A Randomized Study To Evaluate The Efficacy And Safety Of An Investigational Drug In Adolescent And Adult Subjects With Asthma Uncontrolled on Moderate-Dose ICS Therapy.
A Randomized Study To Evaluate The Efficacy And Safety Of An Investigational Drug In Adolescent And Adult Subjects With Asthma Uncontrolled on Moderate-Dose ICS Therapy.
This study is designed to determine if the investigational drug is effective and safe in
 individuals with asthma.
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 Moderate-Dose ICS Therapy
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.

 -  3. 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%-85% of the predicted normal value during the
 morning Visit 1 screening period or a best FEV1 of 40%-90% of the predicted normal
 value during the evening Visit 1 screening period.

 -  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 during the screening period.

 Re-screening of subjects during the Visit 1 screening period: If a subject does not meet
 the inclusion criteria based upon FEV1 percent predicted and/or reversibility, the subject
 may return to the site once within 4 days and repeat the lung function tests.

 -  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 >176 ≤ 440mcg exactuator or > 200 ≤500mcg ex
 valve]; [fluticasone propionate DPI > 200≤500mcg]; [beclomethasone dipropionate DPI >
 420 ≤ 840mcg exactuator or > 500 ≤ 1000mcg ex-valve]; [beclomethasone dipropionate HFA
 Qvar > 160 ≤ 480mcg exactuator or > 200 ≤ 500mcg ex-valve]; [budesonide DPI MDI >400
 ≤1200mcg]; [flunisolide > 1000 ≤ 2000mcg]; [triamcinolone acetonide >1000 ≤1600mcg];
 [mometasone furoate DPI >200 ≤ 440mcg]; [ciclesonide MDI HFA >160 mcg ≤ 320mcg
 ex-actuator dose / >200mcg ≤ 400mcg 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:

 1. Evening pre-dose percent predicted FEV1 of between 40% and 90% of their predicted
 normal.

 2. 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 subject's asthma status or the subject's
 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.

 1. 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.

 2. Changes in asthma medication (excluding albuterol/salbutamol inhalation aerosol
 provided at Visit 1).

 3. 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 subject's asthma status or the subject's ability to participate
 in the study.

 4. 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.

 5. 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).

 6. 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.