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    Summary
    EudraCT Number:2011-003588-31
    Sponsor's Protocol Code Number:CCD-1106-PR-0066
    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:2012-03-08
    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 number2011-003588-31
    A.3Full title of the trial
    A multicentre, randomised, double-blind, active-controlled, 4-way crossover study to evaluate the efficacy and safety of a free combination of 3 doses of Glycopyrrolate with fixed combination Beclomethasone Diproprionate plus Formoterol (Foster) in a metered dose inhaler for the treatment of patients with Chronic Obstructive Pumlonary Disease (COPD
    Studio multicentrico, randomizzato, controllato, in doppio cieco, cross-over a quattro bracci per valutare l'efficacia e la sicurezza di una combinazione libera di 3 dosi di glicopirrolato con una combinazione fissa di beclometasone dipropionato piu' formoterolo (foster ) in un inalatore predosato per il trattamento di pazienti affetti da broncopneumopatia cronica ostruttiva (BPCO)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to assess the most efficacious dose of bronchodilator, Glycopyrrolate, to add to the existing treatment (Foster, Beclomethasone + Formoterol) for the development of a new triple therapy in a single aerosol for the treatment of patients suffering from severe COPD.
    Studio per valutare la dose piu' efficace di broncodilatatore, Glicopirrolato, da aggiugere al trattamento gia' esistente (Foster, beclometasone + formoterolo) per lo sviluppo di una nuova tripla terapia in un solo aerosol per il trattamento di pazienti affetti da broncopneumopatia cronica ostruttiva (BPCO)
    A.4.1Sponsor's protocol code numberCCD-1106-PR-0066
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01476813
    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 SponsorCHIESI
    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 supportChiesi Farmaceutici S.p.A.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationChiesi Farmaceutici S.p.A.
    B.5.2Functional name of contact pointGeraldine Cohuet
    B.5.3 Address:
    B.5.3.1Street AddressVia Palermo 26 A
    B.5.3.2Town/ cityParma
    B.5.3.3Post code41322
    B.5.3.4CountryItaly
    B.5.4Telephone number+33 1 47 68 41 46
    B.5.5Fax number+33 1 47 68 49 04
    B.5.6E-mailg.cohuet@chiesifrance.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 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 nameGlycoppyrrolate
    D.3.2Product code CHF 5259
    D.3.4Pharmaceutical form Pressurised 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 INNGlycopirrolate bromide
    D.3.9.1CAS number 596-51-0
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeNA
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number12.5 to 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 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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 FOSTER*INAL 180D 100/6MCG
    D.2.1.1.2Name of the Marketing Authorisation holderCHIESI FARMACEUTICI SpA
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 Pressurised 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 INNBECLOMETASONE DIPROPIONATE
    D.3.9.1CAS number 5534-09-8
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeSUB00681MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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.IMP: 3
    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 nameGlycopyrrolate
    D.3.2Product code CHF 5259
    D.3.4Pharmaceutical form Pressurised 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 INNGlycopirrolato bromide
    D.3.9.1CAS number 596-51-0
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeNA
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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.IMP: 4
    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 ATROVENT 20*SPRAY FL 10ML 200D
    D.2.1.1.2Name of the Marketing Authorisation holderBOEHRINGER INGELHEIM IT.SpA
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 Pressurised 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 INNIPRATROPIUM BROMIDE
    D.3.9.1CAS number 22254-24-6
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeSUB08276MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 placeboPressurised inhalation, 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 Pumlonary Disease
    Broncopneumopatia cronica ostruttiva
    E.1.1.1Medical condition in easily understood language
    COPD, or chronic obstructive pulmonary disease, is a progressive disease that makes it hard to breathe. "Progressive" means the disease gets worse over time.
    COPD o broncopneumopatia cronica ostruttiva, è una malattia progressiva che rende difficile respirare. “Progressiva” significa che la malattia peggiora nel tempo.
    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 10010952
    E.1.2Term COPD
    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 evaluate the efficacy of a free combination of glycopyrrolate at 3 dose
    levels with fixed combination beclomethasone dipropionate plus
    formoterol (Foster) in a metered dose inhaler by comparison with
    Foster in terms of FEV1 AUC0-12h normalized by time on Day 7.
