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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02497937
• Collaborator: (none)
• Enrollment: 11
• Locations: 2
• Arm: 1
• Actual Duration (Months): 16.3
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: GSK2798745; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Sponsor Un-blinded, Placebo-controlled, Phase 2a Crossover Study to Evaluate the Effect of the TRPV4 Channel Blocker, GSK2798745, on Pulmonary Gas Transfer and Respiration in Patients With Congestive Heart Failure
• Actual Study Start Date: Apr 13, 2016
• Actual Primary Completion Date: Aug 21, 2017
• Actual Study Completion Date: Aug 21, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GSK2798745 and Placebo Each subject will be randomized to receive GSK2798745 2.4 milligrams (mg) and Placebo once daily for 7 days, each in one of the two treatment periods. Two treatment periods will be separated by a 14-day washout period.	Drug: GSK2798745; GSK2798745 will be supplied as granule filled capsule with unit dose strength of 2.4 mg to be administered orally with 240 mL water.; Drug: Placebo; Placebo will be supplied as blend filled capsule to be administered orally with 240 mL water.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Diffusing Capacity of the Lung for Carbon Monoxide (DLco) on Pulmonary Gas Transfer (Site: Mayo) [Baseline, Day 4, Day 5 and Day 7 of each treatment period]

   DLco is a measure of the ability of a gas to transfer from alveoli across the alveolar epithelium and capillary endothelium to the red blood cells. Changes in DLco reflect the alveolar-capillary membrane conductance. Acute pulmonary congestion causes a reduction in DLco. In participants with heart failure, decrease in DLco serves as a predictor of disease progression. An impairment in the diffusing capacity of the lung may be related to symptoms and exercise intolerance associated with heart failure. DLco was measured just prior to and after the 3- minute step test on Days -1, and 7 and just prior to and after an intravenous saline infusion on Day 5. Day -1 was Baseline and change from Baseline was calculated from Day -1 pre-exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as Baseline. Data of DLco (milliliter per millimeter of mercury per minute [mL/mmHg/min]) for Mayo site is presented.

2. Change From Baseline in the Diffusing Capacity of the Lung for DLco on Pulmonary Gas Transfer (Site: Hennepin) [Baseline, Day 4, Day 5 and Day 7 of each treatment period]

   DLco is a measure of the ability of a gas to transfer from the alveoli across the alveolar epithelium and the capillary endothelium to the red blood cells. Changes in DLco reflect the alveolar-capillary membrane conductance. Acute pulmonary congestion cause a reduction in DLco. In participants with heart failure, decrease in DLco serves as a predictor of disease progression. An impairment in the diffusing capacity of the lung may be related to the symptoms and exercise intolerance associated with heart failure. DLco was measured just prior to and after the 3- minute step test on Days -1, and 7 and just prior to and after an intravenous saline infusion on Day 5. Day -1 was Baseline and change from Baseline was calculated from Day -1 Pre-Exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as the Baseline. Statistical analysis was not performed as the sample size was too small

Secondary Outcome Measures

1. Change From Baseline in Diffusing Capacity of the Lung for Nitric Oxide (DLno) and Membrane Conductance (DM) [Baseline, Day 4, Day 5 and Day 7 of each treatment period]

   DLno is a measure of the ability of a gas to transfer from the alveoli across the alveolar epithelium and the capillary endothelium to the red blood cells. Changes in DLco reflect the alveolar-capillary DM. Since nitric oxide has a greater affinity for hemoglobin, transfer of gas mainly limits the diffusion of nitric oxide across the alveolar capillary membrane. Day -1 was Baseline and change from Baseline was calculated from Day -1 pre-exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as Baseline. The data is presented only for participants from the Mayo Clinic as the data was not collected at Hennepin.

2. Change From Baseline in Capillary Blood Volume (Vc) [Baseline, Day 4, Day 5 and Day 7 of each treatment period]

   Vc is defined as volume of blood within the capillaries. Day -1 was Baseline and change from Baseline was calculated from Day -1 pre-exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as the Baseline. The data is presented only for participants from the Mayo Clinic as the data was not collected at Hennepin.

3. Change From Baseline in DLco Following Exercise and Following an Intravenous Saline Infusion (Site: Mayo) [Baseline, Day 5 and Day 7 of each treatment period]

   DLco is a measure of the ability of a gas to transfer from the alveoli across the alveolar epithelium and the capillary endothelium to the red blood cells. Changes in DLco reflect the alveolar-capillary membrane conductance. Acute pulmonary congestion causes a reduction in DLco. In participants with heart failure, decrease in DLco serves as a predictor of disease progression. DLco was measured just prior to and after the 3- minute step test on Days -1, and 7 and just prior to and after an intravenous saline infusion on Day 5. Day -1 was Baseline and change from Baseline was calculated from Day -1 pre-exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as the Baseline. Data for DLco following exercise and following an intravenous saline infusion is presented for Mayo site.

4. Change From Baseline in DLco Following Exercise and Following an Intravenous Saline Infusion (Site: Hennepin) [Baseline, Day 5 and Day 7 of each treatment period]

   DLco is a measure of the ability of a gas to transfer from the alveoli across the alveolar epithelium and the capillary endothelium to the red blood cells. Changes in DLco reflect the alveolar-capillary membrane conductance. Acute pulmonary congestion cause a reduction in DLco. In participants with heart failure, decrease in DLco serves as a predictor of disease progression. DLco was measured just prior to and after the 3- minute step test on Days -1, and 7 and just prior to and after an intravenous saline infusion on Day 5. Day -1 was Baseline and change from Baseline was calculated from Day -1 pre-Exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as the Baseline. Data for DLco following exercise and following an intravenous saline infusion is presented for Hennepin site is presented.

5. Change From Baseline in the Ventilation/Volume of Carbon Dioxide Production (VE/VCO2) Ratio [Baseline and Day 7 of each treatment period]

   Participants were asked to participate in a submaximal exercise test that consisted of 3 parts: a 2-minute (min) resting Baseline, a 3-min step exercise and a 1-min recovery period. Throughout the test, breathing pattern, gas exchange, and heart rate were monitored using a simplified gas analysis system. Respiratory exchange ratio and the Borg Rating of Perceived Exertion measures were utilized to ensure participants perform progressive exercise while maintaining a submaximal level throughout the exercise period. Minute ventilation, breath frequency, tidal volume, oxygen consumption, carbon dioxide (CO2) production, Respiratory exchange ratio (RER) and end tidal CO2 were obtained from the breath-by-breath gas measurements. The VE/VCO2 slope and other variables were derived from this data. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.

6. Change From Baseline in Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 Second (FEV1), Forced Expiratory Flows (FEF) 25-75, FEF50 and FEF75 [Baseline, Day 4 and Day 7 of each treatment period]

   FEV1 was defined as the volume of air that can be forced out in one second after taking a deep breath. FVC is the total amount of air exhaled during the lung function test. FEF is the the flow (or speed) of air coming out of the lung during the middle portion of a forced expiration. FEF 25-75, FEF50 and FEF75 is defined as a reduction in forced expiratory flow at 25 to 75 percent of the pulmonary volume. Results presented combines data across all sites. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.

7. Change From Baseline in Functional Residual Capacity (FRC) [Baseline, Day 4 and Day 7 of each treatment period]

   FRC is the volume of air present in the lungs at the end of passive expiration. FRC was planned to be measured by body plethysmography. Analysis was planned but not performed. FRC parameter was not collected because other measures which were collected served as reasonable surrogates.

8. Change From Baseline in End-expiratory Lung Volume (EELV) Measured by Body Plethysmograph [Baseline, Day 4 and Day 7 of each treatment period]

   EELV corresponds to FRC in the presence of positive end expiration pressure (PEEP). Analysis was planned but not performed. EELV parameter was not collected because other measures which were collected served as reasonable surrogates.

9. Change From Baseline in Dyspnea Score [Baseline, Day 5 and Day 7 of each treatment period]

   Dyspnea was assessed using a standardized, validated 5-point Likert scale. Participants were asked to check the box next to the statement that most accurately described their current state of breathlessness or shortness of breath. Scale consisted of 5 points : 1- Not short of breath, 2- Mildly short of breath, 3- Moderately short of breath, 4- Severely short of breath and 5- Very severely short of breath. Participants rated their current state of breathlessness on this 5 point scale. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point .

10. Respiratory Rate Over Time Continuously Measured by Body Sensor (Site: Mayo Only) [Up to Day 7 of each treatment period]

    Continuous remote monitoring was performed during each 7-day study period utilizing the Preventice BodyGuardian Remote Monitoring System. Participants were instructed to wear the sensor throughout each study period. Respiratory monitoring data was collected in different body positions like standing, leaning, lying and unknown. Data is presented only for participants from Mayo clinic.

11. Change From Baseline in Systolic Blood Pressure(SBP) and Diastolic Blood Pressure (DBP) [Baseline and up to Day 7 of each treatment period]

    SBP and DBP were measured in a semi-supine position after 5 minutes rest at Baseline and up to 7 days of each treatment period. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.

12. Change From Baseline in Heart Rate [Baseline and up to Day 7 of each treatment period]

    Heart rate was measured in a semi-supine position after 5 minutes rest at Baseline and up to 7 days of each treatment period. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.

13. Change From Baseline in Respiration Rate [Baseline and up to Day 7 of each treatment period]

    Respiration rate was measured in a semi-supine position after 5 minutes rest at Baseline and up to 7 days of each treatment period. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.

14. Change From Baseline in Temperature [Baseline and up to Day 7 of each treatment period]

    Body temperature was measured in a semi-supine position after 5 minutes rest at Baseline and up to 7 days of each treatment period. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.

15. Change From Baseline in Percent Oxygen in Blood [Baseline and up to Day 7 of each treatment period]

    Percent oxygen in blood was measured using pulse oximetry in a semi-supine position after 5 minutes rest at Baseline and up to 7 days of each treatment period. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.

16. Number of Participants With Abnormal Electrocardiogram (ECG) Findings [Up to Day 7 in each treatment period]

    Triplicate 12-lead ECG was obtained using an automated ECG machine at Baseline (Day-1) and single ECG measurements (M) were taken on Day 4 and Day 7. Data for number of participants with abnormal-clinically significant (CS) and abnormal-not clinically significant (NCS) ECG data is presented.

17. Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST), Creatine Kinase, Gamma Glutamyl Transferase (GGT) Values [Baseline and up to Day 7 in each treatment period]

    Blood samples were collected to analyze the chemistry parameters including ALT, ALP, AST, creatine kinase and GGT. Change from Baseline is presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.

18. Change From Baseline in Albumin and Total Protein Values [Baseline and up to Day 7 of each treatment period]

    Blood samples were collected to analyze the chemistry parameters including albumin and total protein. Change from Baseline is presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.

19. Change From Baseline in Chemistry: Calcium, Chloride, Glucose, Potassium, Sodium, Urea/Blood Urea Nitrogen (BUN) [Baseline and up to Day 7 of each treatment period]

    Blood samples were collected to analyze the chemistry parameters including Calcium, Chloride, Glucose, Potassium, Sodium, Urea/BUN. Change from Baseline is presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.

20. Change From Baseline in Creatinine, Direct Bilirubin, Total Bilirubin, Uric Acid [Baseline and up to Day 7 of each treatment period]

    Blood samples were collected to analyze the chemistry parameters including Creatinine, Direct Bilirubin, Total Bilirubin and Uric acid. Change from Baseline was presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the baseline value from specified time point value.

21. Change From Baseline in Digoxin Level [Baseline and up to Day 7 in each treatment period]

    Blood samples were collected to analyze the digoxin levels. Change from Baseline is presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the baseline value from specified time point value. NA indicates data not available. Standard deviation could not be calculated as a single participant was analyzed.

22. Change From Baseline in Troponin I Levels and Type I Collagen Cross-linked C-telopeptide [Baseline and up to Day 7 in each treatment period]

    Blood samples were collected to analyze the troponin I level and type I collagen cross-linked C-telopeptide (T1CCT). Change from Baseline was presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.

23. Change From Baseline in Chemistry: N-terminal Pro-Brain Natriuretic Peptide [Baseline and up to Day 7 in each treatment period]

    Blood samples were collected to analyze the Chemistry parameter N-terminal pro-Brain Natriuretic Peptide. Change from Baseline is presented for these parameters. Day -1 was Baseline and change from Baseline is calculated by subtracting the baseline value from specified time point value.

24. Change From Baseline in Hematology: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, White Blood Cell (WBC) Count, Total Neutrophils [Baseline and up to Day 7 in each treatment period]

    Blood samples were collected to analyze the Hematology parameters including Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet count, White Blood Cell (WBC) count, Total Neutrophils. Change from Baseline is presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.

25. Change From Baseline in Hematocrit [Baseline and up to Day 7 in each treatment period]

    Blood samples were collected to analyze the Hematology parameter Hematocrit. Change from Baseline is presented for this parameter. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.

26. Change From Baseline in Hemoglobin [Baseline and up to Day 7 in each treatment period]

    Blood samples were collected to analyze Hemoglobin. Change from Baseline is presented for this parameter. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.

27. Change From Baseline in Mean Corpuscle Volume [Baseline and up to Day 7 in each treatment period]

    Blood samples were collected to analyze Mean Corpuscle Volume. Change from Baseline is presented for this parameter. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.

28. Change From Baseline in Red Blood Cell Count (RBC) and Reticulocytes [Baseline and up to Day 7 in each treatment period]

    Blood samples were collected to analyze the Hematology parameters including RBC and Reticulocytes. Change from Baseline is presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.

29. Change From Baseline in Mean Corpuscle Hemoglobin Concentration [Baseline and up to Day 7 in each treatment period]

    Blood samples were collected to analyze Mean Corpuscle Hemoglobin concentration . Change from Baseline is presented for this parameter. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value. NA indicates data was not available. Standard deviation could not be calculated as a single participant was analyzed at the specified time point

30. Change From Baseline in Mean Corpuscle Hemoglobin [Baseline and up to Day 7 in each treatment period]

    Blood samples were collected to analyze Mean Corpuscle Hemoglobin. Change from Baseline was presented for this parameter. Day -1 was Baseline and change from Baseline was calculated by subtracting the baseline value from specified time point value. NA indicates data was not available. Standard deviation could not be calculated as a single participant was analyzed at the specified time point

31. Number of Participants With All Adverse Events (AE) and Serious Adverse Events (SAE) [Up to Day 46]

    An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinemia were categorized as SAE. Number of participants with AE and SAE are reported.

32. Change From Baseline in Participant Reported Health Status (SF-36) Acute Score [Baseline and Day 7 of each treatment period]

    The SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The vitality sub-score assesses energy and fatigue, and ranges from 0 (worst) - 100 (best). Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.

33. Area Under the Concentration Time Curve (AUC) Time Zero to the Last Time of the Last Quantifiable Concentration (AUC(0-t)), AUC Over the Dosing Interval After First and Last Dose (AUC(0-tau)) and AUCall for GSK2798745 [Day 1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours post-dose), Day 2 (pre-dose, 12 hours post-dose), Days 3 to 6 (pre-dose), Day 7 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 10, 24 and 48 hours post-dose)]

    AUC(0-t), AUC(0-tau) and AUCall for GSK2798745 were determined based on intensive Pharmacokinetic (PK) sampling at the following time points: Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours on Day 1, pre-dose and at 12 hours post dose on Day 2, pre-dose on Days 3 to 6, Pre-dose, 0.5, 1, 1.5, 2, 3, 5 and 10 hours on Day 7 and at 24 and 48 hours. PK parameter population included all participants in the PK Concentration Population for whom valid and evaluable pharmacokinetic parameters were derived

34. Maximum Drug Concentration (Cmax) for GSK2798745 [Day 1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours post-dose), Day 2 (pre-dose, 12 hours post-dose), Days 3 to 6 (pre-dose), Day 7 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 10, 24 and 48 hours post-dose)]

    Blood samples for PK analysis were collected at pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours on Day 1, pre-dose and at 12 hours post dose on Day 2, pre-dose on Days 3 to 6, Pre-dose, 0.5, 1, 1.5, 2, 3, 5 and 10 hours on Day 7 and at 24 and 48 hours on Days 8 and 9. Cmax was defined as maximum observed plasma concentration of drug.

35. Time to Maximum Observed Plasma Concentration (Tmax) for GSK2798745 [Day 1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours post-dose), Day 2 (pre-dose, 12 hours post-dose), Days 3 to 6 (pre-dose), Day 7 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 10, 24 and 48 hours post-dose)]

    Blood samples for PK analysis were collected at pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours on Day 1, pre-dose and at 12 hours post dose on Day 2, pre-dose on Days 3 to 6, Pre-dose, 0.5, 1, 1.5, 2, 3, 5 and 10 hours on Day 7 and at 24 and 48 hours on Days 8 and 9. Tmax was defined as time to maximum observed plasma concentration of drug.

36. Elimination Half Life (T½) for GSK2798745 [Day 1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours post-dose), Day 2 (pre-dose, 12 hours post-dose), Days 3 to 6 (pre-dose), Day 7 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 10, 24 and 48 hours post-dose)]

    Blood samples for PK analysis were planned to be collected at pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours on Day 1, pre-dose and at 12 hours post dose on Day 2, pre-dose on Days 3 to 6, Pre-dose, 0.5, 1, 1.5, 2, 3, 5 and 10 hours on Day 7 and at 24 and 48 hours on Days 8 and 9. T½ was defined as Elimination half life of drug. Data is not available for t1/2. The analysis was planned but not performed. PK sampling scheme was not adequate enough to reliably estimate the t1/2 of GSK2798745.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Minneapolis	Minnesota	United States	55415
2	GSK Investigational Site	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Study Protocol - Apr 19, 2016
• Statistical Analysis Plan - Oct 18, 2017

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT02497937
• Other Study ID Numbers: 201881
• First Posted: Jul 15, 2015
• Last Update Posted: Sep 5, 2018
• Last Verified: Apr 1, 2018

• Keywords provided by GlaxoSmithKline: GSK2798745; TRPV4 Channel Blocker; Pharmacodynamics; Adults; Congestive Heart Failure
• Additional relevant MeSH terms: Heart Failure

Study Results

Participant Flow

Recruitment Details	This was a randomized, double-blind, sponsor-unblinded, placebo-controlled, 2 by 2 crossover study in adults with heart failure. A total of 11 participants with Congestive Heart Failure were enrolled in the study. Study was conducted in the United States.

