A Dose-escalation Study in Subjects With Pulmonary Arterial Hypertension (PAH)

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03177603
• Collaborator: (none)
• Enrollment: 23
• Locations: 8
• Arms: 4
• Actual Duration (Months): 14.5
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

GSK2586881, a purified intravenous (IV) formulation of soluble recombinant human Angiotensin Converting Enzyme (rhACE2) is being investigated as a treatment for PAH. This GlaxoSmithKline (GSK) study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of GSK2586881 in subjects with PAH. This open-label, dose-escalation study will comprise of 4 separate groups based on the planned dose range, and subjects in each group will be administered a single dose of GSK2586881 ranging between 0.1, 0.2, 0.4 and 0.8 milligram per kilogram (mg/kg) via IV route. Dose escalation will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place. A maximum of 27 subjects will be included in the study and the total duration of the study will be up to a maximum of 59 days.

Condition or Disease	Intervention/Treatment	Phase
Hypertension, Pulmonary	Drug: GSK2586881	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Dose-escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Doses of GSK2586881 in Participants With Pulmonary Arterial Hypertension
• Actual Study Start Date: Feb 21, 2018
• Actual Primary Completion Date: May 7, 2019
• Actual Study Completion Date: May 7, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GSK2586881 - 0.1 mg/kg Eligible subjects will receive a single dose of 0.1 mg/kg GSK2586881. Dose escalation up to maximum dose of 0.8 mg/kg will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place.	Drug: GSK2586881; GSK2586881 is a clear colorless liquid for IV infusion over 3- 5 minutes and will be administered a maximum dose of 0.8 mg/kg.
Experimental: GSK2586881 - 0.2 mg/kg Eligible subjects will receive a single dose 0.2 mg/kg of GSK2586881 IV infusion. Dose escalation up to maximum dose of 0.8 mg/kg will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place.	Drug: GSK2586881; GSK2586881 is a clear colorless liquid for IV infusion over 3- 5 minutes and will be administered a maximum dose of 0.8 mg/kg.
Experimental: GSK2586881 - 0.4 mg/kg Eligible subjects will receive a single dose of 0.4 mg/kg of GSK2586881 IV infusion. Dose escalation up to maximum dose of 0.8 mg/kg will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place.	Drug: GSK2586881; GSK2586881 is a clear colorless liquid for IV infusion over 3- 5 minutes and will be administered a maximum dose of 0.8 mg/kg.
Experimental: GSK2586881 - 0.8 mg/kg Eligible subjects will receive single dose of 0.8 mg/kg of GSK2586881 IV infusion. Dose escalation will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place.	Drug: GSK2586881; GSK2586881 is a clear colorless liquid for IV infusion over 3- 5 minutes and will be administered a maximum dose of 0.8 mg/kg.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Pulmonary Vascular Resistance (PVR) [Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)]

   PVR is the resistance generated by pulmonary circulation. Pulmonary arterial catheters were placed in participants and PVR values were recorded from the right heart catheterization. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.

2. Change From Baseline in Cardiac Output (CO) [Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)]

   CO is the amount of blood pumped by the heart per minute. Pulmonary arterial catheters were placed in participants and CO values were recorded from the right heart catheterization. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.

3. Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) [Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)]

   The pulmonary artery pressure is a measure of the blood pressure found in the main pulmonary artery. Pulmonary arterial catheters were placed in participants and mPAP values were recorded from the right heart catheterization. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.

Secondary Outcome Measures

1. Number of Participants With Non-serious Adverse Events (AEs) [Up to Day 28]

   An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.

2. Number of Participants With Serious Adverse Events (SAEs) [Up to Day 28]

   Any untoward event resulting in death, life threatening, requiring hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention were categorized as SAE.

3. Change From Baseline in Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Amino Transferase and Aspartate Amino Transferase [Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

   Blood samples were collected for the assessment of clinical chemistry parameters: alkaline phosphatase, alanine amino transferase (ALT) and aspartate amino transferase (AST). Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

4. Change From Baseline in Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Creatinine [Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

   Blood samples were collected for the assessment of clinical chemistry parameters: direct bilirubin, total bilirubin and creatinine. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

5. Change From Baseline in Clinical Chemistry Parameters: Calcium, Glucose, Potassium, Sodium and Blood Urea Nitrogen (BUN) [Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

   Blood samples were collected for the assessment of clinical chemistry parameters: calcium, glucose, potassium, sodium and BUN. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

6. Change From Baseline in Clinical Chemistry Parameter: Total Protein [Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

   Blood samples were collected for the assessment of clinical chemistry parameter, total protein. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

7. Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell (WBC) Count [Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

   Blood samples were collected for the assessment of hematology parameters: basophils, eosinophils, lymphocytes, monocytes, total neutrophils (T.neutrophils), platelet count and WBC count. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

8. Change From Baseline in Hematology Parameter: Hemoglobin [Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

   Blood samples were collected for the assessment of hematology parameter, hemoglobin. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

9. Change From Baseline in Hematology Parameter: Hematocrit [Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

   Blood samples were collected for the assessment of hematology parameter, hematocrit. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

10. Change From Baseline in Hematology Parameter: Mean Corpuscle Hemoglobin [Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

    Blood samples were collected for the assessment of hematology parameter, mean corpuscle hemoglobin. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

11. Change From Baseline in Hematology Parameter: Mean Corpuscle Volume [Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

    Blood samples were collected for the assessment of hematology parameter, mean corpuscle volume. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

12. Change From Baseline in Hematology Parameter: Red Blood Cell (RBC) Count [Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

    Blood samples were collected for the assessment of hematology parameter: RBC count. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

13. Change From Baseline in Hematology Parameter: Reticulocytes [Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

    Blood samples were collected for the assessment of hematology parameter: reticulocytes. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

14. Number of Participants With Urinalysis Results by Dipstick Method [24 hours post-dose (Day 1)]

    Urine samples were collected to assess urine bilirubin, urine occult blood, urine glucose, urine ketones, and urine protein by dipstick test. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameter of urine bilirubin, urine occult blood, urine glucose, urine ketones and urine protein can be read as negative, trace, 1+, 2+ and 3+ indicating proportional concentrations in the urine sample.

15. Change From Baseline in Pulse Rate [Baseline (Day 1, Pre-dose); 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)]

    Pulse rate was measured in supine position after at least a 5-minute rest. Change from Baseline in pulse rate was evaluated. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

16. Change From Baseline in Respiratory Rate [Baseline (Day 1, Pre-dose); 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)]

    Respiratory rate was measured in supine position after at least a 5-minute rest. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

17. Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) [Baseline (Day 1, Pre-dose); 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)]

    DBP and SBP were measured in supine position after at least a 5-minute rest. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

18. Number of Participants With Abnormal Electrocardiogram (ECG) Findings [4 hours and 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

    12-lead ECGs were obtained at each time point using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and Corrected QT (QTc) intervals. Only those participants who had any abnormal ECG findings are presented. Abnormal ECG findings were categorized as clinically significant (CS) and not clinically significant (NCS) abnormal ECG findings. CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Assessment of follow up visit was conducted between any day of Days 7 to 14.

