| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with Chronic Obstructive Pulmonary Disease (COPD) |
| Pazienti con Broncopneumopatia Cronico-Ostruttiva (BPCO) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic obstructive pulmonary disease (COPD) leads to a limitation of the flow of air to and from the lungs causing shortness of breath. |
| La BPCO è una malattia a lungo termine che colpisce le vie aeree (bronchi), riducendo il flusso d’aria in entrata ed in uscita dai polmoni, e rendendo difficoltosa la respirazione. |
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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 | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 |
| The primary objective of the study is to evaluate the effect of FF/VI Inhalation Powder 100/25 mcg administered once daily (QD) compared with Tiotropium 18 mcg QD on arterial stiffness measured as aortic pulse wave velocity (aPWV) in subjects with COPD and aPWV ≥ 12.0 m/s at baseline. |
| L’obiettivo primario di questo studio e` quello di valutare l’effetto sulla rigidita` arteriosa misurata come velocita` dell’onda di polso (aPWV) di FF/VI polvere per inalazione 100/25 mcg somministrato una volta al giorno (QD) rispetto a Tiotropio 18 mcg somministrato una volta al giorno (QD) in soggetti con BPCO e aPWV ≥ 12m/s al basale. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are to confirm the efficacy of FF/VI Inhalation Powder 100/25 mcg QD compared with Tiotropium 18 mcg QD in improving lung function in subjects with COPD and aPWV≥12.0 m/s at baseline, and to further evaluate the safety in those subjects. |
| Obiettivo secondario dello studio e` quello di confermare l’efficacia di FF/VI polvere per inalazione 100/25 mcg QD rispetto a Tiotropio 18 mcg QD nel migliorare la funzionalita` polmonare in soggetti con BPCO e aPWV ≥ 12m/s al basale e di valutarne ulteriormente la sicurezza in questi soggetti. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Type of subject: Outpatient 2. Informed consent: Subjects must give their signed and dated written informed consent to participate. 3. Gender: Male or female subjects A female is eligible to enter and participate in the study if she is of: Non-child bearing potential OR Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the acceptable contraceptive methods used consistently and correctly 4. Age: ≥40 years of age at Screening (Visit 1) 5. COPD diagnosis: Subjects with a clinical history of COPD in accordance with the following definition by the American Thoracic Society (ATS) /European Respiratory Society(ERS) [Celli, 2004]: COPD is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences. 6. Tobacco use: Subjects with a current or prior history of ≥10 pack-years of cigarette smoking at Screening (Visit 1). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. • Note: Pipe and/or cigar use cannot be used to calculate pack-year history. • Number of pack years = (number of cigarettes per day/20) x number of years smoked 7. Severity of Disease: • Subjects with a measured post-albuterol/salbutamol FEV1 <70% of predicted normal values calculated using NHANES III reference equations [Hankinson, 1999; Hankinson, 2010] at Screening (Visit 1). • Subjects with a measured post-albuterol/salbutamol FEV1/FVC ratio of ≤0.70 at Screening (Visit 1) [Pelligrino, 2005] Post-bronchodilator spirometry will be performed approximately 10-15 minutes after the subject has self-administered 4 inhalations (i.e., total 400mcg) of albuterol/salbutamol. 8. Exacerbation History: Subjects who have been hospitalised or have been treated with oral corticosteroids or antibiotics for their COPD within the last 3 years prior to Screening (V1). 9. Baseline aPWV: subjects with a measured aPWV ≥ 12.0 m/s at Screening (Visit 1). |
| Nell’Investigator’s Brochure vengono fornite informazioni specifiche circa le avvertenze, le precauzioni, le controindicazioni, gli eventi avversi, ed altre informazioni rilevanti che possono avere impatto sull’eleggibilita` dei soggetti. I soggetti che saranno arruolati nello studio dovranno soddisfare tutti i seguenti criteri: 1. pazienti ambulatoriali 2. consenso informato scritto datato e firmato 3. sesso maschile o femminile. I soggetti di sesso femminile possono essere inclusi nello studio se non potenzialmente fertili o con test di gravidanza negativo allo screening e che accettano di utilizzare un metodo contraccettivo adeguato per tutta la durata dello studio 4. eta`  40 anni alla Visita 1 5. diagnosi di BPCO secondo la definizione dell’American Thoracic Society/European Respiratory Society 6. fumatori o ex fumatori di ≥ 10 pacchetti/anno - numero di pacchetti/anno = (numero di sigarette al giorno/20) x numero di anni di fumo - alla Visita 1. Sono definiti ex fumatori i soggetti che hanno smesso di fumare almeno 6 mesi prima della Visita 1 7. soggetti che alla Visita 1 presentano, dopo la somministrazione di salbutamolo,  FEV1  70% del valore predetto, utilizzando le equazioni di riferimento NHANES III  un rapporto FEV1/FVC  0.70 8. soggetti che siano stati ospedalizzati o trattati con corticosteroidi orali o antibiotici per il trattamento dei sintomi della BPCO nei 3 anni precedenti lo screening (Visita 1). 9. Soggetti con aPWV ≥ 12.0 m/s allo Screening (Visita 1) |
