A Study to Evaluate the Effect of the Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Blocker, GSK2798745, on Pulmonary Gas Transfer and Respiration in Patients With Congestive Heart Failure

This study is a single centre, randomised, double-blind, sponsor-unblinded, placebo-controlled, 2 by 2 crossover study in adults with heart failure. In blocking the TRPV4 ion channel and reducing pulmonary interstitial fluid, GSK2798745 may improve pulmonary function, respiration, and gas exchange as well as sleep-disordered breathing in patients with heart failure. Therefore, the current study is designed to investigate the effect of repeat administration of GSK2798745 on pulmonary gas exchange and pulmonary function.

A sufficient number of subjects with heart failure will be enrolled so that 12 subjects complete the two study periods and critical assessments. Subjects will be randomised to receive either GSK2798745 or placebo once daily for a period of 7 days in one treatment period and alternate study medication in the second treatment period. Both the treatment periods will be separated by a washout period of at least 14-days.

This study will consist of a Screening visit within 14 days of the start of Period I and two treatment periods wherein eligible subjects will be randomised to one of the two treatment sequences, a follow-up visit approximately 2 weeks after the completion of second study period. The total duration of the study is approximately 8 weeks from screening to follow-up visit.


Eligibility Criteria:
Inclusion Criteria:

* \>=21 years of age at the time of signing the informed consent form.
* Diagnosis of heart failure (New York Heart Association Class II-IV) for a minimum of 3 months prior to screening.
* Clinically stable with no changes in optimized guidance-directed medications and no hospitalizations for heart failure for at least 1 month prior to Screening.
* N-terminal pro-B-type Natriuretic Peptide (NT-proBNP) \>1000 picogram per milliliter (pg/mL) measured within 6 months prior to OR at Screening.
* Average DLco measurements outside the normal range (percent \[%\] predicted DLco \< 80%) during the Screening Period.
* Body mass index (BMI) \>=18 and \<=40 kilogram per meter square (kg/m\^2).
* Male or female of non-childbearing potential-
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.

Exclusion Criteria:

* History of acute coronary syndromes including unstable angina or myocardial infarction within 6 months of screening.
* Coronary revascularization including angioplasty and stenting within 6 months of Screening.
* History of stroke or seizure disorder within 5 years of Screening.
* Diagnosis of asthma.
* Diagnosis of chronic obstructive pulmonary disease (COPD) with FEV1 \<50% of predicted measured within 4 weeks of Screening.
* History of a condition that required radiation therapy to the thorax.
* History of any type of malignancy within the past five years with the exception of successfully treated basal cell cancer of the skin.
* Active ulcer disease or gastrointestinal bleeding.
* Current or chronic history of liver disease, known hepatic impairment, or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* Alanine transaminase (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%).
* QT interval corrected (QTc) \> 450 millisecond (msec) or QTc \> 480 msec in subjects with Bundle Branch Block.
* History or current evidence of any serious or clinically significant gastrointestinal, renal, endocrine, neurologic, hematologic or other condition that is uncontrolled on permitted therapies or that would, in the opinion of the investigator or the GlaxoSmithKline (GSK) medical monitor, make the subject unsuitable for inclusion in this study.
* Use of medications specified for the treatment of COPD including short- and long acting bronchodilators (beta-agonists and anticholinergics) and inhaled glucocorticoids as well as oxygen therapy.
* Use of a listed prohibited medication within the restricted timeframe relative to the first dose of study medication.
* Use of a strong inhibitors or inducers of cytochrome P450 (CYP) 3A or p-glycoprotein.
* Current smoker.
* History of drug/substance abuse within the past 2 years.
* History of alcohol abuse within 6 months of the study. Defined as an average weekly alcohol consumption of \>14 drinks for men or \>7 drinks for women. One drink is equivalent to 12 grams (g) of alcohol: approximately 12 ounces (360 milliliters \[mL\]) of beer, 5 ounces (150 mL) of wine, or 1.5 ounces of (45 mL) 80 proof distilled spirits.
* 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 Medical Monitor, contraindicates their participation.
* Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months of screening. For potent immunosuppressive agents, subjects with presence of hepatitis B core antibody (HBcAb) should also be excluded.
* A positive pre-study drug/alcohol screen.
* Use of another investigational product in a clinical study within the following time period prior to the first administration 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 administration of study medication.