A multicenter, randomized, 52-week, double-blind, parallelgroup,
active controlled study to compare the efficacy and safety of QVM149 with QMF149 in patients with asthma

Study Objective:

The purpose of the trial is to evaluate the efficacy and safety of two different doses of QVM149 (QVM149 150/50/80 μg and QVM149 150/50/160 μg via Concept1) over two respective QMF149 doses (QMF149 150/160 μg and QMF149 150/320 μg via Concept1 in poorly controlled asthmatics as determined by pulmonary function testing and effects on asthma control.

Participation conditions

Inclusion criteria:

• Male and female adult patient ≥ 18 years old and ≤ 75 years.

• 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 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 ≥ 2 at Visit 101 and at Visit 102 (before randomization) (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 according to ATS/ERS guidelines after withholding bronchodilators at both visits 101 and 102.

• 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.

Exclusion Criteria:

• Patients who have smoked or inhaled tobacco products within the 6 month period prior to Visit 1, or who have a smoking history of greater than 10 pack years (Note:1 pack is equivalent to 20 cigarettes. 10 pack years = 1 pack /day x 10 yrs., or ½ pack/day x 20 yrs.). This includes nicotine inhalers such as e-cigarettes at time of Visit 1.

• 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 3 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 as determined by investigator within 4 weeks prior to Visit 1 (Screening) or between Visit 1 and Visit 102. Patients may be re-screened 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 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 (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 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)

• Patients with a history of hypersensitivity to lactose, 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.

• 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).

Centre Hospitalier de Luxembourg (CHL)