colorado and the University of Colorado School of Medicine, The Breathing Institute,

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13123 E. 16th Avenue, Aurora, CO 80045. Phone: 720-777-0985; Fax: 720-777-7284;

Email: Stanley.Szefler@childrenscolorado.org

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Role of the funding source: This work was supported by Boehringer Ingelheim

Pharmaceuticals. M.E. and P.M.Z. are employees of Boehringer Ingelheim and were

involved in the study design and data analysis and interpretation. G.E.A. is an employee of

Boehringer Ingelheim and was involved in data analysis and interpretation. H.F. is

contracted to Boehringer Ingelheim and was involved in data analysis and interpretation.

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All authors were involved in the writing of the manuscript and the decision to submit the

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manuscript for publication.

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1 Abstract

2 Background: Studies in adults and adolescents have demonstrated that tiotropium is

3 efficacious as an add-on therapy to inhaled corticosteroids (ICS) with or without other

4 maintenance therapies in patients with moderate or severe symptomatic asthma.

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5 Objective: To assess the efficacy and safety of once-daily tiotropium Respimat add-on

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6 therapy to high-dose ICS with 1 or more controller medications, or medium-dose ICS with

7 2 or more controller medications, in the first phase III trial of tiotropium in children with

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8 severe symptomatic asthma.

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9 Methods: In this 12-week, double-blind, placebo-controlled, parallel-group trial,
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10 401 participants aged 6-11 years were randomized to receive once-daily tiotropium 5 µg

11 (2 puffs of 2.5 µg) or 2.5 µg (2 puffs of 1.25 µg), or placebo (2 puffs), administered through
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12 the Respimat device as add-on to background therapy.

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13 Results: Compared with placebo, tiotropium 5 µg add-on therapy, but not 2.5 µg, improved
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14 the primary endpoint, peak forced expiratory volume in 1 second (FEV1) within 3 hours after

15 dosing (5 µg, 139 mL [95% CI, 75-203; P < 0.001]; 2.5 µg, 35 mL [95% CI, −28-99;
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16 P = 0.27]), and the key secondary endpoint, trough FEV1 (5 µg, 87 mL [95% CI, 19-154;

17 P = 0.01]; 2.5 µg, 18 mL [95% CI, −48-85; P = 0.59]). The safety and tolerability of
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18 tiotropium were comparable with those of placebo.

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19 Conclusion: Once-daily tiotropium Respimat 5 µg improved lung function and was well

20 tolerated as add-on therapy to ICS with other maintenance therapies in children with severe

21 symptomatic asthma.

22 ClinicalTrials.gov no. NCT01634152

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23 Clinical implications

24 Once-daily tiotropium Respimat 5 µg improves lung function, with safety and tolerability

25 comparable with those of placebo, in children with severe symptomatic asthma.

26 Capsule summary

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27 Once-daily tiotropium Respimat 5 µg as add-on therapy to ICS with other maintenance

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28 therapy has been shown for the first time to provide improved lung function in children with

29 severe symptomatic asthma.

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30 Key words: Anticholinergic drug, asthma, asthma control, children, efficacy, FEV1, lung

31 function, Respimat, safety, tiotropium

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Abbreviations used

ACQ-IA: Interviewer-administered Asthma Control Questionnaire

AE: Adverse event

FEF(25-75%): Forced expiratory flow between 25% and 75% of the forced vital capacity

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FEV1: Forced expiratory volume in 1 second

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FEV1(0-3h): Forced expiratory volume in 1 second within 3 hours after dosing

FVC: Forced vital capacity

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FVC(0-3h): Forced vital capacity within 3 hours after dosing

ICS: Inhaled corticosteroids

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LABA: Long-acting β2-agonist
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LTRA: Leukotriene receptor antagonist

PEF: Peak expiratory flow

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QD: Once daily

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SD Standard deviation
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SE Standard error
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32 INTRODUCTION

33 Asthma is one of the most prevalent chronic diseases in children and adolescents,1 affecting

34 approximately 1 in 11 children in the UK2 and 10% of adolescents in the USA.3

35 The once-daily long-acting anticholinergic bronchodilator tiotropium, delivered through the

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36 Respimat Soft Mist inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany), has

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37 demonstrated efficacy as an add-on therapy to inhaled corticosteroids (ICS) with or without

38 other maintenance therapies in adults and adolescents. Based on this comprehensive clinical

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39 evidence, tiotropium is approved in several countries for the treatment of symptomatic

40 asthma in adults4-9 and in the USA for the treatment of children aged ≥12 years.10-12

41
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Furthermore, the current Global Initiative for Asthma recommendations include tiotropium
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42 add-on therapy as part of steps 4 and 5 of the stepwise approach for patients aged ≥12 years.13
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43 In children aged 6-11 years, the current Global Initiative for Asthma strategy recommends
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44 treatment with low-dose ICS, followed by a stepwise increase in ICS dose and/or additional

45 (or second class of) maintenance therapy, such as a long-acting β2-agonist (LABA) or
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46 leukotriene receptor antagonist (LTRA), if control has not been achieved.13 However,
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47 treatment according to guidelines has been reported to result in sufficient asthma control in

48 only around 50% of pediatric patients.3,14,15 This may be explained in most cases by low
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49 adherence to asthma treatment, which is of general concern in asthma patients and is notably
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50 poor in the pediatric population.16-21 Prescribing physicians may also not adhere consistently

51 to treatment guidelines and may fail to prescribe appropriate therapy or provide adequate

52 education for pediatric asthma patients, compounding the issue of poor asthma control.22,23

53 However, a proportion of patients have asthma that remains unstable or suffer from frequent

54 exacerbations despite adhering to therapy and after addressing any comorbidities.24-26

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55 Asthma exacerbations are linked with high morbidity, risk of mortality, and high treatment

56 costs.27 The risk of an asthma exacerbation increases with decreasing lung function, and

57 recurring exacerbations may lead to the development of persistent asthma in children28-30 and

58 significantly poorer lung function,28 leading to a potentially higher risk of developing chronic

59 obstructive pulmonary disease in adulthood.31,32 Pediatric patients with asthma also have

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60 higher rates of comorbidities, including depression and behavioral disorders, which rise

further with increasing asthma severity.33 Children with poorly controlled asthma are at a

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61

62 higher risk of suffering from sleep interference and nighttime awakenings, and may miss

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63 school days as a result.3,34-36 Overall, therefore, there is a need to improve adherence through

64 better communication strategies,37 and for additional options for the treatment of

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suboptimally controlled asthma.16 Safety considerations are particularly relevant in younger
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66 patients, and it is important that potential new therapies are both efficacious and well
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67 tolerated.