Arm/Group Title	Sequence A (GSK2798745 2.4 mg)/P (Placebo)	Sequence P (Placebo)/A (GSK2798745 2.4 mg)
Arm/Group Description	Eligible participants were randomized to one of two treatment sequences AP and PA where A=GSK2798745 2.4 mg and P=Placebo. In this sequence, participants received GSK2798745 2.4 milligrams (mg) once daily orally with 240 milliliter (mL) water in Period 1 and placebo in Period 2 for 7 days. Treatment periods were separated by a washout period of 14 days.	Eligible participants were randomized to one of two treatment sequences AP and PA where A=GSK2798745 2.4 mg and P=Placebo. In this sequence, participants received placebo in Period 1 and GSK2798745 2.4mg once daily orally with 240 mL water in Period 2 for 7 days. Treatment periods were separated by a washout period of 14 days.
Period Title: Period 1 (Up to 7 Days)
STARTED	6	5
COMPLETED	6	5
NOT COMPLETED	0	0
Period Title: Period 1 (Up to 7 Days)
STARTED	6	5
COMPLETED	6	5
NOT COMPLETED	0	0
Period Title: Period 1 (Up to 7 Days)
STARTED	6	5
COMPLETED	6	5
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Treatment Combined
Arm/Group Description	Eligible participants were randomized to one of two treatment sequences AP and PA where A=GSK2798745 2.4 mg and P=Placebo. In sequence AP, participants received GSK2798745 2.4 milligrams (mg) once daily orally with 240 milliliter (mL) water in Period 1 and placebo in Period 2 for 7 days. In sequence PA, participants received placebo in Period 1 and GSK2798745 2.4mg once daily orally with 240 mL water in Period 2 for 7 days. In both sequence AP and PA, treatment periods were separated by a washout period of 14 days. Data represents all treatments combined.
Overall Participants	11
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	67.7 (12.90)
Sex: Female, Male (Count of Participants)
Female	2 18.2%
Male	9 81.8%
Race/Ethnicity, Customized (Count of Participants)
African American/African Heritage	4 36.4%
White	7 63.6%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Diffusing Capacity of the Lung for Carbon Monoxide (DLco) on Pulmonary Gas Transfer (Site: Mayo)
Description	DLco is a measure of the ability of a gas to transfer from alveoli across the alveolar epithelium and capillary endothelium to the red blood cells. Changes in DLco reflect the alveolar-capillary membrane conductance. Acute pulmonary congestion causes a reduction in DLco. In participants with heart failure, decrease in DLco serves as a predictor of disease progression. An impairment in the diffusing capacity of the lung may be related to symptoms and exercise intolerance associated with heart failure. DLco was measured just prior to and after the 3- minute step test on Days -1, and 7 and just prior to and after an intravenous saline infusion on Day 5. Day -1 was Baseline and change from Baseline was calculated from Day -1 pre-exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as Baseline. Data of DLco (milliliter per millimeter of mercury per minute [mL/mmHg/min]) for Mayo site is presented.
Time Frame	Baseline, Day 4, Day 5 and Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

Analysis Population comprised of participants in the 'All Subjects' population having Baseline and post-Baseline assessments of the endpoint of interest for both periods. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	7	7
Day -1, post exercise,n =7,7	0.6 (0.98)	1.4 (1.47)
Day 4, n =6,7	-0.4 (0.85)	0.6 (1.16)
Day 5,pre infusion,n =7,7	-1.0 (0.94)	0.4 (1.31)
Day 5,post infusion,n =7,7	-0.8 (0.65)	-0.7 (0.81)
Day 7,pre exercise,n =7,7	-0.6 (1.63)	0.7 (1.91)
Day 7,post exercise,n =7,7	0.4 (1.38)	1.6 (2.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2798745 2.4 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.793
	Confidence Interval	(2-Sided) 95%; -0.925 to 2.512
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference estimate of DLco on Day 7 has been presented for Mayo site

2. Primary Outcome

Title	Change From Baseline in the Diffusing Capacity of the Lung for DLco on Pulmonary Gas Transfer (Site: Hennepin)
Description	DLco is a measure of the ability of a gas to transfer from the alveoli across the alveolar epithelium and the capillary endothelium to the red blood cells. Changes in DLco reflect the alveolar-capillary membrane conductance. Acute pulmonary congestion cause a reduction in DLco. In participants with heart failure, decrease in DLco serves as a predictor of disease progression. An impairment in the diffusing capacity of the lung may be related to the symptoms and exercise intolerance associated with heart failure. DLco was measured just prior to and after the 3- minute step test on Days -1, and 7 and just prior to and after an intravenous saline infusion on Day 5. Day -1 was Baseline and change from Baseline was calculated from Day -1 Pre-Exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as the Baseline. Statistical analysis was not performed as the sample size was too small
Time Frame	Baseline, Day 4, Day 5 and Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

Analysis Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	4	4
Day -1, post exercise, n =4, 3	1.3 (1.32)	1.0 (0.47)
Day 4, n =4, 3	1.5 (1.11)	0.1 (1.05)
Day 5,pre infusion,n =4,3	0.2 (0.53)	-0.3 (0.24)
Day 5,post infusion,n =4,4	0.7 (1.47)	0.8 (1.31)
Day 7,pre exercise, n =4,3	0.4 (1.82)	-0.6 (1.20)
Day 7,post exercise, n =4,3	1.2 (1.01)	0.4 (1.12)

3. Secondary Outcome

Title	Change From Baseline in Diffusing Capacity of the Lung for Nitric Oxide (DLno) and Membrane Conductance (DM)
Description	DLno is a measure of the ability of a gas to transfer from the alveoli across the alveolar epithelium and the capillary endothelium to the red blood cells. Changes in DLco reflect the alveolar-capillary DM. Since nitric oxide has a greater affinity for hemoglobin, transfer of gas mainly limits the diffusion of nitric oxide across the alveolar capillary membrane. Day -1 was Baseline and change from Baseline was calculated from Day -1 pre-exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as Baseline. The data is presented only for participants from the Mayo Clinic as the data was not collected at Hennepin.
Time Frame	Baseline, Day 4, Day 5 and Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

Analysis Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	7	7
DLno,Day -1,post-exercise, n =7, 7	2.1 (1.87)	3.5 (3.66)
DLno,Day 4, n =6, 7	-2.3 (4.01)	5.0 (5.51)
DLno,Day 5,pre-infusion, n =7, 7	-6.0 (6.50)	2.4 (8.56)
DLno,Day 5,post-infusion, n =7, 7	-2.7 (3.83)	-3.3 (3.27)
DLno,Day 7,pre-exercise, n =7, 7	-1.9 (6.19)	6.0 (9.96)
DLno,Day 7, post-exercise,n =7,7	1.5 (5.37)	8.6 (10.19)
DM,Day -1,post-exercise, n =7, 7	1.0 (0.85)	1.7 (1.53)
DM,Day 4, n =6, 7	-1.0 (1.82)	2.4 (2.61)
DM,Day 5,pre-infusion, n =7, 7	-2.7 (2.95)	1.2 (3.92)
DM,Day 5,post-infusion, n =7, 7	-1.2 (1.74)	-1.5 (1.49)
DM,Day 7,pre-exercise, n =7, 7	-0.9 (2.81)	2.8 (4.55)
DM,Day 7, post-exercise,n =7,7	0.7 (2.44)	4.1 (4.74)

4. Secondary Outcome

Title	Change From Baseline in Capillary Blood Volume (Vc)
Description	Vc is defined as volume of blood within the capillaries. Day -1 was Baseline and change from Baseline was calculated from Day -1 pre-exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as the Baseline. The data is presented only for participants from the Mayo Clinic as the data was not collected at Hennepin.
Time Frame	Baseline, Day 4, Day 5 and Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

Analysis Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	7	7
Day -1,post exercise, n =7, 7	1.6 (8.39)	10.4 (14.77)
Day 4, n =6, 7	-2.6 (8.64)	-0.2 (9.40)
Day 5,pre infusion, n =7, 7	-0.1 (11.60)	3.0 (12.99)
Day 5,post infusion, n =7, 7	-4.9 (14.19)	-2.3 (11.70)
Day 7,pre exercise, n =7, 7	-4.7 (12.86)	-2.6 (13.99)
Day 7, post exercise,n =7,7	0.3 (12.33)	3.3 (15.35)

5. Secondary Outcome

Title	Change From Baseline in DLco Following Exercise and Following an Intravenous Saline Infusion (Site: Mayo)
Description	DLco is a measure of the ability of a gas to transfer from the alveoli across the alveolar epithelium and the capillary endothelium to the red blood cells. Changes in DLco reflect the alveolar-capillary membrane conductance. Acute pulmonary congestion causes a reduction in DLco. In participants with heart failure, decrease in DLco serves as a predictor of disease progression. DLco was measured just prior to and after the 3- minute step test on Days -1, and 7 and just prior to and after an intravenous saline infusion on Day 5. Day -1 was Baseline and change from Baseline was calculated from Day -1 pre-exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as the Baseline. Data for DLco following exercise and following an intravenous saline infusion is presented for Mayo site.
Time Frame	Baseline, Day 5 and Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

Analysis Population.

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	7	7
Day -1,post exercise	0.6 (0.98)	1.4 (1.47)
Day 5,post infusion	-0.8 (0.65)	-0.7 (0.81)
Day 7, post exercise	0.4 (1.38)	1.6 (2.45)

6. Secondary Outcome

Title	Change From Baseline in DLco Following Exercise and Following an Intravenous Saline Infusion (Site: Hennepin)
Description	DLco is a measure of the ability of a gas to transfer from the alveoli across the alveolar epithelium and the capillary endothelium to the red blood cells. Changes in DLco reflect the alveolar-capillary membrane conductance. Acute pulmonary congestion cause a reduction in DLco. In participants with heart failure, decrease in DLco serves as a predictor of disease progression. DLco was measured just prior to and after the 3- minute step test on Days -1, and 7 and just prior to and after an intravenous saline infusion on Day 5. Day -1 was Baseline and change from Baseline was calculated from Day -1 pre-Exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as the Baseline. Data for DLco following exercise and following an intravenous saline infusion is presented for Hennepin site is presented.
Time Frame	Baseline, Day 5 and Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

Analysis Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	4	4
Day -1,post exercise,n=4,3	1.3 (1.32)	1.0 (0.47)
Day 5,post infusion,n=4,4	0.7 (1.47)	0.8 (1.31)
Day 7, post exercise,n=4,3	1.2 (1.01)	0.4 (1.12)

7. Secondary Outcome

Title	Change From Baseline in the Ventilation/Volume of Carbon Dioxide Production (VE/VCO2) Ratio
Description	Participants were asked to participate in a submaximal exercise test that consisted of 3 parts: a 2-minute (min) resting Baseline, a 3-min step exercise and a 1-min recovery period. Throughout the test, breathing pattern, gas exchange, and heart rate were monitored using a simplified gas analysis system. Respiratory exchange ratio and the Borg Rating of Perceived Exertion measures were utilized to ensure participants perform progressive exercise while maintaining a submaximal level throughout the exercise period. Minute ventilation, breath frequency, tidal volume, oxygen consumption, carbon dioxide (CO2) production, Respiratory exchange ratio (RER) and end tidal CO2 were obtained from the breath-by-breath gas measurements. The VE/VCO2 slope and other variables were derived from this data. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.
Time Frame	Baseline and Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

