Efficacy and Safety of ICS/LABA vs. LAMA/LABA in Patients With Different COPD Phenotypes.

Study Overview
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Brief Summary
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This is a randomized, blinded, controlled clinical trial for mexican COPD patients. Biomass smoke associated COPD (BS-COPD) clinical spectrum is different to the one seen in tobacco smoke associated COPD (TS-COPD). BS-COPD patients present COPD-asthma phenotype or asthma-COPD overlap syndrome (ACOS), TS-COPD patients present mostly the emphysema phenotype. BS-COPD patients have a greater risk of exacerbations in comparison to the emphysema phenotype. Therefore, individualizing treatment in both phenotypes may be very useful among the clinical practitioners. The investigators expect treatment with FF/V to be superior in preventing COPD exacerbations than the U/V combination in patients with COPD-asthma phenotype; andU/V to be superior than FF/V in patients with the emphysema phenotype. The general objective of the study is to determine the exacerbations outcome in patients with COPD-asthma vs emphysema phenotype patients, treated with both drugs. Secondary objectives include assessment of pulmonary function tests, quality of life, dyspnea and functional capacity change after a 24 weeks treatment.

Detailed Description
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Type and duration of the investigation: A randomized, blinded, controlled clinical trial; longitudinal, prospective, 3 years (Sep-2017 through Sep-2020). Background: COPD associated to biomass smoke (BS-COPD) represents the third of all COPD cases in Latin America, and almost the 2% in general population prevalence studies. BS-COPD clinical spectrum is different to the one seen in COPD associated to tobacco smoke (TS-COPD). While BS-COPD patients present COPD-asthma phenotype or asthma-COPD overlap syndrome (ACOS), TS-COPD patients present mostly the emphysema phenotype. COPD-asthma phenotype in BS-COPD, probably explains that they have a greater risk of exacerbations in comparison to the emphysema phenotype. Therefore, individualizing treatment in both phenotypes may be very useful among the clinical practitioners, because even though those patients are not included in traditional clinical trials, they are part of every day's practice. In this sense, providing a specific treatment in this group of patients could change the disease progression, improving symptoms, quality of life, reducing costs, side effects and exacerbations. The investigators hypothesize that COPD-asthma phenotype or asthma-COPD overlap syndrome (ACOS), may get a greater benefit by using a combination LABA/ICS (Fluticasone Furoate/Vilanterol - FF/V) therapy, whereas those with the emphysema phenotype with LABA/LAMA (Umeclidinium/Vilanterol U/V) therapy The upside of these drugs is that both of them have the same easy-to-use device, and it is inhaled once a day only. Their efficacy and safety have been tested in TS_COPD but not in BS-COPD. This trial will allow us to have a clinically and functionally characterization (using biological markers) of the BS-COPD phenotype and to compare those patients with those with the emphysema phenotype. Hypothesis: Treatment with FF/V will be superior in preventing COPD exacerbations than the U/V combination in patients with COPD-asthma phenotype; while U/V will be superior than FF/V in patients with the emphysema phenotype. General objective: To determine the exacerbations outcome (exacerbations free interval, exacerbations frequency, severe exacerbations that needed hospitalization frequency, exacerbations frequency according to absolute and percentage (>3%) blood eosinophils, exacerbations percentage for emphysema phenotype and COPD-asthma phenotype) in patients with COPD-asthma vs emphysema phenotype patients, treated with Fluticasone Furoate/Vilanterol 100/25 mcg/day vs Umeclidinium/Vilanterol 55/25 mcg/day, after 6 months of treatment. Secondary objectives: To determine in both groups: (1) Pulmonary function change (FEV1, FVC and inspiratory capacity) (2) Impulse oscillometry resistance change (3) FeNO change (5) Quality of life change (CAT and Saint George) (6) Dyspnea change (mMRC, BDI y TDI) (7) Functional capacity change (6MWT distance). (8) To characterize and establish the frequency of the COPD-asthma phenotype in BS-COPD patients and emphysema-phenotype in TS-COPD patients. Methods: Randomized double blind controlled clinical trial. Patients with at least one exacerbation in the last 12 months (confirmed by the prescription of antibiotic and/or oral steroid), and a smoking index > 10 packs/year or a biomass smoke exposition index > 100 hours/year. One hundred BS-COPD patients and one hundred TS-COPD patients will be included; both groups will be exposed to the two treatment options. Fifty patients from each group (BS-COPD and TS-COPD) will be assigned with FF/V and 50 from each group with U/V. Emphysema phenotype and air-trapping pattern will be determined with a CT image. All CTs will be assessed by a radiologist. Baseline DLco will also be correlated with the emphysema CT findings. Blood eosinophils, blood levels IgE, bronchodilator reversibility and baseline FeNO. Rate of exacerbations will be determined in both groups for a time period of 6 months. At the end of the study, the phenotype of each patient will be determined and treatment efficacy will be evaluated according to the phenotype. The sample size was chosen conventionally by considering that there are no other centers with a BS-COPD cohort. Treatment will be randomly assigned using a random numbers table. Safety evaluation includes severe adverse events (SAE) assessment (mainly pneumonia). During the informed consent signing visit (day -15), BS-COPD or TS-COPD diagnosis will be confirmed. There will be four in-clinic visits (baseline; +30 days; +90 days and +180 days) where the symptoms diary will be evaluated to determine the rate of exacerbations or other health resources use. Also, pulmonary function tests (spirometry pre and post-BD, IC) and functional capacity tests (6MWT) will be performed by each patient. Health related quality of life (SGRQ and CAT) and dyspnea (mMRC and BDI/TDI) questionnaires will also performed. There will be three telephonic visits (+60 days, +120 days, +210 days) where adverse events, concomitant medication, other health resources use and exacerbations since last visit will be assessed.

