| 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 objective of this study is to evaluate the dose response, efficacy and safety of four dosage regimens of GW685698X (100mcg, 200mcg, 300mcg and 400mcg) administered once daily in the morning in adolescent and adult subjects 12 years of age and older with persistent bronchial asthma to effectively select the optimum dose of GW685698X for use in further clinical studies of this population. Clinic lung function will be recorded using change in FEV1 from baseline. |
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| E.2.2 | Secondary objectives of the trial |
| To study asthma symptoms (frequency and time of), and requirement for rescue medication in subjects taking GW685698X as recorded by each subject in the daily diary card. Daily changes in lung function will be studied by the subject recording PEF each morning and evening in the diary card. |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
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
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 Section 5.2.1 of the protocol.
A serum pregnancy test is required for all females. This test will be performed at the initial screening visit (Visit 1) and Visit 7. In addition, a urine pregnancy test on the morning of the double-blind treatment visits, prior to randomization, (Visit 2) and at Visits 3 through 6.
4.Asthma Diagnosis: Asthma as defined by the National Institutes of Health [National Institutes of Health, 2002].
5.Severity of Disease: A best FEV1 of 50% 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 12-17 years and race adjusted for African-Americans [American Thoracic Society, 1991].
6.Reversibility of Disease: Demonstrated a ≥ 12% and ≥ 200mL reversibility of FEV1 within 30-minutes following 2-4 inhalations of albuterol/salbutamol HFA inhalation aerosol (or one nebulized treatment with albuterol/salbutamol solution) at the Screening Visit. If a subject fails to demonstrate an increase in FEV1 ≥12% and ≥200mL, then the subject is not eligible for the study and will not be allowed to rescreen.
7.Current 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 the doses specified in the protocol section 5.2.1
8.Short-Acting Beta-2-Agonists: All subjects must be able to replace short-acting 2-agonists with albuterol/salbutamol HFA inhalation aerosol at Visit 1 for use as needed for the duration of the study. Nebulized albuterol/salbutamol will not be allowed during the study with the exception of its 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 study visits.
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.
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 2:
1.Reproducibility: Morning pre-dose percent predicted FEV1 of between 50% and 80% of their predicted normal and within ±15% of the best pre-albuterol/salbutamol HFA FEV1 at Visit 1.
2.Demonstrated and reported in a daily diary, symptoms of asthma (a score of ≥ 1 on the daytime or nighttime asthma symptom scores) on at least 4 of the last 7 consecutive days of the run-in period or daily albuterol/salbutamol HFA use must have been used on at least 4 of the last 7 consecutive days of the run-in period.
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| E.4 | Principal exclusion criteria |
1.History of Life-threatening asthma: Defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures.
2.Respiratory Infection: Cultured documented of 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. In addition, the subject must be excluded, if such infection occurs between Visits 1 and 2.
3.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.
4.Concurrent Respiratory Disease: A subject must not have current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmomary disease, or other respiratory abnormatlities other than asthma
5.Other Concurrent Diseases/Abnormalities: A subjects must not have any clinically significant, uncontrolled condition or disease state, that in the opinion of the investigator, would put the safety of the patient 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 hypertension*, poorly controlled peptic ulcer, hematologic, hepatic, or renal disease, immunologic compromise, current malignancy**, tuberculosis (current or quiescent), Cushing’s disease, Addison’s disease, uncontrolled diabetes mellitus, recent history of drug or alcohol abuse
*systolic BP>170, or diastolic BP >100
6.Oropharyngeal Examination: A subject will not be eligible for the run-in if he/she has an abnormal orophryngeal exam at Visit 1 (culture positive test for candidiasis) (Protocol 6.3.3)
7.Investigational Medications: A subject must not have used any investigational drug within 30 days prior to Visit 1 or within ten half-lives (t ½) of the prior investigational study (which ever is longer of the two) or concurrently during the study.
8.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 new powder inhaler (i.e. lactose or cellobiose octaacetate).
9.Milk Protein Allergy: History of severe milk protein allergy.
10.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 daily dose throughout the study period.
11Tobacco Use. A subject may not have used tobacco products within the past one year (i.e., cigarettes, cigars, or pipe tobacco) or have historical use of >10 pack years (e.g. 20 cigarettes/day for 10 years).
12. Corticosteroid Use: Administration of systemic, oral or depot corticosteroids within 12 weeks of Visit 1.
13.Potent Cytochrome P450 34A (CYP34A) inhibitors: Patients who are receiving potent CYP3A4 inhibitors within 4 weeks of Visit 1 (e.g., ritonavir, ketoconazole, itraconzole).
14. Cllinical 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.
15.Changes in asthma medication (excluding albuterol/salbutamol HFA inhalation aerosol provided at Visit 1).
16.Occurrence of an upper or lower respiratory tract infection during the run-in period.
17.Asthma exacerbation, defined as any worsening of asthma which required treatment with asthma medications other than albuterol/salbutamol HFA inhalation aerosol and the subject’s regular inhaled corticosteroid therapy, resulted in hospitalization for asthma, or resulted in unscheduled urgent care for acute asthma symptoms requiring intervention during the run-in period.
18.A subject will not be eligible for randomization if he/she has an abnormal orophryngeal exam at the randomization Visit 2 (cultured positive test for candidiasis) (Section 6.3.3).
19.Non-compliance with completion of the daily diary reporting defined as completion of all questions on 4 out of the last 7 days during the screening period.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy measure will be the mean change from baseline to the end of the 8-week treatment period (last assessment on treatment using last observation carried forward) in trough (AM 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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | Yes |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
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| Last visit of the last subject undergoing the trial. |
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| 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 | 9 |
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