A Randomized Study To Evaluate The Efficacy And Safety Of An Investigational Drug In Adolescent And Adult Subjects With Asthma Uncontrolled on Low-Dose ICS Therapy.

Study Overview
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Brief Summary
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This study is designed to determine if the investigational drug is effective and safe in individuals with asthma.

Detailed Description
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A Randomized Double-Blind, Double Dummy, Placebo-Controlled, Parallel-Group, Multicenter Dose Ranging Study to Evaluate the Efficacy and Safety of GW685698X Inhalation Powder Once Daily and Fluticasone Propionate Inhalation Powder Twice Daily compared with Placebo for 8 Weeks in Adolescent and Adult Subjects with Persistent Asthma Symptomatic on Low-Dose ICS Therapy

Official Title
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A Randomized Double-Blind, Double Dummy, Placebo-Controlled, Parallel-Group, Multicenter Dose Ranging Study to Evaluate the Efficacy and Safety of GW685698X Inhalation Powder Once Daily and Fluticasone Propionate Inhalation Powder 250mcg Twice Daily Compared With Placebo for 8 Weeks in Adolescent and Adult Subjects With Persistent Asthma Symptomatic on Low-Dose ICS Therapy

Conditions
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Asthma

Intervention / Treatment
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* Drug: GW685698X
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Subjects eligible for enrolment in the study must meet all of the following criteria: Type of Subject: Outpatient Age: 12 years of age or older at Visit 1. For sites in the following countries, subjects recruited will be ≥18 years of age: Bulgaria, Czech Republic, Germany, Greece, Lithuania, New Zealand, Russian Federation, Turkey and any other countries where local regulations or the regulatory status of study medication permit enrolment of adults only. Gender: Male or Eligible Female To be eligible for entry into the study, females of childbearing potential must commit to consistent and correct use of an acceptable method of birth control, as defined by the following: Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject Implants of levonorgestrel Injectable progestogen Oral contraceptive (either combined estrogen/progestin or progestin only) Any intrauterine device (IUD) with a documented failure rate of less than 1% per year. Females of childbearing potential who are not sexually active must commit to complete abstinence from intercourse throughout the clinical trial and for a period after the trial to account for elimination of the drug (minimum of six days). Double barrier method - spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or a spermicide and female diaphragm). NB: For German sites, female subjects must use a method of birth control other than the double barrier method. The contraceptive transdermal patch, Ortho Evra (if the subject is less than 198 pounds) Female subjects should not be enrolled if they are pregnant, lactating or plan to become pregnant during the time of study participation. A serum pregnancy test is required of all females. This test will be performed at the initial screening visit (Visit 1) and Visit 8. In addition, a urine pregnancy test will be performed on the evening of the double-blind treatment visit, prior to randomization (Visit 3) and at Visits 4 through 7. Asthma Diagnosis: Asthma as defined by the National Institutes of Health [National Institutes of Health, 2007]. Severity of Disease: A best FEV1 of 40%-90% of the predicted normal value during Visit 1. NHANES III predicted values will be used for subjects aged ≥ 12 years and adjustments to predicted values will be made for African American subjects. [Hankinson, 1999]. Reversibility of Disease: Demonstrated a ≥ 12% and ≥200mL reversibility of FEV1 within approximately 30-minutes following 4 inhalations of albuterol/salbutamol inhalation aerosol (if required, spacers are permitted for reversibility testing only) or one nebulized albuterol/salbutamol solution at the Screening Visit. If a subject fails to demonstrate an increase in FEV1 ≥12% and ≥200mL, then the subject is not eligible for the study and will not be allowed to re-screen. Current Anti-Asthma Therapy: Subjects must have been using a inhaled corticosteroid for at least 8 weeks prior to Visit 1 and maintained on a stable dose of inhaled corticosteroids for four weeks prior to Visit 1 at one of the following doses: [fluticasone propionate MDI CFC/HFA >220mcg exactuator or ≤250mcg ex valve]; [fluticasone propionate DPI ≤200mcg]; [beclomethasone dipropionate DPI ≤ 420mcg