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    Summary
    EudraCT Number:2017-004405-41
    Sponsor's Protocol Code Number:CLI-05993BA1-02
    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:2020-02-11
    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 number2017-004405-41
    A.3Full title of the trial
    A phase II, multicentre, randomised, double-blind, double-dummy, active-controlled, 3-way cross-over study to evaluate the efficacy of CHF 5993 administered via Dry Powder Inhaler (DPI) versus CHF 5993 via pressurized Metered Dose Inhaler (pMDI) and CHF 1535 pMDI in patients with chronic obstructive pulmonary disease
    Studio di fase II, multicentrico, randomizzato, doppio cieco, “double dummy”, a controllo attivo, incrociato a 3 vie, per valutare l’efficacia di CHF 5993 somministrato per mezzo di inalatore di polvere secca (DPI) rispetto a CHF 5993 somministrato per mezzo di inalatore predosato pressurizzato (pMDI) e CHF 1535 pMDI in pazienti con broncopneumopatia cronica ostruttiva.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to evaluate the efficacy of a drug (CHF 5993) comparing the results obtained with two different pharmaceutical forms and the effects produced by another drug (CHF 1535), in patients with chronic obstructive pulmonary disease
    Uno studio clinico per valutare l'efficacia del farmaco (CHF 5993) confrontando I risultati ottenuti con due diverse forme farmaceutiche e gli effetti prodotti da un altro farmaco (CHF 1535), nei pazienti con broncopneumopatia cronica ostruttiva.
    A.3.2Name or abbreviated title of the trial where available
    Tri-D study
    Tri-D study
    A.4.1Sponsor's protocol code numberCLI-05993BA1-02
    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 FARMACEUTICI S.P.A.
    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 pointClinical Project Manager
    B.5.3 Address:
    B.5.3.1Street Addressvia Palermo 26/A
    B.5.3.2Town/ cityParma
    B.5.3.3Post code43122
    B.5.3.4CountryItaly
    B.5.4Telephone number+33147684137
    B.5.5Fax number+33147684137
    B.5.6E-mailclinicaltrials_info@chiesi.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 nameCHF 5993 DPI NEXThaler®
    D.3.4Pharmaceutical form Inhalation powder
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBECLOMETASONE DIPROPIONATO
    D.3.9.1CAS number 5534-09-8
    D.3.9.2Current sponsor codeCHF 718
    D.3.9.3Other descriptive nameBECLOMETASONE DIPROPIONATO
    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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFORMOTEROLO FUMARATO DIIDRATO
    D.3.9.1CAS number 43229-80-7
    D.3.9.2Current sponsor codeCHF 1531.02
    D.3.9.3Other descriptive nameFORMOTEROLO FUMARATO DIIDRATO
    D.3.9.4EV Substance CodeSUB25660
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGLICOPIRRONIO BROMURO
    D.3.9.1CAS number 596-51-0
    D.3.9.2Current sponsor codeCHF 5259.02
    D.3.9.3Other descriptive nameGLICOPIRRONIO BROMURO
    D.3.9.4EV Substance CodeSUB07951MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12.5
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    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 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 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 nameTrimbow®
    D.3.2Product code CHF 5993 pMDI
    D.3.4Pharmaceutical form Inhalation powder
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBECLOMETASONE DIPROPIONATO
    D.3.9.1CAS number 5534-09-8
    D.3.9.2Current sponsor codeCHF 718
    D.3.9.3Other descriptive nameBECLOMETASONE DIPROPIONATO
    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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFORMOTEROLO FUMARATO DIIDRATO
    D.3.9.1CAS number 43229-80-7
    D.3.9.2Current sponsor codeCHF 1531.02
    D.3.9.3Other descriptive nameFORMOTEROLO FUMARATO DIIDRATO
    D.3.9.4EV Substance CodeSUB25660
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGLICOPIRRONIO BROMURO
    D.3.9.1CAS number 596-51-0
    D.3.9.2Current sponsor codeCHF 5259.02
    D.3.9.3Other descriptive nameGLICOPIRRONIO BROMURO
    D.3.9.4EV Substance CodeSUB07951MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12.5
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    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 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 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 - 100/6 MICROGRAMMI PER EROGAZIONE SOLUZIONE PRESSURIZZATA PER INALAZIONE
    D.2.1.1.2Name of the Marketing Authorisation holderCHIESI FARMACEUTICI S.P.A.
