Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of GSK2292767 in Healthy Participants Who Smoke Cigarettes

This study is the first administration of GSK2292767 to humans. The study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and repeat inhaled doses of GSK2292767 in healthy smokers. This study is intended to provide sufficient confidence in the safety of the molecule and preliminary information on target engagement to allow progression to further repeat dose and proof of mechanism studies. This is a two part, single site, randomized, double-blind (sponsor open), placebo controlled study. Part A will consist of two 3-period interlocking cohorts to evaluate the safety, tolerability and pharmacokinetics of ascending single doses of GSK2292767 administered as a dry powder inhalation. Part B is planned to follow Part A and progression will be based on an acceptable safety, tolerability and pharmacokinetic profiles. Subjects will receive repeat doses of GSK2292767 once daily for 14 days during Part B.


Eligibility Criteria:
Inclusion Criteria:

* Participant must be 18 to 50 years of age inclusive, at the time of signing the informed consent
* Participants who are overtly healthy as determined by medical evaluation including (medical history, physical examination, laboratory tests, and cardiac monitoring). A participant with a clinical abnormality or laboratory parameters outside the reference range expected for them and the population being studied may be included only if the Investigator believes that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures or outcomes
* Participants who are current daily cigarette smokers (manufactured and self-rolled). Must have smoked regularly in the 12-month period preceding the screening visit
* Normal spirometry (FEV1 \>=80% of predicted) at screening
* Body weight \>=50 kilograms (kg) and body mass index (BMI) within the range 18 to 31 kg/square meter (m\^2) (inclusive)
* Male and female

  * Male participants: A male participant must agree to use contraception as detailed in the protocol during the treatment period and for at least from the time of first dose of study medication until at least 55 (5x11) hours plus an additional 90 days after the last dose of study medication and refrain from donating sperm during this period. GSK2292767 has a predicted half-life of approximately 11 hours
  * Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP)
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol

Exclusion Criteria:

* History or presence of current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, haematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data
* Abnormal blood pressure as determined by the investigator
* Alanine transaminase (ALT) \>1.5xupper limit of normal (ULN)
* 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)
* Average corrected QT interval by Fridericia's formula (QTcF) \>450 milliseconds (msec) (based on triplicate ECGs)
* Participants who have asthma or a history of asthma (except in childhood and which has now remitted)
* Past or intended use of over-the-counter or prescription medication including herbal medications within 14 days prior to dosing. Specific concomitant medications listed in protocol may be allowed
* Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during the study
* Participation in the study would result in loss of blood or blood products in excess of 500 milliliters (mL) within 56 days
* Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day
* Current enrolment or past participation within the last 90 days of exposure to any other clinical study involving an investigational study treatment or any other type of medical research
* Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C antibody test result at screening
* Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment
* Positive pre-study drug/alcohol screen
* Positive human immunodeficiency virus (HIV) antibody test
* Regular use of known drugs of abuse
* Regular alcohol consumption within 3 months prior to the study defined as: An average weekly intake of \>14 units for males and females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint (approximately 240 mL of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits
* Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study
* Participants who are unable to produce a total weight of at least 100 milligrams (mg) of selected sputum during sputum induction at screening
* Participants whose primary consumption of tobacco is via methods other than cigarettes (manufactured or self-rolled). Primary methods of tobacco consumption that are excluded include, but are not limited to pipes and cigars