E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic obstructive pulmonary disease (COPD) |
Broncopneumopatia cronica ostruttiva (BPCO) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029977 |
E.1.2 | Term | Obstructive chronic bronchitis |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To identify breathprints of volatile organic compounds (VOC) which are associated with interruption of inhaled steroid therapy and, possibly, loss of COPD control (deterioration in symptoms and lung function, exacerbations). |
Identificare i profili respiratori di composti organici volatili che sono associati alla sospensione della terapia con beclometasone inalatorio e, possibilmente, con la perdita del controllo della BPCO (peggioramento della sintomatologia e della funzionalità respiratoria, riacutizzazioni). |
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E.2.2 | Secondary objectives of the trial |
To investigate the effects of treatment with a combination of inhaled beclomethasone dipropionate and formoterol (Foster) on breath VOC profiles in patients with stable COPD; to investigate the effects of treatment and interruption of inhaled beclomethasone dipropionate/formoterol (Foster) on lung inflammation and oxidative stress in patients with stable COPD as reflected by neutrophil, macrophage, eosinophil and lymphocyte cell counts in sputum, profiles of metabolites in EBC measured by NMR spectroscopy, concentrations of PGE2 and 8-isoprostane in EBC, concentrations of LTB4, PGE2, 8-isoprostane, and cytokines (IL-8, TNF-, IL-1) in sputum supernatants, urinary concentrations of 8-isoprostane, and concentrations of fraction of exhaled nitric oxide (FENO |
Studiare gli effetti della terapia con una associazione di beclometasone e formoterolo inalatori (Foster) sui profili respiratori di composti organici volatili in pazienti con BPCO stabile; studiare gli effetti della terapia e della sospensione della terapia con beclometasone dipropionato/formoterolo inalatori (Foster) sull’infiammazione polmonare e sullo stress ossidativo in pazienti con BPCO stabile misurati mediante conte di neutrofili,macrofagi,eosinofili e linfociti nell’espettorato,profili di metaboliti nel condensato del respiro misurati mediante spettroscopia in NMR,concentrazioni di PGE2 and 8-isoprostano nel condensato del respiro,concentrazioni di LTB4,PGE2,8-isoprostano e citochine (IL-8,TNF-,IL-1) nel sovranatante dell’espettorato,concentrazioni urinarie di 8-isoprostano e concentrazioni di monossido di azoto nell’aria espirata |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Patient is male or female, at least 40 years of age and no more than 85 years.
- Patient has mild, moderate or severe COPD (stage I-III) according to the GOLD guidelines with a FEV1/FVC < 70% and FEV1 > 30% of the predicted value. Diagnosis of COPD will be based on GOLD guideline criteria (16).
- Reversibility to short-acting beta-agonists (SABA) (400 g equivalent of salbutamol) of less than 200 ml or less than 12% predicted value FEV1.
- Patients will be on a constant dose of ICS/LABA (ICS: 1000 g/day of fluticasone or equivalent) for at least 8 weeks before study enrolment.
- No acute exacerbations in the previous 3 months.
- No history of systemic disease or other pulmonary disease.
- No treatment with systemic glucocorticoids in the previous 4 weeks.
- No history of asthma or atopic disease.
- Current treatment for COPD can include SABA alone as needed or long-acting antimuscarinic drugs on regular basis.
- Apart from COPD, subjects are in good psycho-physical conditions based on history, physical examimantion and laboratory tests, and are able to complete the study.
- Ability to perform reproducible spirometry.
- Patient is a nonsmoker and has stopped smoking for at least one year.
- Ability of patient to provide informed consent, as evidenced by signing a copy of the consent form approved by the institutional review board of the subject’s respective study institution. |
1. Pazienti di sesso maschile e femminile, di età compresa tra 40 e 85 anni.
2. Pazienti con BPCO di grado lieve, moderato o grave sulla base delle linee guida GOLD (16) con FEV1/FVC < 70% e FEV1 > 30% del valore teorico. Diagnosi di BPCO basata sui criteri delle linee guida GOLD (16).
3. Reversibilità a beta-agonisti a breve durata di azione (SABA) (400 g di salbutamolo o equivalenti) inferiore a 200 ml FEV1 o inferiore al 12% del valore teorico di FEV1.
4. Pazienti in terapia con una dose costante di glucocorticoide inalatorio/beta-agonista a lunga durata di azione (glucocorticoide inalatorio: 1000 g al giorno di fluticasone o equivalenti) da almeno 8 settimane prima dell’inizio dello studio.
5. Nessuna riacutizzazione di BPCO nei 3 mesi precedenti.
6. Assenza di malattie sistemiche o altre patologie polmonari.
7. Nessun trattamento con glucocorticoidi sistemici nelle 4 settimane precedenti.
8. Assenza di asma o allergia.
9. Terapia ammessa per BPCO comprende SABA quando richiesto e somministrazione cronica di farmaci antimuscarinici inalatori a lunga durata di azione.
10. La persona è in buone condizioni psico-fisiche, tranne che per la presenza di BPCO, sulla base di anamnesi, esame obiettivo e test di laboratorio ed è in grado di completare lo studio.
