A Study to Investigate the Efficacy, Safety, and Tolerability of Repeat Doses of Inhaled GSK2269557 in Adults With Persistent, Uncontrolled Asthma

Inclusion criteria

• Between 18 and 70 years of age inclusive, at the time of signing the informed consent.
• Documented history of bronchial asthma, first diagnosed at least 6 months prior to the screening visit and currently being treated only with an intermittent short acting beta 2 agonist (SABA) or other non-corticosteroid controllers. Non corticosteroid controllers (e.g. leukotriene receptor antagonists [LTRAs]) must be discontinued from Screening until the end of Treatment Period 2.
• Able to replace current SABA treatment with salbutamol metered dose inhaler (MDI) at Screening for use as needed for the duration of the study. Judged capable of withholding salbutamol for at least 4 hours prior to FEV1 assessments.
• No use of an ICS or LABA for at least 12 weeks prior to first dose of study medication.
• A best pre-bronchodilator FEV1 >=60 percent (%) of the predicted normal value at screening.
• FEV1 increase by >=12% and >=200 milliliter (mL) over baseline value within 10-40 minutes of inhalation of 400 mcg salbutamol MDI (a spacer device may be used if required).
• Positive skin prick test to common aero-allergen(s) at screening (not historical).
• Sputum sub-study only: Able to produce >100 milligram (mg) of sputum at screening or during the run-in period.
• Body weight >=45 kilogram (kg) and body mass index (BMI) within the range 18-32 kilogram per meter square (kg/m^2) (inclusive).
• Male subject: Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the first dose of study medication until completion of the follow-up visit.

• Vasectomy with documentation of azoospermia.
• Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant with a <1% rate of failure per year, as stated in the product label; Intrauterine device or intrauterine system with a <1% rate of failure per year, as stated in the product label; Oral contraceptive, either combined or progestogen alone, injectable progestogen; Contraceptive vaginal ring; Percutaneous contraceptive patches.

• Female subject: is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin [hCG] test), not lactating, and at least one of 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.
• Reproductive potential and agrees to follow one of the options listed below in the GlaxoSmithKline (GSK) modified list of highly effective methods for avoiding pregnancy in females of reproductive potential (FRP) requirements from 30 days prior to the first dose of study medication and until completion of the follow-up visit.

Contraceptive subdermal implant that meets the effectiveness criteria including a <1% rate of failure per year, as stated in the product label; Intrauterine device or intrauterine system that meets the effectiveness criteria including a <1% rate of failure per year, as stated in the product label; Oral contraceptive, either combined or progestogen alone; Injectable progestogen; Contraceptive vaginal ring; Percutaneous contraceptive patches; Male partner sterilization with documentation of azoospermia prior to the female subject's entry into the study, and this male is the sole partner for that subject; Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository).

This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long term and persistent basis. These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

• Capable of giving signed informed consent as described in the protocol which includes compliance with the requirements and restrictions listed in the consent form and the protocol. The informed consent must be signed prior to any study related procedure, including change in asthma medication.

Exclusion criteria

• 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.
• Any severe asthma exacerbation, defined as deterioration of asthma requiring the use of systemic corticosteroids (oral, parenteral or depot) within 12 weeks of screening, or an inpatient hospitalisation or emergency department visit due to asthma that required systemic corticosteroids within 6 months of screening.
• Respiratory Infection: culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that has not resolved within 4 weeks of screening and led to a change in asthma management or, in the opinion of the investigator, is expected to affect the subject's asthma status or the subject's ability to participate in the study.
• Concurrent Respiratory Disease: current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, lung cancer, or other respiratory abnormalities other than asthma.
• Alanine aminotransferase (ALT) >2x upper 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).
• QTc >450 millisecond (msec) or QTc >480 msec in subjects with bundle branch block.
• Other laboratory abnormalities or concurrent diseases/clinical: clinically significant laboratory abnormality, uncontrolled condition or disease state that, in the opinion of the investigator (in consultation with the GSK Medical Monitor, if required), 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.
• Use of any of the prohibited medications listed in the protocol.
• Current smokers or subjects with a history of smoking within 6 months of screening, or with a total pack year history of >5 pack years.
• History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 gram (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
• History of sensitivity to any of the study medications, or components thereof (including lactose) or a history of drug or other allergy (including a milk protein allergy) that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
• Sputum sub-study only: History of sensitivity to the induced sputum procedure.
• 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 medication.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dose of study medication 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 dose of study medication.
• Affiliation with investigator site: subject is an investigator; sub-investigator; study co-ordinator; employee of a participating investigator or study site; or, an immediate family member of the aforementioned, that is involved in this study.