E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 | 14.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10010331 |
E.1.2 | Term | Congenital, familial and genetic disorders |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic 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 is to confirm the 12-week efficacy and superiority of tiotropium 5 μg compared to placebo and to provide safety data over a minimum of 6 months.
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E.2.2 | Secondary objectives of the trial |
• Change from baseline in percent predicted forced vital capacity (FVC) (AUC0-4H) at 12 weeks.
• Change from baseline in percent predicted trough FVC at 12 weeks.
• Change from baseline in pre-bronchodilator mean forced expiratory flow between 25 -75% of FVC (FEF25-75) at 12 weeks.
• Proportion of patients with at least 1 pulmonary exacerbation during the treatment period as assessed by the Respiratory and Systemic Symptoms Questionnaire (RSSQ); using the definition as given in Fuchs et al.
•Change from baseline in Cystic fibrosis Questionnaire revised (CFQ-R) at 12 weeks.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
An optional cardiac safety assessment (ECG)
No specific sub-study title, the sub-study is implemented as global amendment in the current trial.
Revised Protocol based on Global Amendments 1 and 2 - Version: 3 Date: 25 November 2011
The ECG data are intended to support the overall assessment of the safety of tiotropium Respimat in cystic fibrosis patients. |
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E.3 | Principal inclusion criteria |
1. Patients with a documented diagnosis of CF (positive sweat chloride ≥60 mEq/liter, by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations consistent with CF accompanied by one or more clinical features with the CF phenotype.
2. Male or female patients (children less than 12 years and adolescents ≥ 12 years). Patients below 1 year of age, if eligible, can be included in the trial only for safety assessment.
3. Patients ≥ 5 years of age must be able to perform acceptable spirometric maneuvers, according to the American Thoracic Society (ATS) standards.
4. Pre-bronchodilator FEV1 >25% of predicted values:
•pediatric/adolescent (≥ 5 years up to 18 years of age, inclusive) predicted equations from: Wang X et al.
•adult (>18 years) predicted equations from: Knudson RJ et al. Changes in normal maximal expiratory flow-volume curve with growth.
5. Patients must be able to inhale medication in a reproducible manner from the Respimat® inhaler and from a metered dose inhaler (MDI) for children of 5 years and above. For children below 5 years, patients must be able to inhale medication in a reproducible manner from the Respimat® inhaler with spacer (the Aerochamber plus® holding chamber with facemask).
6. Pre-bronchodilator FEV1 at Visit 2 must be within 15% of FEV1 at Visit 1. If pre-bronchodilator FEV1 at Visit 2 is not within 15% of FEV1 at Visit 1, Visit 2 can be repeated within 7 days and rescheduled once.
7. Investigator should also ascertain that the patient is symptomatically stable as defined by:
•no evidence of acute upper or lower respiratory tract infection within 2 weeks of screening (Visit 1).
. no pulmonary exacerbation requiring use of i.v./oral/inhaled antibiotics, or oral corticosteroids within 2 weeks of screening (Visit 1).
8. The patient or the patient’s legally acceptable representative must be able to give informed consent in accordance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines and local regulation prior to participation in the trial (i.e. prior to any study procedures, including any pre-study washout of medication and medication restrictions for pulmonary function test at Visit1).
9. Patients who are on a cycling TOBI® regimen must have completed at least 2 cycles every other month TOBI® administration prior to the screening visit. The last TOBI® cycle should have been completed 2 weeks before randomisation visit (visit 2). For other inhaled antibiotics (e.g., colistin, aztreonam), please contact the local clinical monitor (CML) for guidance. For TOBI® cycling during the trial please refer to section 4.2.1.2.
10. Patients who are on daily inhaled antibiotic use must be stabilized for at least 6 weeks prior to Visit 1 (screening).
11. Patients having previously participated in study 205.339 can also be selected.
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E.4 | Principal exclusion criteria |
1. Patients with a known hypersensitivity to study drug or its components
2. Patients who have participated in another study with an Investigational drug within one month preceding the screening visit.
3. Patients who are currently participating in another trial. Observational studies are allowed. Permission should be obtained from sponsor of other study.
4. Patients with known relevant substance abuse, including alcohol or drug abuse. The intention of this criterion is to exclude patients who are considered to be at risk of not complying with or abusing the trial medication administration directives.
5. Adolescent and adult female patients who are pregnant or lactating, including females who have a positive serum pregnancy test at screening (pregnancy tests will be performed for all adolescent and adult females of child bearing potential).
6. Female patients of child bearing potential who are not using a medically approved form of contraception. The ICH (M3) defined highly effective methods of birth control as those, alone or in combination, that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. For patients using a hormonal contraceptive method, information regarding the product under evaluation and its potential effect on the contraceptive should be addressed. Barrier contraceptives (e.g. male condom or diaphragm) are acceptable if used in combination with spermicides (e.g. foam gel).Refer to ICH Topic M3 provided in the ISF.
7. Patients who have started a new chronic medication for CF within 2 weeks before the screening visit (Visit 1).
8. Clinically significant disease or medical condition other than CF or CF-related conditions that, in the opinion of the Investigator, would compromise the safety of the patient or the quality of the data. This includes but is not limited to significant haematological, hepatic, renal, cardiovascular, and neurologic disease. Patients with diabetes may participate if their disease is under good control prior to screening. This criterion provides an opportunity for the investigator to exclude patients based on clinical judgment, even if other eligibility criteria are satisfied.
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E.5 End points |
E.5.1 | Primary end point(s) |
The co-primary endpoints for this trial are:
•Change from baseline in percent predicted forced expiratory volume in one second (FEV1) area under the curve (AUC0-4H) after 12 weeks.
•Change from baseline in percent predicted trough FEV1at 12 weeks.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
•at 12 weeks
•at 12 weeks |
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E.5.2 | Secondary end point(s) |
• Change from baseline in percent predicted forced vital capacity (FVC) (AUC0-4H) at 12 weeks.
• Change from baseline in percent predicted trough FVC at 12 weeks.
• Change from baseline in pre-bronchodilator mean forced expiratory flow between 25 -75% of FVC (FEF25-75) at 12 weeks.
• Proportion of patients with at least 1 pulmonary exacerbation during the treatment period as assessed by the Respiratory and Systemic Symptoms Questionnaire (RSSQ)
• Change from baseline in Cystic fibrosis Questionnaire revised (CFQ-R) at 12 weeks.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• at 12 weeks.
• at 12 weeks.
• at 12 weeks.
• between randomization visit and last patient last visit
• at 12 weeks. |
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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 | 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 | No |
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) | 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 | Yes |
E.8.1.7.1 | Other trial design description |
After having completed the first 12-week treatment period, all |
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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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 61 |
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 |
Australia |
Austria |
Belgium |
Canada |
Czech Republic |
France |
Germany |
Hungary |
Israel |
Italy |
Poland |
Portugal |
Russian Federation |
Slovakia |
South Africa |
Spain |
Switzerland |
United Kingdom |
United States |
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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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End of the trial = last visit of the last patient undergoing the trial.
For countries and sites participating in the ECG assessment part of the trial the LPO will be on 10 March 2012 with a trial duration of 1 year 5 months and 11 days.
For countries not involved in the ECG assessment the LPO date remains unchanged (LPO on 27th Dec 2011). |
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 11 |