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    Summary
    EudraCT Number:2012-001873-10
    Sponsor's Protocol Code Number:205.441
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-07-31
    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 ConcernedAustria - BASG
    A.2EudraCT number2012-001873-10
    A.3Full title of the trial
    A randomised, double- blind, 2 way cross-over study to determine 24-hour FEV1-time profile of inhaled tiotropium, delivered via the Respimat® inhaler, after 4 weeks of once daily [5 µg in the evening (2 actuations of 2.5 µg)] or twice daily [2.5 µg in the morning and evening (2 actuations of 1.25 µg)] administration in patients with moderate persistent asthma.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Comparison of two daily dose regimens of tiotropium 5 µg once daily and tiotropium 2.5 µg twice daily for 4 weeks on top of maintenance therapy with an inhaled corticosteroid controller medication
    A.4.1Sponsor's protocol code number205.441
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBoehringer Ingelheim RCV GmbH & Co KG
    B.1.3.4CountryAustria
    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 supportBoehringer Ingelheim
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBoehringer Ingelheim Pharma GmbH & Co. KG
    B.5.2Functional name of contact pointQRPE PSC CT Information Disclosure
    B.5.3 Address:
    B.5.3.1Street AddressBinger Strasse 173
    B.5.3.2Town/ cityIngelheim am Rhein
    B.5.3.3Post code55218
    B.5.3.4CountryGermany
    B.5.4Telephone number00498002430127
    B.5.5Fax number00498008217119
    B.5.6E-mailclintriage.rdg@boehringer-ingelheim.com
    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 Pharma GmbH Co KG
    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 solution
    D.3.4.1Specific paediatric formulation No
    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.3.9.1CAS number 411207-31-3
    D.3.9.3Other descriptive nameTIOTROPIUM BROMIDE MONOHYDRATE
    D.3.9.4EV Substance CodeSUB21897
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Yes
    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 No
    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.IMP: 2
    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 No
    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.3.1Product nameTiotropium Respimat 1.25 µg
    D.3.4Pharmaceutical form Inhalation solution
    D.3.4.1Specific paediatric formulation No
    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.3.9.1CAS number 411207-31-3
    D.3.9.3Other descriptive nameTIOTROPIUM BROMIDE MONOHYDRATE
    D.3.9.4EV Substance CodeSUB21897
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.25
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Yes
    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 No
    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 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
    E.1.1.1Medical condition in easily understood language
    Asthma bronchiale
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10003555
    E.1.2Term Asthma bronchial
    E.1.2System Organ Class 100000004855
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Determine the 24-hour FEV1-profile of tiotropium solution for inhalation after 4 weeks treatment periods of 5 µg tiotropium administered once daily in the evening and 2.5 µg tiotropium administered twice daily (morning and evening) with the Respimat inhaler.

    In addition, in a subset of patients the pharmacokinetics of tiotropium in patients with asthma will be characterized.
    The objective of the pharmacokinetic subinvestigation is to compare the 24 hours pharmacokinetic profile of 5 µg tiotropium administered once daily and 2.5µg tiotropium administered twice daily.
    E.2.2Secondary objectives of the trial
    Not Applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. All patients must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and local legislation prior to participation in the trial
    2. Male or female patients aged at least 18 years at Visit 0 but not more than 75 years at Visit 0.
    Diagnosis
    3. All patients must have at least a 3 months history of asthma at the time of enrolment (signing ICF) into the trial. The initial diagnosis of asthma must have been made before the patient's age of 40. If the patient is > 40 years and the diagnosis has not yet been recorded in the patient's medical files, the investigator should assess whether the patient's medical history
    4. All patients must have a pre-bronchodilator FEV1 ≥ 60% predicted and ≤ 90% of predicted normal at Visit 1. Predicted normal values will be calculated according to ECSC [R94-1408] (see Appendix 10.3). Variation of absolute pre-bronchodilator FEV1 values at Visit 1 and Visit 2 (randomisation visit) must be within ± 30%.
    5. Patient’s diagnosis of asthma has to be confirmed at Visit 1 with bronchodilator reversibility (ie 10 minutes prior to and 15-30 minutes after inhalation of 400 μg salbutamol) defined as an FEV1 increase of ≥ 12% and ≥ 200 mL. NOTE: If this is not achieved at the screening visit the reversibility test including ACQ may be repeated once within two weeks.
    Symptoms
    6. All patients must have a diagnosis of moderate persistent asthma and must be symptomatic despite their current maintenance treatment with medium doses of ICS.
    7. All patients must be symptomatic at Visit 1 (screening visit) and Visit 2 (randomisation visit) as defined by an ACQ mean score of ≥ 1.5.
    8. All patients must have maintenance treatment with stable medium daily dose of ICS (alone or in a fixed-dose combination with a LABA or SABA) for at least 4 weeks prior to Visit 1.
    9. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack-years at Visit 0.
    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 pulmonary function tests and use of the AM3® (e-diary) compliance of at least 80% is required.
    12. Patients taking a chronic pulmonary medication allowed by the study protocol must be willing to continue this therapy for the entire duration of the study (exception: times of acute disease deterioration).