68 Here we present results from the first completed phase III study of once-daily tiotropium
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69 Respimat add-on therapy in children with asthma, in which the 5 µg and 2.5 µg doses were
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70 administered over 12 weeks in participants aged 6-11 years with severe symptomatic asthma.
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71 METHODS

72 Study design

73 This was a 12-week, phase III, randomized, double-blind, placebo-controlled, parallel-group

74 study (VivaTinA-asthma; NCT01634152) in children aged 6-11 years with severe

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75 symptomatic asthma. The study design is the same as that of the PensieTinA-asthma study in

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76 adolescents (aged 12-17 years) with severe symptomatic asthma12 (Fig 1A), and is part of a

77 larger pediatric investigational program that is linked to the investigational program of

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78 tiotropium conducted in adult and adolescent asthma patients. The trial was conducted at

79 92 sites in 17 countries (Argentina, Australia, Belgium, Brazil, Canada, Czech Republic,

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Germany, Guatemala, Hungary, Latvia, Lithuania, Poland, Romania, Russia, Slovakia,
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81 Ukraine, and the USA).
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82 Study population
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83 Eligible participants were aged 6-11 years with at least a 6-month documented history of
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84 asthma at enrollment, and were symptomatic at screening and before randomization, defined

85 as an interviewer-administered Asthma Control Questionnaire (ACQ-IA)38 mean score of at

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86 least 1.5. Participants were required to: have been receiving maintenance therapy with ICS

87 either at a stable high dose in combination with 1 or more controller medications (e.g. LABA
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88 or LTRA) or at a stable medium dose in combination with 2 or more controller medications

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89 (e.g. LABA and/or LTRA and/or sustained-release theophylline) for at least 4 weeks before

90 screening; and have a prebronchodilator forced expiratory volume in 1 second (FEV1) of 60-

91 90% of predicted normal at screening, FEV1 reversibility of 12% or more 15-30 minutes after

92 200 µg salbutamol (albuterol), and variability of absolute FEV1 values from screening to

93 randomization within ±30%.

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94 A key exclusion criterion was a diagnosis of any significant disease other than asthma.

95 Study procedures

96 Following a 4-week screening period, participants were randomized 1:1:1 to once-daily

97 tiotropium 5 µg (2 puffs of 2.5 µg) or 2.5 µg (2 puffs of 1.25 µg), or placebo (2 puffs),

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98 administered through the Respimat Soft Mist inhaler over 12 weeks, with a 3-week follow-up

99 period after the last dose of treatment (Fig 1A). Participants were required to show

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100 compliance of 80% or more (recorded with the AM3 asthma monitor device [electronic peak

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101 flow meter and eDiary; eResearch Technology, Höchberg, Germany]) at randomization to

102 continue with the trial. Randomization was performed using a pseudo-random number

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generator with a supplied seed number, with a block size of 6.
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104 Study treatments were administered as add-on to high-dose ICS maintenance therapy
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105 (>400 µg budesonide or equivalent) with 1 or more controller medications (e.g. LABA and/or

106 LTRA) or medium-dose ICS (200-400 µg budesonide or equivalent) with 2 or more

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107 controller medications (e.g. LABA and/or LTRA and/or sustained-release theophylline).
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108 Participants self-administered medication once daily in the evening between 4 PM and 7 PM,
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109 taking ICS therapy first (if usually administered in the evening), then other controller

110 therapies, followed by trial medication. Open-label salbutamol hydrofluoroalkane metered-

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111 dose inhalers (100 µg per actuation) were provided as rescue medication during the
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112 screening, treatment, and follow-up periods. Permitted concomitant medications for the

113 treatment of acute asthma exacerbations included: temporary increases in the dose of ICS;

114 temporary addition of systemic corticosteroids, short-acting theophylline preparations,

115 systemic β2-agonists, or inhaled short-acting anticholinergics; and antibiotics.

116 The study complied with the principles of the Declaration of Helsinki and the International

117 Conference on Harmonisation for Good Clinical Practice Guidelines. Before trial initiation,

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118 the trial protocol, participant and parent/guardian information sheets, and consent forms were

119 reviewed and approved by the independent ethics committee and/or institutional review board

120 of each participating institution. Before participation in the trial, written, informed consent

121 was received from each participant’s parent or guardian, and informed assent suitable for this

122 age group was obtained from participants.

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123 Study endpoints

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124 All primary and secondary efficacy endpoints were analyzed at week 12. The primary

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125 efficacy endpoint was change from baseline (response) in peak FEV1 within 3 hours after

126 dosing (FEV1(0-3h)). The key secondary efficacy endpoint was trough FEV1 response

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(measured at the end of the dosing interval, 10 minutes before the administration of the next
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128 dose of trial medication).
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129 Other secondary efficacy endpoints included: peak forced vital capacity (FVC) response

130 within 3 hours after dosing (FVC(0-3h)) and trough FVC response; ACQ-IA score and
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131 responder rate; weekly mean asthma symptom-free days response; weekly mean rescue
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132 medication use response; and weekly mean evening peak expiratory flow (PEF) response,
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133 measured at home.

