Fluticasone Furoate/GW642444 Inhalation Powder Long-Term Safety Study

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the long-term safety of fluticasone furoate/GW642444

Official Title
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A Randomized, Double-Blind, Double Dummy, Active Comparator, Parallel Group, Multicenter Study to Evaluate the Safety of Once-Daily Fluticasone Furoate/GW642444 Inhalation Powder for 52 Weeks in Adolescent and Adult Subjects With Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Fluticasone Furoate/GW642444
* Drug: Fluticasone propionate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of asthma Reversibility FEV1 of twelve percent or greater and two hundred milliliters and greater approximately ten to forty minutes following two to four inhalations of albuterol FEV1 greater than or equal to fifty percent of predicted Currently using moderate to high dose inhaled corticosteroid therapy Exclusion Criteria: History of life threatening asthma Respiratory infection or oral candidiasis Asthma exacerbation Uncontrolled disease or clinical abnormality Allergies Taking another investigational medication or prohibited medication

Ages Eligible for Study
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Minimum Age: 12 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/GW642444<br> | Drug: Fluticasone Furoate/GW642444<br>* Combination inhaled corticosteroid and long-acting beta2-agonist<br>|
| Active Comparator: Fluticasone propionate<br> | Drug: Fluticasone propionate<br>* Inhaled corticosteroid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) During the Treatment Period | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations. Refer to the General Adverse AE/SAE module for a complete list of AEs and SAEs. | From the start of study medication until Visit 11 (Week 52)/Early Withdrawal | 
| Number of Participants With Severe Asthma Exacerbations During the Treatment Period | A severe asthma exacerbation is defined as the deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. Courses of corticosteroids separated by 1 week or more were treated as separate severe exacerbations. | From the start of study medication until Visit 11 (Week 52)/Early Withdrawal | 
| Change From Baseline in Albumin and Total Protein at Week 12, Week 28, and Week 52/Early Withdrawal | Blood samples were collected for the measurement of albumin and total protein values at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 12, Week 28, and Week 52/Early Withdrawal | 
| Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK), and Gamma Glutamyltransferase (GGT) at Week 12, Week 28, and Week 52/Early Withdrawal | Blood samples were collected for the measurement of ALP, ALT, AST, CK, and GGT values at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 12, Week 28, and Week 52/Early Withdrawal | 
| Change From Baseline in Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, and Creatinine at Week 12, Week 28, and Week 52/Early Withdrawal | Blood samples were collected for the measurement of direct bilirubin, indirect bilirubin, total bilirubin, and creatinine values at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 12, Week 28, and Week 52/Early Withdrawal | 
| Change From Baseline in Chloride, Carbon Dioxide Content/Bicarbonate, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) at Week 12, Week 28, and Week 52/Early Withdrawal | Blood samples were collected for the measurement of chloride, carbon dioxide (CO2) content/bicarbonate, glucose, potassium, sodium, and urea/BUN values at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 12, Week 28, and Week 52/Early Withdrawal | 
| Change From Baseline in the Percentage of Basophils, Eosinophils, Hematocrit, Lymphocytes, Monocytes, and Segmented Neutrophils in the Blood at Week 12, Week 28, and Week 52/Early Withdrawal | Blood samples were collected for the measurement of the percentage of basophils, eosinophils, hematocrit, lymphocytes, monocytes, and segmented neutrophils in the blood at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 12, Week 28, and Week 52/Early Withdrawal | 
| Change From Baseline in Eosinophil Count, Total Absolute Neutrophil Count (ANC), Platelet Count, and White Blood Cell (WBC) Count at Week 12, Week 28, and Week 52/Early Withdrawal | Blood samples were collected to determine the eosinophil count, total ANC, platelet count, and WBC count at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 12, Week 28, and Week 52/Early Withdrawal | 
| Change From Baseline in Hematocrit at Week 12, Week 28, and Week 52/Early Withdrawal | Blood samples were collected for the measurement of hematocrit values at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 12, Week 28, and Week 52/Early Withdrawal | 
