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
Condition: Heart Failure
MeSH terms: Heart Failure
Intervention: GSK2798745; Placebo
Intervention description: GSK2798745 will be supplied as granule filled capsule with unit dose strength of 2.4 mg to be administered orally with 240 mL water.; Placebo will be supplied as blend filled capsule to be administered orally with 240 mL water.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 11.0
Sex: All
Minimum age: 21 Years
Healthy volunteers: No
Keywords: GSK2798745; TRPV4 Channel Blocker; Pharmacodynamics; Adults; Congestive Heart Failure

Summary:

      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.