134 Further efficacy endpoints included: mean forced expiratory flow between 25% and 75% of
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135 the FVC (FEF(25-75%)) response at each time point during the 12-week treatment period; peak
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136 FEV1(0-3h) and trough FEV1 percent predicted responses at week 12; and time to first episode

137 of asthma worsening (prespecified as exacerbation; defined as a progressive increase in 1 or

138 more asthma symptoms that were outside a participant’s usual day-to-day variation, lasting

139 for 2 or more consecutive days, and/or a decrease in a participant’s best morning PEF of 30%

140 or more from their mean morning PEF for 2 or more consecutive days, recorded as described

141 below) and first severe exacerbation (defined as an episode of asthma worsening that required

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142 treatment with systemic corticosteroids for 3 or more consecutive days) over the 12-week

143 treatment period.

144 Post hoc analyses were performed on in-clinic trough PEF responses at week 12 and trough

145 FEV1/FVC responses over 12 weeks.

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146 Adverse events were recorded until 30 days after the last dose of trial medication to assess

147 safety and tolerability.

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148 Study assessments

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149 In-clinic lung function testing was conducted at screening and at every visit during the

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treatment period. Spirometers met American Thoracic Society and European Respiratory
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151 Society criteria.39 At each time point, in-clinic FEV1 and FVC responses were measured

152 from at least 3 and up to 8 spirometric maneuvers; the highest FEV1 and FVC responses from
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153 an acceptable maneuver were selected, regardless of whether they came from the same or
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154 different maneuvers.

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155 The ACQ-IA was completed at screening and at every visit during the treatment period.
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156 Rescue medication use, treatment compliance, and any worsening of asthma symptoms were

157 measured by participants at home using the AM3 device. Home-based FEV1 and PEF were
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158 measured twice daily with the AM3 device.

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159 Statistical analyses

160 Efficacy analyses were performed on the full analysis set, which was the same as the treated

161 set. Safety analyses were performed on the treated set, defined as all randomized participants

162 who received at least 1 dose of study medication.

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163 The null hypotheses were tested in a stepwise manner to control the probability of a type I

164 error (1-sided; α = 0.025). First, the superiority of tiotropium 5 µg versus placebo for peak

165 FEV1(0-3h) response at week 12 was tested. If the corresponding null hypothesis was rejected,

166 then the same null hypothesis for the 2.5 µg dose was tested. Testing for the superiority of

167 tiotropium 5 µg, and then 2.5 µg, versus placebo for the key secondary endpoint was then

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168 conducted. If at any stage the previous step was not successful, further analyses were

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169 considered descriptive, i.e. non-confirmatory, only.

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170 All lung function endpoints, ACQ-IA scores, and endpoints from the AM3 device were

171 analyzed using a restricted maximum likelihood-based mixed-effects model with repeated

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172 measures. The model included the fixed, categorical effects of “treatment”, “country”,
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173 “visit”, and “treatment-by-visit interaction”, as well as the covariates of “baseline value” and

174 “baseline value-by-visit interaction”. Baseline was defined as the pretreatment value
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175 measured at randomization in the evening 10 minutes before the evening dose of the

176 participant’s usual asthma medication and first dose of trial medication for lung function
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177 endpoints, and as the average of the 7 days immediately preceding randomization for
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178 endpoints measured using the AM3 device. “Patient” was included as random effect. ACQ-
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179 IA responder analyses were performed using the minimal clinically important difference of

180 0.5.40 Time to first severe exacerbation and time to first episode of asthma worsening were
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181 analyzed using Cox’s proportional hazards regression model with “treatment” fitted as an
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182 effect. Safety analyses were descriptive in nature.

183 Sample size was determined using a conservative 2-group t-test with a power of 80% and a

184 probability of a type I error of 2.5% (1-sided). It was determined that 125 participants per

185 treatment group were required to detect a difference of 150 mL in peak FEV1(0-3h) response,

186 assuming a common standard deviation (SD) of 420 mL.

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187 RESULTS

188 A total of 401 participants were randomized; 392 (97.8%) completed the 12-week treatment

189 period, 1 (0.2%) was not treated, and 8 (2.0%) prematurely discontinued study medication

190 (Fig 1B). Mean treatment exposure ± SD was 86.1 ± 9.1 days, and mean adherence with

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191 study medication ± SD was 82.0 ± 21.6%, recorded with the AM3 device.

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192 Baseline participant demographics and disease characteristics

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193 Overall, baseline demographics and disease characteristics were balanced between treatment

194 groups (Table I). The majority of participants were male (69.8%), 36.3% were aged 6-8

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195 years, and 63.8% were aged 9-11 years, with a mean age ± SD of 9.0 ± 1.6 years overall.
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196 Mean asthma duration ± SD was 4.9 ± 2.5 years, and 7.8% of participants had been exposed

197 to second-hand smoke. In the 3 months before screening, all participants received treatment
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198 with ICS, 78.8% received a LABA, and 85.0% received an LTRA. During the treatment
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199 period, 30.2% of participants received ICS plus 1 other controller, 69.8% received ICS plus

200 2 other controllers, 78.5% received a LABA, and 84.8% received an LTRA.
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201 Efficacy
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202 Primary endpoint

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203 Tiotropium provided a statistically significant improvement versus placebo in the primary
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204 endpoint, peak FEV1(0-3h) response at week 12, with the 5 µg dose (adjusted mean difference:

205 139 mL; 95% CI, 75-203; P < 0.001) but not with the 2.5 µg dose (adjusted mean difference:

206 35 mL; 95% CI, −28-99; P = 0.27) (Fig 2A and Table II); all subsequent analyses were

207 therefore considered descriptive.

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208 Key secondary endpoint

209 Improvements in trough FEV1 response versus placebo after 12 weeks of treatment were

210 statistically significant with the 5 µg dose (adjusted mean difference: 87 mL; 95% CI, 19-

211 154; P = 0.01) but not with the 2.5 µg dose (adjusted mean difference: 18 mL; 95% CI, −48-

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212 85; P = 0.59) (Fig 2B).