exactuator or ≤ 500mcg ex-valve]; [beclomethasone dipropionate HFA (Qvar) ≤ 160mcg exactuator or ≤ 200mcg ex-valve]; [budesonide DPI MDI ≤400mcg]; [flunisolide ≤ 1000mcg]; [triamcinolone acetonide ≤1000mcg]; [mometasone furoate DPI >200mcg or ≤ 220mcg]; [ciclesonide MDI HFA ≤ 160mcg ex-actuator dose / ≤ 200mcg ex-valve dose]. Short- Acting Beta2-Agonists: All subjects must be able to replace their current short-acting beta2-agonists with albuterol/salbutamol inhalation aerosol at Visit 1 for use as needed for the duration of the study. The use of spacer devices with metered dose inhaler (MDI) or nebulized albuterol/salbutamol will not be allowed during the study with the exception of their use during reversibility testing at Visit 1. Subjects must be able to withhold all inhaled short-acting beta sympathomimetic bronchodilators for at least 6 hours prior to all study visits. Informed Consent: All subjects must be able and willing to give written informed consent to take part in the study. Compliance: Subjects must be able to comply with completion of the Daily Diary (includes paper medical conditions diary). French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. Inclusion Criteria for Randomization At the end of the run-in period, a subject will be eligible to enter the treatment period of the study if he/she meets the following criteria at Visit 3: Evening pre-dose percent predicted FEV1 of between 40% and 90% of their predicted normal. Any combination of the daily asthma symptom scores (day-time plus night-time) of ≥1 or albuterol/salbutamol use on at least 4 of the last 7 consecutive days of the run-in period (immediately preceding Visit 3). EXCLUSION CRITERIA: History of Life-threatening asthma: Defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures. Respiratory Infection: Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks of Visit 1 and led to a change in asthma management, or in the opinion of the Investigator is expected to affect the subjects asthma status or the subjects ability to participate in the study. Asthma Exacerbation: Any asthma exacerbation requiring oral corticosteroids within 3 months of Visit 1. A subject must not have had any hospitalization for asthma within 6 months prior to Visit 1. Concurrent Diseases/Abnormalities: Historical or current evidence of clinically significant uncontrolled disease including, but not limited to: cardiovascular disease, hepatic disease, renal disease, hematological disease, neurological disease, or pulmonary disease (including, but not confined to chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis, bronchopulmonary dysplasia, and chronic obstructive pulmonary disease). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study. The list of additional excluded conditions/diseases includes, but is not limited to the following: congestive heart failure, clinically significant coronary artery disease, stroke within 3 months of Visit 1, poorly controlled peptic ulcer, immunologic compromise, tuberculosis (current or untreated), Addison's disease, uncontrolled thyroid disorder, known aortic aneurysm, clinically significant cardiac arrhythmia, uncontrolled hypertension, hematological, hepatic, or renal disease, current malignancy, cushings disease, uncontrolled diabetes mellitus, recent history of drug or alcohol abuse. Oropharyngeal Examination: A subject will not be eligible for the run-in if he/she has clinical visual evidence of oral candidiasis at Visit 1. Investigational Medications: A subject must not have participated in a study or used any investigational drug within 30 days prior to Visit 1. Drug Allergy: Any adverse reaction including immediate or delayed hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of the novel dry powder inhaler or DISKUS/ACCUHALER (i.e., lactose or magnesium stearate). Milk Protein Allergy: History of severe milk protein allergy. Immunosuppressive Medications: A subject must not be using, or require use, of immunosuppressive medications during the study. NOTE: Immunotherapy for the treatment of allergies is allowed during the study provided that the treatment was initiated prior to Visit 1 and the subject is maintained on a stable regimen throughout the study period. Attendance: A subject will not be eligible if he/she or his/her parent or legal guardian has any infirmity, disability, or geographical location which seems likely (in the opinion of the Investigator) to impair compliance with any aspect of this study protocol or scheduled visits to the study center and non-compliant with study medication or procedures (e.g. completion of daily diary). Neurological or psychiatric disease or history of drug or alcohol