Study to Evaluate the Efficacy and Safety of Glycopyrronium or Indacaterol Maleate and Glycopyrronium Bromide Fixed-dose Combination Regarding Symptoms and Health Status in Patients With Moderate COPD Switching From Treatment With Any Standard COPD Regimen

Study Overview
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Brief Summary
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The main goal of this study is to evaluate the efficacy and safety of glycopyrronium bromide and indacaterol maleate and glycopyrronium bromide fixed dose combination (FDC) in patients with moderate COPD who switch from their current COPD therapy. This study aims to provide data on how non-exacerbating, but still symptomatic patients with moderate COPD switching from their current COPD treatment to glycopyrronium bromide or indacaterol maleate and glycopyrronium bromide FDC maintain or improve their symptoms. Another purpose of this study is to increase awareness and usage of validated COPD symptoms tools and dyspnea questionnaires in order to facilitate clinical assessment and improve early diagnosis of symptomatic patients.

Detailed Description
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The treatment epoch will last 12 weeks. The total duration of the study for each patient is 12 weeks (from randomization) plus 30 days of safety follow-up. The study has three phases: screening phase (=wash-out period, if required), treatment phase and safety follow-up phase. Eligible patients will be randomized to either receive glycopyrronium or indacaterol maleate and glycopyrronium bromide fixed dose combination or to remain in their baseline therapy, in an allocation ratio of 3:1 for each cluster (Groups A, B, C, and D), based on their COPD symptoms and baseline treatment: Group A: Patients treated with any SABA ( Short-acting β2-adrenergic agonist) and/or SAMA (Short-acting muscarinic antagonist) as monotherapy or in free or fixed dose combination (FDC) will be assigned to glycopyrronium or will remain in their baseline therapy (3:1) Group B: Patients treated with any LABA (Long-acting β2-adrenergic agonist) or LAMA (Long-acting muscarinic antagonist) monotherapy and mMRC score =1 point will be assigned to glycopyrronium or will remain in their baseline therapy (3:1) Group C: Patients treated with any LABA and ICS (Inhaled corticosteroid) in free or FDC will be assigned to indacaterol maleate and glycopyrronium bromide fixed dose combination or will remain in their baseline therapy (3:1) Group D: Patients treated with any LABA or LAMA monotherapy and mMRC score >1 point will be assigned to indacaterol maleate and glycopyrronium bromide fixed dose combination or will remain in their baseline therapy (3:1) Due to low recruitment in Groups A and B that would lead to a significant delay of trial completion, a protocol amendment was made in order to close the recruitment of Groups A and B at the time the randomization in Groups C and D would be completed. Recruitment of the Groups C and D continued as originally planned

Official Title
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A Prospective, Multicenter, 12-week, Randomized Open-label Study to Evaluate the Efficacy and Safety of Glycopyrronium (50 Micrograms o.d.) or Indacaterol Maleate and Glycopyrronium Bromide Fixed-dose Combination (110/50 Micrograms o.d.) Regarding Symptoms and Health Status in Patients With Moderate Chronic Obstructive Pulmonary Disease (COPD) Switching From Treatment With Any Standard COPD Regimen

Conditions
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COPD

Intervention / Treatment
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* Drug: Glycopyrronium
* Drug: SABA
* Drug: LABA
* Drug: Indacaterol maleate and glycopyrronium bromide
* Drug: LAMA
* Drug: SAMA