213 Other secondary endpoints

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214 Additional secondary endpoints are presented in Table II. No statistically significant

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215 differences compared with placebo were observed for adjusted mean peak FVC(0-3h) and

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216 trough FVC responses at week 12 following treatment with either dose of tiotropium.
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217 Changes in adjusted mean ACQ-IA score with both doses of tiotropium at week 12 were

218 similar to those seen with placebo; the majority of participants in all treatment groups were
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219 responders (ACQ-IA improvement of at least 0.5) after 12 weeks (tiotropium 5 µg, 80.8%;

220 tiotropium 2.5 µg, 79.4%; placebo, 76.9%). The adjusted mean number of asthma symptom-
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221 free days was increased by a similar degree in all treatment groups after 12 weeks, and there
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222 was a non-significant difference versus placebo in adjusted mean daytime rescue medication
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223 use with both tiotropium doses (Table II). Adjusted mean differences in weekly mean

224 evening PEF responses following tiotropium administration, measured at home using an
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225 unsupervised AM3 device (Table II), were inconsistent and did not correlate with the
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226 post hoc in-clinic trough PEF results (see below). When analyzed by age group, the adjusted

227 mean difference versus placebo in weekly mean evening PEF response with tiotropium was

228 inconsistent (for example, in participants aged 6-8 years: tiotropium 5 µg: 6.58 L/min; 95%

229 CI, −9.04-22.19; P = 0.41; tiotropium 2.5 µg: 5.91 L/min; 95% CI, −8.11-19.93; P = 0.41;

230 and in participants aged 9-11 years: tiotropium 5 µg: −10.66 L/min; 95% CI, −22.92-1.61;

231 P = 0.09; tiotropium 2.5 µg: −2.45 L/min; 95% CI, −15.39-10.49; P = 0.71).

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232 Further endpoints

233 Post hoc analysis of in-clinic trough PEF response at week 12 demonstrated a statistically

234 significant improvement compared with placebo for tiotropium 5 µg (adjusted mean

235 difference versus placebo: 13.80 L; 95% CI, 3.47-24.13; P = 0.009); however, the difference

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236 was not significant with the 2.5 µg dose (adjusted mean difference versus placebo: 9.55 L;

237 95% CI, −0.67-19.76; P = 0.07).

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238 Adjusted mean differences in FEF(25-75%) responses between both tiotropium doses and

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239 placebo were statistically significant at all time points throughout the study period, with the

240 exception of the 2.5 µg dose at week 8 (Fig 3). Improvements in adjusted mean peak

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FEV1(0-3h) percent predicted responses were statistically significant compared with placebo
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242 for both tiotropium doses at week 12; improvements in adjusted mean trough FEV1 percent

243 predicted responses were statistically significant with tiotropium 5 µg only (Fig 4). Post hoc
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244 analyses of adjusted mean trough FEV1/FVC responses demonstrated statistically significant
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245 improvements at all time points versus placebo with both tiotropium doses, with the
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246 exception of tiotropium 2.5 µg at week 8 (Fig 5).

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247 Seven participants (5.4%) in the tiotropium 5 µg group, 3 participants (2.2%) in the

248 tiotropium 2.5 µg group, and 8 participants (6.0%) in the placebo group experienced a severe
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249 asthma exacerbation during the treatment period. At least 1 episode of asthma worsening
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250 was reported for 35 participants (26.9%) receiving tiotropium 5 µg, 29 participants (21.3%)

251 receiving tiotropium 2.5 µg, and 47 participants (35.1%) receiving placebo. The risk of

252 severe asthma exacerbations and episodes of asthma worsening was lower with tiotropium

253 than with placebo (hazard ratios <1); however, this difference was significant only for

254 episodes of asthma worsening with tiotropium 2.5 µg versus placebo (P = 0.006).

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255 Safety and tolerability

256 The overall incidence of adverse events was lower with tiotropium 5 µg (n = 56; 43.1%) and

257 2.5 µg (n = 59; 43.4%) compared with placebo (n = 66; 49.3%). The majority of adverse

258 events were mild or moderate in intensity and the most frequently reported adverse events, by

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259 preferred term, included asthma, decreased PEF rate, nasopharyngitis, and respiratory tract

260 infection (Table III). Investigator-defined drug-related adverse events were reported for

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261 3 participants: tiotropium 5 µg, n = 1 (dizziness); placebo, n = 2 (cough, n = 1; asthma,

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262 cough, decreased appetite, fatigue, and metabolic cardiomyopathy, n = 1). Adverse events

263 leading to discontinuation were reported for 4 participants receiving tiotropium 5 µg (asthma,

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264 n = 2) or placebo (cough, n = 1; metabolic cardiomyopathy, n = 1). Eight participants
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265 reported serious adverse events, none of which was considered to be related to the study drug:

266 tiotropium 5 µg, n = 4 (asthma, n = 3; appendicitis, n = 1); tiotropium 2.5 µg, n = 2 (asthma,
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267 n = 1; epilepsy, n = 1); placebo, n = 2 (asthma, n = 1; asthmatic crisis, n = 1). No deaths

268 occurred during the trial.

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269 DISCUSSION

270 In this phase III study in children aged 6-11 years with severe symptomatic asthma, once-

271 daily tiotropium Respimat add-on to ICS plus 1 or more controller medications improved

272 lung function compared with placebo. Statistically significant improvements in the primary

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273 endpoint, peak FEV1(0-3h) response, were observed with tiotropium 5 µg only so all

274 subsequent analyses, including those for the key secondary endpoint of trough FEV1

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275 response, were considered descriptive. Likewise, improvements in the key secondary

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276 endpoint, trough FEV1 response, were statistically significant with tiotropium 5 µg only.

277 Peak FVC(0-3h) and trough FVC responses with tiotropium were not statistically significant.

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278 The safety and tolerability of tiotropium were comparable with those of placebo, consistent
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279 with previously published data in adults and adolescents.9,11,12
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280 The significant improvements in peak and trough FEV1 responses observed with tiotropium

281 in this study of children with severe symptomatic asthma are consistent with published data
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282 in adults and adolescents with comparable asthma severity, suggesting that consistent
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283 findings are generally observed across the tiotropium trial program in both adult and pediatric

284 asthma patients. In the PrimoTinA-asthma studies in adults with severe symptomatic asthma,
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285 tiotropium 5 µg led to significant improvements in both peak and trough FEV1 responses at

weeks 24 and 48.9 The PensieTinA-asthma study in adolescents with severe symptomatic
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286
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287 asthma demonstrated improvements with tiotropium versus placebo in several domains of

288 lung function, including peak and trough FEV1 responses, FEF(25-75%) responses, and morning

289 and evening PEF responses; however, findings were not statistically significant as the trial

290 did not meet the primary endpoint of peak FEV1(0-3h) response at week 12.12

291 Changes in ACQ-IA score in this study were similar between tiotropium and placebo, with

292 more than 75% of participants in all treatment arms showing an ACQ response (improvement

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293 of at least 0.5). These responder rates are similar to those observed in adolescent patients11,12

294 and greater than those observed in adults.5 These data are in line with findings that studies of

295 a second or third controller added on to ICS are unlikely to achieve the minimum important

296 difference (0.5) in ACQ score versus placebo; this may be attributable to improved adherence

297 with background medication in the trial setting, resulting in improvements from baseline in

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298 all treatment arms.41 Interestingly, despite improvements being observed in asthma control in

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299 all treatment arms, a reduction in respiratory adverse events (asthma and decreased PEF rate)

300 was observed with tiotropium compared with placebo, which may be indicative of improved

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301 asthma control, as respiratory adverse events can be considered both a safety and an efficacy

302 parameter.

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303 Statistically significant improvements in FEF(25-75%) response were observed versus placebo

304 with tiotropium across the trial duration (with the exception of tiotropium 2.5 µg at week 8).
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305 FEF(25-75%) is a reflection of small airway function,42,43 and these improvements in

306 conjunction with the observed improvements in FEV1 support the efficacy of tiotropium in
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307 children with severe symptomatic asthma.

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308 Children with severe asthma have been reported to maintain similar levels of lung function to
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309 children with less severe asthma, despite having frequent asthma symptoms.44 However, in

310 the present study, we observed statistically significant improvements with tiotropium in
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311 relation to spirometry but no significant improvements in asthma symptoms. Furthermore, it

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312 has been shown that FEV1/FVC significantly decreases as asthma severity increases in

313 children,44 and that decreases in FEV1/FVC ratio are linked to an increased risk of

314 exacerbations,45 suggesting that the improvements in FEV1/FVC with tiotropium versus

315 placebo observed in our study may be of importance.

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316 In-clinic data demonstrated a significant improvement in trough PEF response with

317 tiotropium 5 µg, whereas analysis of home-based, unsupervised measurements of evening

318 PEF using the AM3 device revealed no significant differences between tiotropium and

319 placebo, overall and by age group. This is in contrast to the significant improvements versus

320 placebo seen in home-based measurements of evening PEF in adolescents with tiotropium

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321 5 µg12 and in adults with tiotropium 5 µg and 2.5 µg.5 Comparison with these other phase III

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322 data suggest that the young participants in the current trial may have experienced difficulty

323 obtaining accurate PEF measurements at home in the absence of supervision by a medical

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324 professional.46

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325 Data on the efficacy and safety of ICS plus tiotropium compared with the combination of ICS
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326 plus LABA are becoming available.5,47,48 The MezzoTinA-asthma study in adults with

327 moderate symptomatic asthma demonstrated that tiotropium shows efficacy and tolerability
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328 comparable with those of the LABA salmeterol5; however, data on the efficacy of ICS plus

329 LABA versus ICS plus anticholinergic drugs in children are lacking. Surveillance studies
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330 have provided further reassuring information in relation to the safety and tolerability of ICS
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331 plus LABA in pediatric patients.49-52

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332 Poor medication adherence is a common issue in children, leading to suboptimal asthma

333 control.53,54 Once-daily dosing with other asthma medications has been shown to improve
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334 adherence versus twice-daily dosing.55 Once-daily dosing of tiotropium may therefore be of
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335 benefit in the stepwise addition of treatments for uncontrolled asthma in children aged 6-11

336 years with severe symptomatic asthma,13 particularly when a LABA is unsuitable or

337 ineffective.56,57 The Respimat Soft Mist inhaler may provide further benefits for pediatric

338 patients with asthma, since it is easy to use and delivers a dose independent of a patient’s

339 variable inspiratory flow, which facilitates superior lung deposition compared with

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340 alternative inhaler devices.58 However, effective and repeated instruction on inhaler

341 technique remains of considerable importance, particularly in pediatric patients.59,60

342 The results of this trial should be interpreted in the light of certain limitations. Improved

343 adherence to background medication in the clinical trial environment can lead to a marked

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344 placebo response.41 Additionally, the short duration of the study limits the analysis of severe

345 or seasonal exacerbations, asthma worsening, and asthma control endpoints, and may have

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346 affected the lung function endpoints. Lung function is the most sensitive assessment for

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347 bronchodilator medications, and was therefore selected as the primary endpoint of this study.

348 However, as a result, this trial was not fully powered for the analysis of FEV1/FVC, which

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349 may provide a more accurate reflection of asthma severity in children than FEV1.44
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350 Similarly, this trial was not powered for the analysis of important patient-reported outcomes

351 such as ACQ score or exacerbations, which require larger, long-term studies to assess.
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352 Furthermore, although smaller, short-term studies can provide valuable information over a

353 short time-frame, they may overestimate the magnitude of treatment effects and can require
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354 validation from larger confirmatory studies.61

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355 Nevertheless, the relatively large participant population in this trial increases the reliability of
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356 the study findings. These data add to the body of evidence from trials in adults and

357 adolescents that demonstrates the efficacy, safety, and tolerability of tiotropium Respimat in
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358 asthma, and provides insight into its real-world efficacy, as tiotropium was studied as an add-
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359 on to participants’ usual background therapy.

360 In conclusion, once-daily tiotropium Respimat 5 µg improves lung function and is a well-

361 tolerated bronchodilator when added to ICS plus 1 or more controller medications in children

362 aged 6-11 years with severe symptomatic asthma.