| Change From Baseline in Hemoglobin at Week 12, Week 28, and Week 52/Early Withdrawal | Blood samples were collected for the measurement of hemoglobin values at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 12, Week 28, and Week 52/Early Withdrawal | 
| Number of Participants With the Indicated Shift From Baseline to High, Normal or no Change, and Low Post-Baseline Values for Urinary Cortisol Excretion | A 24-hour urine sample was collected for the measurement of 24-hour urinary cortisol excretion (UCE) at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. Any visit post-baseline (AVPB) value was derived using laboratory assessments performed at scheduled, unscheduled, and Early Withdrawal visits. Participants who had a shift from Baseline in their post-Baseline UCE values relative to the normal range, are presented in the To high and To low categories. Participants whose post-Baseline UCE values were unchanged (e.g., High to High) or whose value became normal, are presented in the To normal or no change category. The normal range for UCE is defined as: 11 to 138 nanomoles per 24 hours (nmol/24 hr) for participants >=18 years of age, 8.3 to 151.7 nmol/24 hr for participants 14 to 17 years of age, and 2.8 to 124.2 nmol/24 hr for participants 12 and 13 years of age. | Baseline; Week 12, Week 28, and Week 52/Early Withdrawal | 
| Ratio of 24-hour Urinary Cortisol Excretion at Week 12 to Baseline | A 24-hour urine sample was collected, and the least square geometric mean (LSGM) for 24-hour urinary cortisol excretion (UCE) was calculated at Baseline and at Week 12. The ratio of the Week 12 LSGM to the Baseline LSGM was calculated as the value at Week 12 divided by the value at Baseline. Analysis was performed using analysis of covariance (ANCOVA) with covariates of region, sex, age, treatment, and the log of the Baseline values. | Baseline and Week 12 | 
| Ratio of 24-hour Urinary Cortisol Excretion at Week 28 to Baseline | A 24-hour urine sample was collected, and the LSGM for 24-hour UCE was calculated at Baseline and at Week 28. The ratio of the Week 28 LSGM to the Baseline LSGM was calculated as the value at Week 28 divided by the value at Baseline. Analysis was performed using ANCOVA with covariates of region, sex, age, treatment, and the log of the Baseline values. | Baseline and Week 28 | 
| Ratio of 24-hour Urinary Cortisol Excretion at Week 52 to Baseline | A 24-hour urine sample was collected, and the LSGM for 24-hour UCE was calculated at Baseline and at Week 52. The ratio of the Week 52 LSGM to the Baseline LSGM was calculated as the value at Week 52 divided by the value at Baseline. Analysis was performed using ANCOVA with covariates of region, sex, age, treatment, and the log of the Baseline values. | Baseline and Week 52 | 
| Number of Participants With Evidence of Oral Candidiasis at Any Time Post-Baseline | A detailed oropharyngeal examination was done at all clinic visits for visual/clinical evidence of oral candidiasis over the entire Treatment Period (worst case any time post-Baseline). For participants with visual/clinical evidence of candidiasis during the Treatment Phase of the study, a culture swab was taken and analyzed for infection. | From Baseline until Visit 11/Early Withdrawal (52 weeks) | 
| Maximum Change From Baseline in Systolic Blood Pressure (SBP) and Minimum Change From Baseline in Diastolic Blood Pressure (DBP) | SBP and DBP were measured at the following scheduled time points: Screening, Day 1, Week 2, Week 4, Week 8, Week 12, Week 20, Week 28, Week 36, Week 44, and Week 52/Early Withdrawal. Baseline is defined as the Visit 1 (screening) value. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. Maximum and minimum change from Baseline for any post-Baseline visit was derived using all scheduled, unscheduled, and Early Withdrawal visits. | From Baseline until Visit 11/Early Withdrawal (52 weeks) | 
| Maximum Change From Baseline in Pulse Rate | Pulse rate was measured at the following scheduled time points: Screening, Day 1, Week 2, Week 4, Week 8, Week 12, Week 20,Week 28, Week 36, Week 44, and Week 52/Early Withdrawal. Baseline is defined as the Visit 1 (screening) value. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. Maximum change from Baseline for any post-Baseline visit was derived using all scheduled, unscheduled, and Early Withdrawal visits. | From Baseline until Visit 11/Early Withdrawal (52 weeks) | 
| Number of Participants With the Indicated Change From Baseline in Lens Opacities Classification System, Version III (LOCS III) Posterior Subcapsular Opacity (P) at Week 28 and Week 52 | P is defined as the opacification at the back of the lens adjacent to the capsule (or bag) in which the lens sits. An event of P is defined as an increase of >=0.3 from Baseline in LOCS III grade for P in either eye at any time post-Baseline. Per LOC III, P ranges from 0.1 (clear or colorless) to 5.9 (very opaque). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 28, and Week 52 | 
