GSK2190915 Moderate to Severe Asthma Study

Study Overview
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Brief Summary
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A randomised, double-blind, placebo-controlled, parallel group study to evaluate the effect of treatment with GSK2190915, a FLAP inhibitor, as add-on to current inhaled corticosteroid therapy in patients with moderate to severe asthma with elevated sputum neutrophils.

Official Title
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The Efficacy of Orally Administered GSK2190915 as an add-on to Current Therapy in Subjects With Moderate to Severe Asthma Who Have Elevated Sputum Neutrophils

Conditions
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Asthma

Intervention / Treatment
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* Drug: GSK2190195 100mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A subject will be eligible for inclusion in this study only if all of the following criteria apply: Males and females aged 18 to 65 years inclusive. Body mass index within the range 18.5-37.0 kilograms/metre2 (kg/m2). An established clinical history of Asthma in accordance with the definition by the GINA Guidelines [GINA, 2006]. Subjects should have at screening or within the last year documented reversibility (>12 %) to short acting bronchodilator, or positive methacholine challenge, or positive histamine challenge (PC20 <8mg/ml). A female subject is eligible to participate if she is of: non-childbearing potential defined as pre-menopausal females with documented (medical report verification) hysterectomy or double oophrectomy or postmenopausal defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 40 pg/ml (<140 pmol/L) or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy; childbearing potential and agrees to use one of the contracception methods listed in Section 8.1 for an appropriate period of time prior to the start of dosing and until 3 months after last dose. Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until 3 months after the last dose. Subject with moderate to severe asthma with forced expiratory volume in one second (FEV1) ≥ 50% of predicted. Subject who are on regular inhaled corticosteroids without or in combination with a regular long acting Beta 2 Agonist. The dose should be stable for at least 4 weeks before screening. Subjects who are taking a minimum of FP 250mg BID or equivalent. Persistent sputum neutrophilia defined by sputum neutrophils ≥ 65% with TTC < 15 million cells/g with no evidence of eosinophilia (sputum eosinophils < 2%). Persistent is defined as the criteria being met at screening (or within the 6 months preceding screening) and on visit 1. Signed and dated written informed consent is obtained from the subject The subject is able to understand and comply with the protocol requirements, instructions and protocol-stated restrictions. Exclusion Criteria: A subject will not be eligible for inclusion in this study if any of the following criteria apply: Past or present disease, which as judged by the investigator or medical monitor, may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, gastrointestinal disease, hepatic disease, renal disease, haematological disease, neurological disease, endocrine disease or pulmonary disease (excluding asthma but including but not confined to chronic bronchitis, emphysema, bronchiectasis, eosinophilic bronchitis or pulmonary fibrosis). Clinically significant abnormalities in safety laboratory analysis at screening. Subject has uncontrolled hypertension or is hypertensive at screening. Hypertension at screening is defined as persistent systolic BP >150 mmHg or diastolic BP > 90mmHg. History of asthma exacerbations or acute intercurrent respiratory illness (viral respiratory syndrome, bronchitis, pneumonia) for a four week period before the screening visit History of life-threatening asthma, defined as an asthma episode that required intubations and/or was associated with hypercapnoea, respiratory arrest and/or hypoxic seizures. Subject is unable to abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements) including non-steroidal anti-inflammatory drugs (NSAIDs), anti-depressant drugs, anti-histamines and anti-asthma, anti-rhinitis or hay fever medication, with the exception of ICS, LABA and short action beta agonists, from 14 days before screening until the follow-up visit unless in the opinion of the Investigator and sponsor the medication will not interfere with the study Administration of oral or injectable steroids within 6 weeks of screening. The subject has participated in a study with a new molecular entity during the previous 3 months or has participated in 4 or more clinical studies in the previous 12 months prior to the first dosing day. Administration of anti -leukotrienne therapies for 14 days before screening and during the study. Administration of any vaccinations within 1 month of screening or during the study. Administration of biological therapies within 3 months of the screening visit or during the study Subject is undergoing allergen desensitisation therapy. Administration of OATP1B1 substrates from 2 weeks before dosing, and until all follow-up assessments are completed. There is a risk of non-compliance with study procedures. History of blood donation (500 mL) within 3 months of starting the clinical study. The subject regularly drinks more than 28 units of alcohol in a week if male, or 21 units per week if female. One unit of alcohol is defined as a medium (125 ml) glass of wine, half a pint (250 ml) of beer or one measure (25 ml) of spirits. The subject has a screening QTc value of >450msec, PR interval outside the range 120 to 220msec or an ECG that is not suitable for QT measurements (e.g. poorly defined termination of the T-wave). The subject has tested positive for hepatitis C antibody or hepatitis B surface antigen. The subject has tested positive for HIV antibodies. The subject has a positive pre-study urine drug or urine or breath alcohol screen. A minimum list of drugs that will be screened for include Amphetamines, Barbituates, Cocaine, Opiates, Cannabinoids and Benzodiazepines.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

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 |
| --- | --- |
| Placebo Comparator: Placebo<br>12 day repeat dosing with placebo | Drug: Placebo<br>* Placebo : 2% (w/w) Ethanol, sucralose (5 mg/100 mL of oral solution) to 100 % (w/w) aqueous sodium carbonate buffer (0.010 M, pH 9-10)<br>|
| Experimental: GSK2190915 100mg<br>12 day repeat dosing treatment phase with 100mg GSK2190915. | Drug: GSK2190195 100mg<br>* GSK2190915 is a high affinity 5-lipoxygenase-activating protein (FLAP) inhibitor.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Numbers of Neutrophils in Induced Sputum-Absolute Neutrophil Count | The neutrophils play an important role in participants with more severe asthma. The reduction in number of neutrophils in induced sputum was evaluated to study the effect of treatment with repeat oral doses of GSK2190915, in asthma participants. Sputum samples were evaluated at central laboratory. The samples were rejected, if the weight was less than 100 grams (g), or if excessive cell degeneration or due to excessive squamous cells and insufficient inflammatory cells. The total cell count of neutrophil was reported as total cell count × 10^6 /g. | Day -9 to -7, Day 1, Day 12 and follow-up (Day 24-28) | 
| Percentage of Neutrophils in Induced Sputum | The neutrophils play an important role in participants with more severe asthma. The reduction in number of neutrophils in induced sputum was evaluated to study the effect of treatment with repeat oral doses of GSK2190915, in asthma participants. Sputum samples were evaluated at central laboratory. The samples were rejected, if the weight was less than 100 g, or if excessive cell degeneration or due to excessive squamous cells and insufficient inflammatory cells. The total cell count of neutrophil was reported as percentage of cells. | Day -9 to -7, Day 1, Day 12 and follow-up (Day 24-28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of FEV1 on Visit 2, 3 and Visit 4 | FEV1 is the amount of air which can be forcefully exhaled in 1 second. It was assessed using a spirometry. Due to early termination of the study, the data of individual participants is reported. | Visit 2 (Day 1), visit 3 (Day 5 to 7) and visit 4 (Day 12) | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, or is an important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, or a drug-induced liver injury. | From visit 1 (Day -7 to Day -9) to upto follow-up (upto Day 28) | 
| Number of Participants With Vital Sign of Potential Clinical Concern (PCC) | The vital sign measurement included measurement of systolic and diastolic blood pressure alongwith pulse rate. The PCC values reported for systolic blood pressure were < 85 millimeter of mercury (mmHg) and >160 mmHg; that for diastolic was <45 mmHg and >100 mmHg. The PCC values for pulse rate were <40 and > 110 beats per minute. The number of participants with values outside the PCC for systolic, diastolic blood pressure and vitals during the treatment duration were reported. | Visit 2 (Day 1) to Upto follow-up (Day 28) | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings | The number of participants with abnormal ECG values were reported. The data was reported as Abnormal clinically significant (CS), abnormal not clinically significant (NCS), and No result. | Visit 2 (Day 1) to Upto follow-up (Day 28) | 
| Number of Participants With Clinical Chemistry Values of PCC | The clinical chemistry parameters evaluated were albumin, calcium, creatinine, glucose, magnesium, phosphorus, potassium, sodium, urea, gamma glutamyl transferase, and bicarbonate. The number of participants with values outside the PCC values were reported. The PCC value observed for bicarbonate was reported. | Visit 2 (Day 1) to Upto follow-up (Day 28) | 
| Number of Participants With Hematology Values of PCC | The hematology parameters evaluated were white blood cells, neutrophils, hemoglobin, hematocrit, platelets and lymphocytes. The number of participants with values outside the PCC values were reported. The PCC value observed for lymphocyte was reported. | Visit 2 (Day 1) to Upto follow-up (Day 28) | 
| Plasma Concentration of GSK2190915 | The blood samples for analysis of pharmacokinetic parameters were collected at pre-dose and 2 hours post dose on Day 1 and pre-dose trough and 2 hour post dose on Day 12, to evaluate the concentration of the drug GSK2190915 in plasma. | At Day 1, pre-dose; Day 1, 2 hour; Day 12, pre-dose; and Day 12, 2 hour | 
| Percentage Change From Baseline Urine LTE4 Biomarker | The urine spot samples were collected from the participants at pre-dose on day 1 and trough day 12 for evaluation of LTE4 biomarker. This evaluated the level of inflammation in the airways of the asthma participants. The percentage change from baseline was calculated by dividing the post randomization change by the baseline value from the individual and multiplying by a 100. If either the baseline or post-randomization value is missing, the change from baseline is set to missing. Baseline was defined as Day 1(pre-dose). | Day 1 and Day 12 | 
| Percentage Change From Baseline of LTB4 Biomarker in Plasma | The plasma samples were evaluated for presence of LTB4 biomarkers. The percentage change from baseline was calculated by dividing the post-randomization change by the baseline value from the individual and multiplying by a 100. If either the baseline or post-randomization value is missing, the change from baseline is set to missing. Baseline was defined as Day 1(pre-dose). | Day 1 and Day 12 | 
| Concentration of LTB4 in Sputum | The concentration of LTB4 levels in sputum were evaluated. However due to early termination of the study, the data was not collected. | Day 1 and Day 12 | 
| Concentration of Interleukin (IL)-17 and High-sensitivity C-reactive Protein (hsCRP) in Blood | The blood samples were collected to evaluate the concentration of IL-17 and hsCRP in blood. However due to early termination of the study, the data was not collected. | Day 1 and Day 12 | 
| Assessment of Established Markers of Anti-inflammatory Activity in Sputum: the Measurements Will Include IL-17, Neutrophil Elastase, Myeloperoxidase and IL-8 | During the study conduct it was observed that the levels of IL-17, measured in both blood and sputum were below limit of quantification; for neutrophil elastase, in sputum no inference could be made as most levels were above the limit of quantification. Thus due to limited amount of data the analysis was not summarized. | Day 1 and Day 12 | 
| Asthma Control Questionnaire (ACQ) Assessment | ACQ measures the adequacy of asthma control. It includes 5 questions about symptoms of asthma, 1 question about the rescue medication used and 1 about lung function (FEV1% predicted). This is a 7-item scale where the items are equally weighted and the ACQ score is the mean of 7 items which ranges from 0 to 6. 0= Well controlled and 6=extremely poorly controlled. Mean scores of =<0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score >= 1.5 indicates uncontrolled asthma. Thus for ACQ a higher score indicates severe disease and a low score indicative of less severe disease. | At Day 1, Day 5 to 7 and Day 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sputum cell counts, Neutrophils, Severe Asthma, ICS, Inhaled corticosteroids