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363 Acknowledgments

364 The authors take full responsibility for the scope, direction, content of, and editorial decisions

365 relating to the manuscript, were involved at all stages of development, and have approved the

366 submitted manuscript. Stephen P. Peters, MD, PhD (Wake Forest Baptist Medical Center,

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367 Winston-Salem, North Carolina, USA) and H. William Kelly, PharmD, BCPS, FCCP

368 (University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA),

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369 although not contributing authors, acted as advisors in relation to this manuscript. This work

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370 was supported financially by Boehringer Ingelheim. Medical writing assistance, in the form

371 of the preparation and revision of the manuscript, was supported financially by Boehringer

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372 Ingelheim and provided by Helen Woodroof, PhD, of Complete HealthVizion under the
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373 authors’ conceptual direction and based on feedback from the authors.
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374 References

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461 32. McGeachie MJ, Yates KP, Zhou X, Guo F, Sternberg AL, Van Natta ML, et al. Patterns

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482 41. Bateman ED, Esser D, Chirila C, Fernandez M, Fowler M, Moroni-Zentgraf P, et al.

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489 43. Simon MR, Chinchilli VM, Phillips BR, Sorkness CA, Lemanske RF, Jr., Szefler SJ, et

490 al. Forced expiratory flow between 25% and 75% of vital capacity and FEV1/forced vital

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493 44. Bacharier LB, Strunk RC, Mauger D, White D, Lemanske RF, Jr., Sorkness CA.

494 Classifying asthma severity in children: mismatch between symptoms, medication use,
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495 and lung function. Am J Respir Crit Care Med 2004;170:426-32.

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496 45. Quezada W, Kwak ES, Reibman J, Rogers L, Mastronarde J, Teague WG, et al.
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502 is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg

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504 48. Kew KM, Evans DJW, Allison DE, Boyter AC. Long-acting muscarinic antagonists

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515 52. Stempel DA, Raphiou IH, Kral KM, Yeakey AM, Emmett AH, Prazma CM, et al. Serious
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516 asthma events with fluticasone plus salmeterol versus fluticasone alone. N Engl J Med
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517 2016;374:1822-30.

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526 56. Cates CJ, Wieland LS, Oleszczuk M, Kew KM. Safety of regular formoterol or

527 salmeterol in adults with asthma: an overview of Cochrane reviews. Cochrane Database

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533 Inhaler. Int J Pharm 2004;283:1-9.

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TABLE I. Baseline participant demographics and disease characteristics

Tiotropium 5 µg QD Tiotropium 2.5 µg QD Placebo QD

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(n = 130) (n = 136) (n = 134)

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Age (y)* 9.2 ± 1.6 8.8 ± 1.7 9.1 ± 1.6

Age (y), no. (%)

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6-8 36 (27.7) 60 (44.1) 49 (36.6)

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9-11 94 (72.3) 76 (55.9) 85 (63.4)

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Sex, no. (%)

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Male 90 (69.2) 96 (70.6) 93 (69.4)

Body mass index (kg/m2)* 18.6 ± 3.7 17.8 ± 3.5 17.9 ± 3.6

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Exposure to second-hand smoke, no. (%)

No 118 (90.8) 126 (92.6) 125 (93.3)

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Yes 12 (9.2) 10 (7.4) 9 (6.7)
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Duration of asthma (y)* 5.07 ± 2.59 4.96 ± 2.47 4.77 ± 2.39

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Prebronchodilator FEV1 at screening*

Actual (mL) 1512 ± 316 1442 ± 314 1469 ± 291

Percent predicted 76.6 ± 8.0 76.8 ± 7.7 76.2 ± 8.1

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FEV1 reversibility at screening (%)* 27.6 ± 13.1 27.5 ± 13.2 27.1 ± 13.5

FEV1*

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Actual (mL) 1595 ± 353 1569 ± 336 1552 ± 350

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Percent predicted 80.9 ± 11.8 83.6 ± 10.9 80.3 ± 11.6

FVC*

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Actual (mL) 2093 ± 474 2057 ± 494 2013 ± 457

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Percent predicted 92.0 ± 14.1 94.7 ± 12.9 90.3 ± 13.6

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FEF(25-75%)*

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Actual (L/s) 1.4 ± 0.6 1.4 ± 0.5 1.4 ± 0.6

Percent predicted 60.0 ± 21.9 62.3 ± 23.3 61.6 ± 24.4

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Weekly mean evening PEF (L/min)* 235.0 ± 67.7 236.5 ± 58.7 226.3 ± 58.0

ACQ-IA score*
TE 2.0 ± 0.4 1.9 ± 0.3 2.0 ± 0.4
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ICS dose of stable maintenance treatment (µg)*† 453 ± 250 439 ± 218 480 ± 240
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Concomitant therapies in the 3 months before screening, no. (%)

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LABA 101 (77.7) 113 (83.1) 101 (75.4)

LTRA 114 (87.7) 113 (83.1) 113 (84.3)

Concomitant therapies during the treatment period, no. (%)

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LABA 100 (76.9) 113 (83.1) 101 (75.4)

LTRA 113 (86.9) 113 (83.1) 113 (84.3)

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The treated set is shown.

ACQ-IA, Interviewer-administered Asthma Control Questionnaire; FEF(25-75%), Forced expiratory flow between 25% and 75% of the forced vital

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capacity; FEV1, Forced expiratory volume in 1 second; FVC, Forced vital capacity; ICS, Inhaled corticosteroids; LABA, Long-acting β2-agonist;

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LTRA, Leukotriene receptor antagonist; PEF, Peak expiratory flow; QD, Once daily.

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*Values are means ± standard deviation.

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†Budesonide or equivalent dose.