* Drug: ICS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female adults aged ≥ 40 years Patients with moderate COPD according to the GOLD criteria 2013 Current or ex-smokers who have a smoking history of at least 10 pack years Patients with airflow limitation indicated by a postbronchodilator FEV1 ≥50% and <80% of the predicted normal value and a post-bronchodilator FEV1/FVC <0.7 at Visit 2. Post- bronchodilator refers to within 10-15 min of inhalation of 400 μg (4x100 μg) of salbutamol Patients who, at Visit 1, have been for at least 3 months on a stable dose of one of the following COPD baseline treatments: *Any SABA monotherapy (such as, but not limited to, salbutamol) *Any SAMA monotherapy (such as, but not limited to, ipratropium) *Any SABA and SAMA in free or FDC (such as, but not limited to, salbutamol/ipratropium) *Any LABA monotherapy (such as, but not limited to, formoterol, salmeterol, indacaterol) *Any LAMA monotherapy (such as, but not limited to, tiotropium, aclidinium) except glycopyrronium bromide (NVA237) *Any LABA and ICS in free (ICS such as, but not limited to, beclomethasone, fluticasone) or FDC (such as, but not limited to, salmeterol/fluticasone, formoterol/budesonide). Patients with an mMRC score ≥1 at Visit 1. Exclusion Criteria: Patients with conditions contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the following inhaled drugs or to drugs of similar chemical classes or any component thereof: Anti-cholinergic agents, Long- and short-acting 2-adrenergic agonists, Sympathomimetic amines, Lactose or any of the other excipients of the trial medication. Patients with narrow-angle glaucoma or urinary retention, severe renal impairment (history of estimated glomerular filtration rate below 30 ml/min/1.73 m2 within 12 months prior to visit 1), including those with end-stage renal disease requiring dialysis. Patients with active/ clinical history of asthma.If the Investigator finds clear and compelling evidence that a patient was misdiagnosed with asthma in the past, then the burden of proof is on the Investigator to properly document this previous misdiagnosis. This documentation must include the rationale for this change in diagnosis including reference to the differential diagnosis that supports this decision. Patients with a history of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. Patients who have a post-bronchodilator FEV1 decrease more than 10% compared to pre-bronchodilator FEV1 result at Visit 2 (see Appendix 5 for details). A documented history of >1 COPD exacerbation requiring treatment with systemic corticosteroids or antibiotics and/or hospitalization in the previous 12 months. Patients who have NOT had a COPD exacerbation in the previous 12 months and develop a COPD exacerbation between screening (Visit 1) and (Visit 2) 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 suffering an exacerbation between Visit 1 and Visit 2 can only be re-screened in case it is the first one in the previous 12 months. In case this COPD exacerbation has led to an alteration of the patient COPD treatment, before this patient can be re-screened 3 months of stable COPD treatment will be required as described in Inclusion Criterion 6). Patients who, in the judgment of the investigator, have a clinically relevant laboratory abnormality or a clinically significant condition such as (but not limited to): *Unstable ischemic heart disease, left ventricular failure (NYHA Class III & IV), history of myocardial infarction,arrhythmia (excluding chronic stable atrial fibrillation). Patients with such events not considered clinically significant by the investigator may be considered for inclusion in the study.*Uncontrolled hypo-or hyperthyroidism, hypokalaemia or hyperadrenergic state. *Any condition which might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study History of resting QTc (Fridericia preferred, but Bazett acceptable) >450 msec (male) or >460 msec (female) within five years before Visit 1. Patients who are treated with glycopyrronium bromide (NVA237) at visit 1 are not allowed to be included into the trialPatients on non-selective beta-blockers. Those patients may enter the study after non-selective beta-blocker withdrawal during a 7-day wash-out period. Patients receiving any other prohibited COPD-related medications specified in Table 5-2 Prohibited COPD related medications must undergo the required wash-out period prior to Visit 2. Patients who are, in the opinion of the investigator known to be unreliable or non-compliant. Patients with a body mass index (BMI) of more than 40 kg/m2. Use of other investigational drugs within 5 half-lives of enrollment or within 30 days, whichever is longer. 