| 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 | 18.1 |
| 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 μg
o.d. to QMF149 150/160 μg
o.d. or QVM149 150/50/160
μg o.d. to QMF149 150/320
μg o.d on through FEV1 over
26 weeks of treatment. Forced
Expiratory cvolume in 1
second (FEV1) is the amount
of air which can be forcibly
exhaled from the lungs in the
first second of a forced
exhalation, measured through
spirometry testing. |
|
| E.2.2 | Secondary objectives of the trial |
To demonstrate superiority of either doses of QVM versus QMF in terms of:
- FEV1 over 52 weeks
- FEV1 and FVC at weeks 4 and 12
- PEF at weeks 26 and 52
- ACQ-7 at 52 weeks
- Percentage days with no symptoms at 52 weeks
- Perecentage days without rescue medication over 26 weeks and 52 weeks
- Percentage of patients with MID ACQ>= 0.5 at week 26 and 52
- Asthma exacerbations over 52 weeks
-percentage of rescue mdication free daysover 26 and 52 weeks
- AQLQ at 52 weeks
- Through FEV1 at 26 weeks comparison with salmeterol xinafoate/fluticasone proprionate 50/500μg via Accuhaler®
- Asthma comtrol as assessed by the ACQ-7 comparison versus salmeterol xinafoate/fluticasone proprionate 50/500μg via Accuhaler® at 26 weeks
- Serious asthma outcome incidence and CCV events/atrial fibrilation at 52 weeks
- Adverse events, vital sighns, laboratory analysis and ECG at 52 weeks
- |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Patients with a diagnosis of asthma, (GINA 2015 ≥ step 4) for a period of at least 1 year prior to Visit 1 (Screening).
- Patients who have used ICS/LABA combinations (Appendix 10) for asthma for at least 1 year and at stable medium or high doses of ICS/LABA for at least 1 month prior to Visit 1.
- Patients must be symptomatic at screening despite treatment with mid or high stable doses of ICS/LABA.
- Patients with ACQ-7 score ≥ 1.5 at Visit 1 (or 101 if no wash-out required) and at Visit 102 (randomization visit) (GINA 2015≥ step 4).
- Patients with documented history of at least one asthma exacerbation which required medical care from a physician, ER visit (or local equivalent structure) or hospitalization in the 12 months prior to Visit 1 and required systemic corticosteroid treatment.
-Pre-bronchodilator FEV1 of < 80 % of the predicted normal value for the patient after withholding bronchodilators (Table 5-2) at both visits 101 and 102.
- Withholding period of bronchodilators prior to spirometry: SABA for ≥ 6 hrs, LABA (or FDC of ICS/LABA*) for ≥ 24 hrs (48 hrs for indacaterol FDC), SAMA for ≥ 8 hrsxanthines ≥ 7 days.
-Re-testing is allowed once only. Re-assessment of percentage predicted FEV1 should be done in an ad-hoc visit to be scheduled on a date that would provide sufficient time to receive confirmation from the spirometry data central reviewer of the validity of the assessment before randomization. Spacer devices are not permitted during reversibility testing.
- Patients who demonstrate an increase in FEV1 of 12% and 200 mL within 30 minutes after administration of 400 μg salbutamol/360 μg albuterol (or equivalent dose) at Visit 101.All patients must perform a reversibility test at Visit 101. If
reversibility is not demonstrated at Visit 101 then one of the following criteria need to be met : - Reversibility may be repeated once; - Patients may be permitted to enter the study with historical evidence of reversibility that was performed according to ATS/ERS guidelines within 1 year prior to Visit 1; - Alternatively, patients may be permitted to enter the
study with a historical positive bronchoprovocation test that was performed within 2 years prior to Visit 1. If reversibility is not demonstrated at Visit 101 (or after repeated assessment) and historical evidence of reversibility is not available (or was not performed according to the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines patients must be screen failed. |
|
| E.4 | Principal exclusion criteria |
- Patients who have had an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit within 6 weeks of Visit 1 (Screening). If patients experience an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit between Visit 1 and Visit 102 they may be re-screened 6 weeks after recovery from the exacerbation.
