| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| 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 |
| to demonstrate superiority of either QVM149 150/50/80 µgo.d. to QMF149 150/160 µg o.d. or QVM149 150/50/160 µg o.d. to QMF149 150/320µg o.d on through FEV1 over 26 weeks of treatment. Forced Expiratory volume in 1second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in thefirst second of a forced exhalation, measured through spirometry testing. |
| per dimostrare la superiorità di QVM149 150/50/80 µgO.D. a QMF149 150/160 µg o.d. o QVM149 150/50/160 µg o.d. a QMF149 150/320µg o.d attraverso FEV1 per 26 settimane di trattamento. Volume espiratorio forzato in 1secondo (FEV1) è la quantità di aria che può essere espirata forzatamente dai polmoni nelprimo secondo di un'espirazione forzata, misurata mediante test spirometrici. |
|
| E.2.2 | Secondary objectives of the trial |
Through FEV1 at week 52
- FEV1 and FVC at weeks 4 and 12
- PEF at weeks 26 and 52
- ACQ-7 at 26 and 52 weeks
- Percentage days with no symptoms (overall, at awakening and rising)at 52 weeks
- Percentage days without rescue medication use over 26 weeks and 52weeks
- Percentage of patients with MID ACQ>= 0.5 at week 26 and 52
- Asthma exacerbations over 52 weeks
- percentage of rescue medication free days over 26 and 52 weeks
- AQLQ at 52 weeks (at all clinical visits)
- Trough FEV1 at 26 weeks comparison with salmeterolxinafoate/fluticasone proprionate 50/500µg via Accuhaler®
- Asthma control as assessed by the ACQ-7 comparison with salmeterolxinafoate/fluticasone proprionate 50/500µg via Accuhaler® at 26 weeks
- Serious asthma outcome incidence and CCV events/atrial fibrilation at52 weeks
- Adverse events, vital sighns, laboratory analysis and ECG at 52 weeks |
Attraverso FEV1 alla settimana 52
- FEV1 e FVC alle settimane 4 e 12
- PEF alle settimane 26 e 52
- ACQ-7 a 26 e 52 settimane
- Giorni in percentuale senza sintomi (complessivamente, al risveglio e in aumento)a 52 settimane
- Giorni in percentuale senza uso di farmaci di salvataggio per 26 settimane e 52settimane
- Percentuale di pazienti con ACQ MID> = 0,5 alla settimana 26 e 52
- Esacerbazioni dell'asma per 52 settimane
- percentuale di giorni liberi da farmaci di salvataggio per 26 e 52 settimane
- AQLQ a 52 settimane (a tutte le visite cliniche)
- Attraverso FEV1 a confronto di 26 settimane con salmeterolo
xinafoate / fluticasone proprionate 50 / 500µg via Accuhaler®
- Controllo dell'asma valutato dal confronto ACQ-7 con salmeteroloxinafoate / fluticasone proprionate 50 / 500µg via Accuhaler® a 26 settimane
- Incidenza di esiti gravi di asma ed eventi CCV / fibrilazione atriale a52 settimane
- Eventi avversi, sospiri vitali, analisi di laboratorio ed ECG a 52 settimane |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Patients with a diagnosis of asthma, (GINA 2015) for a period of atleast 1 year prior to Visit 1 (Screening).
- Patients who have used medium or high dose of ICS/LABAcombinations for asthma for at least 3 months and at stable medium orhigh doses of ICS/LABA for at least 1 month prior to Visit 1. Patientsmust be symptomatic at screening despite treatment with mid or highstable doses of ICS/LABA.
- Patients with ACQ-7 score = 1.5 at Visit 101 and at Visit 102 (beforerandomization) (GINA 2015).
- Patients with documented history of at least one asthma exacerbationwhich required medical carefrom a physician, ER visit (or local equivalent structure) orhospitalization in the 12 months prior to Visit 1, and required systemiccorticosteroid treatment.
-Pre-bronchodilator FEV1 of < 80 % of the predicted normal value forthe patient according to ATS/ERS guidelines after withholdingbronchodilators at both visits 101 and 102.