19. Change From Baseline in Pulse Oximetry Parameter: Percent Oxygen in Blood [Baseline (Day 1, Pre-dose); 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)]

    Percent oxygen in blood was measured using pulse oximetry after the participant had rested for at least 5 minutes. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

20. Number of Participants With Positive Immunogenicity Results [Up to Day 28]

    Immunogenicity samples were collected into a serum-separating tube, mixed by gentle inversion 5 times and left to coagulate at room temperature for a minimum of 30 minutes and a maximum of 60 minutes. All samples were first tested for anti-angiotensin converting enzyme type 2 (ACE2) binding antibodies by screening and confirmation assay steps. If post-dose samples were found to be positive for anti-ACE2 binding antibodies, they would have been further characterized for anti-ACE2 neutralizing antibodies. Number of participants with positive immunogenicity results post-dosing are presented.

21. Change From Baseline in Systemic Renin-Angiotensin System (RAS) Peptides: Angiotensin II, Angiotensin (1-5) and Angiotensin (1-7) [Baseline (Day 1, Pre-dose); 0.08 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)]

    Blood samples were collected to evaluate systemic RAS peptides: Angiotensin (Ang) II, Ang (1-7) and Ang (1-5). Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value. Assessment of follow up visit was conducted between any day of Days 7 to 14.

22. Change From Baseline in Pulmonary Wedge RAS Peptides: Angiotensin II, Angiotensin (1-5) and Angiotensin (1-7) [Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)]

    Blood samples were collected to evaluate pulmonary wedge RAS peptides: Ang II, Ang (1-5) and Ang (1-7). Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.

23. Systemic RAS Peptide: Angiotensin II/Angiotensin (1-7) Ratio at Indicated Time Points [0.08 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

    Blood samples were collected to assess systemic RAS peptides: Angiotensin II and Angiotensin (1-7). Data for angiotensin II/angiotensin (1-7) ratio is presented. Assessment of follow up visit was conducted between any day of Days 7 to 14.

24. Pulmonary Wedge RAS Peptide: Angiotensin II/Angiotensin (1-7) Ratio at Indicated Time Points [1 hour, 2 hours and 4 hours post-dose (Day 1)]

    Blood samples were collected to assess pulmonary wedge RAS peptides: Angiotensin II and Angiotensin (1-7). Data for angiotensin II/angiotensin (1-7) ratio is presented.

25. Change From Baseline in Disease Biomarkers: N-terminal Pro B-type Natriuretic Peptide (NT Pro-BNP) [Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1)]

    Blood samples were collected at specific time points to evaluate NT pro-BNP, a biomarker of disease activity. NT-pro-BNP is a biomarker of cardiac stress or ventricular workload and decreases as a result of reduced force of contraction if pulmonary blood pressure is reduced. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.

26. Change From Baseline in Nitrite, Nitrate and Endogenous Nitrite (Biomarkers of Nitric Oxide [NO]) [Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1)]

    Blood samples were collected at specific time points to evaluate levels of nitrite, nitrate and endogenous nitrite (En. nitrite) (biomarkers of NO). Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.

27. Change From Baseline in Disease Biomarker: Cardiac Troponin-I [Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1)]

    Blood samples were collected at specific time points to assess cardiac troponin I. Cardiac troponin I is a biomarker of cardiac stress. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.

28. Maximum Observed Plasma Concentration (Cmax) of GSK2586881 [Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

    Blood samples were collected at indicated time points for evaluation of Cmax. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

29. Time to Cmax (Tmax) of GSK2586881 [Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

    Blood samples were collected at indicated time points for evaluation of tmax. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

30. Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-t]) of GSK2586881 [Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

    Blood samples were collected at indicated time points for evaluation of AUC(0-t). Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

31. Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of GSK2586881 [Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

    Blood samples were collected at indicated time points for evaluation of AUC(0-inf). Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

32. Last Observed Quantifiable Concentration (Ct) of GSK2586881 [Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

    Blood samples were collected at indicated time points for evaluation of Ct. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

33. Time of the Last Quantifiable Concentration (Tlast) of GSK2586881 [Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

    Blood samples were collected at indicated time points for evaluation of tlast. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

34. Plasma Clearance (CL) of GSK2586881 [Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

    Blood samples were collected at indicated time points for evaluation of CL. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

35. Apparent Volume of Distribution of GSK2586881 [Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

    Blood samples were collected at indicated time points for evaluation of apparent volume of distribution. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

36. Apparent Terminal Phase Half-life (t1/2) of GSK2586881 [Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

    Blood samples were collected at indicated time points for evaluation of t1/2. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

Other Outcome Measures

1. Change From Baseline in Cardiac Index (CI) [Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)]

   Cardiac index (CI) was measured using thermodilution. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

• Subjects must be between 18-75 years of age (inclusive), at the time of signing the informed consent.

• Documented diagnosis of PAH, defined as mPAP > 25 millimeter of mercury (mmHg) and pulmonary wedge pressure (PWP) <= 15.

• Idiopathic PAH (IPAH), Hereditary PAH (HPAH), or PAH associated with collagen vascular disease, or appetite suppressant use.

• World Health Organization (WHO) functional class I, II, or III, stable for at least 8 weeks prior to enrollment.

• Hemodynamically stable on background therapy with no evidence of uncontrolled right heart failure (historic data), as determined by the investigator.

• Six minute walk (6MW) distance, as performed at screening or within 6 months prior to screening, of >= 100 meters (m) and <= 500 m.

• Mean BP of >60 mmHg.

• Receiving stable doses of one or more medications that are approved for treatment of PAH, including endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and/or prostanoids/prostacyclin receptor agonists, for a minimum of 12 consecutive weeks before enrollment.

• Diuretic dose stable for 8 weeks.

• Body weight <= 100 kg and body mass index (BMI) within the range 18-35 kg per m square (kg/m^2) (inclusive).

• Male and/or female (following confirmation of negative pregnancy test for Women of Childbearing Potential [WOCBP]). Women who are pregnant or breastfeeding are excluded.

• Capable of giving signed informed consent.

Exclusion Criteria

• History of systemic hypotension, defined as systolic BP <90 mmHg and/or diastolic BP <50 mmHg.

• Hospitalization for PAH associated deterioration in the previous 6 months.

• Any additional medical condition, serious intercurrent illness, or other extenuating circumstance that, in the opinion of the Investigator, may significantly interfere with study compliance, including all prescribed evaluations and follow-up activities. Concurrent disease or condition that may interfere with study participation or safety include bleeding disorders, arrhythmia, organ transplant, organ failure, current neoplasm, poorly controlled diabetes mellitus, and serious neurological disorders.

• Complex repaired and unrepaired congenital heart disease.

• Subjects with Eisenmenger physiology.

• Alanine transferase (ALT) >2x upper limit of normal (ULN).

• Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent).

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

• Estimated glomerular-filtration-rate (eGFR) <45 milliliter per minute per 1.73 meter square (mL/min/1.73m^2).

• QTc >480 millisecond (msec) or QTc > 500 msec in subjects with bundle branch block.

• Any bleeding concerns as evidenced by International normalized ratio (INR) >1.5 (in subjects not receiving anticoagulation therapy) or platelet count <80,000.

• Hemoglobin (Hb) <10 gram per deciliter (g/dL).

• Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates participation in the study.