Analysis Population

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Period 1 Day -1,post 1 min	1.3 (3.1)	0.3 (5.0)
Period 1 Day -1,at rest,post 2 min	1.6 (6.40)	1.8 (11.93)
Period 1 Day -1,post 3 min	0.7 (9.15)	-4.5 (6.68)
Period 1 Day -1,recovery	-5.1 (4.17)	-5.7 (4.31)
Period 1 Day 7,at rest	2.4 (10.1)	0.6 (2.1)
Period 1 Day 7,post 1 min	0.7 (10.1)	0.0 (3.8)
Period 1 Day 7,post 2 min	-1.2 (11.99)	1.6 (10.37)
Period 1 Day 7,post 3 min	1.6 (13.29)	-1.2 (3.97)
Period 1 Day 7,recovery	-8.0 (5.68)	-5.4 (3.26)
Period 2 Day -1,post 1 min	-3.6 (4.1)	-2.1 (4.5)
Period 2 Day -1,post 2 min	-3.7 (4.68)	-2.8 (5.74)
Period 2 Day -1,post 3 min	-4.7 (6.65)	-4.2 (5.86)
Period 2 Day -1,Recovery	-9.3 (3.04)	-7.6 (6.13)
Period 2 Day 7 at rest	-2.5 (6.3)	-0.9 (4.2)
Period 2 Day 7,post 1 min	-4.0 (4.4)	-2.5 (3.7)
Period 2 Day 7,post 2 min	-2.6 (4.16)	-3.9 (4.98)
Period 2 Day 7,post 3 min	-0.7 (10.21)	-6.4 (3.65)
Period 2 Day 7,Recovery	-2.1 (22.58)	-7.6 (5.17)

8. Secondary Outcome

Title	Change From Baseline in Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 Second (FEV1), Forced Expiratory Flows (FEF) 25-75, FEF50 and FEF75
Description	FEV1 was defined as the volume of air that can be forced out in one second after taking a deep breath. FVC is the total amount of air exhaled during the lung function test. FEF is the the flow (or speed) of air coming out of the lung during the middle portion of a forced expiration. FEF 25-75, FEF50 and FEF75 is defined as a reduction in forced expiratory flow at 25 to 75 percent of the pulmonary volume. Results presented combines data across all sites. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.
Time Frame	Baseline, Day 4 and Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

Analysis Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
FVC,Day 4,n=10,11	-0.0 (0.11)	-0.1 (0.10)
FVC,Day 7,n=11,11	-0.0 (0.10)	-0.0 (0.19)
FEV1,Day 4,n=10,11	-0.1 (0.09)	-0.0 (0.09)
FEV1,Day 7,n=11,11	-0.1 (0.08)	-0.0 (0.12)
FEF 25-75,Day 4,n=10,11	-0.2 (0.26)	0.1 (0.34)
FEF 25-75,Day 7,n=11,11	-0.1 (0.16)	-0.1 (0.25)
FEF50,Day 4,n=10,11	-0.3 (0.36)	0.0 (0.43)
FEF50,Day 7,n=11,11	-0.2 (0.30)	-0.0 (0.32)
FEF75,Day 4,n=10,11	-0.0 (0.08)	0.0 (0.14)
FEF75,Day 7,n=11,11	-0.0 (0.06)	-0.0 (0.10)

9. Secondary Outcome

Title	Change From Baseline in Functional Residual Capacity (FRC)
Description	FRC is the volume of air present in the lungs at the end of passive expiration. FRC was planned to be measured by body plethysmography. Analysis was planned but not performed. FRC parameter was not collected because other measures which were collected served as reasonable surrogates.
Time Frame	Baseline, Day 4 and Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

Analysis Population. Analysis was planned but not performed. FRC parameter was not collected because other measures which were collected served as reasonable surrogates.

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	0	0

10. Secondary Outcome

Title	Change From Baseline in End-expiratory Lung Volume (EELV) Measured by Body Plethysmograph
Description	EELV corresponds to FRC in the presence of positive end expiration pressure (PEEP). Analysis was planned but not performed. EELV parameter was not collected because other measures which were collected served as reasonable surrogates.
Time Frame	Baseline, Day 4 and Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

Analysis Population. Analysis was planned but not performed. EELV parameter was not collected because other measures which were collected served as reasonable surrogates.

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	0	0

11. Secondary Outcome

Title	Change From Baseline in Dyspnea Score
Description	Dyspnea was assessed using a standardized, validated 5-point Likert scale. Participants were asked to check the box next to the statement that most accurately described their current state of breathlessness or shortness of breath. Scale consisted of 5 points : 1- Not short of breath, 2- Mildly short of breath, 3- Moderately short of breath, 4- Severely short of breath and 5- Very severely short of breath. Participants rated their current state of breathlessness on this 5 point scale. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point .
Time Frame	Baseline, Day 5 and Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

Analysis Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Period 1 Day-1,post exercise,n=4,2	0.5 (0.58)	0.5 (0.71)
Period 1 Day5,pre infusion,n=5,6	0.2 (0.45)	-0.2 (0.41)
Period 1 Day5,pre infusion-Orthopnea,n=5,6	0.2 (0.45)	-0.2 (0.41)
Period 1 Day7,pre exercise,n=5,6	0.0 (0.00)	0.0 (0.63)
Period 1 Day7,post exercise,n=3,2	1.3 (2.31)	0.5 (0.71)
Period 2 Day -1,post exercise,n=2,3	2.0 (2.83)	1.3 (1.15)
Period 2 Day5,pre infusion,n=6,5	-0.3 (1.03)	-0.2 (1.10)
Period 2 Day5,pre infusion-Orthopnea,n=6,5	-0.3 (1.03)	-0.4 (0.89)
Period 2 Day7,pre exercise,n=6,5	-0.5 (0.84)	-0.4 (0.89)
Period 2 Day7,post exercise,n=3,4	-1.0 (1.00)	0.3 (1.71)

12. Secondary Outcome

Title	Respiratory Rate Over Time Continuously Measured by Body Sensor (Site: Mayo Only)
Description	Continuous remote monitoring was performed during each 7-day study period utilizing the Preventice BodyGuardian Remote Monitoring System. Participants were instructed to wear the sensor throughout each study period. Respiratory monitoring data was collected in different body positions like standing, leaning, lying and unknown. Data is presented only for participants from Mayo clinic.
Time Frame	Up to Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects population comprised of all randomized participants who received at least one dose of study medication. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	7	7
Day -1,Not set,n=4,3	22.9 (5.14)	13.3 (1.58)
Day -1,Standing,n=4,4	15.3 (2.79)	16.8 (3.43)
Day -1,Leaning,n=5,4	15.4 (3.06)	17.7 (3.56)
Day -1,Lying,n=4,4	17 (3.08)	15.6 (2.26)
Day -1,Unknown,n=0,2	17.5 (3.75)
Day 4,Not set,n=6,3	14.9 (3.64)	13.8 (1.09)
Day 4,Standing,n=6,6	15.9 (3.39)	15.5 (3.1)
Day 4,Leaning,n=6,6	18.6 (4.19)	17.9 (3.94)
Day 4,Lying,n=6,5	16.8 (3.6)	16.5 (3.41)
Day 4,Unknown,n=2,3	15.5 (2.18)	13.2 (3.54)
Day 7,Not set,n=3,4	15.7 (3.88)	15.1 (2.76)
Day 7,Standing,n=7,4	15.9 (3.54)	15.5 (3.53)
Day 7,Leaning,n=6,4	15.7 (3.89)	17.5 (3.68)
Day 7,Lying,n=7,4	16.8 (3.88)	16 (3.6)

13. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure(SBP) and Diastolic Blood Pressure (DBP)
Description	SBP and DBP were measured in a semi-supine position after 5 minutes rest at Baseline and up to 7 days of each treatment period. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.
Time Frame	Baseline and up to Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
SBP,Period 1, Day 1,n=5,6	-6.8 (7.12)	2.5 (19.56)
SBP,Period 1, Day 2,n=5,6	-7.8 (13.86)	-2.5 (12.49)
SBP,Period 1, Day 3,n=5,6	-8.8 (12.52)	0.0 (10.41)
SBP,Period 1, Day 4,n=5,6	-9.2 (9.71)	0.8 (14.66)
SBP,Period 1, Day 5,n=5,6	-10.4 (11.78)	0.3 (24.91)
SBP,Period 1, Day 6,n=5,6	-12.8 (7.05)	0.0 (14.85)
SBP,Period 1, Day 7,n=5,6	-3.2 (18.74)	9.0 (25.17)
SBP,Period 2, Day 1,n=6,5	-14.0 (22.45)	-9.2 (17.33)
SBP,Period 2, Day 2,n=6,5	-12.7 (31.65)	-6.4 (15.92)
SBP,Period 2, Day 3,n=6,5	-14.5 (34.88)	-8.0 (11.75)
SBP,Period 2, Day 4,n=6,5	-13.5 (25.62)	-4.4 (14.05)
SBP,Period 2, Day 5,n=6,5	-19.0 (23.10)	-10.8 (14.57)
SBP,Period 2, Day 6,n=6,5	-12.5 (16.38)	-7.4 (10.57)
SBP,Period 2, Day 7,n=6,5	-11.5 (27.57)	-2.2 (14.36)
DBP,Period 1, Day 1,n=5,6	-3.4 (10.14)	0.3 (12.06)
DBP,Period 1, Day 2,n=5,6	-7.6 (8.02)	-4.0 (14.03)
DBP,Period 1, Day 3,n=5,6	-14.6 (4.83)	-0.3 (9.99)
DBP,Period 1,Day 4,n=5,6	-5.0 (9.62)	-4.3 (12.21)
DBP,Period 1, Day 5,n=5,6	-8.0 (8.03)	-5.8 (11.20)
DBP,Period 1, Day 6,n=5,6	-9.8 (5.67)	0.2 (8.23)
DBP,Period 1, Day 7,n=5,6	0.2 (13.01)	6.5 (12.00)
DBP,Period 2, Day 1,n=6,5	-9.2 (13.91)	0.4 (9.50)
DBP,Period 2, Day 2,n=6,5	-9.7 (18.41)	-8.0 (8.43)
DBP,Period 2, Day 3,n=6,5	-7.2 (20.47)	-2.0 (6.82)
DBP,Period 2, Day 4,n=6,5	-9.8 (12.27)	1.2 (12.79)
DBP,Period 2, Day 5,n=6,5	-10.7 (15.38)	-3.6 (8.41)
DBP,Period 2, Day 6,n=6,5	-8.2 (11.62)	5.2 (9.26)
DBP,Period 2, Day 7,n=6,5	-9.3 (13.95)	1.2 (11.03)