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| E.4 | Principal exclusion criteria |
| 1. Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study. 2. Asthma: Subjects with a current diagnosis of asthma. Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD. 3. Other respiratory disorders: The investigator must judge that COPD is the primary diagnosis accounting for the clinical manifestations of the lung disease. 4. A cardiovascular event: (e.g., Acute Coronary Syndrome, Stroke, Coronary Artery Bypass Surgery, Percutaneous Coronary Intervention) in the 6 months prior to Visit 1. 5. Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1) or having had lung transplantation. 6. Poorly controlled COPD: Subjects with poorly controlled COPD, defined as the occurrence of ‘acute worsening of COPD that is managed by subject with corticosteroids or antibiotics or that requires treatment prescribed by a physician in the 6 weeks prior to Visit 1’ or ‘subjects who are hospitalized due to poorly controlled COPD within 12 weeks of Visit 1’ 7. Lower respiratory tract infection: Subjects with lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Visit 1. 8. Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, gastrointestinal, neurological, psychiatric, renal, hepatic, immunological, endocrine view protocol for further information. 9. Current severe heart failure (New York Heart Association class IV). Subject will be excluded if they have a known ejection fraction of < 30 %. 10. Hypertension: In the judgment of the investigator the subject does not have uncontrolled hypertension meaning that they are unlikely to require medication adjustments during the study period. 11. Abnormal and clinically significant 12-lead ECG, view protocol for further information. 12. Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years, view protocol for further information. 13. Drug/food allergy: Subjects with a history of hypersensitivity to any of the study medications and or milk allergies view protocol. 14. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years. 15. Medication prior to spirometry, view protocol for further information. 16. Additional medication: view criterion 16 page 24 of the protocol. 17. Initiation, discontinuation and/or changing dose of medications reported to affect a PWV: Subjects who have started, discontinued and/or are receiving the following medications, view protocol for further information. 18. Oxygen therapy: Supplemental oxygen, with the following exceptions: â€¢ï€ Use at high altitude (> 5000 feet) provided subject does not require a flow rate of > 2 L/minute, view protocol for further information. 19. Pulmonary rehabilitation: Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program, view protocol for further information. 20. A body mass index (BMI) of â‰¥ï€ 35kg/m2 21. Lipid Panel: Subjects with LDL>3.3mmol/L, total cholesterol >5.2mmol/L, and triglycerides >2.24mmol/L (based on Visit 1 fasting lipid panel). 22. Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits. 23. Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study. 24. Prior use of study medication/other investigational drugs: Subjects who have previously been randomised to treatment in the HZC113108/110 study. 25. Affiliation with investigator site. |
| Non saranno inclusi i soggetti che rispondono ai seguenti criteri: 1. donne in gravidanza o allattamento o che intendono cominciare una gravidanza nel corso dello studio. 2. soggetti con diagnosi corrente di asma (soggetti con pregressa storia di asma sono eleggibili se hanno una diagnosi corrente di BPCO). 3. soggetti con deficit di α1-antitripsina come causa sottostante della BPCO, con tubercolosi attiva, carcinoma polmonare, bronchiectasia, sarcoidosi, fibrosi polmonare, ipertensione polmonare, patologie polmonari interstiziali e altre patologie polmonari attive. 4. soggetti che abbiano avuto un evento cardiovascolare (es. sindrome coronaria acuta, infarto, intervento di bypass coronario, intervento di chirurgia coronarica percutanea) nei 6 mesi precedenti la Visita 1. 5. soggetti sottoposti a lobectomia polmonare nei 12 mesi precedenti lo screening o a trapianto di polmone 6. soggetti con mancato controllo dei sintomi della BPCO, definito come • manifestazione nelle 6 settimane precedenti lo screening (Visita 1) di peggioramento acuto della BPCO gestito dal soggetto stesso con corticosteroidi o antibiotici o farmaci prescritti dal medico • o soggetti che siano stati ospedalizzati a causa del mancato controllo dei sintomi della BPCO nelle 12 settimane precedenti lo screening (Visita 1) 7. soggetti con infezioni delle basse vie respiratorie che abbiano richiesto l’uso di antibiotici nelle 6 settimane precedenti lo screening (Visita 1) 8. altre patologie/anormalita`: anamnesi positiva per o obiettivita` di patologie non controllate e clinicamente significative di tipo cardiovascolari, gastrointestinali, neurologiche, psichiatriche, renali, epatiche, immunologiche, endocrine, o anormalita` ematologiche. 