A Randomized Study To Evaluate The Efficacy And Safety Of An Investigational Drug In Adolescent And Adult Subjects With Asthma Uncontrolled on Non-steroidal Therapy.
Condition: Asthma
MeSH terms: Asthma
Intervention: GW685698X; Placebo
Intervention description: GW685698X; placebo comparator
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 599.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: Adults; Pharmacokinetics; Pharmacogenetics; Asthma; Adolescents; GW685698X

Summary:

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

Eligibility criteria:

        Inclusion Criteria:

        Subjects eligible for enrollment 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 enrollment
             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%-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 (spacers are permitted for reversibility testing if required) or one nebulized
             albuterol/salbutamol solution at 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 non-corticosteroid
             controller or short acting beta2-agonist bronchodilators alone (with no inhaled
             corticosteroids use for at least 6 weeks) for ≥ 3 months preceding Visit 1.

          -  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 before 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 heart 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 hypertension1,
             hematological, hepatic, or renal disease, current malignancy2, cushings disease,
             uncontrolled diabetes mellitus, recent history of drug or alcohol abuse.

          -  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)

          -  Patients with a history of tuberculosis who have received an approved prophylactic
             treatment regimen or an approved active treatment regimen and who have had no evidence
             of active disease for a minimum of 2 years may be enrolled [American Thoracic Society,
             2003; American Thoracic Society, 2005]"

          -  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.

        Administration of inhaled corticosteroids within 6 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 an 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.

          -  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.