| 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 | 14.1 |
| 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 |
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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 |
| The primary objective is to compare the efficacy of two doses of GSK573719/GW642444 Inhalation Powder (125mcg/25mcg and 62.5mcg/25mcg once-daily) with GW642444 (25mcg once-daily) and with tiotropium (18mcg once-daily) over 24 weeks for the treatment of subjects with COPD |
| L'obiettivo primario è quello di confrontare l'efficacia di due dosi di GSK573719/GW642444 Polvere per Inalazione (125 mcg/25 mcg e 62,5 mcg/25 mcg una volta al giorno) rispetto a GW642444 (25 mcg una volta al giorno) e a tiotropio (18 mcg una volta al giorno) nell’arco di 24 settimane in soggetti con BPCO. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives are to compare effects of two doses of GSK573719/GW642444 Inhalation Powder (125mcg/25mcg and 62.5mcg/25mcg once-daily) with GW642444 (25mcg once-daily) and with tiotropium (18mcg once-daily) on safety and quality of life assessments over 24 weeks in subjects with COPD |
| Gli obiettivi secondari sono confrontare gli effetti di due dosi di GSK573719/GW642444 Polvere per Inalazione (125 mcg/25 mcg e 62,5 mcg/25 mcg una volta al giorno) con GW642444 (25 mcg una volta al giorno) e con tiotropio (18 mcg una volta al giorno) sulla sicurezza e sulla qualità della vita nell’arco di 24 settimane in soggetti con BPCO. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Type of subject: Outpatient. 2. Informed Consent: A signed and dated written informed consent prior to study participation. 3. Age: Subjects 40 years of age or older at Visit 1. 4. Gender: Male or female subjects. A female is eligible to enter and participate in the study if she is of: Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g. age appropriate, > 45 years, in the absence of hormone replacement therapy. However in questionable cases, post-menopause status may be confirmed by analysis of a blood sample with FSH > 40MIU/ml and estradiol <40pg/ml (<140 pmol/L) as confirmatory. OR Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label and the instructions of the physician for the duration of the study – screening to follow-up contact): • Abstinence • Oral Contraceptive, either combined or progestogen alone • Injectable progestogen • Implants of levonorgestrel • Estrogenic vaginal ring • Percutaneous contraceptive patches • Intrauterine device (IUD) or intrauterine system (IUS) that meets the SOP effectiveness criteria as stated in the product label • Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, “documented” refers to the outcome of the investigator's/designee’s medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records. • Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository) 5. Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society [Celli, 2004] as follows: Chronic obstructive pulmonary disease is a preventable and treatable disease state 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. Smoking History: Current or former cigarette smokers with a history of cigarette smoking of =>10 pack-years [number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)]. Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. 7. Severity of Disease: A post-albuterol/salbutamol FEV1/FVC ratio of <0.70 and a post-albuterol/salbutamol FEV1 of <=70% of predicted normal values calculated using NHANES III reference equations at Visit 1 [Hankinson, 1999; Hankinson, 2010] 8. Dyspnea: A score of ≥2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at Visit 1 |
| 1.Tipo di soggetto: pazienti ambulatoriali.2.Consenso Informato: consenso informato firmato e datato prima della partecipazione allo studio. 3.Età: soggetti di almeno 40 anni alla Visita 1.4.Sesso: soggetti di 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.5.Diagnosi: storia clinica confermata di BPCO secondo la definizione dell’American Thoracic Society/European Respiratory Society. 6.Storia di tabagismo: fumatori o ex-fumatori con ≥10 pacchetti/anno [numero di pacchetti/anno = (numero di sigarette al giorno / 20) x numero di anni di fumo. Gli ex-fumatori sono definiti come coloro che hanno smesso di fumare almeno 6 mesi prima della Visita 1. 7.Gravità della malattia: soggetti che alla Visita 1 presentano, dopo la somministrazione di salbutamolo, un rapporto FEV1/FVC <0,70 e un valore di FEV1 <=70% del valore predetto utilizzando le equazioni di riferimento NHANES III 8.Dispnea: soggetti che alla Visita 1 presentano un punteggio ≥ 2 nella scala “Modified Medical Research Council Dyspnea Scale” (mMRC). |
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| E.4 | Principal exclusion criteria |
| 1. Women who are pregnant or lactating or are planning on becoming pregnant during the study 2. Asthma 3. Known respiratory disorders other than COPD including but not limited to alpha-1 antitrypsin deficiency, active tuberculosis, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, and interstitial lung disease. Allergic rhinitis is not exclusionary. 4. Subjects with historical or current evidence of clinically significant (in the investigator opinion) cardiovascular, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled and/or a previous history of cancer in remission for <5 years prior to Visit 1 (localized carcinoma of the skin that has been resected for cure is not exclusionary). 5. A chest X-ray or computed tomography (CT) scan that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray must be taken at Visit 1 if a chest X-ray or CT scan is not available within 6 months prior to Visit 1. 6. A history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the study physician contraindicates study participation or use of an inhaled anticholinergic. 7.Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1 8. Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1) 9. An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1, including the presence of a paced rhythm on a 12-lead electrocardiogram (ECG) which causes the underlying rhythm and ECG to be obscured. 10. Significantly abnormal finding from clinical chemistry or hematology tests at Visit 1 11. Unable to withhold albuterol/salbutamol for the 4 hour period required prior to spirometry testing at each study visit 12. Medications prior to Screening: Please see table page 24 of the protocol. 13. Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day. As-needed oxygen use (i.e., <=12 hours per day) is not exclusionary. 14. Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., albuterol/salbutamol) via nebulized therapy. 15. Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded. 16. A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1. 17. Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study. 18. Previous exposure to GSK573719, GSK573719/GW642444 combination, GW642444 (vilanterol) and fluticasone furoate/GW642444 combination |
| 1.donne in gravidanza o allattamento o che intendono iniziare una gravidanza durante lo studio 2.soggetti con diagnosi corrente di asma. 3.soggetti con disturbi respiratori noti diversi dalla BPCO, come, ad esempio, deficienza di alpha-1 antitripsina, tubercolosi attiva, bronchiettasia, sarcoidosi, fibrosi polmonare, ipertensione polmonare e patologie polmonari interstiziali. La rinite allergica non è motivo di esclusione. 4. soggetti con evidenze pregresse o correnti di anomalie non controllate e clinicamente significative di tipo cardiovascolari, neurologiche, psichiatriche, renali, epatiche, immunologiche, endocrine o ematologiche e/o storia pregressa di cancro in remissione da <5 anni prima della Visita 1 (il carcinoma cutaneo localizzato curato con la resezione non è motivo di esclusione). 5.soggetti con Rx del torace suggestivo di anormalità clinicamente significativa indipendente dalla BPCO. 6.soggetti con storia di allergia o ipersensibilità a qualsiasi anticolinergico/antagonista dei recettori muscarinici, beta2-agonista, lattosio/proteine del latte o magnesio stearato o con una patologia medica come glaucoma ad angolo acuto, ipertrofia prostatica o ostruzione del collo vescicale che, a giudizio del medico sperimentatore, controindichi la partecipazione allo studio o l'uso di anticolinergici inalatori. 7.soggetti cha siano stati ospedalizzati a causa della BPCO o polmonite nelle 12 settimane precedenti la Visita 1.8. soggetti sottoposti a intervento di riduzione del volume polmonare nei 12 mesi precedenti lo Screening 9.soggetti con anormalità clinicamente rilevanti (vedi dettagli nel protocollo) nell’ECG effettuato allo screening 10.soggetti con un risultato significativamente anomalo nei valori di laboratorio per emocromo e biochimica alla Visita 1. 11. soggetti impossibilitati a sospendere il trattamento con albuterolo/salbutamolo nelle 4 ore precedenti la spirometria prevista a ciascuna visita dello studio. 12.Trattamento prima della Screening: vedi tabella a pag. 24 del protocollo 13.soggetti in ossigenoterapia a lunga durata per più di 12 ore al giorno. 14.uso regolare (con prescrizione per l'uso giornaliero, non al bisogno) di broncodilatatori a breve durata d'azione (ad es. albuterolo/salbutamolo) mediante nebulizzazione.15. partecipazione alla fase acuta di un programma di riabilitazione polmonare nelle 4 settimane precedenti la Visita 1. 16. storia nota o sospetta di abuso di alcool o droghe nei 2 anni precedenti la Visita 1.17. soggetti affiliati con il Centro sperimentale 18 esposizione precedente a GSK573719, alla combinazione GSK573719/GW642444, a GW642444 (vilanterolo) e alla combinazione fluticasone furoato/GW642444. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the clinic visit pre-dose trough FEV1 on Treatment Day 169. Trough FEV1 on Treatment Day 169 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after dosing on Day 168 (i.e. at Week 24) |
| L’endpoint primario è il FEV1 trough pre-dose al Giorno di Trattamento 169, definito come la media dei valori di FEV1 ottenuti 23 e 24 ore dopo la somministrazione di farmaco del Giorno precedente (giorno 168). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 169 of the study |
| Giorno 169 dello studio |
|
| E.5.2 | Secondary end point(s) |
| Weighted mean 0-6 hour FEV1 obtained post-dose at Week 24 • Mean SOBDA score during Week 24 |
| - Media ponderata dei valori di FEV1 ottenuti agli intervalli 0-6 ore post-dose alla Settimana 24 - Punteggio medio del questionario SOBDA durante la Settimana 24 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 4 |
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 71 |
| 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 |
| Mexico |
| Peru |
| Russian Federation |
| Ukraine |
| United States |
|
| 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 | 18 |
| 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 | 18 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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