Study Evaluating the Effect of Fluticasone Furoate/ Vilanterol (FF/VI) Inhalation Powder Compared With Vilanterol (VI) Inhalation Powder on Bone Mineral Density (BMD) in Subjects With Chronic Obstructive Pulmonary Disease (COPD).

Study Overview
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Brief Summary
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This is a multi-center, randomized, double-blind, parallel-group study. The FF/VI inhalation powder once daily and VI inhalation powder once daily will be evaluated in subjects with COPD over 156 weeks. The primary objective of this study is to evaluate the effect of the inhaled corticosteroid FF on bone mineral density assessed at the total hip by comparing FF/VI treatment with VI treatment in subjects with moderate COPD.

Official Title
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Multi-centre, Randomized, Double-blind, Parallel-group Study Evaluating the Effect of Fluticasone Furoate/ Vilanterol (FF/VI) Inhalation Powder Once Daily Compared With Vilanterol (VI) Inhalation Powder Once Daily on Bone Mineral Density (BMD) in Subjects With Chronic Obstructive Pulmonary Disease (COPD).

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Fluticasone Furoate/Vilanterol
* Drug: Vilanterol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent: Subjects must give their signed and dated written informed consent to participate. Gender: Male or female subjects. Female subjects must be post-menopausal or using a highly effective method for avoidance of pregnancy. The decision to include or exclude women of childbearing potential may be made at the discretion of the investigator in accordance with local practice in relation to adequate contraception. Age: >= 40 years of age at Screening (Visit 1) COPD diagnosis: Subjects with a clinical history of COPD in accordance with the following definition by the American Thoracic Society/European Respiratory Society: COPD is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences. Tobacco use: Subjects with a current or prior history of >=10 pack-years of cigarette smoking at screening (Visit 1). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Number of pack years = (number of cigarettes per day/20) x number of years smoked Note: Pipe and/or cigar use cannot be used to calculate pack year history. Severity of Disease: Subject with a measured post-albuterol/salbutamol Forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio of <0.70 at Screening (Visit 1). Subjects with a measured post-albuterol/salbutamol 50% <=FEV1 <=70% of predicted normal values calculated using National Health and Nutrition Examination Survey (NHANES III) reference equations at Screening (Visit 1). Native Hip: Have at least one evaluable native hip. Exclusion Criteria: Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study. Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD). Alpha1-antitrypsin deficiency: Subjects with alpha-1 antitrypsin deficiency as the underlying cause of COPD. Other respiratory disorders: Subjects with tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases. Lung resection or transplantation: Subjects with lung volume reduction surgery within the 12 months prior to Screening Visit 1 or having had a lung transplant. Chest X-ray: Subjects with a chest X-ray (or Computer Axial Tomography (CT) scan) that revealed evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray should be taken at Screening Visit 1 if a chest X-ray or CT scan is not available within 12 months prior to Visit 1. Poorly controlled COPD: Subjects with poorly controlled COPD, defined as the occurrence of the following in the 12 weeks prior to Screening Visit 1: Acute worsening of COPD that is managed by the subject with corticosteroids or antibiotics or that requires treatment prescribed by a physician or requires hospitalization. Moderate or severe COPD exacerbation or lower respiratory tract infection: Subjects with 2 or more moderate or severe COPD exacerbations and/or a lower respiratory tract infection (including pneumonia) within the 12 months prior to Screening Visit 1 or experience a moderate or severe COPD exacerbation and/or a lower respiratory infection (including pneumonia) during the Run-In period. NOTE: A moderate COPD exacerbation is defined as requiring systemic corticosteroids and/or antibiotics. A severe COPD exacerbation is defined as requiring hospitalization. Abnormal clinically significant laboratory finding: Subjects who have an abnormal, clinically significant finding in any liver chemistry, biochemical, or haematology tests at Screening Visit 1 or upon repeat prior to randomization. Abnormal and clinically significant 12-lead Electrocardiogram (ECG): Subjects who have an abnormal, clinically significant ECG finding at Screening Visit 1. Non-Compliance during Run-In Period: Failure to demonstrate adequate compliance with run-in medication (< 80% compliant), the ability to withhold COPD medications, and to keep clinic visit appointments. Bone disorders/conditions: Subjects with historical or current evidence of bone cancer, severe scoliosis, rheumatoid arthritis, metabolic bone diseases (other than osteoporosis) including hyper-or hypo-parathyroidism, Paget's disease of bone, osteomalacia, or osteogenesis imperfecta. Removal of vertebrae between L1 and L4 of the lumbar spine and/or presence of metal implants or devices, such as plates, rods, or screws in the lumbar spine and/or hip. Immobility: Wheel chair bound or paraplegic. Low vitamin D: Previously known low-serum 25-hydroxy vitamin D concentration (less than 10ng [25nmoles] per liter). Other diseases/abnormalities: Serious, uncontrolled disease (including serious psychological disorders) likely to interfere with the study within the 3-year study. Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded if the subject has been considered cured within 5 years since diagnosis. Drug/food allergy: Subjects with a history of hypersensitivity to any of the study medications (e.g. beta-agonists, corticosteroid) or components of the inhalation powder (e.g. lactose, magnesium stearate). In addition, patients with a history of severe milk protein allergy that, in the opinion of the study physician, contraindicates the subject's participation will also be excluded. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years. Prohibited medications prior to spirometry at Visit 1: Subjects who are medically unable to withhold the following medications prior to spirometry testing at Visit 1 No use within 48 hours (hrs) prior to Visit 1 Spirometry Testing: Inhaled corticosteroids, Inhaled Inhaled Corticosteroids (ICS)/ long acting beta2-agonist (LABA) combination products, Long-acting anticholinergics (e.g., tiotropium), Theophylline preparations, Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton), Oral PDE-4 inhibitors (e.g. roflumilast), Oral beta-agonists (Long-acting), Inhaled long acting beta2-agonist (LABA)-Indacaterol. No use within 24 hrs prior to Visit 1 Spirometry Testing: Other inhaled LABAs (e.g., salmeterol), Inhaled sodium cromoglycate or nedocromil sodium. No use within 12 hrs prior to Visit 1 Spirometry Testing: Oral beta-agonists (Short-acting). No use within 4 hrs prior to Visit 1 Spirometry Testing: Ipratropium/ albuterol (salbutamol) combination product, Inhaled short-acting beta2-agonists, Short-acting anti-cholinergics (e.g., ipratropium bromide). Additional medication: Use of the following medications within the following time intervals prior to Visit 1 or during the study (unless otherwise specified): No use within 12 weeks prior to Screening Visit 1 or thereafter at any time during the study (unless otherwise specified): Depot corticosteroids. No use within 30 days prior to Screening Visit 1 or thereafter at any time during the study (unless otherwise specified): Systemic, Oral, parenteral, intra-articular corticosteroids (Subjects may take courses of systemic corticosteroids, where necessary, for treatment of an exacerbation during the double-blind treatment period). No use within 30 days or 5 half lives whichever is longer prior to Screening Visit 1 or thereafter at any time during the study (unless otherwise specified): Any other investigational drug. COPD medications: Use of ICS, long-acting beta2-agonists (LABA), or ICS/LABA combination products (other than the study-provided double-blind study medication) at Visit 2 (Randomization) or during the double-blind treatment period. Oxygen therapy: Subjects receiving treatment with long-term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen prn use (i.e., <=12 hours per day) is not exclusionary. Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits. Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study. Affiliation with investigator site: Study investigators, sub-investigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participating in this study.