| Number of Participants With the Indicated Change From Baseline in Intraocular Pressure (IOP) at Week 28 and Week 52 | Intraocular pressure (IOP) is the fluid pressure inside the eye. IOP was measured twice for each eye at Baseline, Week 28, and Week 52 using Goldmann Applanation tonometry. The second IOP reading was used for analysis. The number of participants with a change from Baseline in IOP of <0 mmHg, >=0 to <4 mmHg, >=4 to <7 mmHg, >=7 to <11 mmHg, and >=11 mmHg are presented. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 28 and Week 52 | 
| Change From Baseline in Horizontal Cup-to-disc Ratio at Week 28 and Week 52 | Funduscopic examination was performed at Baseline, Week 28, and Week 52 to measure the horizontal cup-to-disc ratio of both eyes. The horizontal cup-to-disc ratio is the ratio of the horizontal diameter of the physiological cup to that of the horizontal diameter of the optic disc. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 28 and Week 52 | 
| Number of Participants With the Indicated Change From Baseline in Lens Opacities Classification System, Version III (LOCS III) Cortical Opacity (C) at Week 28 and Week 52 | C is defined as the opacification of the cortex (outer layer) of the lens. Per LOC III, C ranges from 0.1 (clear or colorless) to 5.9 (very opaque). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 28 and Week 52 | 
| Change From Baseline in Lens Opacities Classification System, Version III (LOCS III) Nuclear Color (NC) at Week 28 and Week 52 | NC is the color of the nucleus (central layer) of the lens. Per LOC III, NC ranges from 0.1 (clear or colorless) to 6.9 (very opaque or brunescent). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 28 and Week 52 | 
| Change From Baseline in Lens Opacities Classification System, Version III (LOCS III) Nuclear Opalescence (NO) at Week 28 and Week 52 | NO is the opalescence of the nucleus (central layer) of the lens. Per LOC III, NO ranges from 0.1 (clear or colorless) to 6.9 (very opaque or brunescent). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 28 and Week 52 | 
| Change From Baseline in the Logarithm of the Minimum Angle of Resolution (LogMAR) Visual Acuity at Week 28 and Week 52 | Visual acuity is defined as the acuteness or clearness of vision. The minimum angle of resolution (MAR) is the angle a viewed object subtends at the eye, usually stated in degrees/minutes of arc. Visual acuity was measured using Early Treatment Diabetic Retinopathy Study (ETDRS) charts in decimal numbers. The LogMAR scale is used to express the visual acuity in a linear scale as the logarithm to base 10 of the MAR. A lower score indicates better visual acuity; visual acuity decreases with an increasing score. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline; Week 28 and Week 52 | 
| Maximum Change From Baseline in the QT Interval Using Bazett's Correction (QTcB) and QT Interval Using Fridericia's Correction (QTcF) | The QT interval is an electrocardiogram (ECG) parameter that represents the electrical depolarization and repolarization of the left and right ventricles of the heart. The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the ECG. Corrected QT (QTc) is the QT interval corrected for heart rate by using Bazett's formula (QTcB) and Fridericia's formula (QTcF). 12-lead ECG measurements were perfomed at the following scheduled time points: Baseline; Week 2, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the value taken pre-dose at screening. The maximum post-Baseline value was derived using all scheduled, unscheduled, and Early Withdrawal ECG assessments. Maximum change from Baseline was calculated as the maximum post-Baseline value minus the value at Baseline. | Baseline; Week 2, Week 12, Week 28, and Week 52/Early Withdrawal | 
| Mean 24 Hour Holter Heart Rate for Participants With at Least 16 Hours of Recorded Data | Twenty-four hour Holter monitors were obtained using a 12-lead Holter monitor. The Holter monitor is worn by the participant for 24 hours, and the monitor continuously records the heart's rhythm while the monitor is worn. At the end of the 24 hour period, the data from the monitor are downloaded and transmitted to the centralized vendor for analysis and interpretation by a licensed cardiologist. | 0-24 hours at Screening, Day 1, Week 28, and Week 52 | 
| Maximum 24 Hour Holter Heart Rate for Participants With at Least 16 Hours of Recorded Data | Twenty-four hour Holter monitors were obtained using a 12-lead Holter monitor. Holter monitor data were transmitted to a centralized vendor for analysis and interpretation by a licensed cardiologist. | 0-24 hours at Screening, Day 1, Week 28, and Week 52 |