Respiratory Medicine (2014) 108, 1268e1276
Available online at www.sciencedirect.com
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Tiotropium in asthmatic adolescents symptomatic despite inhaled corticosteroids: A randomised dose-ranging study Christian Vogelberg a,*, Michael Engel b, Petra Moroni-Zentgraf b, Migle Leonaviciute-Klimantaviciene c, Ralf Sigmund d, John Downie e, Katja Nething d, Viktorija Vevere f, Mark Vandewalker g a Technische Universita¨t Dresden, University Hospital Carl Gustav Carus, Department of Pediatric Pneumology and Allergology, Fetscherstraße 74, 01307 Dresden, Germany b Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Straße 173, 55218 Ingelheim am Rhein, Germany c Vilnius University Hospital, Santariskiu 7, Vilnius LT-08406, Lithuania d Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88400 Biberach an der Riss, Germany e Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, Ridgefield, CT 06877, USA f zekne LV4601, Latvia Private Practice, 18th Street November 21, Re g Clinical Research of the Ozarks, 601 W Nifong Blvd, Suite 2A, Columbia, MO 65203, USA
Received 10 March 2014; accepted 30 June 2014
Available online 17 July 2014
KEYWORDS Tiotropium; Anticholinergic; Bronchodilator; Asthma; Adolescents; Inhaled corticosteroids
Summary Introduction: Tiotropium, a once-daily long-acting anticholinergic agent, has been shown to be an efficacious and safe add-on treatment for adults with symptomatic asthma, despite treatment with inhaled corticosteroids (ICS). A large proportion of asthmatic adolescents have symptomatic disease despite a wide range of therapeutic options. We investigated the efficacy and safety of three doses of tiotropium, administered in the evening (via Respimat SoftMist inhaler), versus placebo in asthmatic adolescents symptomatic despite ICS treatment. Methods: This randomised, double-blind, placebo-controlled, incomplete crossover study evaluated once-daily tiotropium 5 μg, 2.5 μg and 1.25 μg versus placebo in three 4-week treatment periods. Primary efficacy end point was change in peak forced expiratory volume in 1 s within 3 h post-dose from baseline (peak FEV1(0e3h)).
* Corresponding author. Tel.: þ49 (0) 351 458 5699; fax: þ49 (0) 351 458 4334. E-mail address:
[email protected] (C.Vogelberg). http://dx.doi.org/10.1016/j.rmed.2014.06.011 0954-6111/ª 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/3.0/).
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Results: From 139 enrolled patients, 105 were randomised to receive one of four treatment sequences. Peak FEV1(0e3h) response for tiotropium 5 μg was significantly greater versus placebo (p Z 0.0043). Trough FEV1 responses were significantly greater for tiotropium 5 μg (p < 0.00001) and 1.25 μg (p Z 0.0134) versus placebo, but not for 2.5 μg (p Z 0.0975), while FEV1 area under the curve(0e3h) responses were significant for all doses (p Z 0.00001e0.0398). Overall incidence of adverse events was balanced across treatment groups, with no dosedependent observations. The majority of adverse events were mild to moderate in intensity. Conclusion: This first study of tiotropium in adolescents with symptomatic asthma demonstrates that tiotropium is well tolerated and efficacious as add-on to maintenance treatment with ICS. ClinicalTrials.gov identifier; NCT01122680. ª 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
Introduction Asthma affects 1e18% of the global population [1] and is linked to approximately one in every 250,000 deaths worldwide, many of which are preventable [1]. It is one of the leading causes of childhood morbidity in developed countries [2]. In the USA, it has been estimated that 10% of children aged 12e18 years have asthma, with over half of these patients having symptomatic disease [3]. There are various reasons for this, including: poor adherence to treatment, regarded as most relevant within this specific age group; lack of responsiveness to treatment; genetic components; and misdiagnoses [4,5]. Therefore, a need remains for alternative and potentially improved treatment options that may help to overcome some of these limitations [4]. At least 40% of patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS) as monotherapy or in combination with long-acting b2-agonists (LABAs) [6e8]. The common treatment approach for these patients is a dose increase of ICS, with additional medications such as LABAs, leukotriene modifiers, sustainedrelease methylxanthines, oral glucocorticosteroids or antiimmunoglobulin E prescribed according to individual needs, as outlined in the National Asthma Education and Prevention Program guidelines [9]. However, the high proportion of asthmatic patients who do not achieve control with these medications suggests there is a need for alternative additional treatments, such as bronchodilator maintenance therapy added to ICS. A meta-analysis of 10 randomised, double-blind, controlled studies of asthmatic patients with severe exacerbations demonstrated that the short-acting anticholinergic bronchodilator ipratropium bromide, as add-on therapy to short-acting b2-agonists, improves lung function and reduces hospital admissions [10]. The long-term management of asthma by ipratropium bromide has not been fully elucidated, but global guidelines recommend shortacting anticholinergic bronchodilators, in combination with short-acting b2-agonists, as reliever medication for asthmatic patients [1]. The long-acting anticholinergic bronchodilator tiotropium bromide has demonstrated efficacy and tolerability as a once-daily dose in adult patients with chronic obstructive pulmonary disease [11,12]. More recently in
two proof-of-concept studies, treatment with once-daily tiotropium 5 μg (via the Respimat SoftMist inhaler [Boehringer Ingelheim, Ingelheim am Rhein, Germany], hereinafter referred to as tiotropium Respimat) for 8e16 weeks improved lung function in patients with symptomatic asthma despite receiving ICS with or without LABAs [13,14]. Furthermore, in two replicate placebo-controlled, Phase III studies, once-daily tiotropium Respimat 5 μg has been shown to reduce the risk of exacerbations and improve lung function in adult patients with symptomatic asthma despite the use of ICS plus LABAs [15]. To date, no study data have been published describing the pharmacology, efficacy or safety of tiotropium Respimat add-on to at least ICS maintenance therapy in children or adolescents with asthma. Lung function and safety findings are presented here from the first study of tiotropium Respimat add-on therapy to ICS with or without leukotriene modifiers in adolescents with symptomatic asthma.
Methods Study design This randomised, double-blind, placebo-controlled, doseranging, Phase II, incomplete crossover study was conducted at 19 centres in five countries (Germany, Latvia, Lithuania, Slovenia and the USA) from June 2010 to April 2011. After a 4-week run-in period, patients aged 12e17 years with moderate persistent asthma on medium-dose ICS were randomised in a 1:1:1:1 ratio to receive once-daily placebo or tiotropium 5 μg, 2.5 μg or 1.25 μg, all delivered via the Respimat SoftMist inhaler, every evening during each of the three 4-week treatment periods (for a total of 12 weeks, without washout between treatment periods) according to an incomplete crossover design (Fig. 1). Clinic visits were scheduled at screening (Visit 0), prior to the 4week run-in period (Visit 1), every 4 weeks during the 12week treatment period (Visits 2e5) and at the end of the 3-week follow-up period (Visit 6). Background medium-dose ICS with or without leukotriene receptor antagonists were taken throughout the study with no change in dose. Patients receiving ICS plus LABA discontinued the LABA prior to the run-in period. Open-label short-acting b2-agonist salbutamol
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Asthma Monitor AM3 : electronic diary, PEF, FEV1 Figure 1
Study design. FEV1, forced expiratory volume in 1 s; PEF, peak expiratory flow.
(albuterol) hydrofluoroalkane metered-dose inhaler (100 μg per puff) was provided as rescue medication for use during the study. Patients receiving placebo Respimat continued with background ICS with or without leukotriene receptor antagonists throughout the study, and salbutamol was provided as rescue medication. At both screening and randomisation, patients were trained in the correct use of the Respimat SoftMist inhaler using placebo inhalation solution, and on all lung function test days, trial medication was administered under the supervision of a clinician. A fixed block randomisation was used to ensure that the number of patients allocated to each treatment was balanced. The order of assignment of patients to treatment sequences at Visit 2 was also randomised. The randomisation list was generated by Boehringer Ingelheim using a validated system with a pseudo-random number generator and a supplied seed number. The study met all local legal and regulatory requirements, followed the Declaration of Helsinki and conformed to Good Clinical Practice guidelines. All patients and their parents/legal guardians gave written, informed consent prior to enrolment into the study. The protocol was approved by an independent ethics committee at each study centre. The study was registered at www. clinicaltrials.gov (NCT01122680).
Study population Male and female outpatients aged 12e17 years with a documented minimum 3-month history of asthma were eligible for enrolment into this study. All patients were symptomatic as defined by a seven-question Asthma Control Questionnaire (ACQ-7) mean score of 1.5 at screening (Visit 1) and prior to randomisation (Visit 2), had a prebronchodilator forced expiratory volume in 1 s (FEV1) >60% and 90% of the predicted normal [16], and had an FEV1 increase of at least 12% and 200 mL from baseline 15e30 min after 400 μg salbutamol at Visit 1. In patients aged 12e14 years, who are likely to have a smaller forced vital capacity, positive reversibility testing could be based solely on the relative (12%) post-bronchodilator response. Eligible patients were non-smokers or had not smoked in the year
before enrolment. Key exclusion criteria were: a significant respiratory medical condition, other than asthma (eg cystic fibrosis), or congenital heart disease; an exacerbation or acute respiratory tract infection in the 4 weeks prior to screening or during the run-in period; and treatment with a long-acting anticholinergic or systemic (oral or intravenous) corticosteroid within 4 weeks prior to screening.
Study end points and assessments The primary efficacy end point was peak FEV1 response within 3 h after administration of the maintenance and study drugs (peak FEV1(0e3h)) as a change from baseline FEV1 at the end of each of the three 4-week treatment periods. Secondary end points included: trough FEV1 response as a change from baseline pre-dose FEV1 at the end of each of the three 4-week treatment periods (measured just prior to the last administration of the randomisation treatment); FEV1 area under the curve (AUC)(0e3h) response; and pre-dose morning and evening peak expiratory flow (PEF). As an additional exploratory end point, control of asthma was assessed by ACQ-7 at the end of each 4-week treatment period. Lung function assessments were performed at 30 min, 1 h, 2 h and 3 h after inhalation of the study medication during clinic visits at screening, at the end of the 4-week run-in period and at the end of each 4-week treatment period. At each time point, FEV1 was measured from a series of at least three spirometric manoeuvres that included an acceptable test start and were free from artefacts such as coughing, and the highest FEV1 from an acceptable manoeuvre was recorded. Spirometers and their use, including daily calibration, were required to meet American Thoracic Society criteria. FEV1 and PEF were measured using the Asthma Monitor (AM3; eResearch Technology GmbH, Estenfeld, Germany), which was also used by patients as an e-diary. PEF means were determined in the last week of each treatment period to avoid carry-over of previous treatment effects. Patients completed ACQ-7 at Visit 1 and then at every visit during the treatment period. It comprised six questions for the patient and one question on FEV1 for the clinic personnel [17].
Tiotropium add-on in adolescents with symptomatic asthma Treatment compliance was assessed throughout the study based on the recorded information in the AM3 device and calculated as the number of AM3 entries indicating study medication uptake divided by the number of non-clinic days on treatment then multiplied by 100%. The analysis of safety and tolerability was descriptive in nature, and measured based on the incidence and intensity of adverse events (AEs) and changes in 12-lead electrocardiogram (assessed during screening and at the end of the treatment period), physical examination and vital signs, including pulse rate and seated blood pressure.
1271 A total of 97 patients completed all three treatment periods. Of the eight patients who prematurely discontinued study medication, two discontinued due to AEs, two due to non-compliance, one due to withdrawal of consent, one due to randomisation error, one due to an ACQ-7 score of