    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.3.1Product nameCHF 1535 pMDI
    D.3.4Pharmaceutical form Inhalation powder
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBECLOMETASONE DIPROPIONATO
    D.3.9.1CAS number 5534-09-8
    D.3.9.2Current sponsor codeCHF 718
    D.3.9.3Other descriptive nameBECLOMETASONE DIPROPIONATO
    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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFORMOTEROLO FUMARATO DIIDRATO
    D.3.9.1CAS number 43229-80-7
    D.3.9.2Current sponsor codeCHF 1531.02
    D.3.9.3Other descriptive nameFORMOTEROLO FUMARATO DIIDRATO
    D.3.9.4EV Substance CodeSUB25660
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    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 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 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInhalation powder
    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 (COPD)
    broncopneumopatia cronica ostruttiva (BPCO)
    E.1.1.1Medical condition in easily understood language
    chronic obstructive pulmonary disease (COPD)
    broncopneumopatia cronica ostruttiva (BPCO)
    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 LLT
    E.1.2Classification code 10010952
    E.1.2Term COPD
    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
    •To demonstrate the non-inferiority between CHF 5993 DPI and CHF 5993 pMDI in terms of FEV1 AUC0-12h normalized by time, in COPD patients.
    •To demonstrate the non-inferiority between CHF 5993 DPI and CHF 5993 pMDI in terms of trough FEV1 at 24h on dosing Day 28 in COPD patients.
    - Dimostrare la non inferiorità tra CHF 5993 DPI e CHF 5993 pMDI in termini di FEV1 AUC0-12h normalizzato rispetto al tempo in pazienti affetti da BPCO.
    - Dimostrare la non inferiorità tra CHF 5993 DPI e CHF 5993 pMDI in termini di FEV1 nelle 24h (trough FEV1) al 28esimo giorno di somministrazione del farmaco in pazienti affetti da BPCO.
    E.2.2Secondary objectives of the trial
    •To evaluate the efficacy of CHF 5993 DPI on other lung function parameters and clinical outcome measures.
    •To evaluate the safety and tolerability of the study treatments.
    - Valutare l’efficacia di CHF 5993 DPI su altri parametri e su risultati clinici relativi a funzioni polmonari.
    - Valutare la sicurezza e la tollerabilità dei trattamenti oggetto dello studio
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Age & Informed consent: Male and female adults (40 ≤ age ≤ 85 years) with written informed consent obtained prior to any study-related procedure.
    2.COPD Diagnosis: Established diagnosis of COPD (according to GOLD document updated 2017) at least 12 months prior to screening.
    3.A Post-bronchodilator FEV1 ≥30% and <80% of the predicted normal value and FEV1/FVC < 0.7.
    Post-bronchodilator test will be measured 10-15 min after the administration of 400µg salbutamol (4 puffs x100µg).
    4.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.
    5.Previous medication: Patients’ COPD therapy at screening with either:
    -Inhaled corticosteroids/long-acting β2-agonist/long-acting muscarinic antagonist (free or fixed) combination
    -Inhaled corticosteroids/long-acting β2-agonist (free or fixed) combination
    -Inhaled long-acting β2-agonist/long-acting muscarinic antagonist (free or fixed) combination
    -Inhaled long-acting muscarinic antagonist alone
    if taken at stable regimen at least 30 days before screening
    6.Ability to comply with the protocol
    7.Ability to use the inhaler
    1. Età e consenso informato: Adulti di sesso maschile e femminile (età compresa tra 40 ≤ e ≤ 85) con consenso informato scritto presentato prima di partecipare a qualsiasi fase dello studio.
    2. Diagnosi BPCO: Diagnosi di BPCO confermata (secondo il documento GOLD aggiornato al 2017) almeno 12 mesi prima dello screening.
    3. FEV1 ≥30% e <80% del valore normale previsto e FEV1/FVC < 0,7 dopo broncodilatatore.
    Il test post broncodilatatore viene effettuato 10-15 min dopo la somministrazione di 400 μg di salbutamolo (4 puffs x 100 μg).
    4. Una storia di fumatore di almeno 10 pacchetti di sigarette l’anno [pacchetto-anno = (numero di sigarette al giorno x numero di anni)/20]. Sono eleggibili sia i fumatori che gli ex fumatori.
    5. Farmaci precedenti: Terapia contro la BPCO al momento dello screening con:
    - combinazione (fissa o libera) di corticosteroidi/β2 agonisti a effetto prolungato/antagonista muscarinico a effetto prolungato assunto per inalazione
    - combinazione (fissa o libera) di corticosteroidi/agonisti β2 a effetto prolungato assunta per inalazione
    - combinazione(fissa o libera) di agonisti β2 a effetto prolungato/antagonista muscarinico a effetto prolungato assunta per inalazione
    - antagonista muscarinico a effetto prolungato assunto per inalazione
    se assunti in modo continuativo per almeno 30 giorni prima dello screening.
    6. Capacità di rispettare il protocollo: I pazienti devono avere un approccio cooperativo per rispettare le procedure dello studio.
    7. Capacità di utilizzare l’inalatore
    E.4Principal exclusion criteria
    1.Pregnancy and lactation: Pregnant or lactating women and women of
    childbearing potential with fertile male partners UNLESS they and/or
    their partner are willing to use a highly effective birth control method
    from the signature of the informed consent and until the follow-up
    contact. Being of non-childbearing potential is defined as meeting, at
    least, one of the following criteria:
    •at least 12 months of natural (spontaneous) amenorrhea with an
    appropriate clinical profile
    •previous surgical sterilization.
    2.Diagnosis of asthma: Patients with a current clinical diagnosis of
    asthma.
    3.Respiratory disorders other than COPD that would affect efficacy and
    safety evaluation or place the patient at risk. This can include but is not
    limited to known: alpha 1-antitrypsine deficiency, active tuberculosis,
    bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and
    interstitial lung disease.
    4.Lung cancer or history of lung cancer: Patients with a diagnosis of lung
    cancer or a history of lung cancer
    5.Cancer or history of cancer (other than lung): Patients with active
    cancer or a history of cancer with less than 5 years disease free survival
    time (whether or not there is evidence of local recurrence or
    metastases). Localised carcinoma (e.g. basal cell carcinoma, in situ
    carcinoma of the cervix adequately treated,..) is acceptable
    6.Lung resection: Patients with a history of lung volume resection.
    7.Lower tract respiratory infection that required use of antibiotics within
    6 weeks prior to screening or during the run-in period.
    8.History of exacerbations: Patients with a moderate or severe COPD
    exacerbation [i.e. resulting in the use of systemic corticosteroids
    (oral/IV/IM) and/or antibiotics and/or need for hospitalisation] within
    6 weeks prior to screening or during the run-in period.
    9.Oxygen therapy: Patients requiring long term (at least 12 hours daily)
    oxygen therapy for chronic hypoxemia
    10.Patients participating to a pulmonary rehabilitation programme or
    completing such a programme within 6 weeks prior to screening.
    11.Cardiovascular diseases: Patients who have clinically significant cardiovascular condition
    12.Atrial Fibrillation (AF)
    13.ECG criteria: Any clinically significant abnormal 12-lead ECG that
    would affect efficacy or safety evaluation or place the patients at risk.
    14.Concurrent diseases: Patients with medical history or current
    diagnosis of narrow-angle glaucoma, symptomatic prostatic
    hypertrophy, urinary retention or bladder neck obstruction that would
    prevent use of anticholinergic agents
    15.Other concurrent diseases: Patients with historical or current
    evidence of uncontrolled concurrent disease such as but not limited to
    hyperthyroidism, diabetes mellitus or other endocrine disease;
    haematological disease; autoimmune disorders (e.g. rheumatoid
    arthritis); significant renal impairment or other diseases / conditions
    that might place the patient at undue risk or potentially compromise the
    results or interpretation of the study.
    16.Laboratory abnormalities: Patients with clinically significant
    laboratory abnormalities indicating a significant unstable concomitant
    disease
    17.Patients with hypokalaemia (serum potassium levels <3.5 mEq/L (or
    3.5 mmol/L) or uncontrolled hyperkalaemia.

    1. Gravidanza e allattamento: Donne in gravidanza o in fase di allattamento. Donne potenzialmente fertili con partner di sesso maschile fertili A MENO CHE loro e/o i loro partner acconsentono all’utilizzo di un metodo contraccettivo altamente efficace a partire dalla data della firma del consenso informato e fino alla visita di follow-up. Essere potenzialmente non fertili significa soddisfare almeno uno dei seguenti criteri:
    • almeno 12 mesi di amenorrea naturale (spontanea) con profilo clinico adeguato
    • sterilizzazione per via chirurgica.
    2. Diagnosi di asma: Pazienti con diagnosi attiva di asma.

    3. Patologie respiratorie diverse dalla BPCO che potrebbero compromettere l’efficacia e la sicurezza della valutazione e mettere a rischio il paziente. Queste comprendono, ma non sono limitate a: deficienza di alfa 1-antitripsina, tubercolosi attiva, bronchiectasia, sarcoidosi, fibrosi polmonare, ipertensione polmonare e malattia interstiziale polmonare.
    4. Carcinoma del polmone o storia di carcinoma del polmone: Pazienti ai quali è stato diagnosticato il carcinoma del polmone o con una storia pregressa di carcinoma del polmone
    5. Tumore o storia pregressa di tumore (non ai polmoni): Pazienti con tumore o con storia pregressa di tumore e non liberi dalla malattia da almeno 5 anni (indipendentemente dal fatto che vi siano o meno recidive o metastasi locali). Il carcinoma localizzato (ad es. carcinoma delle cellule basali, carcinoma in situ della cervice trattato adeguatamente,..) è accettabile.