14. Secondary Outcome

Title	Change From Baseline in Heart Rate
Description	Heart rate was measured in a semi-supine position after 5 minutes rest at Baseline and up to 7 days of each treatment period. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.
Time Frame	Baseline and up to Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Period 1, Day 1,n=5,6	-7.0 (7.42)	5.2 (11.46)
Period 1, Day 2,n=5,6	-5.8 (5.36)	-2.8 (15.72)
Period 1, Day 3,n=5,6	-2.4 (9.21)	-0.8 (17.60)
Period 1,Day 4,n=5,6	-4.6 (10.16)	-4.0 (16.84)
Period 1, Day 5,n=5,6	-4.8 (7.79)	2.2 (6.31)
Period 1, Day 6,n=5,6	-6.2 (5.81)	0.8 (4.12)
Period 1, Day 7,n=5,6	-3.2 (7.95)	5.2 (5.08)
Period 2, Day 1,n=6,5	-7.3 (9.46)	7.0 (9.08)
Period 2, Day 2,n=6,5	-8.0 (15.80)	-1.0 (2.35)
Period 2, Day 3,n=6,5	-7.5 (16.34)	-4.0 (4.80)
Period 2, Day 4,n=6,5	-9.0 (13.52)	0.6 (5.86)
Period 2, Day 5,n=6,5	-11.0 (15.67)	0.2 (4.15)
Period 2, Day 6,n=6,5	-11.0 (16.46)	2.2 (9.04)
Period 2, Day 7,n=6,5	-11.2 (14.46)	-1.2 (10.52)

15. Secondary Outcome

Title	Change From Baseline in Respiration Rate
Description	Respiration rate was measured in a semi-supine position after 5 minutes rest at Baseline and up to 7 days of each treatment period. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.
Time Frame	Baseline and up to Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Period 1, Day 1,n=5,6	0.6 (0.89)	1.0 (3.95)
Period 1, Day 2,n=5,6	-0.2 (2.86)	0.7 (3.01)
Period 1, Day 3,n=5,6	0.2 (1.79)	2.0 (3.46)
Period 1,Day 4,n=5,6	0.6 (1.67)	0.8 (1.79)
Period 1, Day 5,n=5,6	1.2 (2.59)	1.8 (4.58)
Period 1, Day 6,n=5,6	-0.2 (3.63)	2.0 (3.10)
Period 1, Day 7,n=5,6	1.2 (4.38)	1.7 (3.44)
Period 2, Day 1,n=6,5	2.3 (3.67)	1.0 (3.74)
Period 2, Day 2,n=6,5	2.7 (2.73)	3.2 (2.39)
Period 2, Day 3,n=6,5	1.7 (3.88)	3.0 (2.00)
Period 2, Day 4,n=6,5	1.7 (3.67)	4.6 (3.58)
Period 2, Day 5,n=6,5	2.3 (3.44)	1.0 (3.00)
Period 2, Day 6,n=6,5	2.7 (1.03)	2.6 (2.41)
Period 2, Day 7,n=6,5	1.0 (2.45)	-1.0 (1.73)

16. Secondary Outcome

Title	Change From Baseline in Temperature
Description	Body temperature was measured in a semi-supine position after 5 minutes rest at Baseline and up to 7 days of each treatment period. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.
Time Frame	Baseline and up to Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Period 1, Day 1,n=5,6	-0.2 (0.55)	-0.0 (0.10)
Period 1, Day 2,n=5,6	-0.1 (0.16)	-0.0 (0.24)
Period 1, Day 3,n=5,6	0.0 (0.15)	-0.0 (0.33)
Period 1,Day 4,n=5,6	0.2 (0.34)	-0.2 (0.12)
Period 1, Day 5,n=5,6	-0.1 (0.11)	-0.1 (0.19)
Period 1, Day 6,n=5,6	0.0 (0.30)	-0.1 (0.32)
Period 1, Day 7,n=5,6	-0.0 (0.16)	-0.2 (0.29)
Period 2, Day 1,n=6,5	0.2 (0.55)	0.1 (0.13)
Period 2, Day 2,n=6,5	0.2 (0.44)	-0.0 (0.28)
Period 2, Day 3,n=6,5	0.0 (0.49)	-0.1 (0.21)
Period 2, Day 4,n=6,5	0.1 (0.46)	-0.2 (0.21)
Period 2, Day 5,n=6,5	-0.2 (0.26)	-0.1 (0.19)
Period 2, Day 6,n=6,5	0.1 (0.42)	-0.1 (0.24)
Period 2, Day 7,n=6,5	0.1 (0.39)	0.1 (0.21)

17. Secondary Outcome

Title	Change From Baseline in Percent Oxygen in Blood
Description	Percent oxygen in blood was measured using pulse oximetry in a semi-supine position after 5 minutes rest at Baseline and up to 7 days of each treatment period. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.
Time Frame	Baseline and up to Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Period 1, Day 1,n=4,6	0.0 (0.82)	-0.3 (1.37)
Period 1, Day 2,n=4,5	1.3 (0.96)	-1.2 (0.84)
Period 1, Day 3,n=3,6	0.7 (1.53)	-0.7 (1.75)
Period 1,Day 4,n=4,6	0.3 (0.96)	0.0 (1.10)
Period 1, Day 5,n=4,6	1.0 (1.63)	0.5 (2.66)
Period 1, Day 6,n=4,6	0.3 (0.96)	-0.2 (1.72)
Period 1, Day 7,n=4,6	-0.3 (1.71)	-0.3 (1.51)
Period 2, Day 1,n=6,5	-1.0 (2.83)	-0.6 (1.82)
Period 2, Day 2,n=6,5	0.2 (2.99)	0.0 (1.22)
Period 2, Day 3,n=6,4	-0.8 (2.64)	-0.3 (2.36)
Period 2, Day 4,n=6,5	-1.0 (2.61)	1.4 (1.82)
Period 2, Day 5,n=6,5	-0.2 (1.33)	0.2 (1.30)
Period 2, Day 6,n=6,5	-0.5 (2.17)	0.2 (1.79)
Period 2, Day 7,n=6,5	0.2 (2.04)	0.0 (1.87)

18. Secondary Outcome

Title	Number of Participants With Abnormal Electrocardiogram (ECG) Findings
Description	Triplicate 12-lead ECG was obtained using an automated ECG machine at Baseline (Day-1) and single ECG measurements (M) were taken on Day 4 and Day 7. Data for number of participants with abnormal-clinically significant (CS) and abnormal-not clinically significant (NCS) ECG data is presented.
Time Frame	Up to Day 7 in each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Period 1, Day -1, M1, NCS,n=5,6	5 45.5%	6 NaN
Period 1, Day -1, M1, CS,n=5,6	0 0%	0 NaN
Period 1, Day -1, M2, NCS,n=5,6	5 45.5%	6 NaN
Period 1, Day -1, M2, CS,n=5,6	0 0%	0 NaN
Period 1, Day -1, M3, NCS,n=5,6	5 45.5%	6 NaN
Period 1, Day -1, M3, CS,n=5,6	0 0%	0 NaN
Period 1, Day 4, NCS,n=5,6	5 45.5%	6 NaN
Period 1, Day 4, CS,n=5,6	0 0%	0 NaN
Period 1, Day 7, NCS,n=5,6	5 45.5%	6 NaN
Period 1, Day 7, CS,n=5,6	0 0%	0 NaN
Period 2, Day -1, M1, NCS,n=6,5	6 54.5%	5 NaN
Period 2 Day -1, M1, CS,n=6,5	0 0%	0 NaN
Period 2, Day -1, M2, NCS,n=6,5	6 54.5%	5 NaN
Period 2, Day -1, M2, CS,n=6,5	0 0%	0 NaN
Period 2, Day -1, M3, NCS,n=6,5	6 54.5%	5 NaN
Period 2, Day -1, M3, CS,n=6,5	0 0%	0 NaN
Period 2, Day 4, NCS,n=6,5	6 54.5%	5 NaN
Period 2, Day 4, CS,n=6,5	0 0%	0 NaN
Period 2, Day 7, NCS,n=6,5	6 54.5%	5 NaN
Period 2, Day 7, CS,n=6,5	0 0%	0 NaN

