A Study to Evaluate the Effect of GW870086X on Allergen Challenge in Mild Asthmatics

Study Overview
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Brief Summary
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The study will measure the early and late asthamtic response using an allergen challenge. This study will evaluate the safety and patients tolerance to repeat inhaled doses of GW870086X using a number of clinical and biological markers.

Official Title
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A Randomised, Placebo-controlled, Incomplete Block, Three-way Cross-over Study to Evaluate the Effect of Treatment With Repeat Inhaled Doses of GW870086X on the Allergen-induced Early and Late Asthmatic Response in Subjects With Mild Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: GW870086X
* Drug: FP
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male subjects between 18 and 65 years of age inclusive. Male subjects must agree to use one of the contraception methods listed in Section 8. This criterion must be followed from the time of the first dose of study medication until 90-95 hours post-last dose. BMI within the range 19.0 - 29.0 kg/m2 (inclusive). Liver function tests (bilirubin, AST, ALT) within normal laboratory parameters at screening. Documented history of bronchial asthma, first diagnosed at least 6 months prior to the screening visit and currently being treated only with intermittent short-acting beta -agonist therapy by inhalation. Pre-bronchodilator FEV1 >65% of predicted at screening. No history of smoking within 6 months of the start of the study, and with a total pack year history of <= 10 pack years Demonstration of a positive wheal and flare reaction (>= 3 mm relative to negative control) to at least one allergen from a battery of allergens (including but not limited to house dust mite, grass pollen, cat dander, hazel, horse and birch) on skin prick testing at screening, or within 12 months of study start. Screening allergen challenge demonstrates that the subject experiences both an early and late asthmatic response. The early asthmatic response must include a fall in FEV1 of >= 20% from the post saline value, on at least one occasion, between 5 and 30 minutes after the final concentration of allergen. The late asthmatic response must include a fall in FEV1 of >= 15% from the post saline value, on at least three occasions, two of which must be consecutive, between 4 and 10 hours after the final concentration of allergen. Reproducible allergen challenge at screening (confirmation of the dose ascending allergen challenge by a bolus allergen challenge at least 14 days later). Sensitivity to methacholine with a provocative concentration of methacholine resulting in a 20% fall in FEV1 (PC20 methacholine) of <8 mg/mL at screening. Subjects who are able to produce acceptable induced sputum samples (as defined in the Study Procedures Manual). Be able to give written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Single QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block. Exclusion Criteria: Past or present disease, which as judged by the investigator, may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, haematological disease, neurological disease, endocrine disease or pulmonary disease (including but not confined to chronic bronchitis, emphysema, bronchiectasis or pulmonary fibrosis). Clinically significant abnormalities in safety laboratory analysis at screening. Subject has known history of hypertension or is hypertensive at screening. Hypertension at screening is defined as persistent systolic BP >140mmHg or diastolic BP > 90mmHg. Respiratory tract infection and/or exacerbation of asthma within 4 weeks prior to the first dose of study medication. 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. Administration of oral, injectable or dermal steroids within 4 weeks or intranasal and/or inhaled steroids within 2 week of the screening visit. The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening. A positive test for HIV antibody. History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males). One unit is equivalent to a half-pint (220mL) of beer or 1 (25ml) measure of spirits or 1 glass (125ml) of wine. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Exposure to more than four new chemical entities within 12 months prior to the first dosing day. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. Paracetamol is an exception and will be permitted at daily doses of up to 4 g from screening to follow-up. Has taken Xanthines (including theophylline, but not including caffeine), anticholinergics, cromoglycates and/or long-acting beta-agonists within 1 week prior to screening and is unable to abstain from them throughout the study. Unable to abstain from other medications including non-steroidal anti-inflammatory drugs (NSAIDs), anti-depressant drugs, anti-histamines and anti-asthma (not including steroids), anti-rhinitis or hay fever medication, other than short acting inhaled beta-agonists and paracetamol (up to 4 g per day) for the treatment of minor ailments eg headache from 7 days before screening until the follow-up visit. Unable to abstain from medication or supplements that significantly inhibit the cytochrome P450 subfamily enzyme CYP3A4, including ritonavir and ketoconazol from screening and throughout the study. Unable to use the DISKHALER and/or DISKUS device correctly. History of being unable to tolerate or complete methacholine or allergen challenge tests. If, after 2 concurrent administrations of saline during the allergen challenge at screening the subjects still have a fall in FEV1 of greater than 10%. Subject is undergoing allergen desensitisation therapy. History of sensitivity to any of the study medications (including lactose), or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period. Unwillingness or inability to follow the procedures outlined in the protocol. Subjects who are kept due to regulatory or juridical order in an institution. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 3 months prior to screening. Consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication.

