| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 |
| Evaluate the efficacy and safety of adding GSK2190915 300mg or placebo tablets administered once daily to FP/SAL 250/50mcg inhalation powder administered twice daily in uncontrolled asthmatic subjects ≥18 years of age over the course of 6 weeks treatment. |
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| E.2.2 | Secondary objectives of the trial |
| Undertake an exploratory analysis of the efficacy and safety of adding montelukast 10mg administered once daily to FP/SAL 250/50mcg inhalation powder administered twice daily and to investigate the pharmacokinetics and pharmacodynamics of GSK2190915 in uncontrolled asthmatic subjects ≥18 years of age over the course of 6 weeks treatment. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 18 years of age or older at Visit 1
2. Gender: Male or eligible female
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 or etonogestrel (e.g. Implanon)
• 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)
•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 6 days).
Female subjects should not be enrolled if they are pregnant or lactating or if they plan to become pregnant during the time of study participation. A serum pregnancy test is required of all females during the initial screening visit (Visit 1 or 1a) and during Visit 5/Early Withdrawal. In addition, a urine pregnancy test will be performed prior to dosing on the morning of randomization (Visit 2 or 2a) and each double-blind treatment cross-over visit (Visits 3 and 4).
3.Tobacco Use:
• Non-smokers or Former Smokers with a documented smoking history of ≤ 10 pack years at Visit 1. A former smoker may not have used tobacco products within the past 6 months (i.e., cigarettes, cigars, or pipe tobacco).
• Current smokers with a documented smoking history of ≤ 10 pack years at Visit 1.
4. Asthma as defined by the National Institutes of Health [National Institutes of Health (NIH), 2007]
5. Severity of Disease: Subjects must have a:
• Best FEV1 of 50% to <80% of the predicted normal value during Visit 1/1a (between 5:00AM and 12:00 noon). NHANES III predicted values will be used [Hankinson, 1999].
AND
• Post-salbutamol FEV1/FVC ratio of >0.70 at Visit 1/1a (between 5:00AM and 12:00 noon).
6. Subjects must demonstrate a ≥ 12% and ≥200mL reversibility of FEV1 within approximately 30 minutes [±15 minutes] following up to 4 inhalations of salbutamol inhalation aerosol (spacer permitted for reversibility testing if required) or one nebulized salbutamol solution during Visit1/1a.
Note: Re-screening of subjects during the Screening Period: If a subject meets all other screening inclusion/exclusion criteria assessed prior to the pulmonary function assessment during Visit 1 but does not meet the inclusion criteria based upon FEV1, percent predicted, FEV1/FVC ratio, and/or reversibility, the subject may return to the site once within 4 days for Visit 1a and repeat the pulmonary function tests and other assessments completed afterwards as per protocol.
7. Subjects must have been using FP/SAL 250/50mcg inhalation powder twice daily for at least 2 weeks just prior to Visit 1.
8. Subjects must be able to replace their current short-acting beta2-agonists with salbutamol inhalation aerosol at Visit 1/1a for use as needed for the duration of the study. The use of spacer devices with the metered dose inhaler is permitted if preferred by the subject. The use or non-use of a spacer for salbutamol inhalation aerosol should be consistent for each subject throughout the study. Subjects must be able to withhold all inhaled short-acting beta sympathomimetic bronchodilators for at least 6 hours prior to all study visits.
9. All subjects must be able and willing to give written informed consent to take part in the study.
10. Subjects must be able and willing to comply with all aspects of the study including completion of daily e-Diary information.
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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 in the previous 5 years.
2. 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.
3. A subject must not have current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, or respiratory abnormalities other than asthma.
4. Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within the 4 weeks before Visit 1 and led to a change in asthma management or treatment with antibiotics, 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.
5. Current or chronic history of liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones), presence of hepatitis B surface antigen (HBsAg), positive hepatitis C test result within 3 months of screening.
6. A subject must not have any clinically significant, uncontrolled condition or 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.
7. A subject will not be eligible for the run-in if he/she has clinical visual evidence of oral candidiasis at Visit 1.
8. Any adverse reaction including immediate or delayed hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy or montelukast. Known or suspected sensitivity to the constituents of the dry powder inhaler (i.e. lactose).
9. History of severe milk protein allergy.
10. 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 at least 4 weeks prior to Visit 1 and the subject is maintained on a stable regimen throughout the study period.
11. Administration of systemic, oral or depot corticosteroids within 12 weeks of Visit 1. Administration of any other prescription or over the counter medication which would significantly affect the course of asthma, or interact with beta-adrenergic receptor agonists, such as: monoamine oxidase (MOA) inhibitors, tricyclic antidepressants, beta-adrenergic receptor blocking agents (both cardio-selective and non-selective) within 4 weeks of Visit 1.
12. Subjects who have received OATP1B1 substrates within 4 weeks of Visit 1 (e.g. rosuvastatin, pravastatin, cerivastatin, pitavastatin, atorvastatin, simvastatin, fluvastatin, lovastatin, rifampicin, bromosulphophthalein, benzylpenicillin, methotrexate).
13. A subject is not eligible if he/she is receiving a strong CYP 3A4 inhibitor within 4 weeks of Visit 1 (e.g., ritonavir, ketoconazole, itraconazole.)
14. A subject is not eligible if he/she is receiving a CYP 3A4 inducer within 4 weeks of Visit 1 (e.g., phenytoin, phenobarbital, rifampicin)
15. A subject must not have participated in a study or used any investigational drug within 30 days prior to Visit 1 or within ten half-lives (t1/2) of the prior investigational study (whichever is longer of the two).
16. 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. This includes the inability or an unwillingness to follow instructions relative to dosing, laboratory assessments and eDiary completion. Additionally, 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.
17. 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) |
| Trough (AM pre-dose and pre-rescue bronchodilator) FEV1 at the end of the 6 week treatment period. |
|
| 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 | No |
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| 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 | 3 |
| 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 | 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 |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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