19. Secondary Outcome

Title	Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST), Creatine Kinase, Gamma Glutamyl Transferase (GGT) Values
Description	Blood samples were collected to analyze the chemistry parameters including ALT, ALP, AST, creatine kinase and GGT. Change from Baseline is presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.
Time Frame	Baseline and up to Day 7 in each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
ALT,Period 1, Day 4,n=5,6	-1.8 (1.92)	-5.5 (10.41)
ALT,Period 1, Day 7,n=5,6	-1.2 (2.77)	-6.2 (8.80)
ALT,Period 2, Day 4,n=5,5	2.8 (5.59)	-3.6 (2.88)
ALT,Period 2, Day 7,n=6,5	5.3 (6.50)	-2.6 (2.70)
ALP,Period 1, Day 4,n=5,6	0.6 (6.54)	-17.8 (35.65)
ALP,Period 1, Day 7,n=5,6	-1.0 (7.00)	-15.2 (30.96)
ALP,Period 2, Day 4,n=5,5	0.4 (6.73)	-0.8 (2.39)
ALP,Period 2, Day 7,n=6,5	8.0 (21.46)	1.2 (6.30)
AST,Period 1, Day 4,n=5,6	-4.0 (4.80)	-6.7 (9.65)
AST,Period 1, Day 7,n=5,5	-3.2 (3.56)	-7.2 (8.04)
AST,Period 2, Day 4,n=5,5	0.0 (9.97)	-8.0 (2.92)
AST,Period 2, Day 7,n=6,5	4.2 (7.00)	-4.8 (1.92)
GGT,Period 1, Day 4,n=5,6	-6.0 (6.86)	-12.5 (20.71)
GGT,Period 1, Day 7,n=5,6	-9.8 (11.82)	-9.5 (11.06)
GGT,Period 2, Day 4,n=5,5	5.8 (16.95)	-4.8 (7.73)
GGT,Period 2, Day 7,n=6,5	9.0 (22.09)	-5.2 (5.54)
Creatine kinase,Period 1, Day 4,n=5,6	-57.4 (90.68)	-27.7 (36.14)
Creatine kinase,Period 1, Day 7,n=5,6	-64.0 (105.02)	-19.5 (54.42)
Creatine kinase,Period 2, Day 4,n=5,4	-18.0 (25.03)	-59.0 (68.33)
Creatine kinase,Period 2, Day 7,n=6,5	-15.8 (22.05)	-47.8 (29.20)

20. Secondary Outcome

Title	Change From Baseline in Albumin and Total Protein Values
Description	Blood samples were collected to analyze the chemistry parameters including albumin and total protein. Change from Baseline is presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.
Time Frame	Baseline and up to Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Albumin,Period 1, Day 4,n=5,6	-1.6 (1.52)	-0.5 (2.59)
Albumin,Period 1, Day 7,n=5,6	-0.6 (2.30)	-0.3 (1.75)
Albumin,Period 2, Day 4,n=5,5	-0.4 (0.55)	-0.2 (1.79)
Albumin,Period 2, Day 7,n=6,5	0.2 (1.83)	0.8 (1.30)
Total protein,Period 1, Day 4,n=5,6	-1.0 (5.15)	-1.5 (5.36)
Total protein,Period 1, Day 7,n=5,6	0.8 (5.22)	-1.2 (4.17)
Total protein,Period 2, Day 4,n=5,5	-1.6 (2.07)	0.4 (3.58)
Total protein,Period 2, Day 7,n=6,5	-0.8 (3.54)	2.8 (1.64)

21. Secondary Outcome

Title	Change From Baseline in Chemistry: Calcium, Chloride, Glucose, Potassium, Sodium, Urea/Blood Urea Nitrogen (BUN)
Description	Blood samples were collected to analyze the chemistry parameters including Calcium, Chloride, Glucose, Potassium, Sodium, Urea/BUN. Change from Baseline is presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.
Time Frame	Baseline and up to Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Calcium,Period 1, Day 4,n=5,6	0.01497 (0.080074)	-0.06653 (0.187817)
Calcium,Period 1, Day 7,n=5,6	0.05988 (0.120434)	-0.05822 (0.185817)
Calcium,Period 2, Day 4,n=5,5	-0.05489 (0.020875)	0.00998 (0.041749)
Calcium,Period 2, Day 7,n=6,5	-0.06238 (0.071880)	0.02994 (0.044632)
Chloride,Period 1, Day 4,n=5,6	-1.8 (1.48)	-1.3 (1.97)
Chloride,Period 1, Day 7,n=5,6	-1.0 (1.87)	0.5 (1.76)
Chloride,Period 2, Day 4,n=5,5	-0.8 (1.79)	-2.0 (2.35)
Chloride,Period 2, Day 7,n=6,5	-2.0 (4.82)	-2.4 (1.82)
Glucose,Period 1, Day 4,n=5,6	3.63035 (4.132346)	2.04462 (3.557566)
Glucose,Period 1, Day 7,n=5,6	2.04277 (2.486018)	0.61986 (5.924289)
Glucose,Period 2, Day 4,n=5,5	1.68750 (2.144009)	3.96341 (3.372569)
Glucose,Period 2, Day 7,n=6,5	1.51727 (4.849639)	1.23232 (2.196471)
Potassium,Period 1, Day 4,n=5,6	0.22 (0.319)	0.33 (0.388)
Potassium,Period 1, Day 7,n=5,6	0.16 (0.270)	0.35 (0.619)
Potassium,Period 2, Day 4,n=5,5	0.04 (0.397)	0.26 (0.270)
Potassium,Period 2, Day 7,n=6,5	-0.23 (0.592)	0.14 (0.378)
Sodium,Period 1, Day 4,n=5,6	-1.0 (4.00)	-2.0 (1.55)
Sodium,Period 1, Day 7,n=5,6	-1.4 (3.36)	-1.2 (2.48)
Sodium,Period 2, Day 4,n=5,5	-1.0 (1.58)	-0.8 (2.59)
Sodium,Period 2, Day 7,n=6,5	-2.2 (2.32)	-1.6 (1.67)
Urea/BUN,Period 1, Day 4,n=5,6	-0.0714 (1.34528)	2.2610 (3.82285)
Urea/BUN,Period 1, Day 7,n=5,6	-0.4284 (1.86188)	-0.1785 (2.17448)
Urea/BUN,Period 2, Day 4,n=5,5	-1.2852 (3.02504)	-0.5712 (2.53193)
Urea/BUN,Period 2, Day 7,n=6,5	-0.2975 (4.41537)	0.0714 (2.84930)

22. Secondary Outcome

Title	Change From Baseline in Creatinine, Direct Bilirubin, Total Bilirubin, Uric Acid
Description	Blood samples were collected to analyze the chemistry parameters including Creatinine, Direct Bilirubin, Total Bilirubin and Uric acid. Change from Baseline was presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the baseline value from specified time point value.
Time Frame	Baseline and up to Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Creatinine,Period 1, Day 4,n=5,6	-8.1328 (17.06601)	11.4920 (29.13179)
Creatinine,Period 1, Day 7,n=5,6	-13.2600 (15.91200)	-9.4293 (12.58472)
Creatinine,Period 2, Day 4,n=5,5	-6.0112 (12.84693)	-2.6520 (14.83172)
Creatinine,Period 2, Day 7,n=6,5	-4.8620 (26.95113)	3.7128 (11.43064)
Direct Bilirubin,Period 1, Day 4,n=5,6	-0.684 (0.9366)	-0.572 (0.8856)
Direct Bilirubin,Period 1, Day 7,n=5,5	-0.342 (0.7647)	-0.344 (1.4331)
Direct Bilirubin,Period 2, Day 4,n=5,5	-0.340 (0.7659)	-1.026 (1.5295)
Direct Bilirubin,Period 2, Day 7,n=6,5	-0.285 (0.6981)	-0.684 (0.9366)
Total Bilirubin,Period 1, Day 4,n=5,6	1.368 (2.8098)	-1.425 (1.6813)
Total Bilirubin,Period 1, Day 7,n=5,6	0.684 (1.9497)	0.002 (2.1646)
Total Bilirubin,Period 2, Day 4,n=5,5	-0.000 (3.1991)	-5.472 (9.2403)
Total Bilirubin,Period 2, Day 7,n=6,5	-0.285 (1.9991)	-5.130 (10.1885)
Uric acid,Period 1, Day 4,n=5,6	-17.8440 (35.43930)	18.8353 (47.19830)
Uric acid,Period 1, Day 7,n=5,6	-42.8256 (40.20954)	-29.7400 (51.57983)
Uric acid,Period 2, Day 4,n=5,5	-17.8440 (29.44110)	-1.1896 (24.66807)
Uric acid,Period 2, Day 7,n=6,5	25.7747 (111.31927)	9.5168 (19.99448)

23. Secondary Outcome

Title	Change From Baseline in Digoxin Level
Description	Blood samples were collected to analyze the digoxin levels. Change from Baseline is presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the baseline value from specified time point value. NA indicates data not available. Standard deviation could not be calculated as a single participant was analyzed.
Time Frame	Baseline and up to Day 7 in each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Period 1 Day 1,n=3,1	-0.17080 (0.322378)	0.38430 (NA)
Period 1 Day 2,n=3,1	0.17080 (0.073959)	0.25620 (NA)
Period 1 Day 3,n=3,1	0.12810 (0.128100)	0.25620 (NA)
Period 1 Day 4,n=3,1	-0.10248 (0.419417)	0.12810 (NA)
Period 1 Day 5,n=3,1	0.25620 (0.221876)	0.38430 (NA)
Period 1 Day 6,n=3,1	0.17080 (0.147917)	0.00000 (NA)
Period 1 Day 7,n=3,1	-0.00000 (0.128100)	0.00000 (NA)
Period 2 Day 1,n=1,3	-0.25620 (NA)	0.34160 (0.266661)
Period 2 Day 2,n=1,3	-0.25620 (NA)	0.46970 (0.295834)
Period 2 Day 3,n=1,3	-0.25620 (NA)	0.17080 (0.195676)
Period 2 Day 4,n=1,3	-0.38430 (NA)	0.42700 (0.195676)
Period 2 Day 5,n=1,3	-0.25620 (NA)	0.25620 (0.128100)
Period 2 Day 6,n=1,3	-0.12810 (NA)	0.29890 (0.391352)
Period 2 Day 7,n=1,3	-0.25620 (NA)	0.42700 (0.369793)

24. Secondary Outcome

Title	Change From Baseline in Troponin I Levels and Type I Collagen Cross-linked C-telopeptide
Description	Blood samples were collected to analyze the troponin I level and type I collagen cross-linked C-telopeptide (T1CCT). Change from Baseline was presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from value at specified time point.
Time Frame	Baseline and up to Day 7 in each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Troponin I,Period 1, Day 2,n=5,6	-0.0044 (0.00658)	-0.0007 (0.00516)
Troponin I,Period 1, Day 4,n=5,6	-0.0118 (0.01117)	-0.0008 (0.00492)
Troponin I,Period 1, Day 7,n=5,5	-0.0112 (0.01314)	-0.0056 (0.00876)
Troponin I,Period 2, Day 2,n=6,5	0.0023 (0.00898)	0.0002 (0.00672)
Troponin I,Period 2, Day 4,n=5,5	-0.0036 (0.00498)	-0.0000 (0.01225)
Troponin I,Period 2, Day 7,n=6,4	-0.0012 (0.01132)	0.0043 (0.01902)
T1CCT,Period 1 Day 7,n=3,3	-0.0133 (0.03774)	-0.1250 (0.16975)
T1CCT,Period 2 Day 7,n=3,3	-0.0343 (0.12948)	-0.0447 (0.11186)

