A Clinical Trial to Test a Study Drug in Volunteers Who D... | NCT00812929

Label	Type	Intervention Names
Placebo	Placebo Comparator	Drug: Placebo
GSK2190915 10 mg	Experimental	Drug: GSK2190915
GSK2190915 50 mg	Experimental	Drug: GSK2190915
GSK2190915 100 mg	Experimental	Drug: GSK2190915
GSK2190915 200 mg	Experimental	Drug: GSK2190915

Name	Type	Description	Arm Group Labels	Other Names
Placebo	Drug	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.	Placebo

Outcomes Module

Primary Outcomes

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 Outcomes

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.

Eligibility Module

Eligibility Criteria

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.

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Denver	Colorado	80230	United States
GSK Investigational Site

PubMed Identifier	Type	Citation	Retractions
24717789	Derived	Kent SE, Bentley JH, Miller D, Sterling R, Menendez R, Tarpay M, Pearlman DS, Norris V. The effect of GSK2190915, a 5-lipoxygenase-activating protein inhibitor, on exercise-induced bronchoconstriction. Allergy Asthma Proc. 2014 Mar-Apr;35(2):126-33. doi: 10.2500/aap.2014.35.3723.

Label	URL
Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.	View source

ID	Type	URL	Comment
112025	Annotated Case Report Form	View IPD

Arm/Group Information

ID	Title	Description
FG000	P/A/D/B/C	In this sequence participants received treatment P of oral single dose of aqueous solution of matching placebo on Day 1 of treatment period 1, treatment A of oral single dose of aqueous solution of 10 milligrams (mg) GSK2190915 on Day 1 of treatment period 2, treatment D of oral single dose of aqueous solution of 200 mg GSK2190915 on Day 1 of treatment period 3, treatment B of oral single dose of aqueous solution of 50 mg GSK2190915 on Day 1 of treatment period 4 and treatment C of oral single dose of aqueous solution of 100 mg GSK2190915 on Day 1 of treatment period 5. Each treatment periods were separated by a minimum 7 days washout period. Each treatment period included an exercise challenge at 2, 9.5, and 24 hours post dose and concluded on completion of the assessments following exercise challenge at 24 hours post dose.
FG001	A/B/P/C/D	In this sequence participants received treatment A of oral single dose of aqueous solution of 10 mg GSK2190915 on Day 1 of treatment period 1, treatment B of oral single dose of aqueous solution of 50 mg GSK2190915 on Day 1 of treatment period 2, treatment P of oral single dose of aqueous solution of matching placebo on Day 1 of treatment period 3, treatment C of oral single dose of aqueous solution of 100 mg GSK2190915 on Day 1 of treatment period 4 and treatment D of oral single dose of aqueous solution of 200 mg GSK2190915 on Day 1 of treatment period 5. Each treatment periods were separated by a minimum 7 days washout period. Each treatment period included an exercise challenge at 2, 9.5, and 24 hours post dose and concluded on completion of the assessments following exercise challenge at 24 hours post dose.
FG002	B/C/A/D/P	In this sequence participants received treatment B of oral single dose of aqueous solution of 50 mg GSK2190915 on Day 1 of treatment period 1, treatment C of oral single dose of aqueous solution of 100 mg GSK2190915 on Day 1 of treatment period 2, treatment A of oral single dose of aqueous solution of 10 mg GSK2190915 on Day 1 of treatment period 3, treatment D of oral single dose of aqueous solution of 200 mg GSK2190915 on Day 1 of treatment period 4, treatment P of oral single dose of aqueous solution of matching placebo on Day 1 of treatment period 5. Each treatment periods were separated by a minimum 7 days washout period. Each treatment period included an exercise challenge at 2, 9.5, and 24 hours post dose and concluded on completion of the assessments following exercise challenge at 24 hours post dose.
FG003	C/D/B/P/A	In this sequence participants received treatment C of oral single dose of aqueous solution of 100 mg GSK2190915 on Day 1 of treatment period 1, treatment D of oral single dose of aqueous solution of 200 mg GSK2190915 on Day 1 of treatment period 2, treatment B of oral single dose of aqueous solution of 50 mg GSK2190915 on Day 1 of treatment period 3, treatment P of oral single dose of aqueous solution of matching placebo on Day 1 of treatment period 4, treatment A of oral single dose of aqueous solution of 10 mg GSK2190915 on Day 1 of treatment period 5. Each treatment periods were separated by a minimum 7 days washout period. Each treatment period included an exercise challenge at 2, 9.5, and 24 hours post dose and concluded on completion of the assessments following exercise challenge at 24 hours post dose.
FG004	D/P/C/A/B	In this sequence participants received treatment D of oral single dose of aqueous solution of 200 mg GSK2190915 on Day 1 of treatment period 1, treatment P of oral single dose of aqueous solution of matching placebo on Day 1 of treatment period 2, treatment C of oral single dose of aqueous solution of 100 mg GSK2190915 on Day 1 of treatment period 3, treatment A of oral single dose of aqueous solution of 10 mg GSK2190915 on Day 1 of treatment period 4, treatment B of oral single dose of aqueous solution of 50 mg GSK2190915 on Day 1 of treatment period 5. Each treatment periods were separated by a minimum 7 days washout period. Each treatment period included an exercise challenge at 2, 9.5, and 24 hours post dose and concluded on completion of the assessments following exercise challenge at 24 hours post dose.
FG005	C/B/D/A/P	In this sequence participants received treatment C of oral single dose of aqueous solution of 100 mg GSK2190915 on Day 1 of treatment period 1, treatment B of oral single dose of aqueous solution of 50 mg GSK2190915 on Day 1 of treatment period 2, treatment D of oral single dose of aqueous solution of 200 mg GSK2190915 on Day 1 of treatment period 3, treatment A of oral single dose of aqueous solution of 10 mg GSK2190915 on Day 1 of treatment period 4, treatment P of oral single dose of aqueous solution of matching placebo on Day 1 of treatment period 5. Each treatment periods were separated by a minimum 7 days washout period. Each treatment period included an exercise challenge at 2, 9.5, and 24 hours post dose and concluded on completion of the assessments following exercise challenge at 24 hours post dose.
FG006	D/C/P/B/A	In this sequence participants received treatment D of oral single dose of aqueous solution of 200 mg GSK2190915 on Day 1 of treatment period 1, treatment C of oral single dose of aqueous solution of 100 mg GSK2190915 on Day 1 of treatment period 2, treatment P of oral single dose of aqueous solution of matching placebo on Day 1 of treatment period 3, treatment B of oral single dose of aqueous solution of 50 mg GSK2190915 on Day 1 of treatment period 4, treatment A of oral single dose of aqueous solution of 10 mg GSK2190915 on Day 1 of treatment period 5. Each treatment periods were separated by a minimum 7 days washout period. Each treatment period included an exercise challenge at 2, 9.5, and 24 hours post dose and concluded on completion of the assessments following exercise challenge at 24 hours post dose.
FG007	P/D/A/C/B	In this sequence participants received treatment P of oral single dose of aqueous solution of matching placebo on Day 1 of treatment period 1, treatment D of oral single dose of aqueous solution of 200 mg GSK2190915 on Day 1 of treatment period 2, treatment A of oral single dose of aqueous solution of 10 mg GSK2190915 on Day 1 of treatment period 3, treatment C of oral single dose of aqueous solution of 100 mg GSK2190915 on Day 1 of treatment period 4, treatment B of oral single dose of aqueous solution of 50 mg GSK2190915 on Day 1 of treatment period 5. Each treatment periods were separated by a minimum 7 days washout period. Each treatment period included an exercise challenge at 2, 9.5, and 24 hours post dose and concluded on completion of the assessments following exercise challenge at 24 hours post dose.
FG008	A/P/B/D/C	In this sequence participants received treatment A of oral single dose of aqueous solution of 10 mg GSK2190915 on Day 1 of treatment period 1, treatment P of oral single dose of aqueous solution of matching placebo on Day 1 of treatment period 2, treatment B of oral single dose of aqueous solution of 50 mg GSK2190915 on Day 1 of treatment period 3, treatment D of oral single dose of aqueous solution of 200 mg GSK2190915 on Day 1 of treatment period 4, treatment C of oral single dose of aqueous solution of 100 mg GSK2190915 on Day 1 of treatment period 5. Each treatment periods were separated by a minimum 7 days washout period. Each treatment period included an exercise challenge at 2, 9.5, and 24 hours post dose and concluded on completion of the assessments following exercise challenge at 24 hours post dose.
FG009	B/A/C/P/D	In this sequence participants received treatment B of oral single dose of aqueous solution of 50 mg GSK2190915 on Day 1 of treatment period 1, treatment A of oral single dose of aqueous solution of 10 mg GSK2190915 on Day 1 of treatment period 2, treatment C of oral single dose of aqueous solution of 100 mg GSK2190915 on Day 1 of treatment period 3, treatment P of oral single dose of aqueous solution of matching placebo on Day 1 of treatment period 4, treatment D of oral single dose of aqueous solution of 200 mg GSK2190915 on Day 1 of treatment period 5. Each treatment periods were separated by a minimum 7 days washout period. Each treatment period included an exercise challenge at 2, 9.5, and 24 hours post dose and concluded on completion of the assessments following exercise challenge at 24 hours post dose.

ID	Title	Description
BG000	Total	Eligible participants completed five treatment periods (single dose 10 mg, 50 mg, 100 mg, 200 mg GSK2190915 oral solution, compared to placebo control which was administered on Day 1 of each treatment period). Each treatment period lasted 2 days, with a minimum 7 day washout period between each treatment periods.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
Primary	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.	The 'Efficacy Population' was defined as all participants who received at least one dose of study medication and are not major protocol violators.	Posted		Least Squares Mean	Standard Error	Percent change		Baseline (pre dose) and 60 minutes following the exercise challenge at 24 hours post dose of each treatment period.

ID	Term
D001249	Asthma
D001250	Asthma, Exercise-Induced

ID	Term
D001982	Bronchial Diseases
D012140	Respiratory Tract Diseases
D008173	Lung Diseases, Obstructive
D008171	Lung Diseases