Official Title
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Efficacy and Safety of Fluticasone Furoate/Vilanterol vs. Umeclidinium/Vilanterol in Patients With COPD-asthma Phenotype vs. Emphysema Phenotype. A Controled Clinical Trial.

Conditions
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COPD

Intervention / Treatment
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* Drug: Fluticasone Furoate/Vilanterol 100/25 mcgs
* Drug: Umeclidinium/Vilanterol 62.5/25 mcgs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 40 to 80 years Men and women (not fertile, not pregnant, or those with a effective birth control method) COPD diagnosis according to GOLD 2017 criteria with a FEV1 ≥ 30% Biomass smoke exposition index ≥ 100 hours/year or smoking index ≥ 10 packs/year, Patients with at least two exacerbations in the last 12 months (confirmed by the prescription of antibiotic and/or oral steroid) Patients with stable COPD (no exacerbations or respiratory infections in the 4 weeks prior inclusion). Exclusion Criteria: Patients with allergies or intolerance to study medications Female patients on pregnancy, lactancy Patients with cancer diagnosis Patients with bronchiectasis, tuberculosis, recent COPD exacerbation, or any respiratory infection or cardiovascular anomaly that withholds the respiratory function test

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Biomass Smoke COPD<br>Fluticasone Furoate/Vilanterol 100/25 mcgs. Dry powder inhaler with 30 blisters. 1 inhalation a day for 24 weeks. Umeclidinium/Vilanterol 62.5/25 mcgs. Dry powder inhaler with 30 blisters. 1 inhalation a day for 24 weeks. | Drug: Fluticasone Furoate/Vilanterol 100/25 mcgs<br>* Dry powder inhaler with 30 blisters. 100/25mcgs a day for 24 weeks.<br>* Other names: Relvare;Drug: Umeclidinium/Vilanterol 62.5/25 mcgs<br>* Dry powder inhaler with 30 blisters. 62.5/25mcgs a day for 24 weeks<br>* Other names: Anoro;|
| Active Comparator: Tobacco Smoke COPD<br>Fluticasone Furoate/Vilanterol 100/25 mcgs. Dry powder inhaler with 30 blisters. 1 inhalation a day for 24 weeks. Umeclidinium/Vilanterol 62.5/25 mcgs. Dry powder inhaler with 30 blisters. 1 inhalation a day for 24 weeks. | Drug: Fluticasone Furoate/Vilanterol 100/25 mcgs<br>* Dry powder inhaler with 30 blisters. 100/25mcgs a day for 24 weeks.<br>* Other names: Relvare;Drug: Umeclidinium/Vilanterol 62.5/25 mcgs<br>* Dry powder inhaler with 30 blisters. 62.5/25mcgs a day for 24 weeks<br>* Other names: Anoro;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exacerbations rate | moderate and severe exacerbations rate | baseline to 24 weeks | 
| Exacerbations free interval | Exacerbations free interval | Baseline to first exacerbation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary function change | Spirometry (FVC and FEV1) and inspiratory capacity | Change from Baseline at 4, 12 and 24 weeks | 
| Impulse oscillometry resistance change | R5, R20, DR5R20, Ax (percentage of expected in all values) | Change from baseline at 24 weeks | 
| FeNO change | ppb | change from Baseline at 24 weeks | 
| Quality of life change | CAT | change from Baseline at 4, 12 and 24 weeks | 
| Dyspnea change | mMRC | Change from Baseline at 4, 12 and 24 weeks | 
| Functional capacity change | 6 minute walk test distance | Change from Baseline at 4, 12 and 24 weeks | 
| SGRQ Quality of life change | SGRQ | Change from Baseline at 4, 12 and 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic obstructive pulmonary disease, Biomass, Tobacco, COPD treatment, COPD phenotypes