E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderate persistent asthma in adolescents (12 to 17 years old) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003555 |
E.1.2 | Term | Asthma bronchial |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this trial is to evaluate the efficacy and safety of tiotropium inhalation solution (doses of 1.25 µg, 2.5 µg and 5 µg) once daily in the evening delivered by the Respimat® inhaler in adolescent asthma patients, compared to placebo and on top of inhaled corticosteroids. Patients need to be still symptomatic, i.e. not fully controlled on their current maintenance treatment |
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E.2.2 | Secondary objectives of the trial |
An optimum dose may be selected based on bronchodilator efficacy, safety evaluations and pharmacokinetic evaluations of tiotropium bromide.
Pharmacokinetic subset: For a subset of patients, it is planned to characterise the pharmacokinetics of tiotropium following the administration of the first dose and up to steady state, evaluated after the first treatment period. An interim analysis of all available PK data of at least 16 patients will be performed. Additionally, urine samples will be obtained from all willing trial participants.
24-hour-lung function subset: In a subset of patients 24h-lung function measurement is performed, with the endpoints FEV1 (AUC0-14h); FEV1 (AUC0-24h); FVC (AUC0-14h); FVC (AUC0-24h); FEV1 (AUC14-24h); FVC (AUC14-24h).
Pharmacogenetic evaluation, unspecified (optional) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. All patients and parents (or legally accepted caregiver) must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and local legislation prior to participation in the trial, i.e. prior to any study procedures including medication washout and restrictions. A separate informed consent is required for pharmacogenomic sampling (consent for pharmacogenomic sampling is not a prerequisite for study entry).
2. Male or female patients between 12 and 17 years of age.
3. All patients must have at least a 3 months history of asthma at the time of enrolment into the trial. The diagnosis must have been confirmed in the past and should be documented by at least one of the following criteria that were adapted from GINA 2008: •an increased hyperresponsiveness to histamine, metacholine, mannitol or exercise challenge or •a positive trial of glucocorticosteroids or a bronchodilator reversibility to a beta-2-adrenergic drug resulting in a FEV1 increase of ≥12% and 200 mL* or resulting in a PEF increase of ≥20% or •a diurnal PEF variability of ≥10% (twice daily measurements) or ≥20% (more than 2 PEF assessments per day). Diurnal variability is defined as the amplitude (difference between maximum and minimum value for the day) expressed as percentage of the mean daily PEF value and averaged over 7 to 14 days or •a bronchodilator reversibility to a beta-2-adrenergic drug resulting in a FEV1 increase of ≥12% and 200 mL* at Visit 1, as per inclusion criterion No.7 *please refer to inclusion criterion No.7 for exceptions
3. All patients must have a documented history of at least 3 months of asthma and fulfill the diagnostic criteria of moderate persistent asthma, according to the current GINA guidelines at the time of enrolment into the trial.
4. All patients must have been on maintenance treatment with inhaled corticosteroids at a stable medium dose (i.e., ≥400 µg to ≤800 µg budesonide or equivalent (see protocol table 3.3.1: 1), either as mono treatment or in combination with a LABA or leukotriene modifier for at least 4 weeks before Visit 1. While the LTRA is permitted throughout the trial, the LABA has to be stopped at least 24 hours prior to Visit 1, as no LABAs are permitted during the run-in and treatment periods of this trial.
5. All patients must be symptomatic (partly controlled) at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an ACQ mean score of ≥1.5.
6. All patients must have a pre-bronchodilator FEV1 >60% and ≤90% of predicted normal at Visit 1. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ±30%.
7. All patients must have an increase in FEV1 of ≥12% and 200 mL 15 minutes after 400 µg salbutamol at Visit 1. If patients in the lower age range (e.g., 12 to 15 year olds) exhibit a very small total lung volume, positive reversibility testing might be based solely on the relative (≥12%) post-bronchodilator response.
8. All patients should be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment.
9. Patients should be able to use the Respimat® inhaler correctly.
10. Patients must be able to perform all trial related procedures including technically acceptable spirometric manoeuvres, according to ATS/ERS standards and the use of the electronic diary/peak flow meter.
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E.4 | Principal exclusion criteria |
1. Patients with a significant disease other than asthma. A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient’s ability to participate in the trial.
2. Patients with clinically relevant abnormal screening haematology or blood chemistry will be excluded if the abnormality defines a significant disease as defined in exclusion criterion 1. For participation in PK sampling, a haemoglobin of less than 12.5 g/dl for female patients and less than 13.5 g/dl for male patients will be regarded as exclusion criterion.
3. Patients with a history of congenital or acquired heart disease, and/or have been hospitalised for cardiac syncope or failure during the past year.
4. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention (pacemaker implantation, catheter ablation etc.) or a change in drug therapy within the past year.
5. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years.
6. Patients with lung diseases other than asthma (e.g. CF). In case of ex-premature infants, a history of significant bronchopulmonary dysplasia (BPD) will be regarded as exclusion criterion.
7. Patients with known active tuberculosis.
8. Patients with significant alcohol or drug abuse within the past two years.
9. Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1.
10. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit (Visit 1).
11. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution.
12. Pregnant or nursing adolescent female patients, including female patients with a positive βHCG (serum pregnancy) testing at screening (Visit 1).
13. Sexually active female patients of child-bearing potential not using a highly effective method of birth control. Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year). Note: sexual abstinence is deemed to be a highly effective contraception method.
14. Patients who have taken an investigational drug within four weeks or six half-lives (whichever is greater) prior to Visit 1.
15. Patients who have been treated with long-acting anticholinergics (e. g. tiotropium - Spiriva®) within 4 weeks prior to screening (Visit 1).
16. Patients who are unable to comply with pulmonary medication restrictions prior to randomisation.
17. Patients who have been treated with Anti-IgE treatment (Omalizumab –Xolair®) within the last 6 months prior to screening.
18. Patients who are being treated with beta-blocker medication. Topical cardio-selective beta-blocker eye medications for treatment of non-narrow angle glaucoma are allowed.
19. Patients who have been treated with systemic (oral or i.v.) corticosteroids within 4 weeks prior to screening (Visit 1).
20. Patients who have been treated with long-acting theophylline preparations within 2 weeks prior to screening (Visit 1) or during the run-in period.
21. Patients who have been treated with other non-approved and according to international guidelines not recommended “experimental” drugs for routine asthma therapy (e.g. TNF-alpha blockers, methotrexate, cyclosporine) within 4 weeks prior to Screening Visit (Visit 1) or during the screening period.
22. Patients with any acute asthma exacerbation or respiratory tract infection in the 4 weeks prior to Visit 1 (screening).
23. Patients requiring more than 10 puffs of rescue medication (salbutamol/albuterol MDI) per day on more than 2 consecutive days during the run-in period.
24. Patients who have previously been randomised in this trial or are currently participating in another study.
25. Patients with a known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated.
26. Patients with moderate to severe renal impairment, as defined by a creatinine clearance <50 mL/min/1.73 m2 BSA (calculated by Schwartz Formula), as tiotropium is a predominantly renally excreted drug.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable will be forced expiratory volume in one second (FEV1). The primary efficacy endpoint is the peak FEV1 response (within 3 hours post dosing) determined at the end of the 4-week treatment period.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The Last-Patient-Out date of the overall trial will be determined by the time point when the last patient finished the complete trial including the 12-week treatment period and 21 days follow-up period. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |