A Clinical Trial to Test a Study Drug in Volunteers Who Develop Asthma Following Exercise

Study Overview
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Brief Summary
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This study is intended to determine the dose response and duration of action of GSK2190915 in mild asthmatic adult subjects who experience exercise-induced bronchoconstriction.

Detailed Description
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This study is intended to determine the dose response and duration of action of GSK2190915 in mild asthmatic adult subjects who experience exercise-induced bronchoconstriction. Subjects will be invited to complete a screening visit, during which time exercise induced bronchoconstriction must be demonstrated, defined as a decrease between 20-40% in FEV1 compared to baseline immediately following exercise challenge. Eligible subjects will complete a randomized, double-blind, five-way crossover study. Subjects will be randomized to a single dose of either 10 mg, 50 mg, 100 mg, 200 mg GSK2190915, or placebo during each treatment period. Each treatment period will last 2 days and will include various assessments following exercise challenge at 2, 9.5, and 24 hours post dose. A minimum 7 day washout between treatment periods will be required. Regardless if a subject completes or prematurely withdraws from the study, a follow up visit will be completed 7-21 days following last dose.

Official Title
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A Multi-centre, Randomized, Double-blind, Five-way Crossover Study Evaluating the Dose Response and Duration of Action of GSK2190915 Compared to Placebo in Subjects With Mild Asthma Who Experience Exercise Induced Bronchoconstriction.

Conditions
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Asthma

Intervention / Treatment
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* Drug: Placebo
* Drug: GSK2190915


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females aged 18 to 55 years inclusive. Female subjects must be of non childbearing potential including pre-menopausal females with documented hysterectomy or double oophorectomy or tubal ligation 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. Hormone replacement therapy (HRT) is permitted for post-menopausal females. Male subjects must agree to use one of the protocol outlined contraception methods. This criterion must be followed from the time of the first dose of study medication until 3 months after administration of last dose. Body weight greater than or equal to 50 kg and Body mass index within range of 18.5-35.0 kg/m2 inclusive. Pre-bronchodilator FEV1 >70% of predicted at screening. Exercise induced bronchoconstriction, as defined as a 20-40% decrease in FEV1 compared to baseline immediately following exercise challenge at screening. Current non-smokers who have not used any tobacco products in the 6-month period preceding the screening visit with a pack history of less than or equal to 10 pack years [number of pack years = (number of cigarettes per day/20) x number of years smoked] Has provided signed and dated written informed consent Is able to understand and comply with the protocol requirements, instructions and protocol-stated restrictions. Exclusion Criteria: Chronic use of inhaled corticosteroids (ICS) for the treatment of persistent asthma. Past or present disease, which as judged by the investigator or medical monitor, may affect the outcome of this study or the subject's safety. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, gastrointestinal disease, renal disease, haematological disease, neurological disease, endocrine disease or pulmonary disease (with the exception of asthma, but including chronic bronchitis, emphysema, bronchiectasis or pulmonary fibrosis). Treated for or diagnosed with clinical depression within six months of screening or has a history of significant psychiatric illness. Known history of hypertension or is hypertensive at screening which, in the opinion of the Investigator, deems the subject unfit to complete exercise challenge. Hypertension at screening is defined as persistent systolic BP >150 mmHg or diastolic BP > 90mmHg. Known history of gastrointestinal bleeding. Respiratory tract infection within 2 weeks prior to the first dose of study medication. Asthma exacerbations requiring treatment with oral corticosteroids: any exacerbations within 4 weeks of the screening visit or two or more exacerbations within 2 months of the screening visit or admittance to hospital for an asthma exacerbation within 6 months of the screening visit. History of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnoea, respiratory arrest and/or hypoxic seizures. History of alcohol/drug abuse or dependence within 12 months of the study. Abuse of alcohol defined as an average weekly intake of >14 drinks/week for men or >7 drinks/week for women. One drink is equivalent to (12 g alcohol) = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits. Use of prescription or non-prescription drugs (including CYP 3A4 inhibitors and inducers, vitamins and dietary or herbal supplements), 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. Inhaled beta-2 agonists and acetaminophen (up to 4 g per day) for the treatment of minor ailments, eg headache, are permitted. Hormone replacement therapy (HRT) is also permitted for post-menopausal females. Unable to washout the following protocol defined prohibited medications within the defined times: Medication Exclusion Period Oral or injectable corticosteroids - No use within 5 weeks of the screening visit Inhaled, Intranasal and topical steroids - No use within 4 weeks of the screening visit Long acting beta-2 agonists - No use within 48 hours of an exercise challenge or dosing or lung function testing Short acting beta-2 agonists - No use within 6 hours of an exercise challenge or dosing or lung function testing Following exercise challenge during the screening visit, the subject experiences a greater than 40% fall in FEV1 compared to baseline. Following exercise challenge during the screening visit, the subject is not able to recover to at least 20% of baseline FEV1 following administration of short acting beta-2 agonists. Requires rescue medication before all lung function assessments are completed following the exercise challenge at screening Symptomatic with hay fever at screening or predicted to have symptomatic hayfever during the time of exercise challenge which, in the opinion of the Investigator, would interfere with the outcome of the study. Participation in a study with a new molecular entity during the previous 3 months or 5 half-lives (whichever is longer), or participation in a study without a new molecular entity during the previous month or 5 half-lives (whichever is longer), prior to the first dose of study medication. Undergoing allergen desensitisation therapy. There is a risk of subject non-compliance with study procedures. History of blood donation (500 mL) within 2 months of starting the clinical study. 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). Positive pregnancy test for females. Positive test for hepatitis C antibody or hepatitis B surface antigen. Positive test for HIV antibodies. Positive pre-study urine cotinine/ breath carbon monoxide test and or urine drug/urine alcohol screen. A minimum list of drugs that will be screened for include Amphetamines, Barbiturates, Cocaine, Opiates, Cannabinoids and Benzodiazepines. Has an affiliation with the Investigative Site. Participation of site personnel, or their spouses or children, is not allowed.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* The current study will include a placebo arm to allow for a valid evaluation of adverse events attributable to GSK2190915 versus those independent of GSK2190915.<br>|
| Experimental: GSK2190915 10 mg<br> | Drug: GSK2190915<br>* This study will assess FEV1 at various intervals following exercise challenge in subjects who have been administered a single dose of 10 mg, 50 mg, 100 mg, or 200 mg GSK2190915, compared to a placebo control.<br>|
| Experimental: GSK2190915 50 mg<br> | Drug: GSK2190915<br>* This study will assess FEV1 at various intervals following exercise challenge in subjects who have been administered a single dose of 10 mg, 50 mg, 100 mg, or 200 mg GSK2190915, compared to a placebo control.<br>|
| Experimental: GSK2190915 100 mg<br> | Drug: GSK2190915<br>* This study will assess FEV1 at various intervals following exercise challenge in subjects who have been administered a single dose of 10 mg, 50 mg, 100 mg, or 200 mg GSK2190915, compared to a placebo control.<br>|
| Experimental: GSK2190915 200 mg<br> | Drug: GSK2190915<br>* This study will assess FEV1 at various intervals following exercise challenge in subjects who have been administered a single dose of 10 mg, 50 mg, 100 mg, or 200 mg GSK2190915, compared to a placebo control.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Percentage Change From Pre-exercise Baseline Forced Expiratory Volume in 1 Second (FEV1) to the Minimum FEV1 Collected Within 60 Minutes Following the Exercise Challenge at 24 Hours Post Dose | FEV1 was recorded in triplicate, with participant encouraged to inhale fully despite any presence of chest tightness. For FEV1, a pre-challenge Baseline was defined for each challenge time point as maximum of triplicate measurements performed prior to challenge. The maximal percentage change within 60 minutes following exercise challenge was derived by taking minimum (i.e., most negative) percentage change in FEV1 over 5, 10, 15, 30, 45 and 60 minutes post challenge. Percent change FEV1 = 100*(FEV1 - Pre-challenge FEV1)/ Pre-challenge FEV1. If the exercise challenge was not completed successfully (i.e. heart rate maintained at >=80% of the predicted value for 6 minutes), FEV1 maximal percent change (0-60)was set to be missing. Analysis was performed using a mixed effects model, including period, treatment and covariates for predose FEV1. Estimates and 95% confidence intervals for treatment difference between each active dose and placebo for each challenge time point were calculated. | Baseline (pre dose) and 60 minutes following the exercise challenge at 24 hours post dose of each treatment period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Percentage Change From Pre-exercise Baseline FEV1 to the Minimum FEV1 Collected Within 60 Minutes Following the Exercise Challenge at 2 and 9.5 Hours Post Dose | FEV1 was recorded in triplicate, with participant encouraged to inhale fully despite any presence of chest tightness. For FEV1, a pre-challenge Baseline was defined for each challenge time point as maximum of triplicate measurements performed prior to challenge. The maximal percentage change within 60 minutes following exercise challenge was derived by taking minimum percentage change in FEV1 over 5, 10, 15, 30, 45 and 60 minutes post challenge. Percent change FEV1 = 100*(FEV1 - Pre-challenge FEV1)/ Pre-challenge FEV1. If the exercise challenge was not completed successfully (i.e. heart rate maintained at >=80% of the predicted value for 6 minutes), the FEV1 maximal percent change (0-60)was set to be missing. Analysis was performed using a mixed effects model, including period, treatment and covariates for predose FEV1. Estimates and 95% confidence intervals for treatment difference between each active dose and placebo for each challenge time point were calculated. | Baseline (pre dose) and 60 minutes following the exercise challenge at 2 and 9.5 hours post dose of each treatment period. | 
| Weighted Mean (WM) for FEV1 Percentage Change From Baseline Recorded During 0 to 60 Minutes Following Exercise Challenge (FEV1 WM0-60) | FEV1 was recorded in triplicate, with participant encouraged to inhale fully despite any presence of chest tightness. For FEV1, a pre-challenge Baseline was defined for each challenge time point as maximum of triplicate measurements performed prior to challenge.Weighted mean FEV1 percentage change recorded during 0-60 minutes post challenge was determined for each challenge, by dividing area under curve (AUC) for percent change from Baseline FEV1 measurements at 5, 10, 15, 30, 45 and 60 minutes post challenge by time interval. Actual times were used to determine time interval where available; otherwise planned relative time was used. If one or more FEV1 values were missing, AUC was calculated over time interval of available values. If intermittent values were missing over a participant's profile,it was assumed to be linear between 2 available values for calculation of AUC. Analysis was performed using a mixed effects model, including period, treatment and covariates for predose FEV1. | Baseline (pre dose) and 0 to 60 minutes following exercise challenge at 2, 9.5 and 24 hours post dose of each treatment period. | 
| Time to FEV1 Recovery to Within 5 Percent of Baseline Following Exercise Challenge | The time from maximal percentage change in FEV1 to recovery to within 5% of pre challenge Baseline (in minutes) was derived using actual sampling times. Time to FEV1 recovery= [SAS date/time of recovery(a) FEV1 - SAS date/time of FEV1 Maximum % Change0-60] / 60, where a is earliest recorded FEV1 either above pre-challenge Baseline or within 5% below pre challenge Baseline. Any unscheduled FEV1 measurements taken after last scheduled post challenge measurement was considered when deriving this endpoint. A corresponding censoring variable was derived for analysis to indicate whether recovery to within 5% of pre-challenge Baseline was achieved. The censoring variable was set to 1 if recovery to within 5% of Baseline was achieved. If recovery was not evident from data collected, time to recovery was calculated using the date/time of the last available post challenge FEV1 assessment and censoring variable was set to zero. Analysis was performed using a Cox proportional hazards model. | 0 to 60 minutes following exercise challenge at 2, 9.5 and 24 hours post dose of each treatment period | 
| Number of Participants Using a Short Acting Beta-2 Agonist (Rescue Medication) During 0 to 90 Minutes Following Exercise Challenge | Rescue medication was provided to participants at any time and it was strongly recommended for participants with a FEV1 decrease of at least 40% following exercise challenge compared to Baseline. Rescue medication was administered 0 to 90 minutes post exercise challenge. Statistical analysis was supposed to be performed using logistic regression, however, the data was too sparse to permit any formal statistical analysis. | 0 to 90 minutes following exercise challenge of each treatment period | 
| Assessment of Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | All participants rested for at least 10 minutes in the supine position prior to vital signs recordings. Vital signs Baseline values for SBP and DBP for each treatment period were calculated using the mean value of triplicate pre dose readings. Triplicate readings were taken at least five minutes apart. Assessment was performed at pre dose, 2 hours, 9.5 hours and 24 hours prior to exercise challenge. | Pre dose, 2 hours, 9.5 hours and 24 hours prior to exercise challenge of treatment period | 
| Assessment of Vital Signs: Heart Rate (HR) | All participants rested for at least 10 minutes in the supine position prior to vital signs recordings. Vital signs Baseline values for HR for each treatment period were calculated using the mean value of triplicate pre dose readings. Triplicate readings were taken at least five minutes apart. Assessment was performed at pre dose, 2 hours, 9.5 hours and 24 hours prior to exercise challenge. | Pre dose, 2 hours, 9.5 hours and 24 hours prior to exercise challenge of each treatment period | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings | All participants rested for at least 10 minutes in the supine position prior to ECG recordings. ECG Baseline values for each treatment period was calculated using the mean value of triplicate pre dose readings. Triplicate readings were taken at least five minutes apart. Assessment was performed at pre dose, 2 hours, 9.5 hours, 24 hours prior to exercise challenge and 60 minutes following exercise challenge at 2 hours. Participants with not clinically significant (NCS) abnormal values were reported. Potential clinical importance range for the ECG parameters are as follows: absolute QTc interval >450 millisecond (msec), increase from Baseline QTc >60 msec, PR interval <110 and >220 msec and QRS interval <75 and >110 msec. No participants reported clinically significant abnormal values. | Pre dose, 2 hours, 9.5 hours and 24 hours prior to exercise challenge and 60 minutes following exercise challenge at 2 hours of each treatment period | 
| Assessment of Clinical Chemistry Parameters: Albumin, Total Protein | Blood samples were collected for the assessment of clinical chemistry parameters for albumin and total protein at pre dose and 25 hours and 30 minutes. Participants had to fast for at least 8 hours prior to visit. During treatment periods, fasting continued until a light meal was allowed 1 hour post dose. | Pre dose and 25 hours and 30 minutes post dose of each treatment period | 
| Assessment of Clinical Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Gamma Glutamyl Transferase (GGT) | Blood samples were collected for the assessment of clinical chemistry parameters for ALP, ALT, AST and GGT at pre dose and 25 hours and 30 minutes. Participants had to fast for at least 8 hours prior to visit. During treatment periods, fasting continued until a light meal was allowed 1 hour post dose. | Pre dose and 25 hours and 30 minutes post dose of each treatment period | 
| Assessment of Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin, Creatinine | Blood samples were collected for the assessment of clinical chemistry parameters for direct bilirubin, total bilirubin and creatinine at pre dose and 25 hours and 30 minutes. Participants had to fast for at least 8 hours prior to visit. During treatment periods, fasting continued until a light meal was allowed 1 hour post dose. | Pre dose and 25 hours and 30 minutes post dose of each treatment period | 
