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    Summary
    EudraCT Number:2008-001413-14
    Sponsor's Protocol Code Number:205.416
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-09-26
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2008-001413-14
    A.3Full title of the trial
    A Phase III randomised, double-blind, placebo-controlled, parallelgroup trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat inhaler (5 mcg/day) over 48 weeks as add-on controller therapy on top of usual care in patients with severe persistent asthma
    A.3.2Name or abbreviated title of the trial where available
    ND
    A.4.1Sponsor's protocol code number205.416
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberND
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBOEHRINGER ING.
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Spiriva Respimat 2.5 microgram, solution for inhalation
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim International GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Inhalation vapour, solution
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTiotropium bromide
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInhalation vapour, solution
    D.8.4Route of administration of the placeboInhalation use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with severe persistent asthma who are still symptomatic despite being treated with high-dose inhaled corticosteroids and long-acting beta2-agonists. Additional asthma treatment are allowed including systemic corticosteroids at stable doses (5mg/day) and others (like montelukast, omalizumab, etc.).
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10049106
    E.1.2Term Asthma chronic
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the long term efficacy and safety of the IMP compared to placebo with regard to lung function an patient-reported outcomes, including exacerbations, quality of life and asthma control. Combine data with twin trial 205.417 (2008-001414-25) to take advantage of higher sample size
    E.2.2Secondary objectives of the trial
    -Evaluate the long term safety of the IMP compared to placebo -Evaluate effects on health care resource utilisation (health economic analysis) -Evaluate pharmacogenomics and impact on efficacy (B16/B27 of beta2 receptor) (partecipation voluntary with a separate consent and independent from trial consent) -Evaluate pharmacokinetics in urine and blood in a subset of app. 40 patients at selected sites
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. All patients must sign and date an Informed Consent Form consistent prior to any trial procedures. 2. Male or female patients aged at least 18 years but not more than 75 years. 3. All patients must have at least a 5-year history of asthma (GINA 2007) at the time of enrolment into the trial (confirmed in the past and documented by an increased hyperresponsiveness to histamine or methacholine; or a positive trial of glucocorticosteroids or a bronchodilator reversibility to a beta-2-adrenergic drug >= 15% of PEF or FEV1; or a PEF variability >= 15%). 4. The diagnosis of asthma must have been made before the patient’s age of 40. 5. All patients must have a diagnosis of severe persistent asthma and must be symptomatic despite treatment with high, stable doses of inhaled corticosteroids and a long-acting beta adrenergic agent. 6. All patients must have been on treatment with a high, stable dose of inhaled corticosteroids and a long-acting beta2 adrenergic agent for at least 4 weeks before the screening visit. Additional sustained release theophylline and/or leukotriene modifier and/or omalizumab and/or oral glucocorticosteroids are allowed in stable doses. 7. All patients must be symptomatic at screening (Visit1) as defined by an ACQ mean score of > 1.5. 8. All patients must have a history of one or more asthma exacerbation in the past year. Previous asthma exacerbation in this context is based on patientŽs recall and is defined by the sponsor as an unplanned need for medical care at any primary care physician, pulmonologist, emergency room or hospital due to an aggravation of asthma symptoms that required an addition or increased dose of systemic corticosteroids. Every effort should be made by the site to have an appropriate source documentation of these previous asthma exacerbations. 9. The patient must meet the following spirometric criteria at the screening (Visit 1): Post bronchodilator (i.e. 30 minutes after inhalation of 4 puffs of 100 mcg salbutamol/albuterol) FEV1 <= 80% of predicted normal and FEV1 <= 70% of FVC 10. Patients should be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment and who have a smoking history of less than 10 pack years. 11. Patients must be able to use the Respimat inhaler correctly. 12. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the electronic diary/peak flow meter.
    E.4Principal 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. 3. Patients with a recent history (i.e. six months or less) of myocardial infarction. 4. Patients who have been hospitalised for cardiac failure during the past year. 5. Patients with any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year. 6. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with treated basal cell carcinoma are allowed. 7. Patients with lung diseases other than asthma (e.g. COPD). 8. Patients with known active tuberculosis. 9. Patients with significant alcohol or drug abuse within the past two years. 10. 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. 11. 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). 12. Patients using oral corticosteroid medication at stable doses exceeding 5 mg prednisolone or prednisolone equivalent every day or 10 mg prednisolone or prednisolone equivalent every second day. 13. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution. 14. Pregnant or nursing women. 15. Women of childbearing potential not using a highly effective method of birth control. 16. Patients who have taken an investigational drug within four weeks or six half-lives (whichever is greater) prior to Visit 1. 17. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva) within four weeks prior to the Screening Visit or during the screening period. 18. Patients who have been treated with beta-blocker medication within four weeks prior to Screening Visit or during the screening period. Topical cardio-selective beta-blocker eye medications for treatment of non-narrow angle glaucoma are allowed. 19. Patients who have been treated with oral beta-adrenergics within four weeks prior to Screening Visit or during the screening period. 20. Patients who have been treated with other non-approved and according to international guidelines not recommended ŽexperimentalŽ drugs for routine asthma therapy within four weeks prior to Screening Visit or during the screening period. 21. Patients with any asthma exacerbation in the four weeks prior to the Screening Visit or during the 2-week screening period. In the case of an asthma exacerbation during the screening period patients may be randomised four weeks following recovery from the exacerbation. 22. Patients with any respiratory tract infection in the four weeks prior to the Screening Visit or during the 2-week screening period. 23. Patients who have previously been randomised in this trial or in the respective twin trial or are currently participating in another trial. 24. Patients with a known narrow-angle glaucoma.
    E.5 End points
    E.5.1Primary end point(s)
    1. The first co-primary efficacy endpoint is the peak FEV1 response (within 3 hours post dosing) determined after a treatment period of 24 weeks. 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 morning 10 minutes prior to the morning dose of patient’s usual asthma medication and first dose of trial medication. 2. The second co-primary endpoint will be trough FEV1 response determined after a treatment period of 24 weeks. Trough FEV1 is defined as the FEV1 measured at the - 10 minute time point at the end of the dosing interval (24 hours post drug administration). Trough FEV1 response is defined as the change from baseline in trough FEV1. Baseline FEV1 will be the pre-treatment FEV1 measured at Visit 2 in the morning 10 minutes prior to the morning dose of patient’s usual asthma medication and first dose of trial medication. One additional co-primary endpoint, the time to first severe asthma exacerbation after 48 weeks, is considered primary only in the analysis of pooled data from the two twin trials 205.416 and 205.417. The two trials will be combined for these analyses to obtain adequate numbers of patients. 3. Time to first severe asthma exacerbation during the 48-week treatment period. This endpoint will be evaluated on pooled data only. An additional report for the pooled data will be prepared.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other 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 Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 230
    F.4.2.2In the whole clinical trial 450
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2008-06-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-06-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-07-25
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