Ages Eligible for Study
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Minimum Age: 40 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fluticasone Furoate/Vilanterol 100/25 micrograms (mcg) QD<br>Subjects will self administer FF/VI 100/25 mcg inhalation powder once daily for 156 weeks via the NDPI. | Drug: Fluticasone Furoate/Vilanterol<br>* Dry white powder containing 100 mcg of Fluticasone Furoate blended with lactose per blister was administered by NDPI. Dry white powder containing 25 mcg of Vilanterol micronised drug (as the 'M' salt triphenylacetate) blended with lactose and magnesium stearate per blister was administered by NDPI.<br>|
| Experimental: Vilanterol 25 mcg QD<br>Subjects will self administer VI 25 mcg inhalation powder once daily for 156 weeks via the NDPI. | Drug: Vilanterol<br>* Dry white powder containing 25 mcg of Vilanterol micronised drug (as the 'M' salt triphenylacetate) blended with lactose and magnesium stearate per blister was administered by NDPI.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline in Bone Mineral Density (BMD) Measured at Total Hip | BMD analysis performed on log (BMD ratio to baseline) using a repeated measures model with covariates of treatment group, age, gender, baseline BMI, visit, log baseline BMD, log baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the While on Treatment estimand of the difference in percentage change from baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100. | Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Male Participants) | BMD analysis performed on log (BMD ratio to baseline) using separate repeated measures models for each gender with covariates of treatment group, age, baseline BMI, visit, log baseline BMD, log baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the While on Treatment estimand of the difference in percentage change from baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100. | Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks | 
| Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Female Participants) | BMD analysis performed on log (BMD ratio to baseline) using separate repeated measures models for each gender with covariates of treatment group, age, baseline BMI, visit, log baseline BMD, log baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the While on Treatment estimand of the difference in percentage change from baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100. | Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks | 
| Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Male Participants) | BMD analysis performed on log (BMD ratio to baseline) using separate repeated measures models for each gender with covariates of treatment group, age, baseline BMI, visit, log baseline BMD, log baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the While on Treatment estimand of the difference in percentage change from baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100. | Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks | 
| Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Female Participants) | BMD analysis performed on log (BMD ratio to baseline) using separate repeated measures models for each gender with covariates of treatment group, age, baseline BMI, visit, log baseline BMD, log baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the While on Treatment estimand of the difference in percentage change from baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100. | Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks | 
| Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) | BMD analysis performed on log (BMD ratio to baseline) using a repeated measures model with covariates of treatment group, age, gender, baseline BMI, visit, log baseline BMD, log baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the While on Treatment estimand of the difference in percentage change from baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100. | Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks |