| 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 | LLT |
| E.1.2 | Classification code | 10003561 |
| E.1.2 | Term | Asthma, unspecified |
| 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 is to assess and compare efficacy and safety of BI 54903 at doses of 45.5, 90.9 and 181.8 µg b.i.d., fluticasone proprionate HFA MDI at a dose of 220 µg b.i.d. and placebo b.i.d. over an 8-week treatment period in asthmatic patients aged 12 to 65 years inadequately controlled on low dose ICS therapy as demonstrated by a decrease in FEV1 (>10 % and ≤ 25%); and an ACQ-6 of > 1.5 at time of randomisation. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To enter run-in period following completion of pre-screening period:
1.All patients [and parents or legal guardian of the adolescent age group (12-17 years)] must sign and date an ICF at Visit 0 consistent with ICH-GCP guidelines and local legislation prior to participation in trial, which includes medication washout and restrictions.
2.Male and female patients aged at least 12 to 65 years.
3.All patients must have a history of asthma diagnosed by a physician for at least three months at the time of enrolment into the trial according to the 2009 Global Initiative for Asthma (GINA) Guidelines [P10-03196]. The initial diagnosis of asthma must have been made before the age of 40 years.
4.All patients must be on a maintenance treatment with either medium-dose ICS plus LABA or high-dose ICS without LABA, stable for at least six weeks prior to Visit 1 (see also Section 3.3.1 and Appendix 10.3).
5.All patients must have a pre-bronchodilator FEV1 of > 60-90% of predicted normal and an ACQ-6 mean score of < 1.5 at the pre-screening Visits 1 and 2.
Age group 12 - 17 years:
Predicted normal values will be calculated according to equations from Wang et al [R02-0874] (refer to Appendix 10.3).
Age group 18 - 65 years:
Predicted normal values will be calculated according to ECSC [R94-1408] (refer to Appendix 10.3).
The spirometer used to assess lung function (MasterScope® CT) will be programmed with the equations for the two age groups.
6.Patients must be never-smokers or ex-smokers with a smoking history of <10 pack-years and smoking cessation at least one year prior to screening (see Appendix 10.3 for calculation).
7.Patients must be able to use Respimat® inhaler and MDI correctly (refer to Appendix 10.1)
8.Patients must be able to perform all trial-related procedures including technically acceptable pulmonary function tests and electronic PEF measurements, and must be able to maintain records during the study period as required in the protocol (AM2+ including eDiary - eDiary compliance of at least 80 % is required, refer to Section 6.2 and Appendix 10.6 for instructions).
To enter treatment period following additional criteria have to be met:
9.All patients must have an improvement in FEV1 > 12 % and an absolute change of at least 200 mL within 15-30 min after administration of 400 µg salbutamol/albuterol HFA MDI as demonstrated at Visit 1 or during one of the visits during the run-in period.
10.During the run-in period (at the same clinic visit) all patients must be both symptomatic (ACQ-6 mean score ≥ 1.5) and have shown a decrease in morning pre-bronchodilator FEV1 ≥ 10% and ≤ 25% from pre-screening baseline FEV1 at Visit 2.
In the event a patient demonstrates a drop in morning FEV1 > 25%, it is the investigator’s clinical judgement whether it is clinically safe to randomise the patient or to withdraw the patient from the study and to re-start pre-trial controller medication and/or an oral steroid treatment.
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| E.4 | Principal exclusion criteria |
1.Patients with significant pulmonary disease* other than asthma or other significant medical conditions (as determined by medical history, examination and clinical investigations at screening)** that may, in the opinion of the investigator, result in any of the following: (i) put the patient at risk because of participation in this trial or (ii) influence the results of the trial or (iii) cause concern regarding the patient’s ability to participate in the trial.
* e.g. COPD, tuberculosis (TB) during the past two years or uncured TB, pulmonary fibrosis, cystic fibrosis and others.
** e.g. cardiac, gastro-intestinal, hepatic, renal, metabolic, dermatologic, neurological, haematological, oncological and psychiatric.
2.Patients with a clinically relevant, abnormal screening haematology and/or blood chemistry finding, if the abnormality indicates a significant disease as defined in exclusion criterion no. 1.
3.Patients with a history of upper or lower respiratory tract infection (URTI/LRTI) in the past four weeks prior to the pre-screening Visit 1, and during pre-screening and run-in periods. Start of run-in or treatment period should be postponed in case of infection. In case of URTI/LRTI during the run-in period, patients can be re-screened again 4 weeks after the resolution of the infection.
4.Patients with any exacerbation of their underlying asthma during the eight weeks prior to the pre-screening Visit 1. Visit 2 should be postponed in case of an exacerbation during the pre-screening period.
5.Patients with active allergic rhinitis requiring treatment with systemic corticosteroids.