-Withholding period of bronchodilators prior to spirometry: SABA for = 6hrs, Twice daily LABA (or FDC of ICS/LABA) for = 12 hrs, Once daily
LABA (or FDC of ICS/LABA) for = 24 hrs, SAMA for = 8 hrs, Short actingxanthines for 12 hrs, Long acting xanthines for 24 hrs.
- Washout period of each drug should be kept as close as possible asabove and should not be longer. If longer washout period is needed dueto scheduling issues, please contact Novartis Medical monitor.
- A one time repeat of percentage predicted FEV1 (Pre-bronchodilator)at visit 101 and/or 102 is allowed in an ad-hoc visit. Repeat of visit 101spirometry should be done in an ad-hoc visit to be scheduled on a datethat would provide sufficient time to receive confirmation from thespirometry data central reviewer of the validity of the assessment before
randomization. Run-in medication should be dispensed once spirometryassessment met inclusion criteria (ATS/ERS quality criteria, FEV1 %predicted normal value, and reversibility) as per equipment.
- A one-time rescreen is allowed in case the patient fails to meet thecriteria at the repeat, provided the patient returned to the requiredtreatment as per inclusion criteria 4
-Patients who demonstrate an increase in FEV1 of 12% and 200 mLwithin 30 minutes after administration of 400 µg salbutamol/360 µgalbuterol (or equivalent dose) at Visit 101.All patients must perform areversibility test at Visit 101. If reversibility is not demonstrated at Visit101 then one of the following criteria need to be met.
-Reversibility should be repeated once.
-Patients may be permitted to enter the study with historical evidence ofreversibility that was performed according to ATS/ERS guidelines within
2 years prior to Visit 1.
-Alternatively, patients may be permitted to enter the study with ahistorical positive broncho provocation test that was performed within 2years prior to Visit 1. If reversibility is not demonstrated at Visit 101 (orafter repeated assessment in an ad-hoc visit) and historical evidence ofreversibility/bronchoprovocation is not available (or was not performed according to theATS/ERS guidelines patients must be screen failed
- Spacer devices are permitted during reversibility testing only. TheInvestigator or delegate may decide whether or not to use a spacer forthe reversibility testing |
1. Pazienti adulti di sesso maschile e femminile di età = 18 anni e = 75 anni.
2. Consenso informato scritto ottenuto prima dell’effettuazione di qualsiasi valutazione dello studio.
3. Pazienti con diagnosi di asma (GINA 2015) da almeno 1 anno prima della Visita 1 (Screening).
4. Pazienti che abbiano utilizzato combinazioni ICS/LABA a dose medio-alta (Appendice 10 del protocollo) per l’asma da almeno 3 mesi e che sono in trattamento con dosi stabili medie oalte di ICS/LABA da almeno 1 mese prima della Visita 1.
5. Pazienti sintomatici allo screening nonostante il trattamento con dosi medie o alte di ICS/LABA. Pazienti con punteggio ACQ-7 =1.5 alla Visita 101 e alla Visita 102 (prima della visita di randomizzazione).
- In caso la spirometria venga ripetuta, perché non si è soddisfatto il criterio n°7, anche l’ACQ-7 dovrebbe essere ripetuto.
6. Pazienti con anamnesi documentata di almeno un’esacerbazione dovuta ad asma che ha richiesto cure mediche, visita in pronto soccorso (o struttura locale equivalente) o ricovero ospedaliero nei 12 mesi precedenti la Visita 1, e che ha richiesto trattamenti con corticosteroidi sistemici.
- La precedente esacerbazione di asma si basa sul ricordo da parte del paziente di una necessità non pianificata di cure mediche presso medico di base, pneumologo, pronto soccorso o ospedale e che ha richiesto trattamento con corticosteroidi sistemici per l’esacerbazione di asma.
- Lo sperimentatore deve utilizzare i mezzi appropriati per assicurare l'accuratezza della storia dell’esacerbazione del paziente (ad esempio, la storia del paziente alla Visita 1 documentata nelle note originarie, nei registri della farmacia, nei registri ospedalieri, o nei registri delle cartelle cliniche è accettabile).
7. FEV1 pre-broncodilatatore < 80% del valore normale predetto per il paziente secondo le linee guida ATS/ERS dopo la sospensione dei broncodilatatori (Tabella 5-2 del protocollo) sia alla Visita 101 che alla Visita 102.