11. Possibilità di eseguire una spirometria in modo riproducibile.
12. Assenza di storia di fumo, compresi prodotti del tabacco non da fumo, nell’ultimo anno.
13. Possibilità di fornire il consenso informato mediante firma del modulo di informazione per il paziente approvato dal Comitato Etico. |
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E.4 | Principal exclusion criteria |
1. Patient is, in the opinion of the investigator, mentally or legally incapacitated preventing informed consent from being obtained, or cannot read or comprehend written material.
2. Patient is hospitalized.
3. Patient has undergone any major surgical procedure in the previous four weeks.
4. Patient has participated in a clinical trial involving an investigational or marketed drug in the previous four weeks.
5. Subjects who were current smokers in the previous year.
Pulmonary
5. Patient has, in addition to COPD, any active, acute or chronic pulmonary disorder documented by history or physical examination.
6. Patient has history of asthma and/or reversibility to short-acting beta-agonists (SABA) (400 g equivalent of salbutamol) 200 ml or 12% predicted value FEV1.
7. Patient has ever been intubated for COPD, has required acute COPD therapy treated in an emergency room/urgent care facility/office setting within one month or has been hospitalized for COPD in the previous three months or required 2 or more hospitalizations for COPD in the past year.
8. Patient had an upper respiratory tract infection (URI) in the previous three weeks.
General Medical
4. Patient is hypersensitive to inhaled -agonists or their components.
5. Patient has a clinically significant, active disease of the gastrointestinal, cardiovascular, hepatic, neurological, renal, genitourinary, or haematological systems, or has uncontrolled hypertension (>160/95), or an immunodeficiency, or an autoimmune disorder.
6. Patient has a history of any illness that could be immediately life threatening (ventricular arrhythmia, neoplasia, incompletely cured or treated in the last three months, 'brittle' diabetes mellitus), or would pose restriction on participation in the study.
Medications
2. Patient has taken the following medications:
5) Oral, intravenous, intramuscular, intra-articular corticosteroids in the previous 4 weeks with the exception of nasal or inhaled corticosteroids administered on a continuous basis.
6) Antibiotics for 7 consecutive days in the previous 4 weeks.
7) IV gammaglobulin or immunosuppressants in the previous 4 weeks.
8) Beta-receptor-blocking agents (including ocular preparations) in individuals known to be sensitive to these compounds in the previous two weeks.
Procedural
3. Patient is unable to perform acceptable, reproducible spirometry, and peak flow measurements.
4. Patient is unable or unwilling to comply with the study procedures. |
Generali
1. Persone che non sono in grado di fornire il consenso informato.
2. Pazienti ricoverati in ospedale.
3. Pazienti che abbiano subito un intervento chirurgico nelle 4 settimane precedenti la visita 1.
4. Pazienti che abbiano partecipato ad uno studio clinico farmacologico nelle 4 settimane precedenti.
5. Soggetti fumatori nell’ultimo anno precedente l’inizio dello studio.
Polmonari
1. Presenza di patologie polmonari acute o croniche, oltre a BPCO, evidenziate dall’anamnesi o esame obiettivo.
2. Pazienti con storia di asma e/o reversibilità a beta-agonisti a breve durata di azione (SABA) (400 g di salbutamolo o equivalenti) superiore a 200 ml FEV1 o superiore al 12% del valore teorico di FEV1.
3. Pazienti che siano stati intubati per BPCO, abbiano richiesto terapia immediata per BPCO in pronto soccorso o in ambulatorio nel mese precedente l’inizio dello studio (visita 1) o siano stati ricoverati per asma nei tre mesi precedenti la visita 1 o siano stati ricoverati per BPCO due o più volte nell’anno precedente.
4. Infezioni delle vie respiratorie superiori nelle tre settimane precedenti la visita 1.
Generali medici
1. Pazienti con ipersensibilità a beta-agonisti inalatori o eccipienti presenti nella formulazione farmaceutica.
2. Patologie gastrointestinali, cardiovascolari, epatiche, neurologiche, renali, genitourinarie, ematologiche o ipertensione non controllata (>160/95) o sindromi da immunodeficienza o malattie autoimmunitarie.
3. Pazienti con storia di malattie per cui sia richiesta terapia con un farmaco la cui somministrazione non è consentita nel presente studio, malattie che possano costituire un pericolo immediato (aritmia ventricolare, neoplasia, incompletamente curata o trattata nei 3 mesi precedenti, diabete mellito non controllato).
Farmaci
1. Pazienti che abbiano preso i seguenti farmaci:
1) glucocorticoidi per os, endovena, intramuscolo, intra-articolari nelle 4 settimane precedenti l’inizio dello studio con l’eccezione degli steroidi intranasali o inalatori somministrati cronicamente.
2) antibiotici per > 7 giorni consecutivi nelle 4 settimane precedenti l’inizio dello studio.
3) gammaglobuline per via endovenosa o farmaci immunosoppressori nel mese precedente l’inizio dello studio.
4) terapia con farmaci beta-bloccanti (comprese preparazioni oftalmiche) nelle 2 settimane precedenti l’inizio dello studio in pazienti con ipersensibilità a questi farmaci
Procedurali
1. Pazienti che non sono in grado di eseguire una spirometria
2. Il paziente non è in grado o non vuole eseguire le procedure previste dallo studio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
. Response of electronic nose after steroid-withdrawal (sensor 19) (post-withdrawal visit compared with baseline visit) |
Risposta del naso elettronico (sensore 19) dopo sospensione della terapia con glucocorticoide inalatorio (visita post-sospensione della terapia in confronto a visita baseline) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
4 and 8 week |
4 e 8 settimane |
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E.5.2 | Secondary end point(s) |
Secondary end-points:
1. Response of electronic nose after re-introduction of steroid treatment (sensor 19) (post-treatment visit compared with post-withdrawal visit)
2. Neutrophil cell counts in sputum after steroid-withdrawal and treatment
3. Macrophage cell counts in sputum after steroid-withdrawal and treatment
4. Eosinophil cell counts in sputum after steroid-withdrawal and treatment
5. Lymphocyte cell counts in sputum after steroid-withdrawal and treatment
6. Profiles of metabolites in EBC after steroid-withdrawal and treatment
7. LTB4 concentrations in sputum supernatants after steroid-withdrawal and treatment
8. PGE2 concentrations in sputum after steroid-withdrawal and treatment
9. 8-Isoprostane concentrations in sputum after steroid-withdrawal and treatment
10. IL-8 concentrations in sputum supernatants after steroid-withdrawal and treatment
11. TNF- concentrations in sputum supernatants after steroid-withdrawal and treatment
12. IL-1 concentrations in sputum supernatants after steroid-withdrawal and treatment
13. PGE2 concentrations in EBC after steroid-withdrawal and treatment
14. 8-Isoprostane concentrations in EBC after steroid-withdrawal and treatment
15. 8-Isoprostane concentrations in urine after steroid-withdrawal and treatment
16. FENO concentrations after steroid-withdrawal and treatment
17. FEV1 (forced expiratory volume in one second) after steroid-withdrawal and treatment
18. FVC (forced vital capacity) after steroid-withdrawal and treatment
19. FEV1/FVC after steroid-withdrawal and treatment
20. PEF (peak expiratory flow) after steroid-withdrawal and treatment
21. FEF25%-75% (forced expiratory flow at 25%-75% of forced vital capacity) after steroid- withdrawal and treatment
22. St. George’s Respiratory Questionnaire (SGRQ) score after steroid-withdrawal and treatment
Safety endpoints
1. COPD exacerbation rate (defined as a symptomatic deterioration requiring treatment with antibiotic agents, systemic corticosteroids, hospitalization, or a combination of these)
2. other adverse events (including oro-pharyngeal candidiasis, dysphonia, pneumonia, fractures, cataract). |
Response of electronic nose after re-introduction of steroid treatment (sensor 19) (post-treatment visit compared with post-withdrawal visit)
2. Neutrophil cell counts in sputum after steroid-withdrawal and treatment
3. Macrophage cell counts in sputum after steroid-withdrawal and treatment
4. Eosinophil cell counts in sputum after steroid-withdrawal and treatment
5. Lymphocyte cell counts in sputum after steroid-withdrawal and treatment
6. Profiles of metabolites in EBC after steroid-withdrawal and treatment
7. LTB4 concentrations in sputum supernatants after steroid-withdrawal and treatment
8. PGE2 concentrations in sputum after steroid-withdrawal and treatment
9. 8-Isoprostane concentrations in sputum after steroid-withdrawal and treatment
10. IL-8 concentrations in sputum supernatants after steroid-withdrawal and treatment
11. TNF- concentrations in sputum supernatants after steroid-withdrawal and treatment
12. IL-1 concentrations in sputum supernatants after steroid-withdrawal and treatment
13. PGE2 concentrations in EBC after steroid-withdrawal and treatment
14. 8-Isoprostane concentrations in EBC after steroid-withdrawal and treatment
15. 8-Isoprostane concentrations in urine after steroid-withdrawal and treatment
16. FENO concentrations after steroid-withdrawal and treatment
17. FEV1 (forced expiratory volume in one second) after steroid-withdrawal and treatment
18. FVC (forced vital capacity) after steroid-withdrawal and treatment
19. FEV1/FVC after steroid-withdrawal and treatment
20. PEF (peak expiratory flow) after steroid-withdrawal and treatment
21. FEF25%-75% (forced expiratory flow at 25%-75% of forced vital capacity) after steroid- withdrawal and treatment
22. St. George’s Respiratory Questionnaire (SGRQ) score after steroid-withdrawal and treatment
Safety endpoints
1. COPD exacerbation rate (defined as a symptomatic deterioration requiring treatment with antibiotic agents, systemic corticosteroids, hospitalization, or a combination of these)
2. other adverse events (including oro-pharyngeal candidiasis, dysphonia, pneumonia, fractures, cataract). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |