Dose Ranging Study Evaluating the Efficacy and Safety of GSK2190915 Administered Once Daily

Study Overview
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Brief Summary
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To evaluate the efficacy, dose response and safety of four doses of GSK2190915 in tablet form (10mg, 30mg, 100mg and 300mg) administered once daily, over 8 weeks compared with placebo in adolescent and adult subjects (12 years of age and older) with persistent asthma. These data will form the basis for the selection of the optimal daily dose of GSK2190915 to be carried forward in Phase III asthma studies. The study also includes Fluticasone Propionate Inhalation Powder (100 mcg, twice daily) and Montelukast (10mg, once daily) to allow for an exploratory analysis of the efficacy of GSK2190915 versus a low dose inhaled corticosteroid and a leukotriene receptor antagonist.

Official Title
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A Randomised Double-Blind, Double-Dummy, Placebo-Controlled, Stratified, Parallel-Group, Multicentre, Dose Ranging Study to Evaluate the Efficacy and Safety of GSK2190915 Tablets Administered Once Daily, Fluticasone Propionate Inhalation Powder 100mcg Twice Daily and Montelukast 10mg Once Daily Compared With Placebo for 8 Weeks in Adolescent and Adult Subjects With Persistent Asthma While Treated With Short Acting Beta2-agonist.

Conditions
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Asthma

Intervention / Treatment
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* Drug: Fluticasone Propionate 100mcg via ACCUHALER/DISKUS
* Drug: GSK2190915 100mg
* Drug: GSK2190915 10mg
* Drug: GSK2190915 300mg
* Drug: GSK2190915 30mg
* Drug: Montelukast 10mg
* Drug: Placebo GSK2190915 one tablet
* Drug: Placebo montelukast
* Drug: Placebo fluticasone propionate via ACCUHALER/DISKUS
* Drug: Placebo GSK2190915 two tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type of Subject: Outpatient Age: ≥12 years of age Gender: Eligible Female (females of childbearing potential must commit to consistent and correct use of an acceptable method of birth control) Asthma Diagnosis: As defined by NIH Severity of Disease: FEV1 50-85% predicted AND in current and former smokers a post salbutamol/albuterol ratio >0.70 Reversibility: ≥12% and ≥200mL in FEV1 within 30 ±15 minutes following salbutamol/albuterol Current anti-asthma therapy: Using short-acting beta-agonist (SABA) for ≥3 months Tobacco use: Non-smoker /former smoker with ≤10 pack years or current smoker with ≤10 pack years QTC: QTc(F)<450msec or QTc(F)<480 for subjects with Bundle Branch Block Liver function: Normal liver function Informed Consent Exclusion Criteria: History of Life-threatening asthma: Within previous 5 years Asthma Exacerbation: Requiring OCS within 3 months or hospitalisation within 6 months Respiratory Infection: Not resolved within the 4 weeks before V1 AND led to a change in asthma management OR treatment with antibiotics OR is expected to affect the subject's asthma status or ability to participate Corticosteroid Use: ICS used within 6 weeks or OCS/depot corticosteroids within 12 weeks OATP1B1 substrates: OATP1B1 substrates (e.g. statins, rifampicin, bromosulphophthalein, benzylpenicillin, methotrexate) within 4 weeks Immunosuppressive medications: Either using or required during the study Liver disease: Current or chronic history Concurrent disease/abnormalities: Clinically significant uncontrolled disease Investigational medications: Participation in a study or used investigational drug within 30 days Drug allergy: β-agonists, corticosteroids, constituents of inhalers Milk Protein Allergy: History of severe milk protein allergy Compliance: Factors likely to impair compliance either with regards to study medication, procedures or attendance Unable or unwilling to follow instructions: Procedures, dosing directions, e-diaries or pMDIs History of alcohol or drug abuse: Likely to interfere with the study Affiliation with Investigator's Site: Relative or employee