9. presenza di scompenso cardiaco severo (NYHA classe IV). Soggetti con frazione di eiezione <30% saranno esclusi. 10. Ipertensione non controllata e che e` probabile richieda modifiche della terapia nel corso dello studio. 11. anormalita` clinicamente rilevanti nell’ECG (vedi dettagli nel protocollo di studio). 12. neoplasia maligna non in remissione completa da almeno 5 anni 13. ipersensibilita` ad uno dei farmaci o ai componenti della polvere inalatoria in studio; storia di grave allergia alle proteine del latte 14. nota o sospetta storia positiva per abuso di alcol o droghe negli ultimi due anni 15. soggetti che non possono sospendere l’assunzione di salbutamolo e/o ipratropio nelle 4 ore precedenti la spirometria a ciascuna visita 16. uso dei farmaci negli intervalli di tempo prima della Visita 1 o durante lo studio come da protocollo 17. Inizio, interruzione e/o modifica della dose di trattamenti che sono noti per influire sulla aPWV: • Antipertensivi • Ipolipemizzanti • Ipoglicemizzanti per il trattamento del diabete • Nitrati 18. ossigenoterapia ad eccezione di•utilizzo ad alte altitudini e con una portata non >2L/minuto•uso sotto sforzo e/o di notte se non richiesto per >12 ore al giorno e con una portata >2L/minuto•uso continuo e stabile nel corso dello studio. 19. fase acuta di riabilitazione polmonare nelle 4 settimane precedenti lo screening o durante lo studio. 20. BMI ≥ 35kg/m2 21. LDL>3.3mmol/L, colesterolo totale >5.2mmol/L e trigliceridi >2.24mmol/L misurati a digiuno alla Visita 1. 22. soggetti a rischio di o incapaci di mantenere un’adeguata compliance alle procedure dello studio. 23. soggetti affetti da patologie psichiatriche, deficienza intellettuale, scarsa motivazione o altre condizioni che potrebbero limitare la validita` del consenso informato. 24. Uso precedente dei medicinali sperimentali: arruolamento negli studi HZC113108/110. 25. affiliazione con il Centro sperimentale |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is change from baseline in aortic pulse wave velocity (aPWV) at the end of the 12-week study treatment period. View protocol page 40 for further information. |
| • Variazione rispetto al basale del aPWV al termine delle 12 settimane di trattamento. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At week 12 |
| Alla settimana 12 |
|
| E.5.2 | Secondary end point(s) |
| Other Efficacy Endpoints: •Change from baseline in morning clinic visit trough FEV1 (pre-bronchodilator and pre-dose) at the end of the 12-week study treatment period, •Change from baseline in morning clinic visit trough IC (pre-bronchodilator and pre-dose) at the end of the 12-week study treatment period. Exploratory: •Change from baseline in Central pulse pressure, •Change from baseline in Augmentation Index (AIx), •Change from baseline in Peripheral pulse pressure, •COPD Assessment Test (CAT), •EuroQol Questionnaire (EQ-5D), •St George’s Respiratory Questionnaire-C (SGRQ-C), •Healthcare resource utilization Safety: •Incidence of Adverse Events (AEs),•Change from baseline in pulse rate (PR) and mean arterial pressure (MAP) at the end of 12-week treatment period, •Oropharyngeal examination findings at the end of the 12-week treatment period, •Incidence of COPD exacerbations |
| Altri endpoint di efficacia: •Variazione rispetto al basale del FEV1 (pre-broncodilatatore e pre-dose) al termine delle 12 settimane di trattamento, •Variazione rispetto al basale della capacità inspiratoria (IC) (pre-broncodilatatore e pre-dose) al termine delle 12 settimane di trattamento. Esploratori: •Variazione rispetto al basale della Pressione Pulsatoria Centrale; •Variazione rispetto al basale del Augmentation Index (AIx) •Variazione rispetto al basale della Pressione Pulsatoria Periferica •Test per la valutazione della (BPCO) – CAT •Questionario sulla Salute EuroQol (EQ-5D)•Questionario Saint George sui disturbi respiratori per pazienti con BPCO (SGRQ-C)•Utilizzo delle risorse sanitarie; Sicurezza: •Incidenza degli eventi avversi, •Variazioni rispetto al basale nella frequenza pulsatoria (Pulse Rate) e pressione arteriosa media (MAP) al termine delle 12 settimane di trattamento, •Risultati dell’esame dell’orofaringe al termine delle 12 settimane di trattamento, •Incidenza di esacerbazioni della BPCO. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At week 12 |
| Alla settimana 12 |
|
| 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 | No |
| 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 | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| DOUBLE-DUMMY |
| DOUBLE-DUMMY |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Russian Federation |
| Ukraine |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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