A Randomised Dose-ranging Study of Tiotropium Respimat® in Children With Symptomatic Asthma Despite Inhaled Corticosteroids

Christian Vogelberg; Petra Moroni-Zentgraf; Migle Leonaviciute-Klimantaviciene; Ralf Sigmund; Eckard Hamelmann; Michael Engel; Stanley Szefler

Disclosures

Respiratory Research. 2015;16(20) 

In This Article

Methods

Study Design

This Phase II, randomised, double-blind, placebo-controlled, incomplete-crossover, dose-ranging study was conducted at 24 centres in six countries from 23 August 2011 to 25 September 2012. The study met all local legal and regulatory requirements and conformed to the Declaration of Helsinki and to Good Clinical Practice and Good Publication Practice guidelines. The protocol was approved by an independent ethics committee at each study centre, and all patients and their parents or legal guardians provided written, informed consent.

Following a 4-week run-in period, during which patients received ICS maintenance therapy with or without a leukotriene modifier, patients were randomised in a 1:1:1:1 ratio to receive once-daily tiotropium 5 μg, 2.5 μg, 1.25 μg or placebo, all delivered via the Respimat® SoftMist™ inhaler (Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany), during three 4-week treatment periods. Patients received three of the four available treatments with no washout between treatment periods (Figure 1) as pharmacodynamic steady state with tiotropium is known to be achieved after 3 weeks in patients with chronic obstructive pulmonary disease.[23,24] All study treatments (tiotropium Respimat® 5 μg, 2.5 μg, 1.25 μg and placebo Respimat®) were self-administered, under parental supervision every evening, double-blind as add-on to maintenance treatment with medium-dose ICS (200–400 μg budesonide or equivalent dose), with or without a leukotriene modifier. Patients and parents received training on the use of the Respimat® SoftMist™ inhaler at Visits 1 (screening) and 2 (randomisation), and at later visits if required. Blinding was maintained up to database lock. Rescue medication (open-label salbutamol inhaler, 100 μg per puff) was permitted during screening and the entire treatment period. The use of antibiotics was not restricted during the trial; temporary increases in the dose of ICS or addition of systemic steroids was permitted as well as the addition of short-acting theophylline preparations for the treatment of acute exacerbations.

Figure 1.

Study design. FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroids; PEF, peak expiratory flow; QD, once-daily.

A fixed block randomisation was used to ensure that a balanced number of patients was allocated to each treatment. The order of patient assignment to treatment sequences was randomised. The randomisation list was generated by Boehringer Ingelheim using a validated system with a pseudo-random number generator and supplied seed number.

Study Population

Male and female patients aged 6–11 years with a ≥6-month history of asthma and diagnosis confirmed at screening were eligible for enrolment into this study. All patients were required to have bronchodilator reversibility resulting in a forced expiratory volume in 1 second (FEV1) increase of ≥12% within 15–30 minutes after the administration of 200 μg salbutamol, and to be symptomatic at screening and prior to randomisation, as defined by a seven-question Asthma Control Questionnaire (ACQ-7) mean score of ≥1.5. All patients received maintenance therapy with ICS at a stable medium dose (200–400 μg budesonide or equivalent dose) either as monotherapy or in combination with a long-acting β2-agonist (LABA) or leukotriene modifier for ≥4 weeks prior to screening (LABAs had to be stopped at least 24 hours prior to screening; however, leukotriene modifiers were permitted throughout the trial). In addition, all patients had to have a pre-bronchodilator FEV1 60–90% of predicted normal at screening and were to demonstrate pre-bronchodilator FEV1 variability at randomisation within ±30% compared with the screening value. Exclusion criteria included a significant medical condition other than asthma, congenital heart disease, any acute asthma exacerbation or acute respiratory tract infection during the 4 weeks prior to screening, and treatment with long-acting inhaled or systemic anticholinergics or systemic (oral or intravenous) corticosteroids within 4 weeks prior to screening.

Study End Points

All study end points were assessed as a response, defined as the difference from baseline (randomisation, Visit 2) at the end of each of the three 4-week treatment periods. The primary efficacy end point was peak FEV1 within 3 hours post-dosing (peak FEV1(0–3h)). Secondary end points included trough FEV1, FEV1 area under the curve within 3 hours post-dosing (AUC(0–3h)), peak forced vital capacity within 3 hours post-dosing (FVC(0–3h)), trough FVC, FVC AUC(0–3h) and pre-dose morning and evening peak expiratory flow (PEF). Additional end points included individual FEV1 measurements over 3 hours post-dosing and mean forced expiratory flow 25–75% of the FVC at 4 weeks. ACQ-7 and Standardised Paediatric Asthma Quality of Life Questionnaire (PAQLQ[S]) were used to assess asthma control and quality of life, respectively.

Assessments

Lung function assessments were performed and vital signs assessed at Visits 1–5. Lung function assessments were performed at 30 minutes, 1 hour, 2 hours and 3 hours after inhalation of study medication at screening, at the end of the 4-week run-in period and at the end of each 4-week treatment period. Patients recorded twice-daily PEF values and details of asthma symptoms, quality of life and use of rescue medication using the Asthma Monitor® AM3® device (Care Fusion, Höchberg, Germany), combining an electronic peak flow meter and electronic diary, which were reviewed by the investigator at the start of each clinic visit. Mean PEF measurements were determined in the last week of each treatment period to avoid carry-over of previous treatment effects. ACQ-7 and PAQLQ(S) data were collected during Visits 1–5 and 2–5, respectively. Adverse events (AEs) were recorded at every visit.

Statistical Analyses

Assuming a standard deviation of 280 mL for within-patient differences in peak FEV1(0–3h), a sample size of 64 completer patients would be required using a full crossover design to detect a treatment difference of 100 mL for peak FEV1(0–3h) based on a two-sample t-test with 80% power and a probability of type I error of 2.5%. Using the equation n = 3*m/2, it was calculated that 96 patients would be required for the incomplete block design used in this study. It was therefore estimated that a sample of approximately 104 patients completing the study would be sufficient for the planned statistical analyses, allowing for a drop-out rate of 8%, as observed in a similar study in adolescent patients.[22]

The primary efficacy analysis was performed using the full analysis set, defined as all randomised patients who were treated with at least one dose of study medication, had baseline data and had at least one on-treatment efficacy measurement after a 4-week treatment period. Superiority of treatment with tiotropium Respimat® over placebo Respimat® was tested in a sequential hierarchical fashion at the level of α = 0.025 (one-sided) using a mixed model repeated measures analysis, with 'treatment' and 'period' as fixed effects and 'patient' as a random effect. The study baseline value for the end point was included in the statistical model as a covariate. Adjusted mean values, treatment contrasts, 95% confidence intervals and p values were calculated. Secondary end points were also analysed using the full analysis set and a mixed model repeated measures analysis. The treated set was used for evaluation of safety and was defined as all randomised patients who received at least one dose of study medication.

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