| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to evaluate the relative efficacy and safety of once daily and twice daily dosing and of morning and evening dosing of GW685698X in adolescent and adult subjects with persistent asthma. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in the run-in period for this study only if all of the following criteria apply:
1. Type of Subject: Outpatient
2. Age: 12 years of age or older at Visit 1 (or 18 years of age or older if local regulations or the regulatory status of study medication permit enrollment of adults only).
3. 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 – spermacide plus a mechanical barrier (e.g., spermacide plus a male condom or a spermacide 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.
• 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)
4. Asthma Diagnosis: Asthma as defined by the National Institutes of Health [National Institutes of Health, 2002; GINA, 2005].
5. 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].
6. Reversibility of Disease: Demonstrated 12% 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 12% and 200mL, the subject is not eligible for the study and will not be allowed to re-screen.
7. 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.
8. 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.
9. Informed Consent: All subjects must be able and willing to give written informed consent to take part in the study.
10. Compliance: Subjects must be able to comply with all the study requirements.
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| E.4 | Principal exclusion criteria |
A subject will be eligible for inclusion in the run-in period for this study only if all of the foA subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. 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.
2. 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)
Note: Subjects must be maintained on a stable dose of ICS within 4 weeks of Visit 1 (see Section 5.2.1).
• 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)
3. 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)
4. 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.
5. 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.
6. 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.
7. 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.
8. Oropharyngeal Examination: A subject will not be eligible for the run-in if he/she has evidence of oropharyngeal candidiasis at Visit 1.
9. Drug Allergy: Any adverse reaction including immediate or delayed hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy.
10. Milk Protein Allergy: History of severe milk protein allergy.
11. 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.
12. 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.
13. 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).
14. 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. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The single efficacy endpoint will be the mean change from baseline at Week 8 (last assessment on treatment using last observation carried forward) in trough (AM or PM pre-dose and pre-rescue bronchodilator) FEV1. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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