Influence Of Salmeterol Xinafoate/Fluticasone Propionate (50/500 µg BID) On The Course Of The Disease And Exacerbation Frequency In COPD Patients Gold Stage III And IV

Study Overview
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Brief Summary
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This is a 12 month randomized, open-label, parallel-group study to obtain data on the frequency and variability of exacerbations in severe and very severe Chronic Obstructive Pulmonary Disease (COPD) patients (Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage III and IV) receiving salmeterol xinafoate and fluticasone propionate either in fixed combination (SFC) or from separate inhalers (Sal/FP) with standard therapy. 200 subjects will be enrolled in approximately 30 study centres in Germany. Data on health care utilisation will be collected to compare direct costs associated with COPD in these two groups. Baseline data will be collected for all subjects at Visit 1 and eligible subjects will be randomized to receive either SFC 50/500 µg bid (twice daily) as fixed combination or Sal 50 µg bid (twice daily) and FP 500 µg bid (twice daily) concurrently over 52 weeks. Subjects will return for study visits every two to three months until week 52. Additional telephone calls will be made between scheduled visits every 4 weeks. Assessments will include monitoring of frequency of exacerbations, health care utilisation (including emergency visits and hospitalizations) and rescue medication, lung function, drug compliance, health-related quality of life (SGRQ = St George's Respiratory Questionnaire) and safety.

Detailed Description
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A 12 month open-label randomized parallel group study to investigate the influence of salmeterol xinafoate/fluticasone propionate either in fixed combination (SFC50/500 µg bid) or separately (SAL 50 µg and FP 500 µg bid) via Diskus inhalers on the course of the disease and frequency of exacerbations in subjects with severe and very severe COPD ( GOLD stage III+IV)

Official Title
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A 12 Month Open-label Randomized Parallel Group Study to Investigate the Influence of Salmeterol Xinafoate/Fluticasone Propionate Either in Fixed Combination or Separately Via Diskus Inhalers on the Course of the Disease and Frequency of Exacerbations in Subjects With Severe and Very Severe COPD.

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Salmeterol / Fluticasone (50/500 µg) BID fixed combination
* Drug: Salmeterol / Fluticasone (50/500 µg) BID separate Inhalers


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Subject must have a diagnosis of COPD based on the American Thoracic Society (ATS)/ European Respiratory Society (ERS) criteria. Male or female subjects, aged >=40 years. Females must be of Non Child Bearing Potential. The definition of Non Child Bearing Potential is as following: Females, regardless of their age, with functioning ovaries and who have a current documented tubal ligation or hysterectomy, or females who are post-menopausal. Have diagnosed COPD stage III or IV according to GOLD criteria: a baseline post-bronchodilator Forced Expiratory Volume, measured at 1 second (FEV1) <50% of predicted normal and a baseline post- bronchodilator FEV1/Inspiratory Vital Capacity (IVC) ratio <70%. Have experienced at least 2 moderate or severe COPD exacerbations leading to medical consultation (requiring oral corticosteroids or increasing dosage of oral corticosteroids and/or antibiotics or hospitalization) within the 12 months preceding Visit 1. Have stable COPD medication within 4 weeks prior to Visit 1 (no new medication added and no dosage changes in medication). Current or ex-smokers with a smoking history of at least 10 pack years (number of pack years = [number of cigarettes per day / 20] x number of years smoked, e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years). Are currently managed at home (outpatients), are ambulatory and able to travel to the clinic. Subjects can be treated with all relevant COPD medication. This includes vaccines, inhaled short-acting beta-2-agonists as needed, short-acting or long-acting anticholinergics (tiotropium), systemic beta-2-agonists, theophylline, mucolytics, antioxidants, beta-1-agonists (for cardiovascular indication), non-invasive ventilation, long term oxygen therapy and can have Cor Pulmonale. A signed and dated written informed consent is obtained prior to participation. Able to comply with the requirements of the protocol and be available for study visits over 52 weeks. Exclusion criteria: Known other respiratory disorders or signs for other respiratory disorders (e.g. asthma, lung cancer, sarcoidosis, tuberculosis, lung fibrosis, cystic fibrosis, bronchoectasis). Known history of significant inflammatory disease, other than COPD (e.g. rheumatoid arthritis and systemic lupus erythematosus). Known to be severely alpha-1-antitrypsin deficient (PI SZ or ZZ) Having undergone lung surgery (e.g. lung resection including lung volume reduction surgery, lung transplant) or subjects scheduled for surgery. Concurrent medication from Visit 1 and for the duration of the study with any of the prohibited medications: monoamine oxidase inhibitors and tricyclic antidepressants, and ritonavir (a highly potent cytochrome P450 3A4 inhibitor). Subjects receiving chronic or prophylactic antibiotic therapy. Serious, uncontrolled disease (including serious psychological disorders) likely to interfere with the study or impact on subject safety. Have, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse. History of depression. History or presence of clinically significant drug sensitivity or clinically significant allergic reaction to corticosteroids or salmeterol. Moderate or severe COPD exacerbation (requiring corticosteroids or increased dosage of corticosteroids and/or antibiotics or hospitalization) within the 4 weeks prior to Visit 1 Lower respiratory tract infection within the 4 weeks prior to Visit 1 . Pregnant or lactating female and female of childbearing potential. Subject is a participating investigator, sub-investigator, study coordinator, or other employee of a participating investigator, or is an immediate family member of the before mentioned. Subject is an employee of GlaxoSmithKline (GSK). Subject participated in an investigational drug study within 30 days prior to Visit 1

