| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| patients of either sex, 12 to 17 years old, with a diagnosis of severe persistent asthma |
|
| E.1.1.1 | Medical condition in easily understood language |
| female or male patients, 12 to 17 years old, with severe persistent asthma |
|
| 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 | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 the trial is to demonstrate superiority of tiotropium (5 µg and possibly 2.5 µg once daily in the evening) over placebo with regard to the primary pulmonary function endpoint after 12 weeks of treatment. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives are to evaluate efficacy of tiotropium with regard to other endpoints, and to evaluate the safety of tiotropium, compared to placebo, as add-on controller therapy on top of usual care in this patient population. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. All patients and their parent(s) (or legally accepted representative) must sign and date respectively an informed assent and an informed consent consistent with ICH GCP guidelines and local legislation prior to the patient’s participation in the trial, i.e. prior to any study procedures including medication wash-out and restrictions. A separate informed consent/assent is required for pharmacogenomic sampling (consent/assent for pharmacogenomic sampling is not a prerequisite for study entry).
2. Male or female patients between 12 and 17 years of age (at date of informed consent/assent).
3. All patients must have at least a 3-month history of asthma at the time of enrolment into the trial.
4. All patients must have been on maintenance treatment with an inhaled corticosteroid either at stable high dose in combination with another controller medication (e.g. a LABA or a leukotriene modifier), OR at stable medium dose in combination with two other controller medications (e.g. a LABA and/or a leukotriene modifier and/or a sustained release theophylline), for at least 4 weeks before Visit 1).For the lower age group (i.e. 12 to 14 year old patients) the inhaled corticosteroid dosing recommendations for “children older than 5 years” may be appropriate.
5. All patients must be symptomatic at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an ACQ mean score of ≥ 1.5.
NOTE: If the patient is not eligible due to the predefined score at Visit 1, the patient should not be further evaluated. If the patient is not eligible due to the predefined score at Visit 2, the patient’s Visit 2 can be repeated once for further assessment (see Section 6.1 for details on visit rescheduling).
6. All patients must have a pre-bronchodilator FEV1 ≥ 60% and ≤ 90% of predicted normal at Visit 1. Predicted normal values will be calculated according to Wang et al..
7. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator, considered as 100%) as compared to Visit 2 (pre-dose) must be within ± 30%.
8. All patients must confirm the diagnosis of asthma by bronchodilator reversibility at Visit 1, resulting in an increase in FEV1 of ≥ 12% and ≥ 200 mL 15 to 30 minutes after 400 μg salbutamol (albuterol). If patients in the lower age range (e.g. 12 to 14 year old patients) exhibit a very small total lung volume, positive reversibility testing might be based solely on the relative (≥12%) post-bronchodilator response.
9. All patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment.
10. Patients must be able to use the Respimat® inhaler correctly.
11. Patients must be able to perform all trial related procedures including technically acceptable spirometric manoeuvres according to ATS/ERS standards and use of the electronic diary/peak flow meter (diary compliance of at least 80% is required).
|
|
| E.4 | Principal exclusion criteria |
1. Patients with a significant disease other than asthma (e.g. cystic fibrosis).
2. Patients with a clinically relevant abnormal haematology or blood chemistry at screening (Visit 1), if the abnormality defines a significant disease as defined in exclusion criterion No. 1.
3. Patients with a history of congenital or acquired heart disease, and/or who 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 (e.g. pacemaker implantation) 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 known active tuberculosis.
7. Patients with significant (in the opinion of the investigator) alcohol or drug abuse within the past two years.
8. Patients who have undergone thoracotomy with pulmonary resection.
9. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the six weeks prior to Visit 1.
10. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the study medication delivery system.
11. Pregnant or nursing adolescent female patients, including female patients with a positive β-HCG (serum pregnancy) testing at Visit 1.
12. Female patients of child-bearing potential not using a highly effective method of birth control.
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 inhaled anticholinergics (e.g. tiotropium - Spiriva®) or systemic anticholinergic treatment such as spasmolytics within four weeks prior to Visit 1 and/or during the screening period (between Visit 1 and Visit 2).
