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    The EU Clinical Trials Register currently displays   43889   clinical trials with a EudraCT protocol, of which   7298   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2019-002256-16
    Sponsor's Protocol Code Number:19-01SPIOMI
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-09-30
    Trial 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 ConcernedGermany - BfArM
    A.2EudraCT number2019-002256-16
    A.3Full title of the trial
    Acute and two-week effects of Spiolto® Respimat® (Tiotropium/Olodaterol) on cardiac function, the autonomic nervous system and small airway function in hyperinflated COPD subjects
    Akute und zweiwöchige Effekte von Spiolto® Respimat® (Tiotropium/Olodaterol) auf die Herzfunktion, das autonome Nervensystem und die kleinen Atemwege bei überblähten COPD-Patienten
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Acute and two-week effects of Spiolto® Respimat® (Tiotropium/Olodaterol) on cardiac function, the autonomic nervous system and small airway function in hyperinflated COPD subjects
    Akute und zweiwöchige Effekte von Spiolto® Respimat® (Tiotropium/Olodaterol) auf die Herzfunktion, das autonome Nervensystem und die kleinen Atemwege bei überblähten COPD-Patienten
    A.4.1Sponsor's protocol code number19-01SPIOMI
    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 SponsorFraunhofer Society
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBoehringer Ingelheim Pharma GmbH & Co. KG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFraunhofer-Institute for Toxicology and Experimental Medicine ITEM
    B.5.2Functional name of contact pointJens Hohlfeld
    B.5.3 Address:
    B.5.3.1Street AddressFeodor-Lynen-Straße 15
    B.5.3.2Town/ cityHannover
    B.5.3.3Post code30625
    B.5.3.4CountryGermany
    B.5.6E-mailjens.hohlfeld@item.fraunhofer.de
    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 Spiolto® Respimat®
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim International GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameSpiolto® Respimat®
    D.3.4Pharmaceutical form Inhalation solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPRespiratory use (Noncurrent)
    Inhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTiotropiumbromid
    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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOlodaterol Hydrochloride
    D.3.9.1CAS number 868049-49-4
    D.3.9.3Other descriptive nameOLODATEROL HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB131075
    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 No
    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
    Chronic Obstructive Pulmonary Disease
    Chronisch obstruktive Lungenerkrankung
    E.1.1.1Medical condition in easily understood language
    Chronic Obstructive Pulmonary Disease
    Chronisch obstruktive Lungenerkrankung
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10009033
    E.1.2Term Chronic obstructive pulmonary disease
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the change from baseline in left ventricular end-diastolic volume (LVEDV) index evaluated by MRI in mL/m2 after single dose administration of Spiolto® Respimat® versus nebulized saline in hyperinflated COPD patients.
    E.2.2Secondary objectives of the trial
    To determine the change from baseline in
    • LVEDV evaluated by MRI in mL/m2 after multiple dose administration of Spiolto® Respimat® compared with single dose administration.
    • muscle sympathetic nerve activity evaluated by microneurography as bursts/ 100 heart beats after single dose administration of Spiolto® Respimat® versus nebulized saline.
    • residual volume and other lung function parameters such as FEV1, FVC, IC, TLC, specific airway resistance, FRC and forced expiratory flows after single dose of Spiolto® Respimat® versus nebulized saline and after multiple dose administration of Spiolto® Respimat® compared with single dose administration
    • exhaled particle numbers per volume after single dose of Spiolto® Respimat® versus nebulized saline.
    • exhaled particle numbers per volume after multiple dose administration of Spiolto® Respimat® compared with single dose administration.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Able and willing to give written informed consent.
    2. Male and female subjects, aged ≥ 40 years. Women will be considered for inclusion if they are:
    Not pregnant, as confirmed by pregnancy test (see flow chart), and not nursing.
    Of non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal, with documented proof of hysterectomy or tubal ligation, or meets clinical criteria for menopause and has been amenorrhoeic for more than 1 year prior to the screening visit).
    Of childbearing potential and using a highly effective method of contraception during the entire study (vasectomised partner, sexual abstinence - the lifestyle of the female should be such that there is complete abstinence from intercourse from two weeks prior to the first dose of study medication until at least 72 hours after treatment -, implants, injectables, combined oral contraceptives, hormonal IUDs or double-barrier methods, i.e. any double combination of IUD, condom with spermicidal gel, diaphragm, sponge, and cervical cap).
    3. Subjects with stable COPD according to the current GOLD guidelines (GOLD 2018).
    4. Subjects with airflow limitation indicated by a post-bronchodilator FEV1 <80% of the predicted normal value and a post-bronchodilator FEV1/FC<0.7 at Visit 1. Post-bronchodilator refers to within 10-15 min after inhalation of 400 µg (4x100 µg) of salbutamol.
    5. Current or ex-smokers who have a smoking history of at least 10 pack years. (Ten pack-years are defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years etc.)
    6. Hyperinflated subjects with RVol>135% predicted as measured at Visit 1, before intake of salbutamol.

    E.4Principal exclusion criteria
    1.Any clinically relevant abnormal findings in physical examination, clinical chemistry, haematology, urinalysis, vital signs, lung function or ECG at screening visit, which, in the opinion of the investigator, may either put the subject at risk because of participation in the study or may influence the results of the study, or the subject’s ability to participate in the study.