• Any use of an Angiotensin-converting enzyme (ACE) inhibitor or Angiotensin receptor blocker or renin inhibitors within 14 days prior to dosing. Therapy can be stopped to enable inclusion if deemed safe by the subject's treating physician.

• Use of any investigational product (IP) or device within 30 days prior to dosing, or known requirement for any investigational agent prior to completion of all scheduled study assessments.

• Positive human immunodeficiency virus (HIV) antibody test.

• Presence of Hepatitis B surface antigen (HBsAg) at screening.

• Positive Hepatitis C antibody test result at screening or within 3 months prior to starting study treatment.

• Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment.

• Participation in the study would result in loss of blood or blood products in excess of 300mL within 65 days.

• Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.

• A known or suspected history of alcohol or drug abuse within the 2 years prior to screening.

• Unable to refrain from smoking during the in-house treatment period.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Pittsburgh	Pennsylvania	United States	15213
2	GSK Investigational Site	Dallas	Texas	United States	75390-8550
3	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg	Germany	69126
4	GSK Investigational Site	Koeln	Nordrhein-Westfalen	Germany	50937
5	GSK Investigational Site	Dresden	Sachsen	Germany	01307
6	GSK Investigational Site	Berlin		Germany	14050
7	GSK Investigational Site	Barcelona		Spain	08035
8	GSK Investigational Site	Madrid		Spain	28041

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Study Protocol - Jul 10, 2018
• Statistical Analysis Plan - Feb 15, 2018

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT03177603
• Other Study ID Numbers: 206246; 2017-000212-41
• First Posted: Jun 6, 2017
• Last Update Posted: Apr 21, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by GlaxoSmithKline: Pulmonary Arterial Hypertension; Dose-escalation; Safety; Tolerability; GSK2586881
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Hypertension

Study Results

Participant Flow

Recruitment Details	This phase 2a, open-label, dose-escalation study comprised of 4 cohorts. Participants received GSK2586881 by single intravenous (IV) infusion at following doses: 0.1 milligram per kilogram (mg/kg) or 0.2 mg/kg or 0.4 mg/kg or 0.8 mg/kg.
Pre-assignment Detail	A total of 31 participants were screened and of them 7 participants were screen failures and one withdrew consent before dosing. Hence, a total of 23 participants received study treatment. This study was conducted at 4 centers in Germany, 2 centers in Spain, and 2 centers in the United States.

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Period Title: Cohort 1: Dose Level 0.1 mg/kg (28 Days)
STARTED	4	0	0	0
COMPLETED	4	0	0	0
NOT COMPLETED	0	0	0	0
Period Title: Cohort 1: Dose Level 0.1 mg/kg (28 Days)
STARTED	0	5	0	0
COMPLETED	0	5	0	0
NOT COMPLETED	0	0	0	0
Period Title: Cohort 1: Dose Level 0.1 mg/kg (28 Days)
STARTED	0	0	6	0
COMPLETED	0	0	6	0
NOT COMPLETED	0	0	0	0
Period Title: Cohort 1: Dose Level 0.1 mg/kg (28 Days)
STARTED	0	0	0	8
COMPLETED	0	0	0	8
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg	Total
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Total of all reporting groups
Overall Participants	4	5	6	8	23
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	32.0 (4.97)	55.4 (14.96)	52.5 (8.67)	50.3 (13.35)	48.8 (13.55)
Sex: Female, Male (Count of Participants)
Female	3 75%	3 60%	4 66.7%	5 62.5%	15 65.2%
Male	1 25%	2 40%	2 33.3%	3 37.5%	8 34.8%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	0 0%	1 20%	1 16.7%	1 12.5%	3 13%
White - White/Caucasian/European Heritage	4 100%	4 80%	5 83.3%	7 87.5%	20 87%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Pulmonary Vascular Resistance (PVR)
Description	PVR is the resistance generated by pulmonary circulation. Pulmonary arterial catheters were placed in participants and PVR values were recorded from the right heart catheterization. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.
Time Frame	Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Evaluable Population comprised of all participants who were in the safety population, who completed all Day 1 assessments (including up to 24 hours post dose) and were not deemed to have had major protocol deviations. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	5	8
1 hour post-dose (Day 1)	0.936	0.885	0.813	1.017
2 hours post-dose (Day 1)	0.926	1.043	0.945	0.974
4 hours post-dose (Day 1)	0.907	0.895	0.924	1.116

2. Primary Outcome

Title	Change From Baseline in Cardiac Output (CO)
Description	CO is the amount of blood pumped by the heart per minute. Pulmonary arterial catheters were placed in participants and CO values were recorded from the right heart catheterization. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.
Time Frame	Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Evaluable Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	5	8
1 hour post-dose (Day 1)	1.046	1.079	1.076	0.990
2 hours post-dose (Day 1)	1.025	1.029	0.929	1.012
4 hours post-dose (Day 1)	1.114	1.138	0.882	1.002

3. Primary Outcome

Title	Change From Baseline in Mean Pulmonary Artery Pressure (mPAP)
Description	The pulmonary artery pressure is a measure of the blood pressure found in the main pulmonary artery. Pulmonary arterial catheters were placed in participants and mPAP values were recorded from the right heart catheterization. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.
Time Frame	Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Evaluable Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	5	8
1 hour post-dose (Day 1)	0.950	0.995	0.939	0.989
2 hours post-dose (Day 1)	0.937	0.994	0.910	0.996
4 hours post-dose (Day 1)	0.991	1.029	0.973	1.062

4. Secondary Outcome

Title	Number of Participants With Non-serious Adverse Events (AEs)
Description	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.
Time Frame	Up to Day 28

Outcome Measure Data

Analysis Population Description

Safety Population comprised of all participants who took at least 1 dose of study treatment.

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
Count of Participants [Participants]	1 25%	3 60%	5 83.3%	2 25%

5. Secondary Outcome

Title	Number of Participants With Serious Adverse Events (SAEs)
Description	Any untoward event resulting in death, life threatening, requiring hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention were categorized as SAE.
Time Frame	Up to Day 28

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

6. Secondary Outcome

Title	Change From Baseline in Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Amino Transferase and Aspartate Amino Transferase
Description	Blood samples were collected for the assessment of clinical chemistry parameters: alkaline phosphatase, alanine amino transferase (ALT) and aspartate amino transferase (AST). Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
Alkaline phosphatase, 24 hours post-dose (Day 1)	4.8 (8.42)	-1.4 (7.44)	5.3 (3.08)	3.1 (3.48)
Alkaline phosphatase, Day 7 to Day 14	6.5 (5.00)	3.2 (4.21)	3.0 (3.52)	2.6 (4.31)
ALT, 24 hours post-dose (Day 1)	-2.0 (2.16)	0.0 (1.58)	-1.8 (3.76)	-0.1 (2.17)
ALT, Day 7 to Day 14	1.3 (0.96)	1.8 (3.27)	-4.3 (12.94)	0.9 (4.85)
AST, 24 hours post-dose (Day 1)	0.0 (1.63)	-0.4 (0.55)	0.5 (1.76)	-1.8 (3.77)
AST, Day 7 to Day 14	2.8 (2.50)	1.4 (1.67)	-0.3 (3.67)	-0.9 (6.71)

7. Secondary Outcome

Title	Change From Baseline in Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Creatinine
Description	Blood samples were collected for the assessment of clinical chemistry parameters: direct bilirubin, total bilirubin and creatinine. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
Direct bilirubin, 24 hours post-dose (Day 1)	2.0 (1.63)	0.4 (0.89)	0.3 (1.97)	1.0 (2.14)
Direct bilirubin, Day 7 to Day 14	1.0 (1.15)	0.0 (0.00)	0.0 (1.26)	0.5 (2.56)
Total bilirubin, 24 hours post-dose (Day 1)	3.0 (4.16)	0.8 (1.79)	0.7 (4.84)	4.8 (6.76)
Total bilirubin, Day 7 to Day 14	1.5 (3.42)	0.4 (2.61)	-1.7 (3.44)	0.0 (4.14)
Creatinine, 24 hours post-dose (Day 1)	5.08 (4.102)	10.80 (6.110)	12.22 (20.214)	1.76 (2.759)
Creatinine, Day 7 to Day 14	-1.12 (6.530)	8.68 (13.353)	4.57 (9.638)	3.20 (4.885)

8. Secondary Outcome

Title	Change From Baseline in Clinical Chemistry Parameters: Calcium, Glucose, Potassium, Sodium and Blood Urea Nitrogen (BUN)
Description	Blood samples were collected for the assessment of clinical chemistry parameters: calcium, glucose, potassium, sodium and BUN. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
Calcium, 24 hours post-dose (Day 1)	0.035 (0.1427)	0.012 (0.0867)	0.047 (0.1033)	0.060 (0.0466)
Calcium, Day 7 to Day 14	0.025 (0.1399)	0.064 (0.0888)	0.047 (0.1250)	0.115 (0.0583)
Glucose, 24 hours post-dose (Day 1)	0.85 (0.957)	1.10 (1.398)	0.50 (1.752)	0.89 (2.039)
Glucose, Day 7 to Day 14	0.95 (1.760)	-0.32 (0.646)	-0.57 (0.635)	-0.20 (1.995)
Potassium, 24 hours post-dose (Day 1)	0.28 (0.377)	0.18 (0.179)	0.08 (0.306)	-0.05 (0.239)
Potassium, Day 7 to Day 14	0.10 (0.356)	0.22 (0.148)	0.25 (0.207)	0.18 (0.301)
Sodium, 24 hours post-dose (Day 1)	-1.3 (1.26)	-0.6 (2.30)	-0.2 (1.47)	-1.0 (1.85)
Sodium, Day 7 to Day 14	-0.3 (4.19)	0.0 (1.87)	0.5 (1.64)	0.0 (1.60)
BUN, 24 hours post-dose (Day 1)	0.00 (1.080)	-0.20 (0.758)	0.83 (1.033)	-0.25 (0.463)
BUN, Day 7 to Day 14	-0.25 (1.258)	1.50 (1.541)	0.00 (1.000)	0.31 (1.067)

9. Secondary Outcome

Title	Change From Baseline in Clinical Chemistry Parameter: Total Protein
Description	Blood samples were collected for the assessment of clinical chemistry parameter, total protein. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
24 hours post-dose (Day 1)	1.3 (6.13)	0.6 (3.78)	1.8 (2.93)	2.6 (3.66)
Day 7 to Day 14	1.5 (2.38)	6.2 (4.55)	2.0 (4.73)	4.9 (3.31)

10. Secondary Outcome

Title	Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell (WBC) Count
Description	Blood samples were collected for the assessment of hematology parameters: basophils, eosinophils, lymphocytes, monocytes, total neutrophils (T.neutrophils), platelet count and WBC count. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
Basophils, 24 hours post-dose (Day 1), n=4,4,6,3	-0.008 (0.0359)	0.013 (0.0206)	-0.005 (0.0302)	0.003 (0.0115)
Basophils, Day 7 to Day 14, n=4,5,6,8	0.000 (0.0327)	0.002 (0.0192)	0.008 (0.0306)	0.003 (0.0238)
Eosinophils, 24 hours post-dose (Day 1), n=4,4,6,3	0.007 (0.0695)	0.018 (0.0222)	0.012 (0.0662)	-0.007 (0.0503)
Eosinophils, Day 7 to Day 14, n=4,5,6,8	-0.035 (0.0835)	0.004 (0.0230)	-0.025 (0.0807)	0.023 (0.1004)
Lymphocytes, 24 hours post-dose (Day 1), n=4,4,6,3	0.000 (0.5509)	-0.070 (0.1612)	-0.157 (0.1558)	0.190 (0.4553)
Lymphocytes, Day 7 to Day 14, n=4,5,6,8	-0.025 (0.4277)	-0.054 (0.1422)	-0.250 (0.2001)	0.130 (0.4032)
Monocytes, 24 hours post-dose (Day 1), n=4,4,6,3	0.050 (0.0673)	-0.028 (0.0914)	0.098 (0.1125)	0.140 (0.0700)
Monocytes, Day 7 to Day 14, n=4,5,6,8	0.038 (0.1066)	0.038 (0.0998)	0.047 (0.1263)	0.091 (0.1654)
T.neutrophils, 24 hours post-dose(Day1),n=4,4,6,3	0.643 (1.0052)	0.415 (0.3924)	0.738 (0.5615)	0.727 (0.7298)
T.neutrophils, Day 7 to Day 14, n=4,5,6,8	0.185 (0.9008)	0.504 (0.4884)	0.397 (1.3173)	0.366 (0.7204)
Platelets, 24 hours post-dose (Day 1), n=4,4,6,5	11.8 (36.28)	-33.0 (73.51)	7.8 (16.65)	12.6 (27.74)
Platelets, Day 7 to Day 14, n=4,5,6,8	35.3 (17.40)	19.8 (45.03)	14.3 (52.89)	23.4 (24.44)
WBC count, 24 hours post-dose (Day 1), n=4,4,6,5	0.35 (1.330)	0.30 (0.183)	0.68 (0.542)	2.16 (2.492)
WBC count, Day 7 to Day 14, n=4,5,6,8	-0.20 (1.334)	0.46 (0.498)	0.20 (1.355)	0.64 (0.588)

11. Secondary Outcome

Title	Change From Baseline in Hematology Parameter: Hemoglobin
Description	Blood samples were collected for the assessment of hematology parameter, hemoglobin. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
24 hours post-dose (Day 1), n=4,4,6,5	1.8 (11.09)	2.0 (5.72)	5.0 (4.77)	3.0 (5.61)
Day 7 to Day 14, n=4,5,6,8	-4.3 (6.55)	3.4 (5.98)	-1.5 (7.09)	4.0 (5.15)

12. Secondary Outcome

Title	Change From Baseline in Hematology Parameter: Hematocrit
Description	Blood samples were collected for the assessment of hematology parameter, hematocrit. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
24 hours post-dose (Day 1), n=4,4,6,5	0.0030 (0.02858)	0.0053 (0.02156)	0.0098 (0.01546)	0.0140 (0.02448)
Day 7 to Day 14, n=4,5,6,8	-0.0225 (0.00929)	0.0104 (0.02173)	0.0030 (0.02391)	0.0135 (0.01891)

