Clinical trial NCT00812929: A Clinical Trial to Test a Study Drug in Volunteers Who Develop Asthma Following Exercise
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Keywords: Asthma, Exercise Induced Asthma, Exercise Induced Bronchospasm
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2008-12-22
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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: 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.

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.

Primary outcomes:
measure: 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
timeFrame: Baseline (pre dose) and 60 minutes following the exercise challenge at 24 hours post dose of each treatment period.
Secondary outcomes:
measure: 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
timeFrame: Baseline (pre dose) and 60 minutes following the exercise challenge at 2 and 9.5 hours post dose of each treatment period.
measure: Weighted Mean (WM) for FEV1 Percentage Change From Baseline Recorded During 0 to 60 Minutes Following Exercise Challenge (FEV1 WM0-60)
timeFrame: Baseline (pre dose) and 0 to 60 minutes following exercise challenge at 2, 9.5 and 24 hours post dose of each treatment period.
measure: Time to FEV1 Recovery to Within 5 Percent of Baseline Following Exercise Challenge
timeFrame: 0 to 60 minutes following exercise challenge at 2, 9.5 and 24 hours post dose of each treatment period
measure: Number of Participants Using a Short Acting Beta-2 Agonist (Rescue Medication) During 0 to 90 Minutes Following Exercise Challenge
timeFrame: 0 to 90 minutes following exercise challenge of each treatment period
measure: Assessment of Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Pre dose, 2 hours, 9.5 hours and 24 hours prior to exercise challenge of treatment period
measure: Assessment of Vital Signs: Heart Rate (HR)
timeFrame: Pre dose, 2 hours, 9.5 hours and 24 hours prior to exercise challenge of each treatment period
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
timeFrame: 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
measure: Assessment of Clinical Chemistry Parameters: Albumin, Total Protein
timeFrame: Pre dose and 25 hours and 30 minutes post dose of each treatment period
measure: Assessment of Clinical Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Gamma Glutamyl Transferase (GGT)
timeFrame: Pre dose and 25 hours and 30 minutes post dose of each treatment period
measure: Assessment of Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin, Creatinine
timeFrame: Pre dose and 25 hours and 30 minutes post dose of each treatment period
measure: Assessment of Clinical Chemistry Parameters: Calcium, Chloride, Glucose, Potassium, Sodium, Urea/Blood Urea Nitrogen (BUN)
timeFrame: Pre dose and 25 hours and 30 minutes post dose of each treatment period
measure: Assessment of Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (TN) (ANC - Absolute Neutrophil Count), Platelet Count, White Blood Cell Count (WBC)
timeFrame: Pre dose and 25 hours and 30 minutes post dose of each treatment period
measure: Assessment of Hematology Parameters: Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC)
timeFrame: Pre dose and 25 hours and 30 minutes post dose of each treatment period
measure: Assessment of Hematology Parameters: Hematocrit
timeFrame: Pre dose and 25 hours and 30 minutes post dose of each treatment period
measure: Assessment of Hematology Parameters: Mean Corpuscle Hemoglobin (MCH)
timeFrame: Pre dose and 25 hours and 30 minutes post dose of each treatment period
measure: Assessment of Hematology Parameters: Mean Corpuscle Volume (MCV)
timeFrame: Pre dose and 25 hours and 30 minutes post dose of each treatment period
measure: Assessment of Hematology Parameters: Red Blood Cell Count (RBC)
timeFrame: Pre dose and 25 hours and 30 minutes post dose of each treatment period
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to follow up (7 to 21 days) following last dose
measure: Percentage Change From Baseline in Blood Leukotriene B4 (LTB4)
timeFrame: Baseline (pre dose) up to 24 Hours post dose of each treatment period
measure: Percentage Change From Baseline in Urine Leukotriene E4 (LTE4)
timeFrame: Baseline (pre dose) up to 24 Hours post dose of each treatment period
measure: Derived Pharmacokinetic (PK) Parameters for GSK2190915
timeFrame: Pre dose, 2 hours, 3.5 hours, 9.5 hours, 11 hours and 24 hours following exercise challenge of each treatment period
Other outcomes:
Locations:
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: North Dartmouth
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Oklahoma City
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Orangeburg
country: United States
facility: GSK Investigational Site
state: South Carolina
city: El Paso
country: United States
facility: GSK Investigational Site
state: Texas
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.