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

Sexes Eligible for Study
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Male

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 |
| --- | --- |
| Experimental: 13 day repeat dose<br> | Drug: GW870086X<br>* Investigational product<br>Drug: FP<br>* Positive control<br>Drug: Placebo<br>* Placebo control<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Late Asthmatic Response (LAR): Minimum FEV1 Between 4-10 Hours After Allergen Challenge on Day 13 of Each Treatment Period | Analyzed using a mixed effects model including covariates for participant level Baseline FEV1 and period level Baseline FEV1. Participant level Baseline defined as the mean of Day 1 pre-dose values across periods for each participant and period level Baseline as the difference between the Day 1 pre-dose value and participant level Baseline for each period. Absolute change from saline Baseline was calculated for each participant and time point as value equal to highest challenge value minus highest saline value. Minimum FEV1 over 4-10 hours post allergen challenge was minimum value of all the post-saline time points between 4 to 10 hours (4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 and 10 hours). The adjusted mean is presented as least square mean (LSM). | 4-10 hours after allergen challenge on Day 13 of each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LAR: Weighted Mean FEV1 Between 4-10 Hours After Allergen Challenge on Day 13 of Each Treatment Period. | Analyzed using a mixed effects model including covariates for participant level Baseline FEV1 and period level Baseline FEV1. Participant level Baseline was defined as the mean of Day 1 pre-dose values across periods for each participant and period level Baseline as the difference between the Day 1 pre-dose value and participant level Baseline for each period. Absolute change from saline Baseline was calculated for each participant and time point as value equal to highest challenge value minus highest saline value. Weighted mean LAR was calculated for FEV1 over 4-10 hours (4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 and 10 hours) post allergen challenge using the linear trapezoidal rule. To calculate weighted mean LAR, all FEV1 values recorded after the administration of rescue medication have been set to the last recorded FEV1 value prior to the administration of rescue medication. The adjusted mean is presented as Least square mean (LSM). | 4-10 hours after allergen challenge on Day 13 of each treatment period | 
| EAR: Minimum FEV1 and Weighted Mean FEV1 Between 0-2 Hours After Allergen Challenge on Day 13 of Each Treatment Period. | Analyzed using a mixed effects model including covariates for participant level Baseline FEV1 and period level Baseline FEV1. Participant level Baseline was defined as the mean of Day 1 pre-dose values across periods for each participant and period level Baseline as the difference between the Day 1 pre-dose value and participant level Baseline for each period. Absolute change from saline Baseline was calculated for each participant and time point as value equal to highest challenge value minus highest saline value. Minimum FEV1 over 0-2 hrs post-allergen challenge (minimum EAR) was the minimum value of all the post-(bolus) allergen challenge. Weighted mean EAR was calculated for FEV1 over 0-2 hours post allergen challenge using the linear trapezoidal rule. It was measured up to and including 2 hours (5, 10, 15, 20, 30, 45 minutes and 1, 1.5 and 2 hours). The adjusted mean is presented as LSM. | 0-2 hours after challenge on Day 13 of each treatment period (approximately 17 weeks) | 
| Concentration of Exhaled NO Pre-dose on Day 13 of Each Treatment Period | Exhaled NO concentration data collected on Day 13 (pre-dose) was log transformed and analysed using a mixed effects model including covariates for participant level Baseline FEV1 and period level Baseline FEV1. Participant level Baseline was defined as the mean of Day 1 pre-dose values across periods for each participant and period level Baseline as the difference between the Day 1 pre-dose value and participant level Baseline for each period. The adjusted mean is presented. | Day 13 of each treatment period (approximately 17 weeks) | 
| Concentration of Exhaled NO Post-dose on Day 13 of Each Treatment Period | Exhaled NO concentration data collected on Day 13 (2 and 12 hours post-dose) and was measured 3 times at each time point. The outcome was not assessed and data not reported. | Day 13 of each treatment period (approximately 17 weeks) | 
