Efficacy And Safety Of GW642444M Comparing Placebo In Adolescent And Adult Subjects With Persistent Asthma.

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

Official Title
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A Randomised, Double-blind, Placebo Controlled, Parallel Group, Dose Ranging Study Evaluating the Efficacy and Safety of GW642444M Administered Once Daily Compared With Placebo for 28 Days in Adolescent and Adult Subjects With Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: GW642444M
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Aged 12 years of age or older at Visit 1 For sites in the following countries, subjects recruited will be ³ 18 years of age: Germany, Hungary and the Russian Federation and any other countries where local regulations or the regulatory status of study medication permit enrolment of adults only. Male or eligible female subjects A female is eligible to enter and participate in the study if she is of: Non-child bearing potential (i.e. physiologically incapable of becoming pregnant), including any female who is post-menopausal. Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label and the instructions of the physician for the duration of the study - screening to follow-up contact): Complete abstinence from intercourse from screening until 2 weeks after the follow-up contact; or Sterilisation of male partner (vasectomy with documentation of azoospermia) prior to female subject entry into the study, and this male partner is the sole partner for that subject; or Implants of levonorgestral inserted for at least 1 month prior to the study medication administration but not beyond the third successive year following insertion; or Injectable progestogen administered for at least 1 month prior to study medication administration and administered for 1 month following study completion; or Oral contraceptive (combined or progestogen only) administered for at least one monthly cycle prior to study medication administration; or Double barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) N.B. For German sites female subjects must use a method of birth control other than the double barrier method An intrauterine device (IUD), inserted by a qualified physician, with published data showing that the highest expected failure rate is less than 1% per year; or Estrogenic vaginal ring inserted for at least 1 month prior to study medication administration; or Percutaneous contraceptive patches in place for at least 1 month prior to study medication administration Female subjects should not be enrolled if they are pregnant, or lactating, or plan to become pregnant during the time of study participation. Documented clinical history of persistent asthma, as defined by the National Institutes of Health [NIH, 2007] first diagnosed at least 6 months prior to Visit 1. Subjects with current reversible airways disease as demonstrated at Visit 1 by an increase in FEV1 of ≥ 12% and ≥ 200ml over the pre-salbutamol/albuterol FEV1 at approximately 30 minutes after the inhalation of 400mcg of salbutamol/albuterol via MDI (spacer permitted for reversibility testing only if required) or one nebulised salbutamol/albuterol solution. Subjects must be using an inhaled corticosteroid and have been maintained on a stable dose for 4 weeks prior to Visit 1 at one of the following doses: Maximum Allowable Concurrent Inhaled Corticosteroid Doses Asthma Therapy(Maximum Daily Dose (mcg/day)) fluticasone propionate MDI CFC/HFA (≤ 880mcg1/ ≤1000mcg2) fluticasone propionate DPI(≤ 1000mcg) beclomethasone dipropionate(≤ 1680mcg1/ ≤ 2000mcg2) beclomethasone dipropionate HFA (QVAR)(≤ 640mcg1/ ≤ 800mcg2) budesonide DPI/MDI(≤ 2000mcg) Flunisolide(≤ 2000mcg) triamcinolone acetonide(≤ 2000mcg) mometasone furoate(≤ 880mcg) Ciclesonide(≤ 320mcg1/ ≤ 400mcg2) CFC=chlorofluorocarbon HFA=hydrofluoroalkane Ex-actuator dose Ex-valve dose Pre-bronchodilator FEV1 between ≥ 40 - ≤ 90% predicted at 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]. Appropriately signed and dated informed consent has been obtained. Capable of withholding salbutamol/albuterol use for ≥ 6 hours prior to clinic visits. 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. Exclusion criteria: An exacerbation of asthma within 4 weeks of Visit 1, or a culture documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear within 4 weeks of Visit 1 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. History of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnoea, respiratory arrest or hypoxia seizures. Asthma exacerbation requiring treatment with oral corticosteroids within 3 months prior to Visit 1. Hospitalised for an asthma exacerbation within 6 months of Visit 1. Hospitalisation is defined as an overnight stay in a hospital. Previously enrolled in this study, or has participated in any study using an investigational drug during the previous 30 days or will participate simultaneously in another clinical trial. A subject must not have any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the subject's safety at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study. The list of additional excluded conditions/diseases includes, but is not limited to the following: congestive heart failure, known aortic aneurysm clinically significant coronary heart disease, clinically significant cardiac arrhythmia stroke within 3 months of Visit 1, uncontrolled hypertension1 poorly controlled peptic ulcer, haematologic, hepatic, or renal disease immunologic compromise, current malignancy2 tuberculosis (current or untreated3), Cushing's disease Addison's disease, uncontrolled diabetes mellitus uncontrolled thyroid disorder, recent history of drug or alcohol abuse neurological disease, pulmonary disease4 systolic blood pressure 160, or diastolic blood pressure >100 history of malignancy is acceptable only if subject has been in remission for one year prior to Visit 1 (remission = no current evidence of malignancy and no treatment for the malignancy in the 12 months prior to Visit 1) Subjects with a history of tuberculosis who have received an approved prophylactic treatment regimen or an approved active treatment regimen and who have no evidence of active disease for a minimum of 2 years may be enrolled [American Thoracic Society Documents, 2005] [American Thoracic Society (ATS), 2003] Including but not limited to chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis, bronchopulmonary dysplasia, and chronic obstructive pulmonary disease. Any adverse reaction including immediate or delayed hypersensitivity to any ß2-agonist or sympathomimetic drug, or known (i.e., patients with a history of severe milk protein allergy) or suspected sensitivity to the constituents of GW642444M inhalation powder (e.g., lactose or magnesium stearate). Subjects who are likely to be non-compliant with study medication and other study-related requirements (e.g. attendance at clinic visits or completion of Daily Diary). Neurological or psychiatric disease or history of drug or alcohol abuse which would interfere with the subject's proper completion of the protocol requirements. Abuse of alcohol is defined as an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males) or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). The number of units of alcohol in a drink can be determined by multiplying the volume of the drink (in millilitres) by its percentage ABV and dividing by 1000 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). Administration of systemic, oral or depot corticosteroids or administration of anti-IgE (e.g. omalizumab [Xolair]) within 12 weeks of Visit 1. Administration of the following asthma medications within 14 days of Visit 1: Theophyllines Oral β2-agonists (e.g. bambuterol) Slow-release bronchodilators Anticholinergics - short or long-acting Oral long acting antihistamines Oral leukotriene receptor antagonists (e.g. montelukast)

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: Placebo<br>Placebo Multi dose dry powder inhlaer | Drug: Placebo<br>* Placebo mulit-dose dry powder inhaler<br>|
| Experimental: GW642444M<br>GW642444M | Drug: GW642444M<br>* GW642444M<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Clinic Visit Trough FEV1 at Day 28 (Last Observation Carried Forward [LOCF]) | 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. Trough FEV1 is defined as the clinic visit (pre-bronchodilator and pre-dose) FEV1 at the end of the 28-day treatment period, with the trough FEV1 defined as the mean of the 23 hour and 24 hour post-dose assessments on Day 28. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed using Analysis of Covariance (ANCOVA) using LOCF with covariates of Baseline (pre-dose on Day 1), country, sex, age, stratum, and treatment. | Baseline and Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Clinic Visit Trough FEV1 at Day 28 Per Stratum (LOCF) | 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. Trough FEV1 is defined as the clinic visit (pre-bronchodilator and pre-dose) FEV1 at the end of the 28-day treatment period, with the trough FEV1 defined as the mean of the 23 hour and 24 hour post-dose assessments on Day 28. Change from Baseline in trough FEV1 at the end of the treatment period (23 hours and 24 hours after dosing on Day 28) was analyzed for each stratum (Lower stratum: FEV1 percent predicted, >=40% to <=65%; Upper stratum: FEV1 percent predicted, >=65% to <=90%). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed using ANCOVA using LOCF with covariates of Baseline (pre-dose on Day 1), country, sex, age, stratum, treatment, and treatment by stratum interaction. | Baseline and Day 28 | 
| Change From Baseline in Weighted Mean 24-hour Serial FEV1 at Day 1 and Day 28 | Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Change from Baseline in weighted mean for 24-hour serial FEV1 on Days 1 and Day 28 was assessed. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed using ANCOVA with covariates of Baseline (pre-dose on Day 1), country, sex, age, stratum, and treatment. | Baseline; Day 1 and Day 28 (mean post-dose FEV1 after 15, 30, and 60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23, and 24 hours) | 
| Mean Change From Baseline in Trough (Pre-dose and Pre-bronchodilator) Daily Evening (PM) Peak Expiratory Flow (PEF) Averaged Over the 28-day Treatment Period | Peak Expiratory Flow (PEF) is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. Change from Baseline was calculated as the value of the averaged PEF daily PM over the 28-day treatment period (at Day 28) minus the Baseline value (defined as the last 7 days prior to randomization of the participants). Analysis was performed using ANCOVA with covariates of Baseline, country, sex, age, stratum, and treatment. | Baseline and Days 1-28 | 
| Mean Change From Baseline in Daily Morning (AM) PEF Averaged Over the 28-day Treatment Period | Peak Expiratory Flow (PEF) is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. Change from Baseline was calculated as the value of the averaged PEF daily AM over the 28-day treatment period (at Day 28) minus the Baseline value (defined as the last 7 days prior to randomization of the participants). Analysis was performed using ANCOVA with covariates of Baseline, country, sex, age, stratum, and treatment. | Baseline and Days 1-28 | 
| Mean Change From Baseline in the Percentage of Symptom-free 24-hour (hr) Periods Averaged Over the 28-day Treatment Period | Participants who were symptom free for 24 hours were assessed. Change from Baseline was calculated as the value at Day 28 minus the value at Baseline (defined as the last 7 days prior to randomization of the participants). Analysis was performed using ANCOVA with covariates of Baseline, country, sex, age, stratum, and treatment. | Baseline and Days 1-28 | 
| Change From Baseline in the Percentage of Rescue-free 24-hour (hr) Periods Averaged Over the 28-day Treatment Period | The time span during which the participants did not have to take any rescue medication (medication intended to relieve symptoms immediately) was considered to be a rescue-free period. Change from Baseline is calculated as the value at Day 28 minus the value at Baseline (defined as the last 7 days prior to randomization of the participants). Analysis was performed using ANCOVA with covariates of Baseline, country, sex, age, stratum, and treatment. | Baseline and Days 1-28 | 
| Difference in Post Salbutamol/Albuterol FEV1 (FEV1 30 Minutes After a Single Dose of 400 µg Salbutamol/Albuterol) Between the Following Time Points: 24 Hours After Dosing on Day 1 and Day 28 | Assessment at Visit 2/2a was made prior to the evening dose of study medication on Day 2. Participants were administered a single 400 µg dose of salbutamol/albuterol, and FEV1 was measured 30 minutes after this administration. The highest of three technically acceptable measurements was recorded. These assessments were performed as follows: between 5 PM and 10 PM, >=6 hours after the last use of salbutamol/albuterol, >=6 hours after the last caffeine consumption, >=2 hours after exercise (or strenuous activity), >=24 hours after the first dose (Visit 2) or last dose (Visit 5) of study medication. Analysis was performed using ANCOVA with covariates of Baseline (pre-salbutamol measurement at Screening), country, sex, age, stratum, and treatment. Analysis is of the differences in absolute FEV1 measurements taken post-salbutamol/albuterol. | 24 hours after dosing on Day 1 (Visit 2) and on Day 28 (Visit 5) | 
| Difference in Post Salbutamol/Albuterol FEV1 (FEV1 30minutes After a Single Dose of 400 µg Salbutamol/Albuterol) Between the Following Time Points: Screening and 24 Hours After Dosing on Day 1 | Assessment at Visit 2/2a was made prior to the evening dose of study medication on Day 2. Participants were administered a single 400 µg dose of salbutamol/albuterol, and FEV1 was measured 30 minutes after this administration. The highest of three technically acceptable measurements was recorded. These assessments were performed as follows: between 5 PM and 10 PM, >=6 hours after the last use of salbutamol/albuterol, >=6 hours after the last caffeine consumption, >=2 hours after exercise (or strenuous activity), Screening and >=24 hours after the first dose (Visit 2) of study medication. Analysis was performed using ANCOVA with covariates of Baseline (pre-salbutamol measurement at Screening), country, sex, age, stratum, and treatment. Analysis is of the differences in absolute FEV1 measurements taken post-salbutamol/albuterol. | Screening (Visit 1) and 24 hours after dosing on Day 1 (Visit 2) | 
| Difference in Post Salbutamol/Albuterol FEV1 (FEV1 30 Minutes After a Single Dose of 400 µg Salbutamol/Albuterol) Between the Following Time Points: Screening and 24 Hours After Dosing on Day 28 | Assessment at Visit 2/2a was made prior to the evening dose of study medication on Day 2. Participants were administered a single 400 µg dose of salbutamol/albuterol, and FEV1 was measured 30 minutes after this administration. The highest of three technically acceptable measurements was recorded. These assessments were performed as follows: between 5 PM and 10 PM, >=6 hours after the last use of salbutamol/albuterol, >=6 hours after the last caffeine consumption, >=2 hours after exercise (or strenuous activity), Screening and >=24 hours after the first dose (Visit 2) of study medication. Analysis was performed using ANCOVA with covariates of Baseline (pre-salbutamol measurement at Screening), country, sex, age, stratum, and treatment. Analysis is of the differences in absolute FEV1 measurements taken post-salbutamol/albuterol. | Screening (Visit 1) and 24 hours after dosing on Day 28 (Visit 5) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dose ranging, placebo, asthma, safety, efficacy, pharmacokinetics