    6. Resezione polmonare: Pazienti con una storia di resezione del volume polmonare.
    7. Infezione del tratto respiratorio inferiore che richiede l’utilizzo di antibiotici nelle 6 settimane antecedenti allo screening o durante il periodo di run-in.
    8. Storia di esacerbazioni: Pazienti con esacerbazione di BPCO moderata o grave [ad es. risultate dall’uso di corticosteroidi sistemici (orale/IV/IM) e/o antibiotici e/o necessità di ricovero in ospedale] nelle 6 settimane antecedenti allo screening o durante il periodo di run-in.
    9. Terapia con ossigeno: Pazienti che richiedono una terapia con ossigeno a lungo termine (almeno 12 ore al giorno) per ipossemia cronica.
    10. Pazienti che partecipano a un programma di riabilitazione polmonare o che hanno completato questo tipo di programma 6 settimane prima dello screening.
    11. Malattie cardiovascolari: Pazienti con condizioni cardiovascolari clinicamente critiche 12. Fibrillazione atriale (AF):
    a. Fibrillazione atriale parossistica.
    b. Persistente. L’episodio di AF dura più a lungo di 7 giorni o richiede la cardioversione con farmaci o con corrente diretta (DCC) entro 6 mesi dallo screening.
    c. Persistente a lungo termine significa una fibrillazione atriale continua diagnosticata meno di 6 mesi fa con o senza strategia di controllo del battito.
    d. Permanente per almeno 6 mesi con una frequenza ventricolare a riposo ≥ 100/min controllata tramite strategia di controllo del battito (ad es. -bloccante selettivo, bloccante dei canali del calcio, impianto di un pacemaker, terapia con digossina o ablazione).
    13. Criteri ECG: Ogni ECG a 12 deviazioni clinicamente anormale potrebbe influire sull’efficacia o la sicurezza della valutazione, mettendo a rischio il paziente. I pazienti di sesso maschile con un QTcF>450 msec e quelli di sesso femminile con una QTcF>470 msec durante la visita di screening non sono eleggibili (non applicabile ai pazienti con fibrillazione atriale permanente o con pacemaker).
    14. Patologie concomitanti: Pazienti con anamnesi o diagnosi attuale di glaucoma ad angolo chiuso, ipertrofia prostatica sintomatica, ritenzione urinaria o ostruzione del collo della vescica che impedirebbero l’utilizzo degli agenti anticolinergici
    15. Altre patologie concomitanti : Pazienti con pregresse o attuali evidenze di patologie concomitanti e non controllate come, ma non limitate a: ipertiroidismo, diabete mellito o altre malattie endocrine; patologie ematologiche; disordini autoimmuni (ad es. artrite reumatoide); patologie renali importanti o altre patologie / condizioni che potrebbero mettere a rischio il paziente o compromettere potenzialmente i risultati dell’interpretazione dello studio.
    16. Anomalie di laboratorio: Pazienti che presentano anomalie di laboratorio clinicamente significative
    17. Pazienti con ipokaliemia (livelli di potassio nel siero <3,5 mEq/L (o 3,5 mmol/L) o ipokaliemia non controllata
    E.5 End points
    E.5.1Primary end point(s)
    1. FEV1 AUC0-12h normalized by time
    2. Trough FEV1 at 24h
    1. FEV1 AUC0-12h normalizzati rispetto al tempo
    2. Trough FEV1 nelle 24h
    E.5.1.1Timepoint(s) of evaluation of this end point
    1.On Day 1 and Day 28 of each treatment period
    2.On Day 28 of each treatment period
    1. Giorno 1 e giorno 28 per ogni periodo di trattamento
    2. Giorno 28 di ogni periodo di trattamento
    E.5.2Secondary end point(s)
    1. other lung function parameters and clinical outcome measures.
    2. safety and tolerability of the study treatments.
    1. Altri parametri e su risultati clinici relativi a funzioni polmonari.
    2. Sicurezza e la tollerabilità dei trattamenti oggetto dello studio.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Across the trial
    Durante lo studio
    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 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 Yes
    E.8.1.7.1Other trial design description
    double-dummy
    double-dummy
    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 trial3
    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 EEA60
    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 Information not present in EudraCT
    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
    Follow up contact 1 week after V7
    Chiamata di follow up una settimana dopo la V7
    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 months1
    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 months1
    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: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 253
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 253
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 506
    F.4.2.2In the whole clinical trial 506
    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)
    Before discharge, the investigator will prescribe the most appropriate treatment or restore the initial therapy or refer to General Practitioner
    Prima della dimissione, lo sperimentatore prescriverà il trattamento più appropriato o ripristinerà la terapia iniziale o farà riferimento al medico di famiglia
    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 Decision2018-06-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-04-18
    P. End of Trial
    P.End of Trial StatusCompleted
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