| Number of Participants With Adverse Events (AE), Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition. | Up to 17 weeks | 
| Mean Values for Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Participants were required to rest in the supine position for at least 10 minutes before each reading. SBP and DBP was measured on Day 1 (pre-dose and 1 hour post dose), Day 7 (any time post morning dose), Day 13 (pre allergen challenge [pre saline]) and Day 14 (pre and 1 hour post methacholine challenge). | Up to Day 14 of each treatment period (approximately 17 weeks) | 
| Mean Values for Heart Rate | Participants were required to rest in the supine position for at least 10 minutes before each reading. Heart rate was measured on Day 1 (pre-dose and 1 hour post dose), Day 7 (any time post morning dose), Day 13 (pre allergen challenge) and Day 14 (pre and 1 hour post methacholine challenge). | Up to Day 14 of each treatment period (approximately 17 weeks) | 
| Number of Participants With Electrocardiogram (ECG) Findings | Single 12-lead ECGs were obtained at each time point during the study using an ECG machine that automatically calculated the heart rate and measures PR, QRS, QT, and QTc intervals. It was measured on Day 1 (pre-dose and 1 hour post dose) and Day 14 (pre and 1 hour post methacholine challenge). Participants with normal (Nr), abnormal not clinically significant (ANCS) and abnormal clinically significant (ACS) ECG was presented. | Up to Day 14 of each treatment period (approximately 17 weeks) | 
| Change From Baseline in FEV1-allergen Challenge at Each Time Point | A mixed model analysis was performed separately for each planned time point during the allergen challenge on Day 13, from 5 minutes to 10 hour, including covariates for participant level Baseline FEV1 and period level Baseline FEV1. Participant level Baseline was defined as the mean of Day 1 pre-dose values across periods for each participant and period level Baseline as the difference between the Day 1 pre-dose value and participant level Baseline for each period. Absolute change from saline Baseline was calculated for each participant and time point as value equal to highest challenge value minus highest saline value. FEV1 was measured at 5, 10, 15, 20, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 and 10 hours. The adjusted mean is presented as LSM. | Up to Day 13 of each treatment period (approximately 17 weeks) | 
| Mean Laboratory Values for Platelet, White Blood Cells (WBC), Neutrophils, Lymphocytes, Monocytes, Eosinophils and Basophils | Blood samples for assessment of hematology was collected on Day 1 (pre-dose) and Day 14 (pre methacholine challenge). | Up to Day 14 of each treatment period (approximately 17 weeks) | 
| Change From Baseline in FEV1-non Allergen Challenge | Non-allergen challenge FEV1 data was measured on Day 1, 7, 13 and 14. The FEV1 assessments on Day 1 was taken at pre-dose and those on Day 7 was taken post-dose. On Day 13, the pre-allergen challenge FEV1 values was used and on Day 14 the pre-methacholine challenge FEV1 values was used. Absolute change in FEV1 on Day 7, 13 and 14 from pre-dose FEV1 was analyzed separately using a mixed-effects ANOVA model. Period-level Baseline was defined as the difference between the Day 1 pre-dose value and participant-level Baseline for each period, each participant. The change from Baseline was calculated by subtracting the Baseline value from the individual post-randomization value. Post-randomization values refer to assessments performed post dose and after the Baseline assessment. The adjusted mean is presented as LSM. | Up to Day 14 of each treatment period (approximately 17 weeks) | 
| Mean Laboratory Values for Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) | Blood samples for assessment of hematology was collected on Day 1 (pre-dose) and Day 14 (pre methacholine challenge). | Up to Day 14 of each treatment period (approximately 17 weeks) | 
| Mean Laboratory Values for Hematocrit | Blood samples for assessment of hematology was collected on Day 1 (pre-dose) and Day 14 (pre methacholine challenge). | Up to Day 14 of each treatment period (approximately 17 weeks) | 
| Mean Laboratory Values for Mean Corpuscle Hemoglobin (MCH) | Blood samples for assessment of hematology was collected on Day 1 (pre-dose) and Day 14 (pre methacholine challenge). | Up to Day 14 of each treatment period (approximately 17 weeks) | 
| Mean Laboratory Values for Mean Corpuscle Volume (MCV) | Blood samples for assessment of hematology was collected on Day 1 (pre-dose) and Day 14 (pre methacholine challenge). | Up to Day 14 of each treatment period (approximately 17 weeks) | 
