QVA vs. Salmeterol/Fluticasone, 52-week Exacerbation Study, FLAME (EFfect of Indacaterol Glycopyronium Vs Fluticasone Salmeterol on COPD Exacerbations)
Condition: Chronic Obstructive Pulmonary Disease (COPD)
MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: QVA149; Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
Intervention description: QVA149 will be supplied in a capsule form in blister packs for use in the Novartis Concept 1 SDDPI.; Salmeterol/fluticasone dry inhalation powder delivered via the Accuhaler device.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 3362.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: COPD, QVA149, FLAME( EFfect of Indacaterol Glycopyronium Vs Fluticasone salmeterol on COPD Exacerbations)

Summary:

      This study will assess the efficacy, safety and tolerability of QVA149 in patients with
      moderate to very severe COPD.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent must be obtained before any assessment is performed

          -  Male or female adults aged ≥40 years

          -  Patients with stable Chronic Obstructive Pulmonary Disease ( COPD) according to the
             current GOLD strategy (GOLD 2011)

          -  Current or ex-smokers who have a smoking history of at least 10 pack years. (Ten
             pack-years are defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for
             20 years)

          -  Patients with a post-bronchodilator Forced Expiratory Volume in one second (FEV1) ≥25
             and < 60% of the predicted normal value, and post-bronchodilator FEV1/FVC (Forced
             Vital Capacity) < 0.70 at day -28. (Post refers to 1 hour after sequential inhalation
             of 84 µg (or equivalent dose) of ipratropium bromide and 400 µg of salbutamol)

          -  A documented history of at least 1 COPD exacerbation in the previous 12 months that
             required treatment with systemic glucocorticosteroids and/or antibiotics

          -  Patients taking stable COPD medication (at least 60 days) prior to day 28

          -  Patients with an mMRC grade of at least 2 at day 28

        Exclusion Criteria:

          -  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
             female after conception and until the termination of gestation, confirmed by a
             positive hCG (human Chorionic Gonadotropin) laboratory test

          -  Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, unless they are using effective methods of contraception during
             dosing of study treatment. Women are considered post-menopausal and not of child
             bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with
             an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms)
             or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal
             ligation at least six weeks ago. In the case of oophorectomy alone, only when the
             reproductive status of the woman has been confirmed by follow up hormone level
             assessment is she considered not of child bearing potential

          -  Patients with Type I or uncontrolled Type II diabetes

          -  Patients with a history of long QT syndrome or whose QTc measured at day 28
             (Fridericia method) is prolonged (>450 ms for males and females) and confirmed by a
             central assessor. These patients should not be re-screened

          -  Patients who have a clinically significant ECG abnormality prior to randomization.
             (These patients should not be re-screened)

          -  Patients who have a clinically significant laboratory abnormality at screening

          -  Patients who have clinically significant renal, cardiovascular (such as but not
             limited to unstable ischemic heart disease, NYHA Class III/IV left ventricular
             failure, myocardial infarction), arrhythmia (see below for patients with atrial
             fibrillation), neurological, endocrine, immunological, psychiatric, gastrointestinal,
             hepatic, or hematological abnormalities which could interfere with the assessment of
             the efficacy and safety of the study treatment

          -  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 blocker, 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 both pre-randomization visits, with a
             resting ventricular rate < 100/min. At screening the atrial fibrillation must be
             confirmed by central reading

          -  Patients contraindicated for treatment with, or having a history of reactions/
             hypersensitivity to any of the following inhaled drugs, drugs of a similar class or
             any component thereof: anticholinergic agents, long and short acting beta-2 agonists,
             sympathomimetic amines, lactose or any of the other excipients of trial medication

          -  Patients with a history of malignancy of any organ system, treated or untreated,
             within the past 5 years whether or not there is evidence of local recurrence or
             metastases, with the exception of localized basal cell carcinoma of the skin

          -  Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or
             bladder-neck obstruction or moderate to severe renal impairment or urinary retention.
             Benign Prostatic Hyperplasia (BPH) patients who are stable on treatment can be
             considered

          -  Patients who have not achieved an acceptable spirometry results at screening in
             accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS)
             criteria for acceptability (one retest may be performed for patients that don't meet
             the acceptability criteria)

          -  Patients who have had a COPD exacerbation that required treatment with antibiotics
             and/or systemic corticosteroids and/or hospitalization in the 6 weeks prior to
             screening

          -  Patients who develop a COPD exacerbation of any severity (mild/moderate/severe)
             between screening and treatment will not be eligible but will be permitted to be
             re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation

          -  Patients who have had a respiratory tract infection within 4 weeks prior to screening

          -  Patients who develop a respiratory tract infection between screening and prior to
             treatment will not be eligible, but will be permitted to be re-screened 4 weeks after
             the resolution of the respiratory tract infection

          -  Patients requiring long term oxygen therapy prescribed for >12 hours per day

          -  Patients with any history of asthma

          -  Patients with an onset of respiratory symptoms, including a COPD diagnosis prior to
             age 40 years

          -  Patients with a blood eosinophil count > 600/mm3 at screening

          -  Patients with allergic rhinitis who use a H1 antagonist or intra-nasal corticosteroids
             intermittently (treatment with a stable dose or regimen is permitted)

          -  Patients with concomitant pulmonary disease (e.g. lung fibrosis, sarcoidosis,
             interstitial lung disease, pulmonary hypertension)

          -  Patients with clinically significant bronchiectasis

          -  Patients with a diagnosis of α-1 anti-trypsin deficiency

          -  Patients with active pulmonary tuberculosis, unless confirmed by imaging to be no
             longer active

          -  Patients with pulmonary lobectomy or lung volume reduction surgery or lung
             transplantation

          -  Patients participating in or planning to participate in the active phase of a
             supervised pulmonary rehabilitation program during the study. (Maintenance program is
             permitted.)

          -  Patients receiving any medications in the classes listed in the protocol

          -  Patients receiving any COPD related medications in the classes specified in the
             protocol must undergo the required washout period prior to screening and follow the
             adjustment to treatment program

          -  Use of other investigational drugs/devices (approved or unapproved) at the time of
             enrollment, or within 30 days or 5 half-lives of screening, whichever is longer

          -  Patients unable to use an electronic patient diary and EXACT pro diary

          -  Patients unable to use a dry powder inhaler device, Metered Dose Inhaler (MDI) or a
             pressurized MDI (rescue medication) or comply with the study regimen.