13. Secondary Outcome

Title	Change From Baseline in Hematology Parameter: Mean Corpuscle Hemoglobin
Description	Blood samples were collected for the assessment of hematology parameter, mean corpuscle hemoglobin. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
24 hours post-dose (Day 1), n=4,4,6,5	-0.08 (0.150)	0.05 (0.507)	0.25 (0.302)	-0.10 (0.235)
Day 7 to Day 14, n=4,5,6,8	0.10 (0.483)	0.04 (0.182)	-0.33 (0.314)	0.15 (0.177)

14. Secondary Outcome

Title	Change From Baseline in Hematology Parameter: Mean Corpuscle Volume
Description	Blood samples were collected for the assessment of hematology parameter, mean corpuscle volume. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
24 hours post-dose (Day 1), n=4,4,6,5	-0.5 (2.52)	0.0 (0.82)	-0.5 (0.84)	0.6 (1.95)
Day 7 to Day 14, n=4,5,6,8	-1.5 (2.08)	-0.2 (0.84)	0.7 (1.03)	0.8 (1.04)

15. Secondary Outcome

Title	Change From Baseline in Hematology Parameter: Red Blood Cell (RBC) Count
Description	Blood samples were collected for the assessment of hematology parameter: RBC count. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
24 hours post-dose (Day 1), n=4,4,6,5	0.03 (0.435)	0.03 (0.287)	0.13 (0.163)	0.12 (0.192)
Day 7 to Day 14, n=4,5,6,8	-0.20 (0.183)	0.14 (0.261)	0.00 (0.310)	0.11 (0.203)

16. Secondary Outcome

Title	Change From Baseline in Hematology Parameter: Reticulocytes
Description	Blood samples were collected for the assessment of hematology parameter: reticulocytes. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
24 hours post-dose (Day 1), n=4,4,6,5	0.0012 (0.00330)	0.0017 (0.00310)	0.0017 (0.00216)	0.0000 (0.00100)
Day 7 to Day 14, n=4,5,6,8	0.0058 (0.00411)	0.0014 (0.00358)	0.0025 (0.00333)	0.0040 (0.00325)

17. Secondary Outcome

Title	Number of Participants With Urinalysis Results by Dipstick Method
Description	Urine samples were collected to assess urine bilirubin, urine occult blood, urine glucose, urine ketones, and urine protein by dipstick test. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameter of urine bilirubin, urine occult blood, urine glucose, urine ketones and urine protein can be read as negative, trace, 1+, 2+ and 3+ indicating proportional concentrations in the urine sample.
Time Frame	24 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
Bilirubin, 24 hours post-dose (Day 1), negative	4 100%	5 100%	6 100%	8 100%
Bilirubin, 24 hours post-dose (Day 1), trace	0 0%	0 0%	0 0%	0 0%
Bilirubin, 24 hours post-dose (Day 1), 1+	0 0%	0 0%	0 0%	0 0%
Bilirubin, 24 hours post-dose (Day 1), 2+	0 0%	0 0%	0 0%	0 0%
Bilirubin, 24 hours post-dose (Day 1), 3+	0 0%	0 0%	0 0%	0 0%
Occult Blood, 24 hours post-dose (Day 1), negative	2 50%	5 100%	4 66.7%	7 87.5%
Occult Blood, 24 hours post-dose (Day 1), trace	0 0%	0 0%	2 33.3%	1 12.5%
Occult Blood, 24 hours post-dose (Day 1), 1+	1 25%	0 0%	0 0%	0 0%
Occult Blood, 24 hours post-dose (Day 1), 2+	1 25%	0 0%	0 0%	0 0%
Occult Blood, 24 hours post-dose (Day 1), 3+	0 0%	0 0%	0 0%	0 0%
Glucose, 24 hours post-dose (Day 1), negative	4 100%	5 100%	5 83.3%	8 100%
Glucose, 24 hours post-dose (Day 1), trace	0 0%	0 0%	0 0%	0 0%
Glucose, 24 hours post-dose (Day 1), 1+	0 0%	0 0%	0 0%	0 0%
Glucose, 24 hours post-dose (Day 1), 2+	0 0%	0 0%	0 0%	0 0%
Glucose, 24 hours post-dose (Day 1), 3+	0 0%	0 0%	1 16.7%	0 0%
Ketones, 24 hours post-dose (Day 1), negative	4 100%	4 80%	3 50%	8 100%
Ketones, 24 hours post-dose (Day 1), trace	0 0%	1 20%	3 50%	0 0%
Ketones, 24 hours post-dose (Day 1), 1+	0 0%	0 0%	0 0%	0 0%
Ketones, 24 hours post-dose (Day 1), 2+	0 0%	0 0%	0 0%	0 0%
Ketones, 24 hours post-dose (Day 1), 3+	0 0%	0 0%	0 0%	0 0%
Protein, 24 hours post-dose (Day 1), negative	4 100%	4 80%	6 100%	8 100%
Protein, 24 hours post-dose (Day 1), trace	0 0%	1 20%	0 0%	0 0%
Protein, 24 hours post-dose (Day 1), 1+	0 0%	0 0%	0 0%	0 0%
Protein, 24 hours post-dose (Day 1), 2+	0 0%	0 0%	0 0%	0 0%
Protein, 24 hours post-dose (Day 1), 3+	0 0%	0 0%	0 0%	0 0%

18. Secondary Outcome

Title	Change From Baseline in Pulse Rate
Description	Pulse rate was measured in supine position after at least a 5-minute rest. Change from Baseline in pulse rate was evaluated. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose); 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
0.5 hour post-dose (Day 1), n=4,5,6,8	-1.3 (5.85)	-0.8 (3.42)	3.5 (8.64)	3.6 (6.00)
1 hour post-dose (Day 1), n=4,5,6,8	-3.0 (6.98)	0.8 (6.69)	-0.7 (3.67)	-1.0 (3.93)
2 hours post-dose (Day 1), n=4,5,6,8	-5.0 (7.62)	-0.4 (1.95)	-1.8 (6.65)	1.0 (5.93)
4 hours post-dose (Day 1), n=4,5,6,8	-1.8 (6.80)	11.6 (13.67)	-1.2 (6.40)	-0.8 (7.42)
8 hours post-dose (Day 1), n=4,4,6,8	2.8 (6.90)	1.8 (5.19)	5.7 (5.85)	8.6 (9.83)
24 hours post-dose (Day 1), n=4,5,6,8	4.3 (11.27)	3.6 (6.50)	7.5 (7.12)	13.0 (9.20)
Day 7 to Day 14, n=4,5,6,8	10.0 (14.31)	4.4 (5.86)	5.3 (6.25)	9.8 (8.36)

19. Secondary Outcome

Title	Change From Baseline in Respiratory Rate
Description	Respiratory rate was measured in supine position after at least a 5-minute rest. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose); 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
0.5 hour post-dose (Day 1), n=4,5,6,8	-2.5 (3.11)	-3.4 (4.39)	-2.2 (4.92)	0.1 (1.13)
1 hour post-dose (Day 1), n=4,5,6,8	-2.8 (1.71)	-3.2 (5.67)	1.8 (9.22)	0.0 (0.76)
2 hours post-dose (Day 1), n=4,5,6,8	-2.0 (2.16)	-2.6 (2.97)	-3.0 (4.52)	-1.0 (4.50)
4 hours post-dose (Day 1), n=4,5,6,8	-2.5 (2.08)	-2.2 (5.63)	-2.2 (3.54)	0.1 (0.64)
8 hours post-dose (Day 1), n=4,4,6,8	-2.0 (1.63)	-0.3 (3.50)	0.2 (2.56)	1.1 (2.59)
24 hours post-dose (Day 1), n=4,5,6,8	-1.8 (0.96)	0.8 (2.28)	0.3 (2.58)	-0.1 (1.81)
Day 7 to Day 14, n=4,5,6,8	-0.5 (1.73)	-0.4 (3.58)	2.0 (2.28)	0.3 (1.16)

20. Secondary Outcome

Title	Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
Description	DBP and SBP were measured in supine position after at least a 5-minute rest. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose); 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
DBP, 0.5 hour post-dose (Day 1), n=4,5,6,8	-3.5 (8.58)	-1.0 (10.42)	-5.0 (14.67)	-3.3 (4.53)
DBP, 1 hour post-dose (Day 1), n=4,5,6,8	-2.0 (6.22)	0.6 (8.56)	-4.3 (9.73)	-2.3 (3.73)
DBP, 2 hours post-dose (Day 1), n=4,5,6,8	0.5 (12.40)	1.2 (10.55)	-5.8 (8.80)	3.3 (5.87)
DBP, 4 hours post-dose (Day 1), n=4,5,6,8	-1.5 (2.65)	3.0 (8.37)	-2.7 (13.22)	1.6 (6.07)
DBP, 8 hours post-dose (Day 1), n=4,4,6,8	-12.3 (6.65)	-6.3 (8.66)	-10.2 (9.15)	-1.0 (9.32)
DBP, 24 hours post-dose (Day 1), n=4,5,6,8	-7.5 (7.94)	-8.6 (9.61)	-2.8 (10.61)	-3.1 (8.46)
DBP, Day 7 to Day 14, n=4,5,6,8	-4.5 (7.19)	-2.2 (6.91)	-2.5 (11.78)	2.8 (12.83)
SBP, 0.5 hour post-dose (Day 1), n=4,5,6,8	-2.3 (12.28)	-0.2 (12.60)	-5.2 (6.11)	-0.1 (5.03)
SBP, 1 hour post-dose (Day 1), n=4,5,6,8	-1.8 (9.91)	3.4 (12.68)	-2.7 (9.37)	3.0 (8.07)
SBP, 2 hours post-dose (Day 1), n=4,5,6,8	1.0 (15.12)	2.0 (10.20)	-0.7 (18.84)	2.0 (11.80)
SBP, 4 hours post-dose (Day 1), n=4,5,6,8	5.5 (19.69)	4.2 (9.34)	6.3 (13.03)	6.1 (13.53)
SBP, 8 hours post-dose (Day 1), n=4,4,6,8	-4.5 (10.38)	3.0 (16.57)	-5.2 (7.63)	-4.8 (9.65)
SBP, 24 hours post-dose (Day 1), n=4,5,6,8	-2.5 (4.51)	-0.2 (14.72)	-4.7 (11.41)	-3.8 (14.85)
SBP, Day 7 to Day 14, n=4,5,6,8	2.0 (21.37)	6.0 (6.78)	-5.8 (15.07)	-2.1 (9.63)

21. Secondary Outcome

Title	Number of Participants With Abnormal Electrocardiogram (ECG) Findings
Description	12-lead ECGs were obtained at each time point using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and Corrected QT (QTc) intervals. Only those participants who had any abnormal ECG findings are presented. Abnormal ECG findings were categorized as clinically significant (CS) and not clinically significant (NCS) abnormal ECG findings. CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	4 hours and 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
Abnormal NCS, 4 hours post-dose (Day 1), n=4,5,6,8	1 25%	3 60%	3 50%	7 87.5%
Abnormal CS, 4 hours post-dose (Day 1), n=4,5,6,8	0 0%	0 0%	0 0%	0 0%
Abnormal NCS, 24 hours post-dose(Day 1), n=3,5,6,8	1 25%	3 60%	4 66.7%	5 62.5%
Abnormal CS, 24 hours post-dose (Day 1), n=3,5,6,8	0 0%	0 0%	0 0%	0 0%
Abnormal NCS, Day 7 to Day 14, n=4,5,6,8	1 25%	3 60%	3 50%	3 37.5%
Abnormal CS, Day 7 to Day 14, n=4,5,6,8	0 0%	0 0%	0 0%	0 0%

22. Secondary Outcome

Title	Change From Baseline in Pulse Oximetry Parameter: Percent Oxygen in Blood
Description	Percent oxygen in blood was measured using pulse oximetry after the participant had rested for at least 5 minutes. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose); 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
0.5 hour post-dose (Day 1), n=4,5,6,8	-1.0 (2.30)	-1.7 (2.77)	0.8 (2.31)	-0.5 (2.03)
1 hour post-dose (Day 1), n=4,5,6,8	-0.7 (2.87)	-2.1 (2.79)	-0.3 (1.03)	-0.9 (2.48)
2 hours post-dose (Day 1), n=4,5,6,8	-1.5 (1.91)	-0.7 (1.99)	0.6 (1.21)	0.9 (1.37)
4 hours post-dose (Day 1), n=4,5,6,8	-0.7 (2.21)	-1.0 (1.87)	-0.3 (1.96)	0.5 (2.13)
8 hours post-dose (Day 1), n=4,4,6,8	-0.7 (2.50)	-0.2 (3.58)	0.8 (2.31)	0.4 (2.98)
24 hours post-dose (Day 1), n=4,5,6,8	-1.0 (2.00)	-2.3 (3.06)	2.1 (1.60)	1.0 (3.28)
Day 7 to Day 14, n=4,5,6,8	-0.2 (0.95)	-2.9 (2.37)	0.5 (3.33)	0.8 (2.49)

23. Secondary Outcome

Title	Number of Participants With Positive Immunogenicity Results
Description	Immunogenicity samples were collected into a serum-separating tube, mixed by gentle inversion 5 times and left to coagulate at room temperature for a minimum of 30 minutes and a maximum of 60 minutes. All samples were first tested for anti-angiotensin converting enzyme type 2 (ACE2) binding antibodies by screening and confirmation assay steps. If post-dose samples were found to be positive for anti-ACE2 binding antibodies, they would have been further characterized for anti-ACE2 neutralizing antibodies. Number of participants with positive immunogenicity results post-dosing are presented.
Time Frame	Up to Day 28

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

24. Secondary Outcome

Title	Change From Baseline in Systemic Renin-Angiotensin System (RAS) Peptides: Angiotensin II, Angiotensin (1-5) and Angiotensin (1-7)
Description	Blood samples were collected to evaluate systemic RAS peptides: Angiotensin (Ang) II, Ang (1-7) and Ang (1-5). Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	Baseline (Day 1, Pre-dose); 0.08 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	5	8
Ang II, 0.08 hour post-dose (Day 1), n=4,5,5,8	0.143	0.185	1.020	0.254
Ang II, 0.5 hour post-dose (Day 1), n=4,5,5,8	0.179	0.210	0.500	0.211
Ang II, 1 hour post-dose (Day 1), n=4,5,5,8	0.238	0.162	0.420	0.235
Ang II, 2 hours post-dose (Day 1), n=4,5,5,8	0.230	0.166	0.393	0.211
Ang II, 4 hours post-dose (Day 1), n=4,5,5,8	0.372	0.187	0.398	0.387
Ang II, 8 hours post-dose (Day 1), n=4,5,5,8	0.889	0.669	0.503	0.277
Ang II, 24 hours post-dose (Day 1), n=4,5,5,8	2.329	1.372	0.763	0.939
Ang II, Day 7 to Day 14, n=4,5,5,7	1.625	2.380	0.616	1.826
Ang (1-5), 0.08 hour post-dose (Day 1), n=4,5,4,6	1.884	4.696	2.222	2.982
Ang (1-5), 0.5 hour post-dose (Day 1), n=4,5,4,6	2.342	5.325	2.895	3.187
Ang (1-5), 1 hour post-dose (Day 1), n=4,5,4,6	2.427	4.263	2.572	3.264
Ang (1-5), 2 hours post-dose (Day 1), n=4,5,4,6	2.269	3.499	3.423	2.463
Ang (1-5), 4 hours post-dose (Day 1), n=4,5,4,6	2.442	2.740	3.513	2.717
Ang (1-5), 8 hours post-dose (Day 1), n=4,5,4,6	4.365	4.125	6.691	4.882
Ang (1-5), 24 hours post-dose (Day 1), n=4,5,4,6	2.397	3.701	2.573	5.117
Ang (1-5), Day 7 to Day 14, n=4,5,3,6	1.469	2.110	0.548	1.642
Ang (1-7), 0.08 hour post-dose (Day 1), n=4,5,5,7	2.252	4.392	3.465	1.817
Ang (1-7), 0.5 hour post-dose (Day 1), n=4,5,5,7	2.943	4.935	2.242	2.205
Ang (1-7), 1 hour post-dose (Day 1), n=4,5,5,7	3.002	3.494	2.362	1.780
Ang (1-7), 2 hours post-dose (Day 1), n=4,5,5,7	2.311	4.025	3.471	1.949
Ang (1-7), 4 hours post-dose (Day 1), n=4,5,5,7	3.350	3.115	3.623	1.818
Ang (1-7), 8 hours post-dose (Day 1), n=4,5,5,7	4.910	3.517	6.002	4.229
Ang (1-7), 24 hours post-dose (Day 1), n=4,5,5,7	3.423	4.096	2.812	7.095
Ang (1-7), Day 7 to Day 14, n=4,5,5,6	1.190	1.904	0.925	1.932

25. Secondary Outcome

Title	Change From Baseline in Pulmonary Wedge RAS Peptides: Angiotensin II, Angiotensin (1-5) and Angiotensin (1-7)
Description	Blood samples were collected to evaluate pulmonary wedge RAS peptides: Ang II, Ang (1-5) and Ang (1-7). Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.
Time Frame	Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	4	4	8
Ang II, 1 hour post-dose (Day 1), n=4,4,4,8	0.270	0.190	0.394	0.369
Ang II, 2 hours post-dose (Day 1), n=4,4,4,8	0.310	0.193	0.505	0.369
Ang II, 4 hours post-dose (Day 1), n=4,4,3,8	0.332	0.191	0.183	0.420
Ang (1-5), 1 hour post-dose (Day 1), n=4,4,4,7	2.985	3.313	2.709	1.834
Ang (1-5), 2 hours post-dose (Day 1), n=4,4,3,7	3.443	4.621	5.246	1.562
Ang (1-5), 4 hours post-dose (Day 1), n=4,4,3,7	2.373	3.213	5.239	1.472
Ang (1-7), 1 hour post-dose (Day 1), n=4,4,4,8	2.840	4.150	2.993	1.558
Ang (1-7), 2 hours post-dose (Day 1), n=4,4,4,8	3.376	3.792	4.476	1.589
Ang (1-7), 4 hours post-dose (Day 1), n=4,4,3,8	2.857	3.151	8.521	1.693

26. Secondary Outcome

Title	Systemic RAS Peptide: Angiotensin II/Angiotensin (1-7) Ratio at Indicated Time Points
Description	Blood samples were collected to assess systemic RAS peptides: Angiotensin II and Angiotensin (1-7). Data for angiotensin II/angiotensin (1-7) ratio is presented. Assessment of follow up visit was conducted between any day of Days 7 to 14.
Time Frame	0.08 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	5	8
0.08 hour post-dose (Day 1), n=4,5,5,8	0.752	0.463	1.450	0.843
0.5 hour post-dose (Day 1), n=4,5,5,8	0.718	0.468	1.097	0.590
1 hour post-dose (Day 1), n=4,5,5,8	0.937	0.509	0.875	0.794
2 hours post-dose (Day 1), n=4,5,5,8	1.174	0.455	0.558	0.657
4 hours post-dose (Day 1), n=4,5,5,8	1.312	0.659	0.540	1.283
8 hours post-dose (Day 1), n=4,5,5,8	2.139	2.093	0.412	0.439
24 hours post-dose (Day 1), n=4,5,5,8	8.041	3.682	1.335	0.946
Day 7 to Day 14, n=4,5,5,7	16.132	13.742	3.278	6.156

27. Secondary Outcome

Title	Pulmonary Wedge RAS Peptide: Angiotensin II/Angiotensin (1-7) Ratio at Indicated Time Points
Description	Blood samples were collected to assess pulmonary wedge RAS peptides: Angiotensin II and Angiotensin (1-7). Data for angiotensin II/angiotensin (1-7) ratio is presented.
Time Frame	1 hour, 2 hours and 4 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	4	4	8
1 hour post-dose (Day 1), n=4,4,4,8	0.888	0.443	0.620	0.789
2 hours post-dose (Day 1), n=4,4,4,8	0.858	0.493	0.531	0.774
4 hours post-dose (Day 1), n=4,4,3,8	1.085	0.587	0.148	0.826

28. Secondary Outcome

Title	Change From Baseline in Disease Biomarkers: N-terminal Pro B-type Natriuretic Peptide (NT Pro-BNP)
Description	Blood samples were collected at specific time points to evaluate NT pro-BNP, a biomarker of disease activity. NT-pro-BNP is a biomarker of cardiac stress or ventricular workload and decreases as a result of reduced force of contraction if pulmonary blood pressure is reduced. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.
Time Frame	Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Evaluable Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	4	8
2 hours post-dose (Day 1)	1.034	1.005	0.923	1.015
4 hours post-dose (Day 1)	1.025	1.042	0.944	1.074
24 hours post-dose (Day 1)	0.606	0.896	0.703	0.810