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK2190915 10mg and placebo<br>GSK2190915 10mg (1 x 10mg, 1 x placebo tablets) once daily in the morning and placebo caspule once daily in the evening and inhaled placebo twice daily via ACCUHALER/DISKUS | Drug: GSK2190915 10mg<br>* GSK2190915 10mg (1 x 10mg) once daily in the morning<br>Drug: Placebo GSK2190915 one tablet<br>* Placebo tablet, one tablet once daily in the morning<br>Drug: Placebo montelukast<br>* Placebo capsule once daily in the evening<br>Drug: Placebo fluticasone propionate via ACCUHALER/DISKUS<br>* Inhaled placebo twice daily via ACCUHALER/DISKUS<br>|
| Experimental: GSK2190915 30mg and placebo<br>GSK2190915 30mg (1 x 30mg, 1 x placebo tablets) once daily in the morning and placebo caspule once daily in the evening and inhaled placebo twice daily via ACCUHALER/DISKUS | Drug: GSK2190915 30mg<br>* GSK2190915 30mg (1 x 30mg) once daily in the morning<br>Drug: Placebo GSK2190915 one tablet<br>* Placebo tablet, one tablet once daily in the morning<br>Drug: Placebo montelukast<br>* Placebo capsule once daily in the evening<br>Drug: Placebo fluticasone propionate via ACCUHALER/DISKUS<br>* Inhaled placebo twice daily via ACCUHALER/DISKUS<br>|
| Experimental: GSK2190915 100mg QD and placebo<br>GSK2190915 100mg (1 x 100mg, 1 x placebo tablets) once daily in the morning and placebo caspule once daily in the evening and inhaled placebo twice daily via ACCUHALER/DISKUS | Drug: GSK2190915 100mg<br>* GSK2190915 100mg (1 x 100mg) once daily in the morning<br>Drug: Placebo GSK2190915 one tablet<br>* Placebo tablet, one tablet once daily in the morning<br>Drug: Placebo montelukast<br>* Placebo capsule once daily in the evening<br>Drug: Placebo fluticasone propionate via ACCUHALER/DISKUS<br>* Inhaled placebo twice daily via ACCUHALER/DISKUS<br>|
| Experimental: GSK2190915 300mg QD and placebo<br>GSK2190915 300mg (1 x 100mg, 1 x 200mg tablets) once daily in the morning and placebo caspule once daily in the evening and inhaled placebo twice daily via ACCUHALER/DISKUS | Drug: GSK2190915 300mg<br>* GSK2190915 300mg (1 x 100mg, 1 x 200mg tablets) once daily in the morning<br>Drug: Placebo montelukast<br>* Placebo capsule once daily in the evening<br>Drug: Placebo fluticasone propionate via ACCUHALER/DISKUS<br>* Inhaled placebo twice daily via ACCUHALER/DISKUS<br>|
| Active Comparator: Fluticasone propionate 100mcg and placebo<br>Fluticasone propionate 100mcg twice daily via ACCUHALER/DISKUS and two placebo tablets in the morning and one placebo capsule in the evening | Drug: Fluticasone Propionate 100mcg via ACCUHALER/DISKUS<br>* Fluticasone propionate 100mcg twice daily via ACCUHALER/DISKUS<br>Drug: Placebo montelukast<br>* Placebo capsule once daily in the evening<br>Drug: Placebo GSK2190915 two tablets<br>* Placebo tablet, two tablets once daily in the morning<br>|
| Active Comparator: Montelukast 10mg and placebo<br>Montelukast 10mg (1 x 10mg capsule) once daily in the evening and two placebo tablets in the morning and inhaled placebo twice daily via ACCUHALER/DISKUS | Drug: Montelukast 10mg<br>* Montelukast 10mg (1 x 10mg capsule) once daily in the evening<br>Drug: Placebo fluticasone propionate via ACCUHALER/DISKUS<br>* Inhaled placebo twice daily via ACCUHALER/DISKUS<br>Drug: Placebo GSK2190915 two tablets<br>* Placebo tablet, two tablets once daily in the morning<br>|
| Placebo Comparator: Placebo Comparator<br>Two GSK2190915 placebo tablets once daily in the morning, montelukast placebo capsule once daily in the evening and fluticasone propionate placebo twice daily via ACCUHALER/DISKUS | Drug: Placebo montelukast<br>* Placebo capsule once daily in the evening<br>Drug: Placebo fluticasone propionate via ACCUHALER/DISKUS<br>* Inhaled placebo twice daily via ACCUHALER/DISKUS<br>Drug: Placebo GSK2190915 two tablets<br>* Placebo tablet, two tablets once daily in the morning<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to the End of the 8-Week Treatment Period in Trough Forced Expiratory Volume in One Second (FEV1) | Pulmonary function was measured by forced expiratory volume in one second, defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 is defined as the morning (AM) pre-dose and pre-rescue bronchodilator FEV1 at the clinic visit. Baseline was the pre-dose value obtained at Visit 3. Change from Baseline was calculated as the end of Week 8 value minus the Baseline value. Analysis of covariance (ANCOVA) model used for statistical analysis. ITT Population was comprised of all participant randomized to treatment who received at least one dose of double-blind study medication. | Baseline and Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Daily Evening (PM) Peak Expiratory Flow (PEF) Averaged Over the 8-Week Treatment Period | Peak expiratory flow is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. Change from Baseline was calculated as the value of the averaged PEF daily (pre-dose and pre-rescue bronchodilator) evening over the 8-Week treatment period minus the Baseline value (defined as the last 7 days prior to randomization of the participants) | Baseline up to Week 8 | 
| Mean Change From Baseline in Daily Trough AM PEF Averaged Over the 8-Week Treatment Period | The PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. Trough AM PEF is defined as the AM pre-dose and pre-rescue bronchodilator at the clinic visit. Change from Baseline was calculated as the value of the averaged PEF daily (pre-dose and pre-rescue bronchodilator) AM over the 8-Week treatment period minus the Baseline value (defined as the last 7 days prior to randomization of the participants). | Baseline up to Week 8 | 
| Mean Change From Baseline in the Percentage of Symptom-free Days Averaged Over the 8-Week Treatment Period | Asthma symptoms were recorded in a daily electronic diary (eDiary) by the participants every day in the evening at bedtime and before taking any rescue or study medication and before the assessment of the PEF measurement. Participant's responses to evening assessments indicated no symptoms were considered to be symptom free. For participants, the symptom free days were assessed during the 8-Week treatment period. Change from Baseline was calculated as the averaged of symptom-free days during the 8-Week treatment period minus the Baseline value. Baseline was defined as the last 7 days prior to randomization of the participants. | Baseline up to Week 8 | 
| Mean Change From Baseline in the Percentage of Symptom-free Nights Averaged Over the 8-Week Treatment Period | Asthma symptoms were recorded in a daily eDairy by the participants every day in the morning upon rising and before taking any rescue or study medication and before the assessment of the PEF measurement. Participant's responses to the morning assessments indicated no symptoms were considered to be symptom free. For participants, the symptom free nights were assessed during the 8-Week treatment period. Change from Baseline was calculated as the averaged of symptom-free nights during the 8-Week treatment period minus the Baseline value (defined as the last 7 days prior to randomization of the participants). | Baseline up to Week 8 | 
| Mean Change From Baseline in the Percentage of Rescue-free Days Averaged Over the 8-Week Treatment Period | The number of inhalations of rescue salbutamol/albuterol inhalation aerosol used during the day and night was recorded by the participants in an eDiary. The time span during which the participants did not have to take any rescue medication (medication intended to relieve symptoms immediately) was considered to be a rescue-free period. For participants, the rescue-free days were assessed during the 8-Week treatment period. Change from Baseline was calculated as the averaged of rescue-free days during the 8-Week treatment period minus the Baseline value (defined as the last 7 days prior to randomization of the participants). | Baseline up to Week 8 | 
| Mean Change From Baseline in the Percentage of Rescue-free Nights Averaged Over the 8-Week Treatment Period | The number of inhalations of rescue salbutamol/albuterol inhalation aerosol used during the day and night was recorded by the participants in an eDiary. The time span during which the participants did not have to take any rescue medication (medication intended to relieve symptoms immediately) was considered to be a rescue-free period. For participants, the rescue-free nights were assessed during the 8-Week treatment period. Change from Baseline was calculated as the averaged of rescue-free nights during the 8-Week treatment period minus the Baseline value (defined as the last 7 days prior to randomization of the participants). | Baseline up to Week 8 | 
| Mean Change From Baseline in Day-time Asthma Symptom Score Over the 8-Week Treatment Period | Participants recorded their day-time asthma symptom score in an eDiary each PM at bedtime and before taking any rescue or study medication and before assessing the PEF measurement during the 8-Week treatment period. Day-time asthma symptom scores, as: 0=no asthma symptoms, 1=one episode of short-time asthma symptoms, 2=two or more episodes of short-time asthma symptoms, 3=asthma symptoms occurring during most part of daytime without interference with daily life activities, 4=asthma symptoms occurring during most part of daytime with interference with daily life activities, 5=severe asthma symptoms that disable working or perform normal daily activities. Change from Baseline was calculated as the averaged of day-time asthma symptom score during the 8-Week treatment period minus the Baseline value (defined as the last 7 days prior to randomization of the participants). | Baseline up to Week 8 | 
| Mean Change From Baseline in Night-time Asthma Symptom Score Over the 8-Week Treatment Period | Participants recorded their night-time asthma symptom score in an eDiary each AM upon rising and before taking any rescue or study medication and before assessing the PEF measurement during the 8-Week treatment period. Night-time asthma symptom scores, as: 0=no asthma symptoms, 1= one awakening or waking early due to asthma symptoms, 2= two or more awakenings due to asthma symptoms (including waking early), 3= asthma symptoms almost prevented the participant from sleeping, 4= severe asthma symptoms completely prevented from sleeping. Change from Baseline was calculated as the averaged of night-time asthma symptom score during the 8-Week treatment period minus the Baseline value (defined as the last 7 days prior to randomization of the participants). | Baseline up to Week 8 | 
| Mean Change From Baseline in Day-time Rescue Short Acting beta2-agonist (SABA) Usage Over the 8-Week Treatment Period | The number of inhalations of rescue SABA, salbutamol/albuterol inhalation aerosol used during the day and night was recorded by the participants in an eDiary. Participants who used salbutamol/albuterol inhalation aerosol at day-time were assessed during the 8-Week treatment period. Change from Baseline was calculated as the averaged number of day-time salbutamol/albuterol inhalation aerosol used during the 8-Week treatment period minus the Baseline value (defined as the last 7 days prior to randomization of the participants). | Baseline up to Week | 
| Mean Change From Baseline in Night-time Rescue SABA Usage Over the 8-Week Treatment Period | The numbers of inhalations of rescue SABA, salbutamol/albuterol inhalation aerosol used during the day and night was recorded by the participants in an eDiary. Participants who used salbutamol/albuterol inhalation aerosol at night-time were assessed during the 8-Week treatment period. Change from Baseline was calculated as the averaged number of night-time salbutamol/albuterol inhalation aerosol used during the 8-Week treatment period minus the Baseline value (defined as the last 7 days prior to randomization of the participants). | Baseline up to Week 8 | 
| Number of Participants Who Withdrew Due to Lack of Efficacy During the 8-Week Treatment Period | The participants who met any of the following withdrawal criteria were considered to be withdrawn due to lack of efficacy: 1) Clinic FEV1 below stability limit calculated at Visit 3. 2) More than three days between two consecutive visits, PEF has fallen below stability limit calculated at Visit 3. 3) Use of 12 or more inhalations of SABA per day for more than two days between consecutive visits. 4) Asthma exacerbation defined as worsening requiring any treatment other than study medication or rescue medication. This included requiring the use of systemic or inhaled corticosteroids and /or emergency room visit or hospitalization for the treatment of asthma. The stability limit was calculated as best pre-salbutamol/albuterol FEV1 at Visit 3 x 80 percent (%). | Upto 8 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FLAP, Efficacy, Asthma, Safety, Fluticasone Propionate, Beta-agonists, GSK2190915, Montelukast, Placebo, FLAIR