abuse which in the opinion of the investigator could interfere with the subject's proper completion of the protocol requirements excludes study participation. Tobacco Use : Current smoker or a smoking history of 10 pack years or more (e.g. 20 cigarettes/day for 10 years). A subject may not have used tobacco products within the past one year (i.e., cigarettes, cigars, or pipe tobacco). Affiliation with Investigator's Site: A subject will not be eligible for this study if he/she is an immediate family member of the participating Investigator, sub-Investigator, study coordinator, or employee of the participating Investigator. Corticosteroid Use: Administration of systemic, oral or depot corticosteroids within 12 weeks of Visit 1. Potent Cytochrome P450 3A4 (CYP3A4) inhibitors: Patients who are receiving potent CYP3A4 inhibitors within 4 weeks of Visit 1 (e.g., ritonavir, ketoconazole, itraconazole). Exclusion Criteria for Randomization At the end of the run-in period, a subject will not be eligible to enter the treatment period of the study if they meet any of the following criteria. Clinical Laboratory Abnormalities: Clinically significant abnormal laboratory tests during Visit 1 which are still abnormal upon repeat analysis and are not believed to be due to disease(s) present. Each Investigator will use his/her own discretion in determining the clinical significance of the abnormality. When in doubt, GlaxoSmithKline, or designee, should be notified so that a joint decision can be made. Changes in asthma medication (excluding albuterol/salbutamol inhalation aerosol provided at Visit 1). Occurrence of a culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear during the run-in period that led to a change in asthma management, or in the opinion of the Investigator is expected to affect the subjects asthma status or the subjects ability to participate in the study. Asthma exacerbation, defined as any worsening of asthma requiring any treatment other than rescue albuterol/salbutamol or regular inhaled corticosteroid use. This includes requiring the use of systemic corticosteroids and / or emergency room visit or hospitalization or a change in subject's regular inhaled corticosteroid dose. A subject will not be eligible for randomization if he/she has an abnormal visual oropharyngeal exam at the randomization Visit 3 (visual clinical evidence of oral candidiasis). Non-compliance with completion of the Daily Diary, defined as: -Completion of AM and PM symptom scores on less than 4 days out of the last 7 days immediately preceding Visit 3. Completion of AM and PM rescue use on less than 4 days out of the last 7 days immediately preceding Visit 3. Completion of AM and PM PEF measurements on less than 4 days out of the last 7 days immediately preceding Visit 3. Recording run-in asthma medication use on less than 4 days out of the last 7 days immediately preceding Visit 3.

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 |
| --- | --- |
| Placebo Comparator: Arm 1<br> | Drug: placebo<br>* placebo<br>|
| Experimental: Arm 2<br> | Drug: GW685698X<br>* GW685698X<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Trough (Evening Pre-dose and Pre- Rescue Bronchodilator) FEV1 at Week 8 | Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled in one second. Pre-dose and pre-rescue bronchodilator (albuterol/salbutamol) trough FEV1 (the measurement of FEV1 performed at the end of the dosing interval) was measured electronically by spirometry in the evening at the Baseline (BL) through Week 8 clinic visits. The highest of 3 technically acceptable measurements was recorded. The Visit 3 FEV1 assessment was used as the Baseline value. Change from Baseline in trough FEV1 was calculated as the value at Week 8 minus the value at Baseline. The analysis was performed using an Analysis of Covariance (ANCOVA) model with covariates of Baseline trough FEV1, country, sex, age, and treatment group. | Baseline and Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Daily Trough (Pre-dose and Pre-rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Averaged Over the 8-week Treatment Period | PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. Trough PEF is defined as the PEF measurement performed at the end of the dosing interval. PEF was measured by the participants using a hand-held electronic peak flow meter each evening prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. The best of three attempts was recorded by the participants in a daily diary. The Baseline value was derived from the last 7 days of the daily diary prior to the randomization of the participant. Change from Baseline was calculated as the value of the averaged daily evening PEF over the 8-week treatment period minus the value at Baseline. The analysis was performed using an ANCOVA model with covariates of Baseline trough evening PEF, country, sex, age, and treatment group. | From Baseline up to Week 8 | 