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 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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 95 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A1 (any SABA and/or SAMA)<br>Patients treated with any SABA and/or SAMA as monotherapy or in free or fixed dose combination will be assigned to glycopyrronium or will remain in their baseline therapy (3:1) during 90 days of treatment | Drug: Glycopyrronium<br>* Glycopyrronium 50 µg capsule for inhalation via SDDPI once per day<br>* Other names: glycopyrronium bromide;Drug: SABA<br>* Short-acting β2-adrenergic agonist (SABA) as per approved by each country and as prescribed for each patient, used as background therapy<br>Drug: SAMA<br>* Short-acting muscarinic antagonist (SAMA) as per approved by each country and as prescribed for each patient, used as background therapy<br>|
| Experimental: A2 (glycopyrronium)<br>Patients treated with any SABA and/or SAMA as monotherapy or in free or FDC at enrollment and randomized to switch in treatment with glycopyrronium (50 μg o.d.) | Drug: Glycopyrronium<br>* Glycopyrronium 50 µg capsule for inhalation via SDDPI once per day<br>* Other names: glycopyrronium bromide;Drug: SABA<br>* Short-acting β2-adrenergic agonist (SABA) as per approved by each country and as prescribed for each patient, used as background therapy<br>Drug: LABA<br>* Long Acting Beta Agonist (LABA) as per approved by each country and as prescribed for each patient, used as background therapy<br>Drug: SAMA<br>* Short-acting muscarinic antagonist (SAMA) as per approved by each country and as prescribed for each patient, used as background therapy<br>|
| Experimental: B1 (any LAMA or LABA and mMRC=1)<br>Patients treated with any LABA or LAMA monotherapy and mMRC score =1 point at Visit 1 and randomized to remain in their baseline treatment with LABA or LAMA | Drug: LABA<br>* Long Acting Beta Agonist (LABA) as per approved by each country and as prescribed for each patient, used as background therapy<br>Drug: Indacaterol maleate and glycopyrronium bromide<br>* Indacaterol maleate and glycopyrronium bromide fixed dose combination (110/50 µg) capsule for inhalation via SDDPI, once a day<br>Drug: LAMA<br>* Long Acting Muscarinic Antagonist (LAMA) as per approved by each country and as prescribed for each patient, used as background therapy<br>Drug: ICS<br>* Inhaled corticosteroid (ICS) as per approved by each country and as prescribed for each patient, used as background therapy<br>|
| Experimental: B2 (glycopyrronium and mMRC=1)<br>Patients treated with any LABA or LAMA monotherapy and mMRC score =1 point at Visit 1 and randomized to switch in treatment with glycopyrronium (50 μg o.d.) | Drug: LABA<br>* Long Acting Beta Agonist (LABA) as per approved by each country and as prescribed for each patient, used as background therapy<br>Drug: Indacaterol maleate and glycopyrronium bromide<br>* Indacaterol maleate and glycopyrronium bromide fixed dose combination (110/50 µg) capsule for inhalation via SDDPI, once a day<br>Drug: LAMA<br>* Long Acting Muscarinic Antagonist (LAMA) as per approved by each country and as prescribed for each patient, used as background therapy<br>|
| Experimental: C1 (any LABA and ICS)<br>Patients treated with any LABA and ICS in free or FDC at enrollment and randomized to remain in their baseline treatment with LABA and ICS in free or FDC | Drug: LABA<br>* Long Acting Beta Agonist (LABA) as per approved by each country and as prescribed for each patient, used as background therapy<br>Drug: ICS<br>* Inhaled corticosteroid (ICS) as per approved by each country and as prescribed for each patient, used as background therapy<br>|
| Experimental: C2 (indacaterol/glycopyrronium)<br>Patients treated with any LABA and ICS in free or FDC at enrollment and randomized to switch in treatment with indacaterol maleate and glycopyrronium bromide FDC (110/50 μg o.d.) | Drug: LABA<br>* Long Acting Beta Agonist (LABA) as per approved by each country and as prescribed for each patient, used as background therapy<br>Drug: ICS<br>* Inhaled corticosteroid (ICS) as per approved by each country and as prescribed for each patient, used as background therapy<br>|
| Experimental: D1 (any LAMA or LABA and mMRC>1)<br>Patients treated with any LABA or LAMA monotherapy and mMRC score >1 point at Visit 1 and randomized to remain their baseline in treatment with LABA or LAMA | Drug: LAMA<br>* Long Acting Muscarinic Antagonist (LAMA) as per approved by each country and as prescribed for each patient, used as background therapy<br>|
| Experimental: D2 (indacaterol/glycopyrronium and mMRC>1)<br>Patients treated with any LABA or LAMA monotherapy and mMRC score >1 point at Visit 1 and randomized to switch in treatment with indacaterol maleate and glycopyrronium bromide FDC (110/50 μg o.d.). | Drug: LAMA<br>* Long Acting Muscarinic Antagonist (LAMA) as per approved by each country and as prescribed for each patient, used as background therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough FEV1 at Week 12 for Group: Glycopyrronium vs. Short-acting Bronchodilators (SABA and/or SAMA as Monotherapy or in Free or FDC) | Trough FEV1 at visit 4 is defined as FEV1, computed as the mean of forced expiratory volume in 1 second 15min and 45 min pre dose measurements, at the end of the dosing interval | Week 12 (Visit 4) | 
| Trough FEV1 at Week 12 for Group: Glycopyrronium vs. Long-acting Bronchodilators (LABA or LAMA Monotherapy) | Trough FEV1 at visit 4 is defined as FEV1, computed as the mean of forced expiratory volume in 1 second 15min and 45 min pre dose measurements, at the end of the dosing interval | Week 12 (Visit 4) | 
| Trough FEV1 at Week 12 for Group: Indacaterol Maleate and Glycopyrronium Bromide FDC vs. LABA and ICS in Free or FDC | Trough FEV1 at visit 4 is defined as FEV1, computed as the mean of forced expiratory volume in 1 second 15min and 45 min pre dose measurements, at the end of the dosing interval. | Week 12 (Visit 4) | 
| Trough FEV1 at Week 12 for Group: Indacaterol Maleate and Glycopyrronium Bromide FDC vs. Long-acting Bronchodilators (LABA or LAMA Monotherapy) | Trough FEV1 at visit 4 is defined as FEV1, computed as the mean of forced expiratory volume in 1 second 15min and 45 min pre dose measurements, at the end of the dosing interval. | Week 12 (Visit 4) | 
| Change From Baseline on Transition Dyspnea Index (TDI) for Groups: Glycopyrronium vs. Short-acting Bronchodilators (SABA and/or SAMA as Monotherapy or in Free or FDC) | Transition Dyspnea Index (TDI) captures changes from baseline. The TDI score is based on three domains with each domain scored from -3 (major deterioration) to +3 (major improvement), to give an overall score of -9 to +9, a negative score indicating a deterioration from baseline. A TDI focal score of 1 is considered to be a clinically significant improvement from baseline. | Day 1 (baseline) and week 12 | 
| Change From Baseline on Transition Dyspnea Index (TDI) for Groups: Glycopyrronium vs. Long-acting Bronchodilators (LABA or LAMA Monotherapy) | Transition Dyspnea Index (TDI) captures changes from baseline. The TDI score is based on three domains with each domain scored from -3 (major deterioration) to +3 (major improvement), to give an overall score of -9 to +9, a negative score indicating a deterioration from baseline. A TDI focal score of 1 is considered to be a clinically significant improvement from baseline. | Day 1 (baseline) and week 12 | 
| Change From Baseline on Transition Dyspnea Index (TDI) for Groups: Indacaterol Maleate and Glycopyrronium Bromide FDC vs. LABA and ICS in Free or FDC | Transition Dyspnea Index (TDI) captures changes from baseline. The TDI score is based on three domains with each domain scored from -3 (major deterioration) to +3 (major improvement), to give an overall score of -9 to +9, a negative score indicating a deterioration from baseline. A TDI focal score of 1 is considered to be a clinically significant improvement from baseline. | Day 1 (baseline) and week 12 | 
| Change From Baseline on Transition Dyspnea Index (TDI) for Groups: Indacaterol Maleate and Glycopyrronium Bromide FDC vs. Long-acting Bronchodilators (LABA or LAMA Monotherapy) | Transition Dyspnea Index (TDI) captures changes from baseline. The TDI score is based on three domains with each domain scored from -3 (major deterioration) to +3 (major improvement), to give an overall score of -9 to +9, a negative score indicating a deterioration from baseline. A TDI focal score of 1 is considered to be a clinically significant improvement from baseline. | Day 1 (baseline) and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough FEV1 at Week 12 for Group: Glycopyrronium vs. Short-acting Bronchodilators (SABA and/or SAMA as Monotherapy or in Free or FDC) or vs. Long-acting Bronchodilators (LABA or LAMA Monotherapy) | Trough FEV1 at visit 4 is defined as FEV1, computed as the mean of forced expiratory volume in 1 second 15min and 45 min pre dose measurements, at the end of the dosing interval | 12 Weeks | 
| Change From Baseline on on Transition Dyspnea Index (TDI) for Groups: Glycopyrronium vs. Short-acting Bronchodilators (SABA and/or SAMA as Monotherapy or in Free or FDC) or Long-acting Bronchodilators (LABA or LAMA Monotherapy) | Transition Dyspnea Index (TDI) captures changes from baseline. The TDI score is based on three domains with each domain scored from -3 (major deterioration) to +3 (major improvement), to give an overall score of -9 to +9, a negative score indicating a deterioration from baseline. A TDI focal score of 1 is considered to be a clinically significant improvement from baseline. | Day 1 (baseline) and week 12 | 
| Trough FEV1 at Week 12 for Group: Indacaterol Maleate and Glycopyrronium Bromide FDC vs. LABA or LAMA Monotherapy or LABA and ICS in Free or FDC on Trough FEV1 at Week 12. | Trough FEV1 at visit 4 is defined as FEV1, computed as the mean of forced expiratory volume in 1 second 15min and 45 min pre dose measurements, at the end of the dosing interval. | 12 Weeks | 
| Change From Baseline on Transition Dyspnea Index (TDI) for Groups: Indacaterol Maleate and Glycopyrronium Bromide FDC vs. LABA or LAMA Monotherapy or LABA and ICS in Free or FDC | Transition Dyspnea Index (TDI) captures changes from baseline. The TDI score is based on three domains with each domain scored from -3 (major deterioration) to +3 (major improvement), to give an overall score of -9 to +9, a negative score indicating a deterioration from baseline. A TDI focal score of 1 is considered to be a clinically significant improvement from baseline. | Day 1 (baseline) and week 12 | 
| Change From Baseline on Total Score of COPD Assessment Test (CAT) for Groups: Glycopyrronium and Indacaterol Maleate and Glycopyrronium Bromide FDC | Total score of COPD Assessment Test (CAT) will be measured at baseline and at week 12. This questionnaire is completed by the patient. The score ranges from 0-40 where higher scores represent worse health status. CAT scores ≥ 10 are associated with significantly impaired health status. | Day 1 (baseline) and Week 12 | 
| Change From Baseline on Total Score of Clinical COPD Questionnaire (CCQ) for Groups: Glycopyrronium and Indacaterol Maleate and Glycopyrronium Bromide FDC | The Clinical COPD Questionnaire (CCQ) is a self-administered 10-item questionnaire developed to measure clinical control in patients with COPD. Patients will be instructed to recall their experiences during the previous week. They respond to each question using a 7-point scale from 0 = asymptomatic/no imitation to 6 = extremely symptomatic/totally limited. The questionnaire is divided into 3 domains (symptoms [items 1, 2, 5, and 6] functional [items 7, 8, 9, and 10] and mental state [items 3 and 4]). The overall clinical COPD control score and the scores of the domains are calculated by adding all the scores together and dividing this sum by the number of questions. Thus, the overall clinical COPD control score as well as the score on each of the three domains varies between 0 (very good control) to 6 (extremely poor control). | Day 1 (baseline) and Week 12 | 
| Mean Number of Puffs of Rescue Medication Use for Groups: Glycopyrronium and Indacaterol Maleate and Glycopyrronium Bromide FDC | Mean number of puffs of rescue medication use will be measured using eDiary data over 12 weeks of treatment. | 12 weeks | 
| Mean Change From Baseline Reported Symptoms of COPD for Groups: Glycopyrronium and Indacaterol Maleate and Glycopyrronium Bromide FDC | Patient-reported symptoms of COPD combined will be measured using eDiary data reported over the 12 week treatment period. The mean total symptom scores and mean individual symptom scores for the patient were calculated for the whole study period. The mean change from baseline in the total scores and in the individual scores were summarized by treatment and were analyzed for the percentage of nights with no nighttime awakenings and percentage of days with no symptoms. | Baseline, 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Moderate COPD, glycopyrronium bromide, indacaterol maleate and glycopyrronium bromide FDC, NVA237, QVA149