A Proof of Mechanism Study With GSK2126458 in Patients With Idiopathic Pulmonary Fibrosis (IPF)

This is a dose escalation/dose finding, double-blind, placebo-controlled, parallel study of GSK2126458 in subjects with IPF. The study is designed to explore a number of doses of GSK2126458 for engagement of pharmacology after short term dosing. It is anticipated that approximately 24 subjects will be enrolled in this study. Actual number of cohorts in this study could vary up to a maximum of 6 cohorts (n=4/cohort; 3 on active and 1 on placebo).

Each cohort will consist of four subjects who will be randomised to receive GSK2126458 (three subjects) or placebo (one subject) for approximately 8 days (7 to 10 days). On Day 1 they will receive their first dose of GSK2126458 (or placebo) and safety, tolerability and PK/PD in the blood will be measured for up to 8 hours post-dose. Subjects will then be discharged from the site with study drug until the last day of dosing. They will also receive hand held spirometers and instructions on action to be taken in case of deterioration in pulmonary function or any other adverse events (AEs). On the last day of dosing they will return to the site for a repeat of the Day 1 procedures.

A bronchoalveolar lavage (BAL) and \[18F\]-fluoro-deoxyglucose (FDG)- positron emission tomography / computed tomography (PET/CT) scan will be conducted twice during the study; once, at least 2 days before dosing commences and again during the course of the dosing period.

After the final subject in each cohort has completed dosing, a dose escalation meeting will take place. Safety and tolerability and PK data will be reviewed during this meeting and decisions made may include but are not limited to: escalate the dose, decrease the dose or repeat the same dose in the next cohort; stop the study.


Eligibility Criteria:
Inclusion Criteria:

* Diagnosis of IPF as determined by a responsible and experienced chest physician and based on established criteria defined by the American Thoracic Society/European Respiratory Society: American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias.
* FVC greater than (\>) 40% predicted and Diffusing capacity of the Lung for Carbon Monoxide (DLCO) \>30% predicted
* Alanine aminotransferase (ALT) less than (\<) 2x upper limit of normal (ULN); alkaline phosphatase and bilirubin less than or equal to (\<=) 1.5xULN.
* QTcB \<450 milliseconds (msec) and QTc interval \<=480 msec; or QTc \<480 msec in subjects with Bundle Branch Block.
* Male over 45 years of age inclusive, or female over 50 years of age inclusive at the time of signing the informed consent
* A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhoea. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception, 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. For most forms of HRT, at least 2 to 4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
* Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study medication until the follow-up contact.
* Body weight \>=40 kilogram (kg) (female), \>=50 kg (male), and body mass index (BMI) between 20 and 35 kg/meter squared (m\^2) inclusive.
* Subjects must have left ventricular ejection fraction (LVEF) \>=50 % as demonstrated by a recent echocardiogram (at screening or within 3 months prior to screening).

Exclusion Criteria:

* Current IPF exacerbation
* History of acute coronary syndromes, atrial fibrillation, coronary angioplasty, or stenting within the past 24 weeks.
* Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
* Uncontrolled hypertension or a history of conditions which could increase the risk of complications from hypertension
* Current upper or lower respiratory tract infection
* Repeated systolic BP \>=160 millimeters of mercury (mmHg) and/or diastolic BP \>=90 mmHg unless they are diabetic, in which case subjects with repeated systolic BP \>=145 mmHg and/or diastolic \>=85 mmHg
* Poorly controlled diabetes (HbA1c \[glycated hemoglobin (hemoglobin A1c)\] \>7.5%).
* Clinically significant laboratory assessment outside the reference range unless the Investigator considers that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities
* Previous exposure to ionising radiation \>5 millisievert (mSv) in the 3 years prior to enrolment
* 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 g of alcohol: a half-pint (approximately 240 milliliters \[mL\]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits
* 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
* Currently taking Pirfenidone or have received Pirfenidone within the previous 30 days
* Unable to refrain from the use of prohibited prescription or non-prescription drugs, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety
* History of sensitivity to any of the study medications, or components there of 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
* History of sensitivity to heparin or heparin-induced thrombocytopenia