| Mean Change From Baseline in Daily Morning PEF Averaged Over the 8-week Treatment Period | PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. Trough PEF is defined as the PEF measurement performed at the end of the dosing interval. PEF was measured by the participants using a hand-held electronic peak flow meter each morning prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. The best of three attempts was recorded by the participants in a daily diary. The Baseline value was derived from the last 7 days of the daily diary prior to the randomization of the participant. Change from Baseline was calculated as the value of the averaged daily morning PEF over the 8-week treatment period minus the value at Baseline. The analysis was performed using an ANCOVA model with covariates of Baseline trough morning PEF, country, sex, age, and treatment group. | From Baseline up to Week 8 | 
| Mean Change From Baseline in the Percentage of Symptom-free 24-hour (hr) Periods During the 8-week Treatment Period | Asthma symptoms were recorded in a daily dairy by the participants every day in the morning and evening before taking any rescue or study medication and before PEF measurement. A 24-hour period in which a participant's responses to both the morning and evening assessments indicated no symptoms was considered as symptom-free. The Baseline value was derived from the last 7 days of the daily diary prior to the randomization of the participant. Change from Baseline was calculated as the averaged value during the 8-week Treatment Period minus the value at Baseline. The analysis was performed using an ANCOVA model with covariates of Baseline, country, sex, age, and treatment group. | From Baseline up to Week 8 | 
| Mean Change From Baseline in the Percentage of Rescue Free 24-hour (hr) Periods During the 8-week Treatment Period | The number of inhalations of rescue albuterol/salbutamol inhalation aerosol used during the day and night was recorded by the participants in a daily diary. A 24-hr period in which a participant's responses to both the morning and evening assessments indicated no use of rescue medication was considered as rescue-free. The Baseline value was derived from the last 7 days of the daily diary prior to the randomization of the participant. Change from Baseline was calculated as the averaged value during the 8-week Treatment Period minus the value at Baseline. The analysis was performed using an ANCOVA model with covariates of baseline, country, sex, age, and treatment group. | From Baseline up to Week 8 | 
| Number of Participants Who Withdrew Due to Lack of Efficacy During the 8-Week Treatment Period | The number of participants whose primary reason for withdrawal was lack of efficacy was analyzed. | From the first dose of study medication up to Week 8/Early Withdrawal | 
| Number of Participants With Any On-treatment Adverse Events or Serious Adverse Events Throughout the 8-week Treatment Period | An adverse event (AE) is defined as any untoward medical occurrence in a 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 have been exercised in other situations. Refer to the general AE/SAE module for a list of AEs (occurring at a frequency threshold >=3%) and SAEs. | From the first dose of study medication up to Week 8/Early Withdrawal | 
| Number of Participants With Clinical/Visual Evidence of Oropharyngeal Candidiasis | A detailed oropharyngeal examination for visual evidence of oral candidiasis was performed for the entire Treatment Period. | From Baseline up to Week 8/Early Withdrawal | 
| Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in the Blood at Baseline and Week 8 | Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, and total neutrophils at Baseline (BL) and Week 8 (W8). The Baseline value was the measurement taken at screening (Visit 1). | Baseline and Week 8 | 
| Hematocrit at Baseline and Week 8 | Blood samples were collected for the measurement of Hematocrit at Baseline (BL) and Week 8 (W8). The Baseline value was the measurement taken at screening (Visit 1). | Baseline and Week 8 | 
| Hemoglobin at Baseline and Week 8 | Blood samples were collected for the measurement of hemoglobin at Baseline (BL)and Week 8 (W8). The Baseline value was the measurement taken at screening (Visit 1). | Baseline and Week 8 | 