- Periodo di sospensione dei broncodilatatori prima della spirometria:
- SABA per = 6 ore.
- LABA (o combinazione a dose fissa(FDC) di ICS/LABA) due volte al giorno per = 12 ore LABA una volta al giorno (o FDC di ICS/LABA) per =24 ore
- SAMA per = 8 ore
- Xantine a breve durata d’azione = 12 ore.
- Xantine a lunga durata d’azione =12 ore
- E’ consentita la replica della percentuale del FEV1 predetto (prima del broncodilatatore) a Visita 101 e/o Visita 102 una sola volta. La ripetizione della spirometria dovrà essere effettuata nel corso di una visita ad hoc da programmare in una data che garantisca un tempo sufficiente per la ricezione della conferma, da parte del revisore centralizzato dei dati di spirometria, della validità della valutazione prima della randomizzazione in caso di ripetizione a Visita 101.
- E’ ammesso un rescreening se il paziente è ritornato al trattamento richiesto secondo criterio di inclusione n°4
8. Pazienti che dimostrano un aumento di FEV1 = 12% e 200 mL entro 15-30 minuti dalla somministrazione di 400 µg di salbutamolo/360 µg di albuterolo (o dose equivalente) alla Visita 101. Tutti i pazienti devono effettuare un test di reversibilità alla Visita 101. Se non viene dimostrata la reversibilità alla Visita 101, deve essere soddisfatto uno dei seguenti criteri:
- Il test di reversibilità dovrebbe essere ripetuto una sola volta.
- Ai pazienti può essere consentito l’ingresso in studio con evidenza storica di reversibilità effettuata in base alle linee guida ATS/ERS nei 2 anni prima della Visita 1.
- In alternativa, ai pazienti può essere consentito l’ingresso in studio con un test storico di broncoprovocazione positivo effettuato nei 2 anni precedenti la Visita 1. |
|
| E.4 | Principal exclusion criteria |
- Patients who have had an asthma attack/exacerbation requiringsystemic steroids or hospitalization or emergency room visit within 6weeks of Visit 1 (Screening). If patients experience an asthmaattack/exacerbation requiring systemic steroids or hospitalization oremergency room visit between Visit 1 and Visit 102 they may be rescreened6 weeks after recovery from the exacerbation.
- Patients who have ever required intubation for a severe asthmaattack/exacerbation.
- Patients who have a clinical condition which is likely to be worsened byICS administration (e.g. glaucoma, cataract and fragility fractures) whoare according to investigator's medicaljudgment at risk participating inthe study.
- Patients treated with a LAMA for asthma within 3 months prior Visit 1(Screening).
- Patients with narrow-angle glaucoma, symptomatic benign prostatichyperplasia (BPH) or bladder-neck obstruction or severe renalimpairment or urinary retention. BPH patients who are stable ontreatment can be considered).
- Patients who have had a respiratory tract infection or asthmaworsening as determined by investigator within 4 weeks prior to Visit 1(Screening) or between Visit 1 and Visit 102. Patients may be rescreened4 weeks after recovery from their respiratory tract infection orasthma worsening.
- Patients with evidence upon visual inspection (laboratory culture is notrequired) of clinically significant (in the opinion of investigator)oropharyngeal candidiasis at Visit 102 or earlier, with or withouttreatment. Patients may be rescreened once their candidiasis has beentreated and has resolved.
- Patients with any chronic conditions affecting the upper respiratorytract (e.g. chronic sinusitis) which in the opinion of the investigator mayinterfere with the study evaluation or optimal participation in the study.
- Patients with a history of chronic lung diseases other than asthma,including (but not limited to) chronic obstructive pulmonary disease,sarcoidosis, interstitial lung disease, cystic fibrosis, clinically significantbronchiectasis and active tuberculosis.
- Patients with Type I diabetes or uncontrolled Type II diabetes. -Patients who, either in the judgment of theinvestigator or the responsible Novartis personnel, have a clinicallysignificant condition such as (but not limited to) unstable ischemic heartdisease, New York Heart Association (NYHA) Class III/IV left ventricularfailure arrhythmia, uncontrolled hypertension, cerebrovascular disease,psychiatric disease, neurodegenerative diseases, or other neurologicaldisease, uncontrolled hypo- and hyperthyroidism and other autoimmune
diseases, hypokalemia, hyperadrenergic state, or ophthalmologicdisorder or patients with amedical condition that might compromise patient safety or compliance,interfere with evaluation, or preclude completion of the study.
