| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate persistent asthma in children 6 to 11 years old |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003555 |
| E.1.2 | Term | Asthma bronchial |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 p.m. delivered by the Respimat® inhaler in children (6 to 11 yrs old) with moderate persistent asthma on top of iCS and in comparison to placebo. 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 |
In addition, pharmacokinetic profiling in this age group should be evaluated. An optimum dose may be selected based on bronchodilator efficacy, safety evaluations and pharmacokinetics of tiotropium bromide.
There is the option to take part in pharmacogenetic testing (unspecified). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. All patients' parents (or legally accepted caregivers) must sign and date an informed consent consistent with ICH-GCP guidelines and local legislation prior to participation in the trial, i.e. prior to any study procedures including medication wash-out and restrictions. In addition, an informed assent suitable for this age group has to be obtained from patients. 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 6 and 11 years of age (up to 1 day prior to their 12th birthday at Visit 1).
3. All patients must have at least a 6-month history of asthma 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, either as mono treatment or in combination with a LABA or leukotriene modifier for at least 4 weeks before Visit 1.
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% 15 to 30 min. after 200 mcg salbutamol (albuterol) at Visit 1.
8. Patients must be able to inhale from the Respimat® inhaler correctly.
9. 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, if the abnormality defines a significant disease as defined in exclusion criterion 1. For participation in PK sampling, a haemoglobin of less than 11.3 g/dL will be regarded as exclusion criterion.
3. Patients with a history of congenital or acquired heart disease, or patients who have been hospitalised for cardiac syncope or failure during the past year.
4. Patients with any unstable or life-threatening cardiac arrhythmia, including cardiac arrhythmia requiring intervention (e.g. pacemaker implantation, catheter ablation etc.) or a chnage in drug therapy within the past year.
5. Patients with a malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years.
6. Patients with clinically significant lung diseases other than asthma, such as CF or bronchopulmonary dysplasia.
7. Patients with known active tuberculosis.
8. 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.
9. 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).
10. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution.
The following will be rarely applicable in this age group, but are mentioned for safety reasons:
11. Pregnant or nursing adolescent female patients, including female patients with a positive βHCG (serum pregnancy) testing at screening (Visit 1).
12. 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.
13. Patients who have taken an investigational drug within four weeks or six half-lives (whichever is greater) prior to Visit 1.
14. Patients who have been treated with long-acting anticholinergics (e. g. tiotropium - Spiriva®) or systemic anticholinergic treatment such as spasmolytics within 4 weeks prior to screening (Visit 1).
15. Patients who are unable to comply with pulmonary medication restrictions prior to randomisation.
16. Patients who have been treated with Anti-IgE treatment (Omalizumab –Xolair®) within the last 6 months prior to screening.
17. 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.
18. Patients who have been treated with systemic (oral or i.v.) corticosteroids within 4 weeks prior to screening (Visit 1).
19. Patients who have been treated with long-acting theophylline preparations within 4 weeks prior to screening (Visit 1) or during the run-in period.
20. 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 run-in period.
21. Patients with any acute asthma exacerbation or respiratory tract infection in the 4 weeks prior to Visit 1 (screening).
22. 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.
23. Patients with a known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated.
24. 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.5.1.1 | Timepoint(s) of evaluation of this end point |
at the end of the 4-week treatment period.
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| E.5.2 | Secondary end point(s) |
1. Trough FEV1
2. FVC peak0-3h (within 3 hours post dosing) and trough FVC (Forced Vital Capacity)
3. FEV1 (AUC0-3h) and FVC (AUC0-3h)
4. PEFam/pm: Pre-dose morning (a.m.) and evening (p.m.) peak expiratory flow (PEF), assessed by patients at home
5. Use of PRN rescue medication: number of inhalations (puffs) of unscheduled rescue salbutamol therapy used per day
6. ACQ: control of asthma as assessed by the Asthma Control Questionnaire (ACQ)
7. Night time awakenings due to asthma symptoms |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 | No |
| 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 |
| Germany |
| Hungary |
| Latvia |
| Lithuania |
| Russian Federation |
| Ukraine |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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