    Valutare l'efficacia di una combinazione libera di glicopirrolato a 3 differenti dosaggi in aggiunta auna combinazione fissa di beclometasone dipropionato più formoterolo (Foster) in un inalatore predosato rispetto a Foster in termini di AUC0-12h per FEV1 normalizzata per il tempo al Giorno 7.
    E.2.2Secondary objectives of the trial
    To evaluate the effect of the free combination glycopyrrolate + Foster on
    other lung function parameters and on clinical outcome measures. To
    assess the safety and the tolerability of the study treatments.
    Valutare l'effetto della combinazione libera di glicopirrolato + Foster sugli altri parametri di funzionalità polmonare e sulle valutazioni di esito clinico.
    Valutare la sicurezza e la tollerabilità dei trattamenti oggetto dello studio.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male and female adults (40 ≤ age ≤ 80 years) with written informed
    consent obtained prior to any study-related procedure.
    2. Outpatients with a diagnosis of COPD (according to GOLD guidelines)
    with:
    A smoking history of at least 10 pack years (pack-years = ((number of
    cigarettes per day x number of years)/20). Current and ex-smokers are
    eligible.
    (Smoking cessation therapy must be completed within 3 months prior to
    screening visit and smoking status shall not change after screening and
    during the study period)
    - A Post-bronchodilator 30%≤FEV1<60% of the predicted normal value
    - A Post-bronchodilator FEV1/FVC < 0.7
    - An increase from baseline of FEV1 value 30 min after 80μg ipratropium
    of at least 60mL
    3. Patients treated with double therapy with inhaled
    corticosteroids/long-acting β-agonist combination or with triple therapy
    with inhaled corticosteroids/long-acting β-agonist combination and
    long-acting anticholinergic (tiotropium) if taken for not more than one month at stable regimen before screening.
    4. A cooperative attitude and ability to be trained to use correctly the
    pMDI inhalers.
    1. Adulti di entrambi i sessi, di età compresa tra 40 e 80 anni, che hanno accordato il proprio consenso informato scritto prima di iniziare qualsiasi procedura correlata allo studio.
    2. Pazienti ambulatoriali con diagnosi di BPCO (secondo le linee guida GOLD), con:
    - Anamnesi di tabagismo di almeno 10 pacchetti-anno (pacchetti-anno = ((numero di sigarette per giorno x numero di anni)/20). Sono eleggibili sia i fumatori attivi che gli ex fumatori.
    (La terapia per smettere di fumare deve essere stata ultimata 3 mesi primadella visita di screening e lo stato di fumatore non deve cambiare dopo la visita di screening e durante il periodo dello studio)
    - FEV1 ≤30% - &lt;60% del valore normale predetto
    - Rapporto FEV1/FVC &lt;0,7 dopo il broncodilatatore
    - Aumento di almeno 60 ml di FEV1 dal valore basale 30 minuti dopo l'assunzione di 80 µg di ipratropio
    3. Pazienti in doppia terapia inalatoria con una combinazione di corticosteroidi/β-agonisti a lunga durata d'azione, oppure in triplice terapia inalatoria di corticosteroidi/β-agonisti a lunga durata d'azione più un anticolinergico (tiotropio), se assunto per non più di un mese a regime stabile prima dello screening.
    4. Attitudine alla collaborazione e capacità di apprendere l'uso corretto degli inalatori pMDI.
    E.4Principal exclusion criteria
    1.Pregnant or lactating women.
    In case of childbearing potential, patients and/or their partner must be willing to use an approved method of contraception unless they meet the post-menopausal definition (amenorrhea>12 Mo or >6 Mo with FSH >40 mIU/ml). Methods of contraception may include one or more of the following ones: Surgical sterilization, hormonal contraception, doublebarrier methods and periodic abstinence. Reliable contraception should be maintained throughout the study.
    2.Diagnosis of asthma or history of allergic rhinitis or atopy.
    3.Participation in another clinical trial where investigation drug was received less than 8 weeks prior to first intake of the study medication.
    4.Hospitalisation for COPD or pneumonia within 3 month prior to screening
    5.Patients experiencing a COPD exacerbation requiring use of systemic steroids and/or antibiotics in the 4 weeks prior to screening and during the run-in period.
    6.Patients treated with oral/parenteral β2-agonists or nebulised bronchodilators or PDE inhibitors in the 4 weeks prior to screening and during the run-in period.
    7.Use of antibiotics for a lower respiratory tract infection in the 4 weeks prior to screening and during the run-in period.
    8.Patients requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxemia.
    9.Known respiratory disorders other than COPD including but not limited to alpha-1 antitrypsin deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and
    interstitial lung disease.
    10.Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the investigator would prevent use of anticholinergic.
    11.History of hypersensitivity to M3 Antagonists, β2-agonist, corticosteroids or any of the excipients contained in any of the formulations used in the trial.
    12.History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening visit
    13.An abnormal and clinically significant 12-lead ECG that results in active medical problem.
    14.Electrocardiogram (ECG) (12 lead) with QTcF >450 ms for males or QTcF > 470 ms for females.
    15.Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may impact the feasibility of the results of the study according to investigator's judgement.
    16.Patients with serum potassium levels < 3.5 mEq/L (or 3.5 mmol/L).
    17.Unstable concurrent disease: e.g. uncontrolled hyperthyroidism, uncontrolled diabetes mellitus or other endocrine disease; significant hepatic impairment; significant renal impairment; cardiovascular disease
    (e.g. uncontrolled coronary artery disease, uncontrolled hypertension); uncontrolled gastrointestinal disease (e.g. active peptic ulcer); neurological disease; uncontrolled haematological disease; uncontrolled autoimmune disorders, or other which may impact the feasibility of the
    results of the study according to investigator's judgment.
    18.Evidence of heart failure (NYHA class IV).
    19.Changes in dose, schedule, formulation or product of oral xanthine derivatives (eg theophylline) in the three months prior to screening visit.
    20.Change in dose, schedule, formulation or product of β-blockers in the month prior to screening.
    1. Donne in gravidanza o che allattano.
    In caso di donne potenzialmente fertili, le pazienti e/o il loro partner devono essere disposti ad adottare un metodo contraccettivo approvato, a meno che non soddisfino la definizione di postmenopausale (amenorrea &gt;12 mesi o &gt;6 mesi con valori di FSH &gt;40 mUI/ml). I metodi contraccettivi possono includere uno o più dei seguenti: sterilizzazione chirurgica, contraccettivo ormonale, metodi di doppia barriera e astinenza periodica. L'uso del metodo contraccettivo affidabile deve essere continuato per l'intera durata dello studio.
    2. Diagnosi di asma o anamnesi di rinite allergica o atopia.
    3. Partecipazione ad un altro studio clinico durante il quale il farmaco sperimentale è stato assunto per meno di 8 settimane prima della prima inalazione del farmaco in studio.
    4. Ricovero per BPCO o polmonite nei 3 mesi precedenti lo screening.
    5. Pazienti presentanti un'esacerbazione della BPCO, che necessitano di terapia con steroidi sistemici e/o antibiotici nelle 4 settimane precedenti lo screening e durante il periodo di run-in.
    6. Pazienti trattati con β2-agonisti per via orale o parenterale, oppure broncodilatatori nebulizzati o inibitori della PDE nelle 4 settimane precedenti lo screening e durante il periodo di run-in.
    7. Uso di antibiotici per infezione delle basse vie respiratorie nelle 4 settimane precedenti lo screening e durante il periodo di run-in.
    8. Pazienti che necessitano di ossigenoterapia a lungo termine (almeno 12 ore/die) per ipossiemia cronica.
    9. Note patologie respiratorie diverse dalla BPCO, compresi a mero titolo esemplificativo ma non esaustivo: deficit di -1-antitripsina, tubercolosi in atto, carcinoma polmonare, bronchiectasia, sarcoidosi, fibrosi polmonare, ipertensione polmonare e malattia interstiziale polmonare.
    10. Diagnosi medica di glaucoma ad angolo acuto, ipertrofia prostatica o ostruzione del collo vescicale che, a giudizio dello sperimentatore, potrebbe impedire l'uso di anticolinergici.
    11. Anamnesi di ipersensibilità ad antagonisti M3, β2-agonisti, corticosteroidi o a uno qualsiasi degli eccipienti contenuti nelle formulazioni utilizzate nella sperimentazione.
    12. Anamnesi di abuso di sostanze alcoliche e/o stupefacenti nei 12 mesi precedenti la visita di screening.
    13. Referto anomalo e clinicamente significativo dell'ECG a 12 derivazioni, che risulta in una condizione patologica attiva.
    14. Elettrocardiogramma (ECG) (a 12 derivazioni) con QTcF &gt;450 ms negli uomini o QTcF &gt;470 ms nelle donne.
    15. Referti di laboratorio anomali, clinicamente significativi, suggestivi di una patologia concomitante importante o instabile che, a giudizio dello sperimentatore potrebbe influire sulla possibilità di realizzazione dei risultati dello studio.
    16. Pazienti con livelli sierici di potassio &lt;3,5 mEq/l (o 3,5 mmol/l).
    17. Patologia concomitante instabile: ad es. ipertiroidismo non controllato, diabete mellito non controllato o altra malattia endocrina non controllata; importante alterazione della funzionalità epatica, importante alterazione della funzionalità renale; patologia cardiovascolare (ad es. coronaropatia non controllata, ipertensione non controllata); patologia gastrointestinale non controllata (ad es. ulcera peptica in atto); patologia neurologica; patologia ematologica non controllata; malattia autoimmune non controllata o altra condizione patologica che, a giudizio dello sperimentatore potrebbe influire sulla fattibilità dei risultati dello studio.
    18. Evidenza di insufficienza cardiaca (IV classe NYHA).
    19. Variazioni di dose, posologia, formulazione o prodotto dei derivati xantinici orali (ad es. teofillina) nei tre mesi precedenti la visita di screening.
    20. Variazione di dose, posologia, formulazione o prodotto dei betabloccanti nel mese precedente lo screening.
    E.5 End points
    E.5.1Primary end point(s)
    FEV1 AUC0-12h normalized by time on Day 7
    AUC0-12h per FEV1 normalizzata per il tempo al Giorno 7
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 7
    Giorno 7
    E.5.2Secondary end point(s)
    Efficacy variables:
    •Trough FEV1, FVC and IC at 12 h on Day 1 and Day 7 (mean of the two
    measurements at 12h and 12.5h post-dose)
    •Trough FEV1, FVC and IC at 24h (mean of the two measurements at
    23.5h and 24h post-dose) on Day 7 (i.e. on the morning of Day 8)
    •FEV1 AUC0-12h normalised by time on Day 1
    •FEV1 AUC0-24h and AUC12-24h normalised by time on Day 7
    •Peak FEV1, FVC and IC on Day 1 and Day 7
    •FEV1, FVC and IC at each time point on Day 1 and Day 7
    •Transition Dyspnoea Index (TDI) score on Day 8
    •Average use of rescue medication (number of puffs/day) during the
    treatment period
    •Percentage of rescue use-free days during the treatment period
    Safety variables:
    •Adverse events and adverse drug reactions
    •Vital signs (systolic and diastolic blood pressure, heart rate)
    •Standard haematology and blood chemistry
    •12-lead ECG
    VAriabili di efficacia:
    • Valore minimo di FEV1, FVC e CI a 12 ore ai Giorni 1 e 7 (media delle due misurazioni a 12 e 12,5 ore post-dose)
    • Valore minimo di FEV1, FVC e CI a 24 ore (media delle due misurazioni a 23,5 e 24 ore post-dose) al Giorno 7 (ossia la mattina del Giorno 8)
    • AUC0-12h per FEV1 normalizzata per il tempo al Giorno 1
    • AUC0-24h e AUC12-24h per FEV1 normalizzate per il tempo al Giorno 7
    • Valore di picco di FEV1, FVC e CI ai Giorni 1 e 7
    • FEV1, FVC e CI a ciascuno dei punti temporali ai Giorni 1 e 7
    • Punteggio dell'Indice di dispnea transitorio (TDI) al Giorno 8
    • Uso medio del farmaco di emergenza (numero di erogazioni/die) durante il periodo di trattamento
    • Percentuale dei giorni senza farmaco di emergenza durante il periodo di trattamento
    Variabili di sicurezza:
    • Eventi avversi e reazioni avverse da farmaco
    • Segni vitali (pressione sistolica e diastolica, frequenza cardiaca)
    • Analisi ematologiche e chimico-chimiche routinarie
    • ECG a 12 derivazioni
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 1, 7 and 8
    Giorno 1, 7 e 8
    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 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) 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 EEA42
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Russian Federation
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months9
    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.1.1Number of subjects for this age range: 0
    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: 72
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 108
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 180
    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)
    Expected normal treatment of the condition
    Normale trattamento
    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 Decision2012-03-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-01-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-09-28
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