| Mean Laboratory Values for Reticulocytes | Blood samples for assessment of hematology was collected on Day 1 (pre-dose) and Day 14 (pre methacholine challenge). | Up to Day 14 of each treatment period (approximately 17 weeks) | 
| Mean Laboratory Values for Albumin and Total Protein | Blood samples for assessment of clinical chemistry was collected on Day 1 (pre-dose) and Day 14 (pre methacholine challenge). | Up to Day 14 of each treatment period (approximately 17 weeks) | 
| Mean Laboratory Values for Alkaline Phosphatase (ALP), Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST) and Gamma Glutamyl Transferase (GGT) | Blood samples for assessment of clinical chemistry was collected on Day 1 (pre-dose) and Day 14 (pre methacholine challenge). Liver safety parameters (ALT and AST) were also assessed on Day 7 (pre-dose). | Up to Day 14 of each treatment period (approximately 17 weeks) | 
| Mean Laboratory Values for Total Bilirubin, Direct Bilirubin and Creatinine | Blood samples for assessment of clinical chemistry was collected on Day 1 (pre-dose) and Day 14 (pre methacholine challenge). Total bilirubin and direct bilirubin were also assessed on Day 7 (pre-dose). | Up to Day 14 of each treatment period (approximately 17 weeks) | 
| Mean Laboratory Values for Calcium, Glucose, Potassium, Chloride and Sodium | Blood samples for assessment of clinical chemistry was collected on Day 1 (pre-dose) and Day 14 (pre methacholine challenge). | Up to Day 14 of each treatment period (approximately 17 weeks) | 
| Provocative Concentration of Methacholine Resulting in a 20% Reduction in FEV1 (PC20) on Day 14 of Each Treatment Period. | Methacholine challenge PC20 data the concentration of methacholine to cause >= 20% decrease (that is change <= -20%) in FEV1 compared with saline [Baseline]) was log transformed and analysed using a mixed effects model including covariates for participant level Baseline FEV1 and period level Baseline FEV1. Participant level Baseline was defined as the mean of Day 1 pre-dose values across periods for each participant and period level Baseline as the difference between the Day 1 pre-dose value and participant level Baseline for each period. The PC20 was obtained by linear interpolation (on the log 2 concentration scale) between the lowest concentration of methacholine that caused at least 20% decrease from Baseline and the preceding concentration. The adjusted mean is presented as LSM. | Day 14 of each treatment period (approximately 17 weeks) | 
| Assessment of Established Markers of Anti-inflammatory Activity in Sputum on Day 14-cell Counts of Eosinophils and Neutrophils | Sputum induction was performed during each treatment period for biomarker analysis 1-2 hour after the methacholine challenge on Day 14. Sputum samples were collected from a minimum of 10 participants in the study. | Day 14 of each treatment period (approximately 17 weeks) | 
| Assessment of Established Markers of Anti-inflammatory Activity in Sputum on Day 14-myeloperoxidase (MPO) | Sputum induction was performed during each treatment period for biomarker analysis 1-2 hour after the methacholine challenge on Day 14. Sputum samples were collected from a minimum of 10 participants in the study. | Day 14 of each treatment period (approximately 17 weeks) | 
| Assessment of Established Markers of Anti-inflammatory Activity in Sputum on Day 14-interleukin-8 (IL-8) | Sputum induction was performed during each treatment period for biomarker analysis 1-2 hour after the methacholine challenge on Day 14. Sputum samples were collected from a minimum of 10 participants in the study. | Day 14 of each treatment period (approximately 17 weeks) | 
| Assessment of Established Markers of Anti-inflammatory Activity in Sputum on Day 14-total Protein | Sputum induction was performed during each treatment period for biomarker analysis 1-2 hour after the methacholine challenge on Day 14. Sputum samples were collected from a minimum of 10 participants in the study. | Day 14 of each treatment period (approximately 17 weeks) | 
| Number of Participants With Established Markers of Anti-inflammatory Activity in Sputum on Day 14-messenger Ribonucleic Acid (mRNA) | Sputum induction was performed during each treatment period for biomarker analysis 1-2 hour after the methacholine challenge on Day 14. Sputum samples were collected from a minimum of 10 participants in the study. The outcome is not assessed. | Day 14 of each treatment period (approximately 17 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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asthma, late phase response, allergen, challenge, GW870086X