- Patients who have ever required intubation for a severe asthma attack/exacerbation.
- Patients who have a clinical condition which is likely to be worsened by ICS administration (e.g. glaucoma, cataract and fragility fractures) who are according to investigator’s medical judgment at risk participating in the study.
- Patients treated with a LAMA for asthma within 12 months prior Visit 1 (Screening).
- Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia (BPH) or bladder-neck obstruction or severe renal impairment or urinary retention. BPH patients who are stable on treatment can be considered).
- Patients who have had a respiratory tract infection or asthma worsening according to the within 4 weeks prior to Visit 1 (Screening) or between Visit 1 and Visit 102. Patients may be rescreened 4 weeks after recovery from their respiratory tract infection or asthma worsening.
- Patients with evidence upon visual inspection (laboratory culture is not required) of clinically significant (in the opinion of
investigator) oropharyngeal candidiasis at Visit 102 or earlier, with or without treatment. Patients may be re-screened once their candidiasis has been treated and has resolved.
- Patients with any chronic conditions affecting the upper respiratory tract (e.g. chronic sinusitis) which in the opinion of the investigator may interfere 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 significant bronchiectasis and active tuberculosis.
- Patients with diabetes Type I diabetes or uncontrolled Type II diabetes.
- Patients who, either in the judgment of the investigator or the responsible Novartis personnel, have a clinically significant condition such as (but not limited to) unstable ischemic heart disease, New York Heart Association (NYHA) Class III/IV left ventricular failure arrhythmia, uncontrolled hypertension, cerebrovascular disease, psychiatric disease, neurodegenerative diseases, or other neurological disease, uncontrolled hypo- and hyperthyroidism and other autoimmune diseases, hypokalemia, hyperadrenergic state, or ophthalmologic disorder or patients with a medical 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 are excluded. Patients with persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months and controlled with a rate control strategy (i.e., selective beta blockers, calcium channel blocker, pacemaker placement, digoxin or ablation therapy) for at least 6 months may be considered for inclusion. In such patients, atrial fibrillation must be present at the run-in (Visit 101) and end of run-in (Visit 102) visits 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 12 months. -Concomitant use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of study - Patients with a history of long QT syndrome or whose QTc measured at Visit 101 (Fridericia method) is prolonged (> 450 msec for males and > 460 msec for females) and confirmed by a central assessor (these patients should not be rescreened).
- Patients with a history of hypersensitivity to any of the study drugs or to similar drugs within the class including untoward
reactions to sympathomimetic amines or inhaled medication or any component thereof. - Patients who have not achieved an acceptable spirometry result at Visit 101 in accordance with ATS /ERS criteria for acceptability and repeatability (rescreening allowed only once).
- Patients unable to use the Concept1 dry powder inhaler, Accuhaler® or a metered dose inhaler. Spacer devices are not permitted. History of alcohol or other substance abuse.
- Patients with a known history of non-compliance to medication or who were unable or unwilling to complete a patient diary or who are unable or unwilling to use Electronic Peak Flow with e-diary device.
- Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift workers) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To demonstrate superiority of either QVM149 doses to either QMF doses on through FEV1 over 26 weeks of treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| To demonstrate superiority of either QVM149 doses to either QMF149 doses ACQ-7 |
|
| 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 | 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 |
|
| 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 | 10 |
| 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 | 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| Croatia |
| Denmark |
| Estonia |
| Finland |
| France |
| Germany |
| Greece |
| Hungary |
| India |
| Israel |
| Italy |
| Japan |
| Latvia |
| Lebanon |
| Lithuania |
| Luxembourg |
| Mexico |
| Netherlands |
| Norway |
| Philippines |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Slovakia |
| Slovenia |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Thailand |
| United Arab Emirates |
| United Kingdom |
| Vietnam |
| Jordan |
|
| 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
|
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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