    2.Past or present disease, which as judged by the investigator, may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease (including but not confined to aneurysm, hypokalemia, decompensated heart failure or hypertrophic obstructive cardiomyopathy), malignancy, hepatic disease, renal disease, haematological disease, neurological disease, endocrine disease (including but not confined to thyrotoxicosis) or pulmonary disease other than COPD (including but not confined to tuberculosis, bronchiectasis, cystic fibrosis, pulmonary hypertension, sarcoidosis, interstitial lung disease or lung fibrosis).
    3.Use of other investigational drug (approved or unapproved) at the time of enrolment, or within 30 days or 5 half-lives prior to Visit 1, whichever is longer.
    4.History of drug or alcohol abuse.
    5.Risk of non-compliance with study procedures.
    6.Suspected inability to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study.
    7.History of an acute respiratory infection four weeks prior to Visit 1 and between Visit 1 and 3. These patients will not be eligible, but will be permitted to rescreened 4 weeks after the resolution of the respiratory tract infection.
    8.Subjects with conditions contraindicated for treatment with, or having a history of reactions/hypersensitivity to any of the following inhaled drugs, drugs of a similar class or any component thereof:
    •anticholinergics
    •long and short acting beta-2 agonists
    •sympathomimetic amines
    9.Subjects with a history of long QT syndrome or whose QTcF (Fridericia method) measured at Visit 1 is prolonged (>450 ms for males and >470 ms for females). These subjects should not be re-screened.
    10.Subjects who have clinically significant cardiovascular abnormalities, which could interfere with the assessment of the study treatment (such as but not limited to cardiac arrhythmias, heart failure with left ventricular ejection fraction < 40 % as determined by MRI scan at Visit 2, unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, history of myocardial infarction 6 months prior to Visit 1 or uncontrolled hypertension)
    11.Subjects with a known history or current atrial fibrillation to be confirmed by ECG at Visit 1.
    12.Subjects with pacemaker or bypass.
    13.Subjects with extensive tattoos.
    14.Subjects with a mean sitting systolic blood pressure >160 mmHg and/or mean sitting diastolic blood pressure > 90 mmHg at Visit 1. These subjects will be permitted to be re-screened after initiation or intensification of an antihypertensive therapy and achieving a controlled disease status.
    15.History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
    16.Subjects with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or bladder-neck obstruction or severe renal impairment (GFR ≤ 50 mL/min/1.73 m2) including those with end-stage renal disease requiring dialysis or urinary retention. Benign Prostatic Hyperplasia (BPH) subjects who are stable on treatment can be considered.
    17.Subjects with insulin-dependent diabetes mellitus.
    18.Clinically evident polyneuropathy.
    19.Subjects with active/ clinical history of asthma.
    20.Subjects unable to undergo MRI scans, including claustrophobia or presence of any metal objects within the patient, preventing from MRI scan (e.g. pacemaker, aneurysm clips).
    21.History of one COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization within 3 months prior to Visit 1, to 3. Subjects may be re-screened after a minimum of 3 months after the resolution of the COPD exacerbation.
    22.More than one COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization within one year before Visit 1.
    23.Subjects requiring long term oxygen therapy on a daily basis for chronic hypoxemia.
    24.Subjects with pulmonary lobectomy or lung volume reduction surgery or lung transplantation.
    25.Subjects with a pre-existing diagnosis of alpha-1 antitrypsin deficiency or an alpha-1 antitrypsin blood level below the normal range on Visit 1
    26.Subjects with a body mass index (BMI) of more than 35 kg/m2.
    27.Subjects participating in or planning to participate in the active phase of a supervised pulmonary rehabilitation program during the study.
    E.5 End points
    E.5.1Primary end point(s)
    To determine the change from baseline in left ventricular end-diastolic volume index evaluated by MRI in mL/m2 after single dose administration of Spiolto® Respimat® versus nebulized saline in hyperinflated COPD patients.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Visit number 2, 3, 4
    E.5.2Secondary end point(s)
    To determine the change from baseline in
    • LVEDV evaluated by MRI in mL/m2 after multiple dose administration of Spiolto® Respimat® compared with single dose administration.
    • muscle sympathetic nerve activity evaluated by microneurography as bursts/ 100 heart beats after single dose administration of Spiolto® Respimat® versus nebulized saline.
    • residual volume and other lung function parameters such as FEV1, FVC, IC, TLC, specific airway resistance, FRC and forced expiratory flows after single dose of Spiolto® Respimat® versus nebulized saline and after multiple dose administration of Spiolto® Respimat® compared with single dose administration
    • exhaled particle numbers per volume after single dose of Spiolto® Respimat® versus nebulized saline.
    • exhaled particle numbers per volume after multiple dose administration of Spiolto® Respimat® compared with single dose administration.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Visit number 2, 3, 4, 5
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 Yes
    E.8.1.4Double blind No
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months18
    E.8.9.1In the Member State concerned days
    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: 24
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 24
    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 state48
    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
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-12-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-28
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-04-18
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