29. Secondary Outcome

Title	Change From Baseline in Nitrite, Nitrate and Endogenous Nitrite (Biomarkers of Nitric Oxide [NO])
Description	Blood samples were collected at specific time points to evaluate levels of nitrite, nitrate and endogenous nitrite (En. nitrite) (biomarkers of NO). Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.
Time Frame	Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	4	5	8
Nitrite, 2 hours post-dose (Day 1), n=4,4,5,8	1.246	1.029	0.530	0.858
Nitrite, 4 hours post-dose (Day 1), n=4,4,5,8	0.760	0.992	0.679	0.770
Nitrite, 24 hours post-dose (Day 1), n=4,4,4,7	1.038	1.146	0.667	0.914
Nitrate, 2 hours post-dose (Day 1), n=4,4,5,8	1.251	1.025	0.485	0.836
Nitrate, 4 hours post-dose (Day 1), n=4,4,5,8	0.739	0.977	0.655	0.762
Nitrate, 24 hours post-dose (Day 1), n=4,4,4,7	1.017	1.149	0.641	0.911
En. nitrite, 2 hours post-dose (Day 1), n=4,4,5,8	1.099	2.036	1.171	0.975
En. nitrite, 4 hours post-dose (Day 1), n=4,4,5,8	1.245	2.819	1.329	0.820
En. nitrite, 24 hours post-dose (Day 1), n=4,4,4,7	1.290	1.399	1.289	1.271

30. Secondary Outcome

Title	Change From Baseline in Disease Biomarker: Cardiac Troponin-I
Description	Blood samples were collected at specific time points to assess cardiac troponin I. Cardiac troponin I is a biomarker of cardiac stress. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.
Time Frame	Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Evaluable Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	5	8
2 hours post-dose (Day 1)	1.565	1.320	1.585	1.414
4 hours post-dose (Day 1)	1.968	1.149	1.695	2.030
24 hours post-dose (Day 1)	1.316	1.000	1.000	1.000

31. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of GSK2586881
Description	Blood samples were collected at indicated time points for evaluation of Cmax. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time Frame	Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population comprised of participants in the Safety Population for whom a pharmacokinetic sample was obtained and analyzed.

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
Geometric Mean (Geometric Coefficient of Variation) [Micrograms per milliliter]	1.5159 (37.0)	4.0229 (37.4)	8.9701 (26.1)	14.8042 (33.1)

32. Secondary Outcome

Title	Time to Cmax (Tmax) of GSK2586881
Description	Blood samples were collected at indicated time points for evaluation of tmax. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time Frame	Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
Median (Full Range) [Hours]	0.08333	0.16667	0.10000	0.13333

33. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-t]) of GSK2586881
Description	Blood samples were collected at indicated time points for evaluation of AUC(0-t). Pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time Frame	Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
Geometric Mean (Geometric Coefficient of Variation) [Hours*micrograms per milliliter]	3.941 (53.6)	17.874 (30.9)	46.789 (16.3)	68.042 (37.0)

34. Secondary Outcome

Title	Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of GSK2586881
Description	Blood samples were collected at indicated time points for evaluation of AUC(0-inf). Pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time Frame	Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	2	6	7
Geometric Mean (Geometric Coefficient of Variation) [Hours*micrograms per milliliter]	NA (NA)	25.26 (7.7)	52.46 (20.0)	76.87 (42.1)

35. Secondary Outcome

Title	Last Observed Quantifiable Concentration (Ct) of GSK2586881
Description	Blood samples were collected at indicated time points for evaluation of Ct. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time Frame	Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
Geometric Mean (Geometric Coefficient of Variation) [Micrograms per milliliter]	0.2563 (22.8)	0.3327 (54.4)	0.4800 (44.9)	0.6380 (54.9)

36. Secondary Outcome

Title	Time of the Last Quantifiable Concentration (Tlast) of GSK2586881
Description	Blood samples were collected at indicated time points for evaluation of tlast. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time Frame	Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	6	8
Median (Full Range) [Hours]	8.000	24.000	24.017	24.117

37. Secondary Outcome

Title	Plasma Clearance (CL) of GSK2586881
Description	Blood samples were collected at indicated time points for evaluation of CL. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time Frame	Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	2	6	7
Geometric Mean (Geometric Coefficient of Variation) [Liters per hour]	NA (NA)	0.5838 (10.1)	0.6207 (16.8)	0.8170 (30.8)

38. Secondary Outcome

Title	Apparent Volume of Distribution of GSK2586881
Description	Blood samples were collected at indicated time points for evaluation of apparent volume of distribution. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time Frame	Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	2	6	7
Geometric Mean (Geometric Coefficient of Variation) [Liters]	NA (NA)	6.443 (2.4)	6.593 (20.5)	8.084 (20.6)

39. Secondary Outcome

Title	Apparent Terminal Phase Half-life (t1/2) of GSK2586881
Description	Blood samples were collected at indicated time points for evaluation of t1/2. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time Frame	Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	2	6	7
Geometric Mean (Geometric Coefficient of Variation) [Hours]	NA (NA)	7.651 (7.7)	7.362 (23.2)	6.858 (19.6)

40. Other Pre-specified Outcome

Title	Change From Baseline in Cardiac Index (CI)
Description	Cardiac index (CI) was measured using thermodilution. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.
Time Frame	Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)

Outcome Measure Data

Analysis Population Description

Evaluable Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	GSK2586881 0.1 mg/kg	GSK2586881 0.2 mg/kg	GSK2586881 0.4 mg/kg	GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.	Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
Measure Participants	4	5	5	8
1 hour post-dose (Day 1)	1.045	1.076	1.084	0.990
2 hours post-dose (Day 1)	1.021	1.029	0.926	1.020
4 hours post-dose (Day 1)	1.107	1.128	0.889	1.000

Adverse Events

Time Frame	Non-SAEs and SAEs were reported from start of study treatment and up to Day 28
Adverse Event Reporting Description	Non-SAEs and SAEs were reported for Safety Population. Adverse events were presented treatment-wise.
Arm/Group Title	GSK2586881 0.1 mg/kg		GSK2586881 0.2 mg/kg		GSK2586881 0.4 mg/kg		GSK2586881 0.8 mg/kg
Arm/Group Description	Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.		Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose.		Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose.		Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose.
All Cause Mortality
	GSK2586881 0.1 mg/kg		GSK2586881 0.2 mg/kg		GSK2586881 0.4 mg/kg		GSK2586881 0.8 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/5 (0%)		0/6 (0%)		0/8 (0%)
Serious Adverse Events
	GSK2586881 0.1 mg/kg		GSK2586881 0.2 mg/kg		GSK2586881 0.4 mg/kg		GSK2586881 0.8 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/5 (0%)		0/6 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	GSK2586881 0.1 mg/kg		GSK2586881 0.2 mg/kg		GSK2586881 0.4 mg/kg		GSK2586881 0.8 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/4 (25%)		3/5 (60%)		5/6 (83.3%)		2/8 (25%)
Cardiac disorders
Bradycardia	0/4 (0%)	0	0/5 (0%)	0	0/6 (0%)	0	1/8 (12.5%)	1
Infections and infestations
Pneumonia	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1	0/8 (0%)	0
Upper respiratory tract infection	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0	0/8 (0%)	0
Viral upper respiratory tract infection	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1	0/8 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	1/4 (25%)	1	0/5 (0%)	0	2/6 (33.3%)	2	0/8 (0%)	0
Pain in extremity	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1	0/8 (0%)	0
Nervous system disorders
Headache	0/4 (0%)	0	0/5 (0%)	0	0/6 (0%)	0	1/8 (12.5%)	1
Respiratory, thoracic and mediastinal disorders
Cough	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0	0/8 (0%)	0
Skin and subcutaneous tissue disorders
Erythema	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0	0/8 (0%)	0

Limitations/Caveats

[Not Specified]

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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.