Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multicenter Study to Evaluate the Efficacy and Safety of GW685698X 200 mcg Twice Daily, GW685698X 200 mcg and 400 mcg Once Daily in the Morning, and GW685698X 200 mcg and 400 mcg Once Daily in the Evening Compared With Placebo for 8 Weeks in Adolescent and Adult Subjects (12 Years of Age and Older) With Persistent Asthma
Brief Summary: This study is designed to determine if the investigational drug is effective and safe in individuals with asthma.


Options:
A: Inclusion criteria:

* Male or female (of non-childbearing potential) \> or = 40 years
* History of COPD
* Smoker or ex-smoker
* Body weight \> or = 50 kg with BMI 18-32 kg/m2

Exclusion criteria:

* History of significant disease
* Subjects with a primary asthma diagnosis
* Alpha-1 antitrypsin deficiency as underlying cause of COPD
* Recent respiratory tract infection
* Poorly controlled COPD
* Blood potassium level \< 3.5mmol/L
* Short-term or long tern oxygen therapy
* Recent participation in another trial
* History of drug or alcohol abuse
* Known allergies
* Recent blood donation
* ECG abnormalities
B: Inclusion criteria:

* Type of Subject: Outpatient
* Age: 12 years of age or older at Visit 1 (or ³18 years of age or older if local regulations or the regulatory status of study medication permit enrollment of adults only).
* Gender: Male or eligible female - Females are eligible to participate only if they are currently non-pregnant and non-lactating. 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, Double-barrier method - spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or a spermicide and female diaphragm), The contraceptive transdermal patch, Ortho Evra (if the subject is less than 198 pounds), Female subjects should not be enrolled if they plan to become pregnant during the time of study participation. A urine pregnancy test is required for all subjects at all visits, Female subjects should not be enrolled if they plan to become pregnant during the time of study participation. A urine pregnancy test is required for all subjects at all visits, Female subjects should not be enrolled if they plan to become pregnant during the time of study participation. A urine pregnancy test is required for all subjects at all visits, 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),
* Asthma Diagnosis: Asthma as defined by the National Institutes of Health \[National Institutes of Health, 2002; GINA, 2005\].
* Severity of Disease: A best AM FEV1 of 50% to 80% of the predicted value during Visit 1 based on the "Standardization of Lung Function Tests" \[European Respiratory Society, 1993\] standards for 18 years and older or Polgar \[Polgar, 1971\] standards for 12 to 17 years and race adjusted for African-Americans \[American Thoracic Society, 1991\].
* Reversibility of Disease: Demonstrated ³12% and 200mL reversibility of FEV1 within 30 minutes following 200 to 400mcg of albuterol/salbutamol inhalation aerosol (or one nebulized albuterol/salbutamol treatment) at Visit 1. If a subject fails to demonstrate an increase in FEV1 of ³12% and 200mL, the subject is not eligible for the study and will not be allowed to re-screen.
* Concurrent Anti-Asthma Therapy: Subjects must be using an inhaled corticosteroid for at least 3 months prior to Visit 1 and be maintained on a stable dose for four weeks prior to Visit 1 at one of the following doses: Anti-Asthma Therapy Maximum Daily Dose (mcg/day) Fluticasone propionate MDI CFC/HFA ≤220mcg1/≥250mcg2 Fluticasone propionate DPI 200mcg Beclomethasone dipropionate 420mcg1/500mcg2 Beclomethasone dipropionate HFA 160mcg1/200mcg2 Budesonide DPI 400mcg Flunisolide 1000mcg Triamcinolone acetonide 1000mcg Mometasone furoate 200mcg Ciclesonide 160mcg1/200mcg2

  1. Ex-actuator dose: dose delivered to the lungs
  2. Ex-valve dose: dose expressed from the valve
* Short-Acting Beta2-Agonist: All subjects must be able to replace short-acting beta2-agonists with albuterol/salbutamol inhalation aerosol at Visit 1 for use as-needed for the duration of the study. Subjects must be able to withhold all inhaled short-acting beta-sympathomimetic bronchodilators for at least 6 hours prior to study visits.Note: Nebulized albuterol/salbutamol will not be allowed during the study with the exception of its use during reversibility testing at Visit 1. The use of albuterol/salbutamol through the DISKUS/ACCUHALER device will not be allowed during the study.
* 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 all the study requirements.

Exclusion criteria:

* History of Life-Threatening Asthma: History of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures.
* Anti-Asthma Medications: Asthma medications listed below must not have been used prior to Visit 1 for the required interval listed below, and not taken during the study: Within 24 hours of Visit 1: Oral short-acting beta2-agonists: Within 2 weeks of Visit 1:Combination therapy containing inhaled beta2-agonists and ICS for asthma (e.g., fluticasone propionate/salmeterol combination, budesonide/formoterol combination);Slow-release bronchodilators (e.g., aminophylline, theophylline);Anticholinergics; Long-acting beta2-agonists (e.g., salmeterol); Ketotifen; Nedocromil sodium; Sodium cromoglycate; Oral long-acting beta2-agonists. Within 4 weeks of Visit 1: Anti-leukotrienes including suppressors of leukotriene production and antagonists. Within 12 weeks of Visit 1: Systemic, oral, parenteral, or depot corticosteroids; Anti-IgE (e.g., omalizumab).
* Other Medications: The medications listed below must not have been used prior to Visit 1 for the required interval indicated below, and not taken during the study: Within 4 weeks of Visit 1: Known potent inhibitors of CYP3A4 (e.g., ritonavir, ketoconazole)
* Respiratory Infection: History of a respiratory tract infection within 4 weeks of Visit 1. In addition, the subject must be excluded, if such infection occurs between Visits 1 and 2.
* Asthma Exacerbation: History of a an asthma exacerbation within 4 weeks of Visit 1, any asthma exacerbation requiring oral corticosteroids within 3 months of Visit 1, or any hospitalization due to asthma exacerbation within 6 months of Visit 1.
* Investigational Medications: A subject must not have used any investigational drug within 30 days prior to Visit 1 or within ten half-lives (t1/2) of the prior investigational study (which ever is longer of the two) or concurrently during the study.
* Concurrent Diseases/Abnormalities: Historical or current evidence of clinically significant uncontrolled disease including, but not limited to: cardiovascular disease, malignancy, 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.
* Oropharyngeal Examination: A subject will not be eligible for the run-in if he/she has evidence of oropharyngeal candidiasis at 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.
* 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 it was initiated prior to Visit 1 and the subject is maintained on a stable daily dose 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 compliance with study medication or procedures (e.g., 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 excludes study participation.
* Tobacco Use: A subject may not have used tobacco products within the past one year (i.e., cigarettes, cigars, or pipe tobacco) and must not have historical use of \>10 pack years (e.g., 20 cigarettes/day for 10 years).
* 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.
C: 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.
D: Inclusion Criteria:

* Outpatients at least 12 years of age
* Male and female; female subjects of childbearing potential must be willing to use birth control
* Pre-bronchodilator FEV1 of 40-90% predicted normal
* Reversibility FEV1 of at least 12% and 200mL
* Current asthma therapy includes inhaled corticosteroid use for at least 12 weeks prior to first visit

Exclusion Criteria:

* History of life-threatening asthma during last 10 years
* Respiratory infection or oral candidiasis
* Asthma exacerbation requiring oral corticosteroids or that required overnight hospitalisation requiring additional asthma treatment
* Uncontrolled disease or clinical abnormality
* Allergies to study drugs or the excipients
* Taking another investigational medication or prohibited medication
* Night shift workers
* Current smokers or subjects with a smoking history of at least 10 pack years

Answer: B