Study to Compare the Efficacy and Safety of QVM149 With QMF149 in Patients With Asthma

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

The purpose of the trial was 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.

This study used a 52-week treatment, randomized, double-blind, double-dummy, parallel-group design. A total of 3092 asthma patients were randomized into the 5 treatment groups with a randomization ratio of 1:1:1:1:1 (approximately 617 patients per treatment group): QVM149 150/50/80 μg once daily (o.d.), QVM149 150/50/160 μg o.d., QMF149 150/160 μg o.d. and QMF149 150/320 μg o.d., all delivered via the Concept1 device, and salmeterol/fluticasone 50/500 μg twice daily (b.i.d.) delivered via Accuhaler. The 52 week treatment period was followed by a 30-day Follow-up.

The primary objective of this study was 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 in terms of trough Forced Expiratory Volume in One Second (Trough FEV1) (FEV1) at Week 26, all delivered via Concept1.

Inclusion Criteria:

• Patients with a diagnosis of asthma, (GINA 2015) for a period of at least 1 year prior to Visit 1 (Screening).
• Patients who have used medium or high dose of ICS/LABA combinations for asthma for at least 3 months 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 101 and at Visit 102 (before randomization).
• 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.
• Withholding period of bronchodilators prior to spirometry: SABA for ≥ 6 hrs, 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 acting xanthines for 12 hrs, Long acting xanthines for 24 hrs, .
• Washout period of each drug should be kept as close as possible as above and should not be longer. If longer washout period is needed due to scheduling issues, please contact Novartis Medical monitor.
• A one-time repeat of percentage predicated FEV1 (Pre-bronchodilator) at Visit 101 and/or Visit 102 is allowed in an ad-hoc visit. Repeat of Visit 101 spirometry 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. Run-in medication should be dispensed once spirometry assessment 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 the criteria at the repeat, provided the patient returned to the required treatment as per inclusion criteria 4
• 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 should 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 2 years 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 in an ad-hoc visit) and historical evidence of reversibility/bronchoprovocation is not available (or was not performed according to the ATS/ERS guidelines patients must be screen failed
• Spacer devices are permitted during reversibility testing only. The Investigator or delegate may decide whether or not to use a spacer for the reversibility testing

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 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 (this should be confirmed clinically by the investigator) 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 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. A one-time repeat spirometry is allowed in an ad-hoc visit scheduled as close as possible from the first attempt (but not on the same day) if the spirometry did not qualify due to ATS/ERS criteria at Visit 101 and/or Visit 102. If the patient fails the repeat assessment, the patient may be rescreened once, provided the patient returns to the required treatment as per inclusion criteria 4.
• 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).