    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 a clinically relevant abnormal screening hematology or blood chemistry at Visit 1 if the abnormality defines a significant disease as defined in exclusion criterion no. 1.
    3. Patients requiring more than 12 puffs of rescue medication (salbutamol MDI) per 24 hours for more than 2 consecutive days between Visit 1 and Visit 2 (screening period).
    4. Patients with a recent history (ie six months or less) of Acute Coronary Syndrome (STEMI, non-STEMI, Unstable Angina Pectoris) prior to Visit 1 (screening).
    5. Patients who have been hospitalised for cardiac failure during the past year prior to Visit 1 (screening).
    6. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year prior to Visit 1 (screening).
    7. Patients with lung diseases other than asthma (eg COPD).
    8. Patients with known active tuberculosis.
    9. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years prior to Visit 1 (screening). Patients with treated basal cell carcinoma are allowed.
    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 with significant alcohol or drug abuse on Investigator’s assessment within the past two years prior to Visit 1 (screening).
    12. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening).
    13. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the study medication delivery systems.
    14. Pregnant or nursing women, including female patients with positive ß-HCG test at Visit 1.
    15. Female patients of child-bearing potential not using highly effective method of birth control. As defined in ICH (M3) [R09-1400], note 3, highly effective methods of birth control are defined as those, alone or in combination, that result in a low failure rate (ie less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner. Barrier contraceptives (eg male condom or diaphragm) are acceptable if used in combination with spermicides (eg foam, gel).
    Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years.
    16. Patients who have been treated with restricted medication (refer to Table 4.2.2.1) prior to Visit 1 and/or during the screening period.
    17. Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 or during the screening period. Visit 1 and/or Visit 2 should be postponed in case of an asthma exacerbation or respiratory tract infection. Refer to Section 6.1 for information on re-scheduling of visits.
    18. Patients who are currently participating in another trial or who have been participating in another trial within one month prior to Visit 0, and patients who have previously been randomised in this trial.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable will be the forced expiratory volume in one second (FEV1).
    The primary endpoint is the FEV1 AUC0-24h (L) response determined at the end of each 4-week randomised treatment period. The FEV1 AUC0-24h is defined as the mean FEV1 over the 24-hour observation period (0-24 h) normalized for time after inhalation of the last evening dose of study medication. The mean FEV1 will be calculated as area under the curve from zero time to 24 hours, using the trapezoidal rule divided by the corresponding duration (ie 24 hours) to give the result in litres. The pre-dose FEV1 measurement obtained at the end of each 4-week treatment period prior to inhalation of the last evening dose of study medication will be assigned to zero time. Value recorded at 11h 50min and at 23h 50min post dosing will be assigned to 12 and 24 hours, respectively.
    FEV1 AUC0-24h response is defined as the change of FEV1 AUC0-24h from the baseline FEV1 value, which is the measurement obtained on Visit 2 (randomisation visit) prior to the first evening dose of randomised study medication.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of each 4-week randomised treatment period.
    E.5.2Secondary end point(s)
    1. FEV1 AUC0-12h (L) response determined at the end of each 4-week period of randomised treatment.
    2. FEV1 AUC12-24h (L) response determined at the end of each 4-week period of randomised treatment.
    FEV1 AUC over the first 12 hours (0-12 h) and the second 12 hours will be calculated similar to FEV1 AUC0-24h. AUC0-12h and AUC12-24h responses will be calculated similar to FEV1 AUC0-24h response.
    3. Peak FEV1 (L) response, determined at the end of each 4-week period of randomised treatment, is defined as the highest FEV1 reading observed within the 24-hour period following inhalation of the last evening dose of study medication.
    4. Trough FEV1 (L) response, determined at the end of each 4-week period of randomised treatment, is defined as the FEV1 value just prior to the last evening dose of study medication.
    5. Forced vital capacity (FVC) AUC0-24h response determined at the end of each 4-week period of randomised treatment.
    6. FVC AUC0-12h response (L) determined at the end of each 4-week period of randomised treatment.
    7. FVC AUC12-24h response (L) determined at the end of each 4-week period of randomised treatment.
    8. Peak FVC (L) response determined at the end of each 4-week period of randomised treatment.
    9. Trough FVC (L) responses determined at the end of each 4-week period of randomised treatment.
    AUC0-12h, AUC12-24h, AUC0-24h, trough and peak FVC responses will be calculated similar to FEV1 response endpoints.
    10. Peak expiratory flow (PEF) AUC0-24h (L/min) response determined at the end of each 4-week period of randomised treatment.
    PEF AUC0-24h response will be calculated similar to FEV1 AUC0-24h response.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the end of each 4-week randomised treatment period.
    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 Yes
    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 No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    5 mcg once daily versus 2.5 mcg twice daily
    E.8.2.4Number of treatment arms in the trial2
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA23
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    LVLS (last visit of the last subject)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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.1.2.1Number of subjects for this age range: 82
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 92
    F.4.2.2In the whole clinical trial 92
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    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 Decision2012-09-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-08-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-09-26
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