| Platelet Count and White Blood Cell (WBC) Count at Baseline and Week 8 | Blood samples were collected for the measurement of platelet count and WBC count at Baseline (BL) and Week 8 (W8). The Baseline value was the measurement taken at screening (Visit 1). | Baseline and Week 8 | 
| Red Blood Cells (RBC) Count at Baseline and Week 8 | Blood samples were collected for the measurement of RBC count at Baseline (BL) and Week 8 (W8). The Baseline value was the measurement taken at screening (Visit 1). | Baseline and Week 8 | 
| Clinical Chemistry Parameters of Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Lactate Dehydrogenase (LD), and Gamma Glutamyltransferase (GGT) at Baseline and Week 8 | Blood samples were collected for the measurement of ALP, ALT, AST, LD and GGT at Baseline (BL) and Week 8 (W8). The Baseline value was the measurement taken at Screening (Visit 1). | Baseline and Week 8 | 
| Clinical Chemistry Parameters of Albumin and Total Protein at Baseline and Week 8 | Blood samples were collected for the measurement of albumin and total protein at Baseline (BL) and Week 8 (W8). The Baseline value was the measurement taken at Screening (Visit 1). | Baseline and Week 8 | 
| Clinical Chemistry Parameters of Chloride, Calcium, Carbon Dioxide Content/Bicarbonate (CO2/BI), Cholesterol, Glucose, Phosphorus Inorganic(PI), Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) at Baseline and Week 8 | Blood samples were collected for the measurement of chloride, calcium, CO2/BI, cholesterol, glucose, PI, potassium, sodium, and urea/blood urea nitrogen (BUN) at Baseline (BL) and Week 8 (W8). The Baseline value was the measurement taken at screening (Visit 1). | Baseline and Week 8 | 
| Clinical Chemistry Parameters of Direct Bilirubin (DBIL), Total Bilirubin (TBIL), Uric Acid and Creatinine at Baseline and Week 8 | Blood samples were collected for the measurement of DBIL, TBIL, uric acid and creatinine at Baseline (BL) and Week 8 (W8). The Baseline value was the measurement taken at screening (Visit 1). | Baseline and Week 8 | 
| Number of Participants With the Indicated Result for the Indicated Urinalysis Parameters Tested by Dipstick at Baseline and Week 8/Early Withdrawal | Urinalysis parameters included: Urine Occult Blood (UOB), Urine Glucose (UG), Urine Ketones (UK), Urine Protein (UP), and Urine Leukocyte Esterase test for detecting White Blood Cell (UWBC). The dipstick was a strip used to detect the presence or absence of these parameters in the urine sample. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as negative (Neg), Trace, 1+, 2+, 3+ and 4+, and for UG the result can be read as Neg, Trace, Trace or 1/10 grams per deciliter (G/dL), 1+ or 1/4 G/dL, 3+ or 1 G/dL, indicating proportional concentrations in the urine sample. Data are reported as the number of participants who had neg, Trace, 1+, 2+, 3+ and 4+ levels at Baseline (BL) and Week 8 (W8)/Early Withdrawal (WD). The Baseline value was the measurement taken at screening (Visit 1). | Baseline and Week 8/Early Withdrawal | 
| Urine Specific Gravity at Baseline and Week 8/Early Withdrawal | Urine samples were collected for the measurement of urine specific gravity by dipstick method at Baseline and at Week 8/Early Withdrawal. The Baseline value was the measurement taken at screening (Visit 1). Specific gravity is a measure of the amount of material dissolved in the urine. Specific gravity is the ratio of the density (mass of a unit volume) of a substance to the density (mass of the same unit volume) of a reference substance. Normal urine has a specific gravity between 1.010 and 1.020. | Urine specific gravity at Baseline and Week 8/Early Withdrawal | 
| Urine pH at Baseline and Week 8/Early Withdrawal | Urine samples were collected for the measurement of urine pH by dipstick method at Baseline and at Week 8/Early Withdrawal. The Baseline value was the measurement taken at screening (Visit 1). Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). | Baseline and Week 8/Early Withdrawal | 
| 24-hour Urinary Cortisol Excretion at Baseline and Week 8 | A 24-hour urine sample was collected for the measurement of 24-hour urinary cortisol excretion at the following scheduled time points: within 7 days prior to Study Visit 3 (Baseline; Week 0) and Study Visit 8 (Week 8). The Baseline value for 24-hour urinary cortisol was taken from Visit 3. | Baseline and Week 8 | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 8 | Change from Baseline was calculated as the Week 8 value minus the Baseline value. | Baseline and Week 8 | 
| Change From Baseline in Heart Rate at Week 8 | Change from Baseline was calculated as the Week 8 value minus the Baseline value. | Baseline and Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adolescents, Adults, Pharmacokinetics, Asthma, GW685698X, Pharmacogenetics