15. Patients who have been treated with systemic (oral or intravenous) corticosteroids at a high dose (prednisolone or prednisolone equivalent > 5mg/day or > 10 mg every second day) or at a not stable low dose (prednisolone or prednisolone equivalent < 5mg/day or < 10 mg every second day) within four weeks prior to Visit 1 and/or during the screening period (between Visit 1 and Visit 2).
16. Patients who have been treated with leukotriene modifiers if not stabilised for at least four weeks prior to Visit 1 or during the screening period (between Visit 1 and Visit 2).
17. Patients who have been treated with long-acting theophylline preparations if not stabilised for at least two weeks prior to Visit 1 or during the screening period (between Visit 1 and Visit 2).
18. Patients who have been treated with anti-IgE treatment (e.g. omalizumab - Xolair®) if not stabilised for at least six months prior to Visit 1 or during the screening period (between Visit 1 and Visit 2).
19. Patients who have been treated with cromones (e.g. sodium cromoglycate and nedocromil sodium) if not stabilised within four weeks prior to Visit 1 and/or during the screening period (between Visit 1 and Visit 2).
20. Patients who have been treated with oral beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period (between Visit 1 and Visit 2).
21. Patients who have been treated with systemic oral or i.v. or s.c. beta-adrenergics within four weeks prior to Visit 1 and/or during the screening period (between Visit 1 and Visit 2).
22. Patients who have been treated with other non-approved and according to international guidelines not recommended ‘experimental’ drugs for routine asthma therapy within four weeks prior to Visit 1 or during the screening period (between Visit 1 and Visit 2).
23. Patients with any acute asthma exacerbation or respiratory tract infection in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2. In case of an asthma deterioration occurring in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2, the visit must be postponed.
24. Patients who have previously been randomised in this trial or are currently participating in another trial.
25. Patients with a known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated (in the opinion of the investigator).
26. Patients with moderate to severe renal impairment, as defined by a creatinine clearance <50 mL/min/1.73 m2 BSA, as tiotropium is a predominantly renally excreted drug. Creatinine clearance will be calculated according to Schwartz Formula.
27. Patients requiring 10 or more puffs of rescue medication (salbutamol/albuterol MDI) per day on more than 2 consecutive days in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2. In case of an asthma deterioration occurring in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2, the visit must be postponed. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the peak FEV1 response within 3 hours post dosing (FEV1 peak0-3h response) determined at the end of the 12-week treatment period.
Peak FEV1 is defined as the highest FEV1 reading observed within 3 hours after administration of the evening dose of each randomised treatment. Peak FEV1 response is defined as the change from baseline in peak FEV1.
Baseline is the pre-treatment FEV1 measured at Visit 2 in the evening 10 minutes prior to the evening dose of the patient’s usual asthma medication (if regular posology) and first dose of trial medication.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks after start of treatment with IMP |
|
| E.5.2 | Secondary end point(s) |
1.Change from baseline at the end of the 12-week treatment period in the trough forced expiratory volume in one second (trough FEV1 response).
2.Change from baseline at the end of the 12-week treatment period in the highest forced vital capacity reading observed within 3 hours after administration of the evening dose of each randomised treatment.
3.Change from baseline at the end of the 12-week treatment period in the area under the curve from zero to 3 hours of the trough forced expiratory volume and the forced vital capacity.
4.The number of responders (improvement of at least 0.5 for the ACQ) as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 12-week treatment period.
5.Number of inhalations of salbutamol (albuterol) rescue medication used per day during the 12-week treatment period.
6.Time to first severe asthma exacerbation during the 12-week treatment period.
7.Time to first asthma exacerbation during the 12-week treatment period.
8.All adverse events |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-5.12 weeks after start of treatment with IMP.
6-7.First occurrence since start of treatment with IMP within 12 weeks.
8.12 weeks after start of treatment with IMP.
|
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 30 |
| 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 |
| Argentina |
| Australia |
| Bulgaria |
| Germany |
| Guatemala |
| Hungary |
| Israel |
| Italy |
| Latvia |
| Mexico |
| Norway |
| Philippines |
| Portugal |
| South Africa |
| Ukraine |
| United States |
|
| 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
|
| last visit of the last subject undergoing the trial |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
| 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 |
Print