25. Secondary Outcome

Title	Change From Baseline in Chemistry: N-terminal Pro-Brain Natriuretic Peptide
Description	Blood samples were collected to analyze the Chemistry parameter N-terminal pro-Brain Natriuretic Peptide. Change from Baseline is presented for these parameters. Day -1 was Baseline and change from Baseline is calculated by subtracting the baseline value from specified time point value.
Time Frame	Baseline and up to Day 7 in each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Period 1 Day 7,n=5,6	-279.0 (455.83)	214.2 (702.54)
Period 2 Day 7,n=6,5	-347.7 (1134.08)	-121.6 (340.70)

26. Secondary Outcome

Title	Change From Baseline in Hematology: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, White Blood Cell (WBC) Count, Total Neutrophils
Description	Blood samples were collected to analyze the Hematology parameters including Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet count, White Blood Cell (WBC) count, Total Neutrophils. Change from Baseline is presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.
Time Frame	Baseline and up to Day 7 in each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Basophils,Period 1, Day 4,n=5,6	0.004 (0.0089)	0.007 (0.0320)
Basophils,Period 1, Day 7,n=5,6	0.000 (0.0100)	0.010 (0.0358)
Basophils,Period 2, Day 4,n=5,5	-0.002 (0.0110)	0.002 (0.0130)
Basophils,Period 2, Day 7,n=6,5	0.002 (0.0098)	-0.004 (0.0089)
Eosinophils,Period 1, Day 4,n=5,6	0.042 (0.0239)	0.033 (0.0859)
Eosinophils,Period 1, Day 7,n=5,6	0.058 (0.0512)	0.038 (0.0412)
Eosinophils,Period 2, Day 4,n=5,5	-0.012 (0.0482)	-0.022 (0.0920)
Eosinophils,Period 2, Day 7,n=6,5	-0.007 (0.0301)	-0.018 (0.1154)
Lymphocytes,Period 1, Day 4,n=5,6	0.128 (0.2876)	-0.110 (0.4315)
Lymphocytes,Period 1, Day 7,n=5,6	0.054 (0.1014)	-0.122 (0.4964)
Lymphocytes,Period 2, Day 4,n=5,5	-0.024 (0.1636)	0.098 (0.3725)
Lymphocytes,Period 2, Day 7,n=6,5	0.025 (0.1512)	0.126 (0.2508)
Monocytes,Period 1, Day 4,n=5,6	-0.044 (0.0611)	-0.082 (0.1628)
Monocytes,Period 1, Day 7,n=5,6	0.006 (0.0853)	0.012 (0.1700)
Monocytes,Period 2, Day 4,n=5,5	-0.064 (0.1236)	-0.014 (0.1150)
Monocytes,Period 2, Day 7,n=6,5	-0.015 (0.1280)	0.008 (0.1087)
Platelet count,Period 1, Day 4,n=5,6	-1.0 (9.87)	-3.2 (27.26)
Platelet count,Period 1, Day 7,n=5,6	-0.8 (17.46)	-2.7 (25.23)
Platelet count,Period 2, Day 4,n=5,5	-12.8 (9.36)	1.0 (12.79)
Platelet count,Period 2, Day 7,n=6,5	-6.7 (21.50)	9.0 (18.40)
WBC,Period 1, Day 4,n=5,6	0.614 (1.2143)	-0.100 (1.3130)
WBC,Period 1, Day 7,n=5,6	0.034 (0.6344)	0.250 (0.8118)
WBC,Period 2, Day 4,n=5,5	0.156 (0.6105)	0.252 (1.0176)
WBC,Period 2, Day 7,n=6,5	-0.252 (0.6902)	0.064 (0.3369)
Total Neutrophils,Period 1, Day 4,n=5,6	0.472 (1.0817)	0.043 (0.8491)
Total Neutrophils,Period 1, Day 7,n=5,6	-0.064 (0.6789)	0.345 (0.4476)
Total Neutrophils,Period 2, Day 4,n=5,5	0.252 (0.6034)	0.162 (0.8436)
Total Neutrophils,Period 2, Day 7,n=6,5	-0.267 (0.6555)	-0.080 (0.5928)

27. Secondary Outcome

Title	Change From Baseline in Hematocrit
Description	Blood samples were collected to analyze the Hematology parameter Hematocrit. Change from Baseline is presented for this parameter. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.
Time Frame	Baseline and up to Day 7 in each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Period 1, Day 4,n=5,6	-0.0084 (0.01910)	-0.0092 (0.01641)
Period 1, Day 7,n=5,6	-0.0086 (0.02329)	-0.0045 (0.02336)
Period 2, Day 4,n=5,5	0.0046 (0.00513)	-0.0138 (0.02905)
Period 2, Day 7,n=6,5	-0.0120 (0.01381)	-0.0164 (0.02519)

28. Secondary Outcome

Title	Change From Baseline in Hemoglobin
Description	Blood samples were collected to analyze Hemoglobin. Change from Baseline is presented for this parameter. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.
Time Frame	Baseline and up to Day 7 in each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Period 1, Day 4,n=5,6	-1.0 (6.67)	-4.3 (7.42)
Period 1, Day 7,n=5,6	0.8 (10.87)	-2.2 (6.55)
Period 2, Day 4,n=5,5	1.6 (2.41)	-3.8 (7.85)
Period 2, Day 7,n=6,5	-3.5 (4.93)	-3.4 (7.89)

29. Secondary Outcome

Title	Change From Baseline in Mean Corpuscle Volume
Description	Blood samples were collected to analyze Mean Corpuscle Volume. Change from Baseline is presented for this parameter. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.
Time Frame	Baseline and up to Day 7 in each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Period 1, Day 4,n=5,6	0.20 (1.402)	0.97 (1.218)
Period 1, Day 7,n=5,6	-0.92 (1.152)	0.55 (0.946)
Period 2, Day 4,n=5,5	0.04 (0.493)	0.08 (0.926)
Period 2, Day 7,n=6,5	0.23 (1.003)	-0.50 (1.086)

30. Secondary Outcome

Title	Change From Baseline in Red Blood Cell Count (RBC) and Reticulocytes
Description	Blood samples were collected to analyze the Hematology parameters including RBC and Reticulocytes. Change from Baseline is presented for these parameters. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.
Time Frame	Baseline and up to Day 7 in each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
RBC,Period 1, Day 4,n=5,6	-0.100 (0.1943)	-0.160 (0.2555)
RBC,Period 1, Day 7,n=5,6	-0.056 (0.2637)	-0.083 (0.2700)
RBC,Period 2, Day 4,n=5,5	0.014 (0.0937)	-0.146 (0.2708)
RBC,Period 2, Day 7,n=6,5	-0.188 (0.2360)	-0.150 (0.2270)
Reticulocytes,Period 1, Day 4,n=5,6	-0.00148 (0.002167)	-0.00388 (0.012096)
Reticulocytes,Period 1, Day 7,n=5,6	0.00049 (0.004412)	0.00021 (0.010985)
Reticulocytes,Period 2, Day 4,n=5,5	0.00367 (0.032819)	0.00051 (0.007178)
Reticulocytes,Period 2, Day 7,n=6,5	0.00868 (0.019263)	0.00086 (0.001831)

31. Secondary Outcome

Title	Change From Baseline in Mean Corpuscle Hemoglobin Concentration
Description	Blood samples were collected to analyze Mean Corpuscle Hemoglobin concentration . Change from Baseline is presented for this parameter. Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value. NA indicates data was not available. Standard deviation could not be calculated as a single participant was analyzed at the specified time point
Time Frame	Baseline and up to Day 7 in each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Period 1, Day 4,n=3,1	8.0 (7.94)	-3.0 (NA)
Period 1, Day 7,n=3,1	13.7 (12.22)	-8.0 (NA)
Period 2, Day 4,n=1,3	-1.0 (NA)	2.7 (6.66)
Period 2, Day 7,n=1,3	-2.0 (NA)	6.0 (8.66)

32. Secondary Outcome

Title	Change From Baseline in Mean Corpuscle Hemoglobin
Description	Blood samples were collected to analyze Mean Corpuscle Hemoglobin. Change from Baseline was presented for this parameter. Day -1 was Baseline and change from Baseline was calculated by subtracting the baseline value from specified time point value. NA indicates data was not available. Standard deviation could not be calculated as a single participant was analyzed at the specified time point
Time Frame	Baseline and up to Day 7 in each treatment period

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Period 1, Day 4,n=3,1	0.70 (0.656)	0.20 (NA)
Period 1, Day 7,n=3,1	0.70 (1.044)	-0.20 (NA)
Period 2, Day 4,n=1,3	0.00 (NA)	0.27 (0.231)
Period 2, Day 7,n=1,3	0.40 (NA)	0.33 (0.503)

33. Secondary Outcome

Title	Number of Participants With All Adverse Events (AE) and Serious Adverse Events (SAE)
Description	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinemia were categorized as SAE. Number of participants with AE and SAE are reported.
Time Frame	Up to Day 46

Outcome Measure Data

Analysis Population Description

All Subjects Population.