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: arm 1<br> | Drug: Salmeterol / Fluticasone (50/500 µg) BID fixed combination<br>* comparator<br>|
| Active Comparator: arm 2<br> | Drug: Salmeterol / Fluticasone (50/500 µg) BID separate Inhalers<br>* comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Number of Exacerbations Per Year: Negative Binomial Model | During regular visits, participants were asked whether they experienced any exacerbation since last contact. Between visits, COPD participants were contacted by phone by the staff and asked about exacerbation details. Exacerbations were defined according to Rodriguez-Roisin: moderate (grade II) exacerbations include a worsening of COPD symptoms that require both a change of respiratory medication (increased dose of prescribed or addition of new drugs) and medical assistance; severe (grade III) exacerbations include deterioration in COPD resulting in hospitalization or emergency room treatment. | Baseline through Week 52 | 
| Mean Number of Exacerbations Per Year: Poisson Model | During regular visits, participants were asked whether they experienced any exacerbation since last contact. Between visits, COPD participants were contacted by phone by the staff and asked about exacerbation details. Exacerbations were defined according to Rodriguez-Roisin: moderate (grade II) exacerbations include a worsening of COPD symptoms that require both a change of respiratory medication (increased dose of prescribed or addition of new drugs) and medical assistance; severe (grade III) exacerbations include deterioration in COPD resulting in hospitalization or emergency room treatment. | Baseline through Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compliance and Adherence to Study Medication | Compliance is calculated as the ratio (in percent) between the number of actual doses taken during the total treatment period divided by the number of doses that should have been taken during the total treatment period. | Baseline through Week 52 | 
| Mean Number of COPD-related Visits at/by Physician | The total number of COPD-related visits, i.e., from baseline through week 52, the number of visits at physician's office, the number of home visits made by physician, the number of visits at an emergency outpatient clinic, as well as the number of home visits by an emergency physician were summed up. | Baseline through Week 52 | 
| Number of Participants With the Indicated Number of Days at the Intensive Care Unit (ICU) | The number participants with the indicated number of days at the ICU was recorded. | Baseline through Week 52 | 
| Number of Participants With the Indicated Number of Hospital Stays | The number of participants with the indicated number of hospitalizations was recorded. | Baseline through Week 52 | 
| Mean Number of Days Rescue Medication Was Used | Participants were asked for the number of days they used rescue medication within the 7 days before Week 8 and Week 52. | The 7 days before baseline (=Visit 2 [Week 8]) and the last 7 days of study (=Visit 6 [Week 52]) | 
| Mean Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 52 | Change from baseline was calculated as the FEV1 percent predicted value at Week 52 minus the percent predicted value at baseline. The post-bronchodilator lung function test was performed to measure FEV1 30 minutes after inhaling salbutamol. The most reliable result of three different consecutive measurements was documented. | Baseline and Week 52 | 
| Mean Change From Baseline in Inspiratory Vital Capacity (IVC) at Week 52 | Change from baseline was measured as the IVC value at Week 52 minus the value at baseline. The post-bronchodilator lung function test was performed to measure IVC 30 minutes after inhaling salbutamol. The most reliable result of three different, consecutive measurements was documented. | Baseline and Week 52 | 
| Mean Change From Baseline in the Tiffeaneau Index at Week 52 | The Tiffeneau index is defined as the FEV1 divided by the IVC (i.e., forced expiratory volume in one second relative to the inspiratory capacity) in percent. Change from baseline is calculated as the FEV1/IVC value at Week 52 minus the value at baseline. | Baseline and Week 52 | 
| Mean Change From Baseline in the Symptom Score of the St. George's Respiratory Questionnaire (SGRQ) at Week 52 | Change from baseline is calculated as the symptom score at Week 52 minus the symptom score at baseline. The SGRQ (a self-administered questionnaire) subscale symptom score ranges from 0 to 100% and measures the effect of respiratory symptoms, frequency, and severity on quality of life (summed weights of 8 questions). A score of 0 indicates the best possible status. | Baseline and Week 52 | 
| Mean Change From Baseline in the Activity Score of the St. George's Respiratory Questionnaire (SGRQ) at Week 52 | Change from baseline is calculated as the activity score at Week 52 minus the score at baseline. The SGRQ (a self-administered questionnaire) subscale activity score ranges from 0 to 100% and is concerned with activities that cause or are limited by breathlessness (summed weights of 2 questions). A score of 0 indicates the best possible status. | Baseline and Week 52 | 
| Mean Change From Baseline in the Impact Score of the St. George's Respiratory Questionnaire (SGRQ) at Week 52 | Change from baseline was calculated as the impact score at Week 52 minus the score at baseline. The SGRQ (a self-administered questionnaire) subscale impact score ranges from 0 to 100% and is concerned with social functioning and psychological disturbances (summed weights of 5 questions). A score of 0 indicates the best possible status. | Baseline and Week 52 | 
| Mean Change From Baseline in the Total Score of the St. George's Respiratory Questionnaire (SGRQ) at Week 52 | Change from baseline was calculated as the total score at Week 52 minus the score at baseline. The SGRQ (a self-administered questionnaire) total score ranges from 0 to 100% and summarizes the impact of COPD on overall health status (summed weights of 15 questions). A total score of 0 indicates the best possible status. | Baseline and Week 52 | 
| Mean Total Costs (Related to COPD) Per Participant | Total costs include costs for hospitalization, medication, and visits to/by physician. Medications that were used as required were assumed to be used every second day. | Baseline through Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Severe and very severe COPD (GOLD stage III / IV) exacerbations, health care utilisation, Chronic Obstructive Pulmonary Disease (COPD), quality of life, compliance, salmeterol/fluticasone combination