| Assessment of Clinical Chemistry Parameters: Calcium, Chloride, Glucose, Potassium, Sodium, Urea/Blood Urea Nitrogen (BUN) | Blood samples were collected for the assessment of clinical chemistry parameters for calcium, chloride, glucose, potassium, sodium and urea/BUN at pre dose and 25 hours and 30 minutes post dose. Participants had to fast for at least 8 hours prior to visit. Participants fasted for glucose blood sample. During treatment periods, fasting continued until a light meal was allowed 1 hour post dose. | Pre dose and 25 hours and 30 minutes post dose of each treatment period | 
| Assessment of Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (TN) (ANC - Absolute Neutrophil Count), Platelet Count, White Blood Cell Count (WBC) | Blood samples were collected for the assessment of hematology parameters for basophils, eosinophils, lymphocytes, monocytes, TN, platelet count, WBC at pre dose and 25 hours and 30 minutes post dose. Participants had to fast for at least 8 hours prior to visit. During treatment periods, fasting continued until a light meal was allowed 1 hour post dose. | Pre dose and 25 hours and 30 minutes post dose of each treatment period | 
| Assessment of Hematology Parameters: Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC) | Blood samples were collected for the assessment of hematology parameters for hemoglobin and MCHC at pre dose and 25 hours and 30 minutes post dose. Participants had to fast for at least 8 hours prior to visit. During treatment periods, fasting continued until a light meal was allowed 1 hour post dose. | Pre dose and 25 hours and 30 minutes post dose of each treatment period | 
| Assessment of Hematology Parameters: Hematocrit | Blood samples were collected for the assessment of hematology parameters for hematocrit at pre dose and 25 hours and 30 minutes post dose. Participants had to fast for at least 8 hours prior to visit. During treatment periods, fasting continued until a light meal was allowed 1 hour post dose. | Pre dose and 25 hours and 30 minutes post dose of each treatment period | 
| Assessment of Hematology Parameters: Mean Corpuscle Hemoglobin (MCH) | Blood samples were collected for the assessment of hematology parameter for MCH at pre dose and 25 hours and 30 minutes post dose. Participants had to fast for at least 8 hours prior to visit. During treatment periods, fasting continued until a light meal was allowed 1 hour post dose. | Pre dose and 25 hours and 30 minutes post dose of each treatment period | 
| Assessment of Hematology Parameters: Mean Corpuscle Volume (MCV) | Blood samples were collected for the assessment of hematology parameter for MCV at pre dose and 25 hours and 30 minutes post dose. Participants had to fast for at least 8 hours prior to visit. During treatment periods, fasting continued until a light meal was allowed 1 hour post dose. | Pre dose and 25 hours and 30 minutes post dose of each treatment period | 
| Assessment of Hematology Parameters: Red Blood Cell Count (RBC) | Blood samples were collected for the assessment of hematology parameter for RBC at pre dose and 25 hours and 30 minutes post dose. Participants had to fast for at least 8 hours prior to visit. During treatment periods, fasting continued until a light meal was allowed 1 hour post dose. | Pre dose and 25 hours and 30 minutes post dose of each treatment period | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is 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, is a congenital anomaly/birth defect and medically significant. | Up to follow up (7 to 21 days) following last dose | 
| Percentage Change From Baseline in Blood Leukotriene B4 (LTB4) | Analysis LTB4 levels in the blood samples indicated the extent of LTB4 inhibition following administration of GSK2190915 compared to Baseline. Baseline was the pre dose value. Change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. | Baseline (pre dose) up to 24 Hours post dose of each treatment period | 
| Percentage Change From Baseline in Urine Leukotriene E4 (LTE4) | Analysis of LTE4 levels in the urine samples indicated the extent of LTE4 inhibition following administration of GSK2190915 compared to Baseline. Baseline was the pre dose value. Change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. | Baseline (pre dose) up to 24 Hours post dose of each treatment period | 
| Derived Pharmacokinetic (PK) Parameters for GSK2190915 | PK samples were supposed to be collected at 10 minutes prior to the exercise challenge at 2 hours, 9.5 hours and 24 hours. | Pre dose, 2 hours, 3.5 hours, 9.5 hours, 11 hours and 24 hours following exercise challenge of each treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Exercise Induced Asthma, Exercise Induced Bronchospasm