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Any AE	5 45.5%	7 NaN
Any SAE	0 0%	1 NaN

34. Secondary Outcome

Title	Change From Baseline in Participant Reported Health Status (SF-36) Acute Score
Description	The SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The vitality sub-score assesses energy and fatigue, and ranges from 0 (worst) - 100 (best). Day -1 was Baseline and change from Baseline was calculated by subtracting the Baseline value from specified time point value.
Time Frame	Baseline and Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

Analysis Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11	11
Physical Functioning, Period 1, Day 7,n=5,6	3.0 (4.00)	1.2 (0.75)
Physical Functioning, Period 2, Day 7,n=5,5	1.0 (1.22)	-0.4 (2.19)
Role-Physical, Period 1, Day 7,n=4,6	-0.5 (3.11)	3.7 (3.93)
Role-Physical, Period 2, Day 7,n=5,5	2.0 (3.67)	0.4 (2.70)
Bodily Pain, Period 1, Day 7,n=5,5	-1.0 (1.41)	-1.2 (1.10)
Bodily Pain, Period 2, Day 7,n=5,5	-0.2 (1.10)	0.4 (1.14)
General Health,Period 1, Day 7,n=5,6	1.8 (2.49)	-1.5 (5.79)
General Health,Period 2, Day 7,n=5,5	0.0 (0.71)	-1.4 (2.97)
Vitality, Period 1, Day 7,n=5,6	1.2 (1.79)	-1.2 (1.17)
Vitality, Period 2, Day 7,n=5,5	-0.4 (1.14)	-0.8 (2.17)
Social Functioning, Period 1, Day 7,n=5,6	-0.6 (0.55)	0.5 (1.22)
Social Functioning, Period 2, Day 7,n=5,5	0.6 (0.89)	-0.2 (1.10)
Role- Emotional, Period 1, Day 7,n=4,6	1.3 (2.50)	1.0 (1.55)
Role- Emotional, Period 2, Day 7,n=5,5	-0.2 (3.19)	1.2 (4.09)
Mental Health, Period 1, Day 7,n=5,6	0.6 (0.55)	0.3 (0.52)
Mental Health, Period 2, Day 7,n=5,5	0.2 (1.79)	1.2 (1.79)
Physical Health Score,Period 1, Day 7,n=5,6	5.8 (8.23)	1.7 (3.83)
Physical Health Score,Period 2, Day 7,n=5,5	2.8 (3.03)	-1.0 (5.61)
Mental Health Score, Period 1, Day 7,n=5,6	5.2 (6.53)	0.7 (1.97)
Mental Health Score, Period 2, Day 7,n=5,5	0.2 (4.09)	1.4 (3.85)

35. Secondary Outcome

Title	Area Under the Concentration Time Curve (AUC) Time Zero to the Last Time of the Last Quantifiable Concentration (AUC(0-t)), AUC Over the Dosing Interval After First and Last Dose (AUC(0-tau)) and AUCall for GSK2798745
Description	AUC(0-t), AUC(0-tau) and AUCall for GSK2798745 were determined based on intensive Pharmacokinetic (PK) sampling at the following time points: Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours on Day 1, pre-dose and at 12 hours post dose on Day 2, pre-dose on Days 3 to 6, Pre-dose, 0.5, 1, 1.5, 2, 3, 5 and 10 hours on Day 7 and at 24 and 48 hours. PK parameter population included all participants in the PK Concentration Population for whom valid and evaluable pharmacokinetic parameters were derived
Time Frame	Day 1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours post-dose), Day 2 (pre-dose, 12 hours post-dose), Days 3 to 6 (pre-dose), Day 7 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 10, 24 and 48 hours post-dose)

Outcome Measure Data

Analysis Population Description

PK Parameter Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	GSK2798745 2.4 mg
Arm/Group Description	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11
AUC(0-tau), Period 1, Day 1,n=6	128.3513 (70.4)
AUC(0-tau), Period 1, Day 7,n=5	202.2948 (132.1)
AUC(0-tau), Period 2, Day 1,n=5	137.7473 (38.4)
AUC(0-tau), Period 2, Day 7,n=5	274.0828 (70.9)
AUCall, Period 1, Day 1,n=6	127.9049 (70.4)
AUCall Period 1, Day 7,n=5	174.7273 (121.5)
AUCall Period 2, Day 1,n=5	137.5038 (38.4)
AUCall, Period 2, Day 7,n=5	269.0902 (70.5)
AUC(0-t), Period 1, Day 1,n=6	127.9049 (70.4)
AUC(0-t) Period 1, Day 7,n=5	174.7273 (121.5)
AUC(0-t) Period 2, Day 1,n=5	137.5038 (38.4)
AUC(0-t), Period 2, Day 7,n=5	269.0902 (70.5)

36. Secondary Outcome

Title	Maximum Drug Concentration (Cmax) for GSK2798745
Description	Blood samples for PK analysis were collected at pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours on Day 1, pre-dose and at 12 hours post dose on Day 2, pre-dose on Days 3 to 6, Pre-dose, 0.5, 1, 1.5, 2, 3, 5 and 10 hours on Day 7 and at 24 and 48 hours on Days 8 and 9. Cmax was defined as maximum observed plasma concentration of drug.
Time Frame	Day 1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours post-dose), Day 2 (pre-dose, 12 hours post-dose), Days 3 to 6 (pre-dose), Day 7 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 10, 24 and 48 hours post-dose)

Outcome Measure Data

Analysis Population Description

PK Parameter. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	GSK2798745 2.4 mg
Arm/Group Description	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11
Period 1, Day 1,n=6	10.214 (36.3)
Period 1, Day 7,n=5	15.687 (73.6)
Period 2, Day 1,n=5	10.017 (48.3)
Period 2, Day 7,n=5	15.428 (68.1)

37. Secondary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) for GSK2798745
Description	Blood samples for PK analysis were collected at pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours on Day 1, pre-dose and at 12 hours post dose on Day 2, pre-dose on Days 3 to 6, Pre-dose, 0.5, 1, 1.5, 2, 3, 5 and 10 hours on Day 7 and at 24 and 48 hours on Days 8 and 9. Tmax was defined as time to maximum observed plasma concentration of drug.
Time Frame	Day 1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours post-dose), Day 2 (pre-dose, 12 hours post-dose), Days 3 to 6 (pre-dose), Day 7 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 10, 24 and 48 hours post-dose)

Outcome Measure Data

Analysis Population Description

PK Parameter population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	GSK2798745 2.4 mg
Arm/Group Description	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	11
Period 1, Day 1,n=6	3.0
Period 1, Day 7,n=5	3.0
Period 2, Day 1,n=5	3.0
Period 2, Day 7,n=5	2.0

38. Secondary Outcome

Title	Elimination Half Life (T½) for GSK2798745
Description	Blood samples for PK analysis were planned to be collected at pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours on Day 1, pre-dose and at 12 hours post dose on Day 2, pre-dose on Days 3 to 6, Pre-dose, 0.5, 1, 1.5, 2, 3, 5 and 10 hours on Day 7 and at 24 and 48 hours on Days 8 and 9. T½ was defined as Elimination half life of drug. Data is not available for t1/2. The analysis was planned but not performed. PK sampling scheme was not adequate enough to reliably estimate the t1/2 of GSK2798745.
Time Frame	Day 1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours post-dose), Day 2 (pre-dose, 12 hours post-dose), Days 3 to 6 (pre-dose), Day 7 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 10, 24 and 48 hours post-dose)

Outcome Measure Data

Analysis Population Description

PK Parameter Population. Data is not available for t1/2. The analysis was planned but not performed. PK sampling scheme was not adequate enough to reliably estimate the t1/2 of GSK2798745.

Arm/Group Title	GSK2798745 2.4 mg
Arm/Group Description	Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
Measure Participants	0

Adverse Events

Time Frame	AEs and SAEs were collected from the start of study treatment until follow-up (Up to 46 days)
Adverse Event Reporting Description	All subject population was used to collect adverse events.
Arm/Group Title	Placebo		GSK2798745 2.4 mg
Arm/Group Description	Participants received placebo capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.		Participants received GSK2798745 2.4 mg capsule orally once daily with 240 mL water for a period of 7 days in Periods 1 and 2.
All Cause Mortality
	Placebo		GSK2798745 2.4 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/11 (0%)
Serious Adverse Events
	Placebo		GSK2798745 2.4 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		1/11 (9.1%)
Vascular disorders
Orthostatic hypotension	0/11 (0%)		1/11 (9.1%)
Other (Not Including Serious) Adverse Events
	Placebo		GSK2798745 2.4 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/11 (45.5%)		7/11 (63.6%)
Cardiac disorders
Ventricular extrasystoles	0/11 (0%)		1/11 (9.1%)
Ventricular tachycardia	1/11 (9.1%)		0/11 (0%)
Ear and labyrinth disorders
Ear discomfort	0/11 (0%)		1/11 (9.1%)
Eye disorders
Lacrimation increased	0/11 (0%)		1/11 (9.1%)
Visual impairment	1/11 (9.1%)		0/11 (0%)
Vitreous haemorrhage	1/11 (9.1%)		0/11 (0%)
Gastrointestinal disorders
Nausea	0/11 (0%)		1/11 (9.1%)
General disorders
Chest pain	0/11 (0%)		1/11 (9.1%)
Cyst	0/11 (0%)		1/11 (9.1%)
Hepatobiliary disorders
Liver injury	1/11 (9.1%)		0/11 (0%)
Injury, poisoning and procedural complications
Fall	0/11 (0%)		1/11 (9.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/11 (9.1%)		1/11 (9.1%)
Arthropathy	0/11 (0%)		1/11 (9.1%)
Back pain	0/11 (0%)		1/11 (9.1%)
Nervous system disorders
Dizziness	1/11 (9.1%)		0/11 (0%)
Headache	1/11 (9.1%)		0/11 (0%)
Neuropathy peripheral	1/11 (9.1%)		0/11 (0%)
Psychiatric disorders
Nightmare	1/11 (9.1%)		0/11 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/11 (0%)		1/11 (9.1%)
Dyspnoea exertional	1/11 (9.1%)		0/11 (0%)
Rhinorrhoea	1/11 (9.1%)		0/11 (0%)
Skin and subcutaneous tissue disorders
Dermatitis contact	0/11 (0%)		1/11 (9.1%)
Vascular disorders
Hypotension	1/11 (9.1%)		0/11 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.