A Study to Evaluate the Effect of GW870086X on Allergen Challenge in Mild Asthmatics
Condition: Asthma
MeSH terms: Asthma
Intervention: GW870086X; FP; Placebo
Intervention description: Investigational product; Positive control; Placebo control
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 24.0
Sex: Male
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: asthma; late phase response; allergen; challenge; GW870086X

Summary:

      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.
    

Eligibility criteria:

        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.