Effect of the GSK2245035 on the Allergen-induced Asthmatic Response
Condition: Asthma
MeSH terms: Asthma
Intervention: GSK2245035 Nasal Spray Solution; Placebo Nasal Spray Solution
Intervention description: GSK2245035 Nasal Spray Solution 0.2 microgram (mcg)/mL delivering 10 ng GSK2245035 per actuation. A solution formulation in saline, preserved with Benzalkonium Chloride and Disodium Edetate.; Nasal Spray Solution as for GSK2245035 without active ingredient.
Intervention MeSH terms: Pharmaceutical Solutions
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 36.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: GSK2245035; TLR7 agonist; allergic asthma; FEV1

Summary:

      This study will assess whether Toll like receptor 7 (TLR7)-mediated pharmacology, with
      intranasal (i.n.) GSK2245035 20 nanogram (ng) administered weekly for a period of 8 weeks,
      will lead to reduced allergic reactivity in the lower airways in subjects with mild allergic
      asthma.

      This will be a randomised, double-blind (sponsor open), placebo-controlled, parallel group,
      8-week treatment study.

      The study will consist of a screening period of up to approximately 4 weeks (involving two
      screening visits), a blinded treatment period of 8 weeks, followed by a follow-up period of
      up to 3 months. The total duration of the study for each subject will therefore be a maximum
      of approximately 6 months.
    

Eligibility criteria:

        Inclusion Criteria

          -  Between 18 and 65 years of age inclusive, at the time of signing the informed consent.

          -  Diagnosis of asthma, as defined by the history of respiratory symptoms such as wheeze,
             shortness of breath, chest tightness and cough that vary over time and in intensity,
             together with variable expiratory airflow limitation for at least 6 months prior to
             screening

          -  Current asthma therapy. Intermittent short-acting beta-agonist (SABA) alone (on
             average for no more than 2 days per week)

          -  Positive skin prick test (3 mm or more greater than negative control) to common
             perennial or seasonal aeroallergen(s) (i.e., house dust mite, cat dander, grass
             pollen) at screening

          -  Pre-bronchodilator FEV1 > 70 % predicted normal at Screening Visit 1

          -  EAR with >=20 % FEV1 decrease between 5 and 30 minutes after the final allergen
             concentration is obtained at the screening bronchial allergen challenge (BAC)
             (decreases relative to the saline)

          -  LAR with three FEV1 decreases of >= 15 % between 4 and 10 hours after the final
             allergen concentration is obtained at the screening bronchial allergen challenge, with
             two FEV1 decreases being at consecutive time points (decreases relative to the saline)

          -  Subjects who are current non-smokers (defined as no use of any tobacco products in the
             6-month period preceding the screening visit) and have a pack history of < 10 pack
             years. Number of pack years = (number of cigarettes per day/20) x number of years
             smoked

          -  Bodyweight >= 45kilograms (kg)

          -  Male OR female of non-reproductive potential Male subjects with female partners of
             child bearing potential complying with contraception requirements from the time of
             first dose of study medication until the final follow-up visit: Vasectomy with
             documentation of azoospermia, male condom plus partner use of one of the following
             contraceptive options: Contraceptive subdermal implant, Intrauterine device or
             intrauterine system, Oral contraceptive, either combined or progestogen alone,
             Injectable progestogen, Contraceptive vaginal ring, Percutaneous contraceptive
             patches. This is an all-inclusive list of those methods that meet the following GSK
             definition of highly effective: having a failure rate of less than 1% per year when
             used consistently and correctly and, when applicable, in accordance with the product
             label. For non-product methods (e.g., male sterility), the investigator determines
             what is consistent and correct use. The GSK definition is based on the definition
             provided by the International Conference on Harmonization of Technical Requirements
             for Registration of Pharmaceuticals for Human Use (ICH). The investigator is
             responsible for ensuring that subjects understand how to properly use these methods of
             contraception

          -  A female subject is eligible to participate if she is not pregnant, (as confirmed by a
             negative [serum or urine] human chorionic gonadotrophin [hCG] test), not lactating and
             where the following conditions applies: Non-reproductive potential: defined as
             pre-menopausal females with one of the following Documented tubal ligation, Documented
             hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal
             occlusion, Hysterectomy, Documented Bilateral Oophorectomy. Postmenopausal defined as
             12 months of spontaneous amenorrhea (in questionable cases a blood sample with
             simultaneous follicle stimulating hormone [FSH] and estradiol levels consistent with
             menopause [refer to laboratory reference ranges for confirmatory levels]). Females on
             hormone replacement therapy (HRT) and whose menopausal status is in doubt will be
             required to use one of the highly effective contraception methods if they wish to
             continue their HRT during the study. Otherwise, they must discontinue HRT to allow
             confirmation of post-menopausal status prior to study enrolment

          -  Capable of giving signed informed consent

        Exclusion Criteria

          -  Alanine transaminase (ALT) >2xUpper Limit of Normal (ULN) and bilirubin >1.5xULN
             (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct
             bilirubin <35%)

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones)

          -  Heart rate corrected QT interval (QTc) > 450 milliseconds (msec) or QTc > 480 msec in
             subjects with Bundle Branch Block

          -  Asthma exacerbation requiring treatment with oral corticosteroids or hospitalization
             within 3 months prior to screening

          -  History of life-threatening asthma, defined as an asthma episode that required
             intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic
             seizures within the last 10 years

          -  Evidence of concurrent respiratory diseases such as pneumonia, pneumothorax,
             atelectasis, pulmonary fibrotic disease, allergic bronchopulmonary aspergillosis,
             cystic fibrosis, bronchopulmonary dysplasia, or other respiratory abnormalities other
             than asthma

          -  Other concurrent diseases/abnormalities: A subject must not have any clinically
             significant, uncontrolled condition or disease state that, in the opinion of the
             investigator, would put the safety of the subject at risk through study participation
             or would confound the interpretation of the efficacy results if the condition/disease
             exacerbated during the study

          -  Respiratory tract infection that is not resolved within 2 weeks prior to screening

          -  Treatment with intranasal steroid, inhaled corticosteroid (ICS) with or without
             long-acting beta2-agonist (LABA), and treatment with non-ICS controller asthma
             medications (i.e., leukotriene modifier, methylxanthines) within 4 weeks prior to
             screening

          -  Use of long-acting antihistamines within 7 days' or short-acting antihistamines within
             72 hours prior to the screening skin prick test

          -  Treatment with systemic corticosteroids within 6 weeks prior to screening

          -  Use of inhaled SABAs as rescue treatment on average for more than 2 days per week

          -  History of regular alcohol consumption within 6 months of the study defined as: An
             average weekly intake of >14 units for males and females. One unit is equivalent to 8
             gram (g) of alcohol: a half-pint (~240 mililiter [ml]) of beer, 1 glass (125 ml) of
             wine or 1 (25 ml) measure of spirits

          -  Patient known to be intolerant to salbutamol or albuterol

          -  History of sensitivity to any of the study medications, 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

          -  Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test
             result at screening or within 3 months prior to first dose of study treatment

          -  A positive pre-study drug/alcohol screen

          -  A positive test for Human Immunodeficiency Virus (HIV) antibody

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within a 56 day period

          -  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 4 investigational medicinal products within 12 months prior to
             the first dosing day