- Patients with paroxysmal (e.g., intermittent) atrial fibrillation areexcluded. Patients with persistent atrial fibrillation as defined bycontinuous atrial fibrillation for at least 6 months and controlled with arate control strategy (i.e., selective beta blockers, calcium channelblocker, pacemaker placement, digoxin or ablationtherapy) for at least 6 months may be considered for inclusion. In such patients, atrial fibrillation must be present at the run-in visit (Visit 101)with a resting ventricular rate < 100/min. At Visit 101 the atrial
fibrillation must be confirmed by central reading.
- Patients with a history of myocardial infarction within the previous 12months.
- Concomitant use of agents known to prolong the QT interval unless itcan be permanently discontinued for the duration of study
- Patients with a history of long QT syndrome or whose QTc measured atVisit 101 (Fridericia method) is prolonged (> 450 msec for males and >460 msec for females) and confirmed by a central assessor (thesepatients should not be rescreened). |
1. Pazienti che hanno avuto un attacco/esacerbazione di asma che ha richiesto steroidi sistemici o ricovero ospedaliero o visita in pronto soccorso nelle 6 settimane precedenti la Visita 1 (Screening).
2. Pazienti che hanno richiesto intubazione per un attacco/esacerbazione severa di asma.
3. Pazienti che hanno avuto una condizione clinica che è probabile subisca un peggioramento con la somministrazione di ICS (ad es. glaucoma, cataratta e fratture da fragilità) che, in base al giudizio medico dello sperimentatore, sono esposti a rischi dalla partecipazione allo studio.
4. Pazienti trattati con un LAMA per l’asma nei 12 mesi precedenti la Visita 1 (Screening).
5. Pazienti con glaucoma ad angolo stretto, iperplasia prostatica benigna od ostruzione del collo della vescica o disfunzione renale severa o ritenzione urinaria. I pazienti con iperplasia prostatica benigna che sono in trattamento stabile possono essere presi in considerazione per l’inclusione.
6. Pazienti che hanno avuto un’infezione delle vie respiratorie o un peggioramento dell’asma come stabilito dallo sperimentatore nelle 4 settimane precedenti la Visita 1 (Screening) o tra la Visita 1 e la Visita 102. I pazienti possono essere nuovamente sottoposti a screening 4 settimane dopo la risoluzione dell’infezione delle vie respiratorie o del peggioramento dell’asma.
7. Pazienti con anamnesi di patologia polmonare cronica diversa dall’asma comprese, ma non limitate a, BPCO, sarcoidosi, patologia polmonare interstiziale, fibrosi cistica, bronchiectasia clinicamente significativa, o tubercolosi attiva.
8. Pazienti con grave narcolessia e/o insonnia.
9. Pazienti con immunoterapia di mantenimento (desensibilizzazione) per allergie da meno di 3 mesi prima della Visita 101 o pazienti con immunoterapia di mantenimento da più di 3 mesi prima della Visita 101 ma per cui ci si aspetta che tale terapia cambi nel corso dello studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To demonstrate superiority of either QVM149 doses to either QMF149 doses on trough FEV1 over 26 weeks of treatment. |
| Per dimostrare la superiorità di entrambe le dosi QVM149 rispetto alle dosi QMF149 sul trogolo FEV1 oltre 26 settimane di trattamento. |
|
| E.5.1.1 | 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 175 |
| 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 | Information not present in EudraCT |
| 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 |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| China |
| Colombia |
| Croatia |
| Denmark |
| Estonia |
| Finland |
| France |
| Germany |
| Greece |
| Hungary |
| India |
| Ireland |
| Israel |
| Italy |
| Japan |
| Jordan |
| Latvia |
| Lebanon |
| Lithuania |
| Luxembourg |
| Mexico |
| Netherlands |
| Peru |
| Philippines |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Slovakia |
| Slovenia |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Thailand |
| United Arab Emirates |
| United Kingdom |
| Vietnam |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| Last patient Last visit |
| Utlima Visita Ultimo Paziente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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