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TABLE II. Primary and other secondary endpoints at week 12

Active versus placebo Respimat

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Adjusted Adjusted mean of

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Treatment and parameter mean ± SE (mL) difference ± SE (mL) 95% CI P value

Peak FEV1(0-3h) response (mL)

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Tiotropium Respimat 5 µg QD (n = 128) 391 ± 26 139 ± 33 75-203 <0.0001

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Tiotropium Respimat 2.5 µg QD (n = 135) 287 ± 25 35 ± 32 −28-99 0.27

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Placebo Respimat QD (n = 130) 252 ± 25

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Peak FVC(0-3h) response (mL)

Tiotropium Respimat 5 µg QD (n = 128) 275 ± 28 30 ± 36 −40-101 0.40

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Tiotropium Respimat 2.5 µg QD (n = 135) 201 ± 27 −43 ± 36 −113-27 0.23

Placebo Respimat QD (n = 130) 244 ± 28

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Trough FVC response (mL)
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Tiotropium Respimat 5 µg QD (n = 128) 150 ± 30 9 ± 38 −66-83 0.82

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Tiotropium Respimat 2.5 µg QD (n = 135) 94 ± 29 −48 ± 37 −121-26 0.20

Placebo Respimat QD (n = 130) 141 ± 29

ACQ-IA score

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Tiotropium Respimat 5 µg QD (n = 126) 0.95 ± 0.06 −0.08 ± 0.08 −0.23-0.08 0.32

Tiotropium Respimat 2.5 µg QD (n = 136) 1.05 ± 0.06 0.02 ± 0.08 −0.13-0.17 0.80

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Placebo Respimat QD (n = 130) 1.03 ± 0.06

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Weekly mean asthma symptom-free days response

Tiotropium Respimat 5 µg QD (n = 127) 0.17 ± 0.03 0.03 ± 0.04 −0.06-0.11 0.55

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Tiotropium Respimat 2.5 µg QD (n = 136) 0.13 ± 0.03 −0.02 ± 0.04 −0.10-0.06 0.68

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Placebo Respimat QD (n = 128) 0.15 ± 0.03

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Weekly mean daytime rescue medication use
response (puffs)

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Tiotropium Respimat 5 µg QD (n = 126) −0.37 ± 0.06 −0.09 ± 0.08 −0.23-0.06 0.25

D
Tiotropium Respimat 2.5 µg QD (n = 136) −0.29 ± 0.06 −0.02 ± 0.07 −0.16-0.13 0.84

TE
Placebo Respimat QD (n = 127) −0.28 ± 0.06
EP
Weekly mean evening PEF response measured at
home (L/min)
C

Tiotropium Respimat 5 µg QD (n = 126) 3.79 ± 3.73 −4.11 ± 4.87 −13.66-5.44 0.40

AC

Tiotropium Respimat 2.5 µg QD (n = 136) 8.46 ± 3.60 0.57 ± 4.81 −8.87-10.00 0.91

Placebo Respimat QD (n = 127) 7.89 ± 3.72

35
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The full analysis set is shown. Results are adjusted for treatment, country, visit, baseline, treatment-by-visit interaction, and baseline-by-visit

interaction. Common baseline mean ± standard deviation: FEV1 = 1572 ± 346; FVC = 2.05 ± 0.48; weekly mean asthma symptom-free days =

PT
0.27 ± 0.35; daytime rescue medication use = 0.70 ± 0.78; weekly mean evening PEF = 232.60 ± 61.56.

RI
ACQ-IA, Interviewer-administered Asthma Control Questionnaire; FEV1(0-3h), Forced expiratory volume in 1 second within 3 hours after dosing;

FVC, Forced vital capacity; FVC(0-3h), Forced vital capacity within 3 hours after dosing; PEF, Peak expiratory flow; QD, Once daily.

U SC
AN
M
D
TE
C EP
AC

36
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TABLE III. Overall summary of adverse events

Tiotropium 5 µg QD Tiotropium 2.5 µg QD Placebo QD Total

PT
(n = 130) (n = 136) (n = 134) (n = 400)

RI
Participants with any AE 56 (43.1) 59 (43.4) 66 (49.3) 181 (45.3)

Participants with investigator-defined drug-related AEs 1 (0.8) 0 2 (1.5) 3 (0.8)

SC
Participants with AEs leading to discontinuation 2 (1.5) 0 2 (1.5) 4 (1.0)

U
Participants with serious AEs 4 (3.1) 2 (1.5) 2 (1.5) 8 (2.0)

AN
AEs in >2% of participants in total, by preferred term*

M
Asthma 24 (18.5) 20 (14.7) 30 (22.4) 74 (18.5)

Decreased PEF rate 15 (11.5) 15 (11.0) 20 (14.9) 50 (12.5)

D
TE
Nasopharyngitis 6 (4.6) 6 (4.4) 11 (8.2) 23 (5.8)

Viral respiratory tract infection 5 (3.8) 2 (1.5) 4 (3.0) 11 (2.8)

EP
Respiratory tract infection 3 (2.3) 1 (0.7) 5 (3.7) 9 (2.3)
Values are presented as numbers (percentages). A participant can be counted in more than 1 category. The treated set is shown.
C
AC

AE, Adverse event; PEF, Peak expiratory flow; QD, Once daily.

*Medical Dictionary for Regulatory Activities, version 18.0.

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Figure legends

FIG 1. Study design (A) and CONSORT diagram (B). Usual background therapy is defined

as high-dose ICS (>400 µg budesonide or equivalent) plus 1 or more controller therapies (e.g.

a LABA or LTRA) or medium-dose ICS (200-400 µg budesonide or equivalent) plus 2 or

PT
more controller therapies (e.g. a LABA and/or LTRA and/or sustained-release theophylline).

ICS, Inhaled corticosteroids; LABA, Long-acting β2-agonist; LTRA, Leukotriene receptor

RI
antagonist; QD, Once daily.

SC
FIG 2. Peak FEV1(0-3h) (A) and trough FEV1 (B) responses at week 12: full analysis set.

Results are adjusted for treatment, country, visit, baseline, treatment-by-visit interaction, and

U
baseline-by-visit interaction. Error bars are ± SEs. Common baseline mean FEV1 ± standard
AN
deviation is 1572 ± 346 mL. *P < 0.05; **P < 0.001 versus placebo Respimat. FEV1, Forced
M

expiratory volume in 1 second; FEV1(0-3h), Forced expiratory volume in 1 second within

3 hours after dosing; QD, Once daily; SE, Standard error.