6.Any of the following criteria are met during the pre-screening / run-in period (Visits 1 - 6):
- in clinic pre-bronchodilator FEV1 % predicted less than 40%,
- more than 12 puffs rescue salbutamol/albuterol HFA MDI per day for > 2 consecutive days,
- exacerbation of asthma.
7.Patients with a history of pneumonectomy or who are planning to undergo thoracotomy for any reason. Patients with a history of thoracotomy other than pneumonectomy should be evaluated as per exclusion criterion no.1.
8.Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the six weeks prior to the first screening visit 1.
9.Patients with two or more hospitalizations for asthma within the previous 12 months.
10.Patients with a recent history of myocardial infarction during the last twelve months or known coronary heart disease that requires treatment
11.Patients with a history of hospitalisation due to heart failure in the past twelve months
12.Patients with myocarditis or any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year
13.Patients with significant alcohol or drug abuse in the opinion of the investigator within the past two years
14.Patients with rheumatoid arthritis or other systemic diseases that require immune system modulating treatment
15.Patients with known hypersensitivity to ciclesonide or any other component of the trial medication
16.Patients suffering from or with a history of glaucoma, increased intraocular pressure, and/or cataracts
17.Pregnant or nursing women
18.Women of childbearing potential not using a highly effective method of birth control.
19.Patients who have been treated with anti-IgE-antibodies (e.g. omalizumab – Xolair®) or other immune system modulating antibodies such as TNF-blockers within six months prior to Visit 1.
20.Patients who have been treated with the following drugs during the past four weeks prior to Visit 1 or are foreseen to need this during the study:
– Non-selective ß-blockers (topical cardio-selective beta-blocker eye
medications for non-narrow angle glaucoma are allowed),
– Oral or other systemic corticosteroids,
– Oral beta-agonists,
– Changes in allergen desensitisation therapy in last 6 months,
– Immune system modulating agents such as methotrexate or cyclosporine,
– Inhibitors of cytochrome P450 3A4 such as antifungals (e.g. ketoconazole, itraconazole), antibiotics (e.g. erythromycin) or antiretroviral drugs.
21.Patients who have been treated with leukotriene modifiers, cromones or theophylline within two weeks prior to Visit 1.
22.Patients who have been treated with tiotropium within 3 weeks prior to Visit 1.
23.Patients who have taken an investigational drug within the past four weeks prior to Visit 1.
24.Patients who have previously been randomised in this trial or are currently participating in another interventional trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint will be the mean change from randomisation baseline to the end of the 8-week treatment period in trough (morning pre-dose and pre-rescue bronchodilator) FEV1.
Endpoints of safety
Adverse events will be recorded throughout the trial, including asthma exacerbations (as defined in Section 5.1.2).
In addition, the following efficacy endpoints will be analysed (explorative):
•Mean change from randomisation baseline in ACQ-7 scores at subsequent study visits,
•Weekly mean pre-dose (and pre-rescue) PEF as assessed via AM2+ in the morning and evening,
•Weekly mean diurnal PEF variability; diurnal PEF variability will be described as the amplitude (the difference between the maximum and the minimum value of the day) expressed as a percentage of the mean daily PEF value and averaged over the week [P10-03196].
•Asthma symptom-free days, defined as a day with no asthma symptoms, no night-time awakenings due to asthma, no rescue bronchodilator use and no asthma exacerbations,
•Weekly mean rescue medication use (daytime and nighttime) as assessed via AM2+ in the morning and evening,
•Weekly mean pre-dose (and pre-rescue) FEV1 as assessed with the AM2+ in the morning and evening.
•Time to first asthma deterioration (definition see section 5.1.2).
•Time to withdrawal due to asthma deterioration
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End of the 8-week treatment period |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints are:
• Mean changes from randomisation baseline in trough (morning pre-dose and pre-rescue bronchodilator) FVC after 2, 4 and 8-week treatment periods,
• Mean changes from randomisation baseline in trough (morning pre-dose and pre-rescue bronchodilator) FEV1 after 2 and 4-week treatment periods,
• Mean pre-dose (and pre-rescue) PEF as assessed via AM2+ in the morning and evening, of the last week of the 8-week treatment period,
• Mean rescue medication use (daytime and night-time) as assessed via AM2+ in the morning and evening, of the last week of the 8-week treatment period,
• Mean change from randomisation baseline in ACQ-6 scores at subsequent study visits,
• Mean change from randomisation baseline in AQLQ(S)+12 scores at subsequent study visits,
• Time to withdrawal due to first asthma exacerbation.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 2, 4 and 8-week treatment periods
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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 | 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) | 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 | 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 53 |
| 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 |
| Bulgaria |
| Czech Republic |
| France |
| Germany |
| Israel |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Poland |
| Slovakia |
| South Africa |
| Ukraine |
| United States |
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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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| 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 | 16 |
| 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 | 16 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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