D

FIG 3. FEF(25-75%) responses over 12 weeks: full analysis set. Results are adjusted for
TE

treatment, country, visit, baseline, treatment-by-visit interaction, and baseline-by-visit

EP

interaction. Error bars are ± SEs. Common baseline mean FEF(25-75%) ± standard deviation is

1393 ± 571 mL. *P < 0.05; **P < 0.001 versus placebo Respimat. FEF(25-75%), Forced
C

expiratory flow between 25% and 75% of the forced vital capacity; QD, Once daily;
AC

SE, Standard error.

FIG 4. Peak FEV1(0-3h) percent predicted (A) and trough FEV1 percent predicted (B)

responses at week 12: full analysis set. Results adjusted for treatment, country, visit,

baseline, treatment-by-visit interaction, and baseline-by-visit interaction. Error bars are ±

SEs. Common baseline mean FEV1 percent predicted ± standard deviation is 81.6 ± 11.5.

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*P < 0.05; **P < 0.001 versus placebo Respimat. FEV1, Forced expiratory volume in 1

second; FEV1(0-3h), Forced expiratory volume in 1 second within 3 hours after dosing;

QD, Once daily; SE, Standard error.

FIG 5. Trough FEV1/FVC responses over 12 weeks: full analysis set. Results are adjusted

PT
for treatment, country, visit, baseline, treatment-by-visit interaction, and baseline-by-visit

interaction. Error bars are ± SEs. Common baseline mean FEV1/FVC ± standard deviation is

RI
77.4 ± 10.1. *P < 0.05 versus placebo Respimat. FEV1, Forced expiratory volume in 1

SC
second; FVC, Forced vital capacity; QD, Once daily; SE, Standard error.

U
AN
M
D
TE
C EP
AC

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Figure 1A

PT
RI
A

SC
Screening Treatment: add-on to usual background therapy Follow-up

Tiotropium Respimat 5 µg QD

U
Tiotropium Respimat 2.5 µg QD
AN Placebo Respimat QD

Visit 0 1 2 3 4 5 6
M
Week –4 0 4 8 12 15

Randomization
D
TE
C EP
AC
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Figure 1B

PT
B

Participants enrolled

RI
(n = 635)

Participants excluded

SC
(n = 234)
– Adverse event
(n = 1; 0.4%)
– Did not meet inclusion

U
criteria or met
exclusion criteria
AN (n = 204; 87.2%)
– Lost to follow-up
(n = 6; 2.6%)
– Consent withdrawn
M
(n = 15; 6.4%)
– Other (n = 8; 3.4%)

Participants randomized Participants not treated

D

(n = 401) (n = 1)
TE
EP

Tiotropium Respimat Tiotropium Respimat Placebo Respimat

5 µg QD 2.5 µg QD QD
Treated set (n = 130) Treated set (n = 136) Treated set (n = 134)
Full analysis set (n = 130) Full analysis set (n = 136) Full analysis set (n = 134)
C
AC

Discontinued treatment Discontinued treatment Discontinued treatment

(n = 4; 3.1%) (n = 0) (n = 4; 3.0%)
– Adverse event – Adverse event
(n = 2; 1.5%) (n = 2; 1.5%)
– Consent withdrawn – Consent withdrawn
(n = 1; 0.8%) (n = 1; 0.7%)
– Other (n = 1; 0.8%) – Other (n = 1; 0.7%)

Completed
(n = 392; 98.0%)
 ACCEPTED MANUSCRIPT

PT
RI
Figure 2A

U SC
AN
M
D
TE

A
EP

600 ∆35 mL (–28-99)

500 ∆139 mL (75-203)

**
C
peak FEV1(0-3h) response (mL)
Adjusted mean ± SE

AC

400

300

200

100

0
Tiotropium Respimat Tiotropium Respimat Placebo Respimat
5 µg QD 2.5 µg QD QD
(n = 128) (n = 135) (n = 130)
 ACCEPTED MANUSCRIPT

PT
RI
Figure 2B

U SC
AN
M
D
TE

B
EP

500
C

400
trough FEV1 response (mL)

∆18 mL (–48-85)
Adjusted mean ± SE

AC

300
∆87 mL (19-154)*

200

100

0
Tiotropium Respimat Tiotropium Respimat Placebo Respimat
5 µg QD 2.5 µg QD QD
(n = 128) (n = 135) (n = 130)
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
Figure 3
M
D
TE

Tiotropium Respimat 5 µg QD Tiotropium Respimat 2.5 µg QD Placebo Respimat QD

0.50
EP

0.45 ** **
Adjusted mean ± SE FEF(25-75%) response (L/s)

0.40
**
C

0.35
AC

0.30 * *
0.25

0.20

0.15

0.10

0.05

0.00
Week 4 Week 8 Week 12
 ACCEPTED MANUSCRIPT

PT
RI
Figure 4A

U SC
AN
M
D
TE

A
*
∆3.6% (0.5-6.6)

**
∆6.3% (3.3-9.4)
EP

20
Adjusted mean ± SE peak FEV1(0-3h)
percent predicted response (%)

16
C
AC

12

0
Tiotropium Respimat Tiotropium Respimat Placebo Respimat
5 µg QD 2.5 µg QD QD
(n = 128) (n = 135) (n = 130)
 ACCEPTED MANUSCRIPT

PT
RI
Figure 4B

U SC
AN
M
D
TE

B
∆2.4% (–0.9-5.6)
EP

12
*
∆3.8% (0.6-7.1)
Adjusted mean ± SE trough FEV1
percent predicted response (%)

9
AC

0
Tiotropium Respimat Tiotropium Respimat Placebo Respimat
5 µg QD 2.5 µg QD QD
(n = 128) (n = 135) (n = 130)
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
Figure 5
M
D

Tiotropium Respimat 5 µg QD Tiotropium Respimat 2.5 µg QD Placebo Respimat QD

TE

90
Adjusted mean ± SE trough FEV1/FVC response (%)

EP

** * **
C

80
AC

70

0
4 8 12
Week