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| ID | Type | Description | Link |
|---|---|---|---|
| 2017-000212-41 | EudraCT Number |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| GSK2586881 - 0.1 mg/kg | Experimental | 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. |
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| GSK2586881 - 0.2 mg/kg | Experimental | 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. |
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| GSK2586881 - 0.4 mg/kg | Experimental | 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. |
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| GSK2586881 - 0.8 mg/kg | Experimental | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GSK2586881 | Drug | 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. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Pulmonary Vascular Resistance (PVR) | 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. | Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1) |
| Change From Baseline in Cardiac Output (CO) | 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. | Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1) |
| Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) | 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. | Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1) |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Non-serious Adverse Events (AEs) | 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. | Up to Day 28 |
| Number of Participants With Serious Adverse Events (SAEs) |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Cardiac Index (CI) | 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. | Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1) |
Inclusion Criteria
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Pittsburgh | Pennsylvania | 15213 | United States | ||
| GSK Investigational Site |
IPD for this study will be made available via the Clinical Study Data Request site.
IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | GSK2586881 0.1 mg/kg | Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose. |
| FG001 | GSK2586881 0.2 mg/kg | Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose. |
| FG002 | GSK2586881 0.4 mg/kg | Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose. |
| FG003 | GSK2586881 0.8 mg/kg | Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cohort 1: Dose Level 0.1 mg/kg (28 Days) |
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| Cohort 2: Dose Level 0.2 mg/kg (28 Days) |
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| Cohort 3: Dose Level 0.4 mg/kg (28 Days) |
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| Cohort 4: Dose Level 0.8 mg/kg (28 Days) |
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| ID | Title | Description |
|---|---|---|
| BG000 | GSK2586881 0.1 mg/kg | Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose. |
| BG001 | GSK2586881 0.2 mg/kg | Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline in Pulmonary Vascular Resistance (PVR) | 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. | 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. | Posted | Geometric Mean | 95% Confidence Interval | Ratio | Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1) |
|
Non-SAEs and SAEs were reported from start of study treatment and up to Day 28
Non-SAEs and SAEs were reported for Safety Population. Adverse events were presented treatment-wise.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | GSK2586881 0.1 mg/kg | Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| GSK Response Center | GlaxoSmithKline | 866-435-7343 | GSKClinicalSupportHD@gsk.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jul 10, 2018 | Mar 25, 2020 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 15, 2018 | Mar 25, 2020 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D006976 | Hypertension, Pulmonary |
| D000081029 | Pulmonary Arterial Hypertension |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D006973 | Hypertension |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| C000711750 | alunacedase alfa |
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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. |
| Up to Day 28 |
| Change From Baseline in Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Amino Transferase and Aspartate Amino Transferase | 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. | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
| Change From Baseline in Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Creatinine | 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. | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
| Change From Baseline in Clinical Chemistry Parameters: Calcium, Glucose, Potassium, Sodium and Blood Urea Nitrogen (BUN) | 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. | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
| Change From Baseline in Clinical Chemistry Parameter: Total Protein | 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. | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
| Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell (WBC) Count | 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. | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
| Change From Baseline in Hematology Parameter: Hemoglobin | 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. | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
| Change From Baseline in Hematology Parameter: Hematocrit | 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. | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
| Change From Baseline in Hematology Parameter: Mean Corpuscle Hemoglobin | 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. | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
| Change From Baseline in Hematology Parameter: Mean Corpuscle Volume | 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. | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
| Change From Baseline in Hematology Parameter: Red Blood Cell (RBC) Count | 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. | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
| Change From Baseline in Hematology Parameter: Reticulocytes | 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. | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
| Number of Participants With Urinalysis Results by Dipstick Method | 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. | 24 hours post-dose (Day 1) |
| Change From Baseline in Pulse Rate | 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. | 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) |
| Change From Baseline in Respiratory Rate | 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. | 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) |
| Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) | 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. | 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) |
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings | 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. | 4 hours and 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
| Change From Baseline in Pulse Oximetry Parameter: Percent Oxygen in Blood | 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. | 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) |
| Number of Participants With Positive Immunogenicity Results | 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. | Up to Day 28 |
| Change From Baseline in Systemic Renin-Angiotensin System (RAS) Peptides: Angiotensin II, Angiotensin (1-5) and Angiotensin (1-7) | 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. | 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) |
| Change From Baseline in Pulmonary Wedge RAS Peptides: Angiotensin II, Angiotensin (1-5) and Angiotensin (1-7) | 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. | Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1) |
| Systemic RAS Peptide: Angiotensin II/Angiotensin (1-7) Ratio at Indicated Time Points | 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. | 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) |
| Pulmonary Wedge RAS Peptide: Angiotensin II/Angiotensin (1-7) Ratio at Indicated Time Points | 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. | 1 hour, 2 hours and 4 hours post-dose (Day 1) |
| Change From Baseline in Disease Biomarkers: N-terminal Pro B-type Natriuretic Peptide (NT Pro-BNP) | 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. | Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1) |
| Change From Baseline in Nitrite, Nitrate and Endogenous Nitrite (Biomarkers of Nitric Oxide [NO]) | 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. | Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1) |
| Change From Baseline in Disease Biomarker: Cardiac Troponin-I | 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. | Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1) |
| Maximum Observed Plasma Concentration (Cmax) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of Cmax. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
| Time to Cmax (Tmax) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of tmax. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-t]) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of AUC(0-t). Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
| Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of AUC(0-inf). Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
| Last Observed Quantifiable Concentration (Ct) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of Ct. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
| Time of the Last Quantifiable Concentration (Tlast) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of tlast. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
| Plasma Clearance (CL) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of CL. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
| Apparent Volume of Distribution of GSK2586881 | Blood samples were collected at indicated time points for evaluation of apparent volume of distribution. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
| Apparent Terminal Phase Half-life (t1/2) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of t1/2. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
| Dallas |
| Texas |
| 75390-8550 |
| United States |
| GSK Investigational Site | Heidelberg | Baden-Wurttemberg | 69126 | Germany |
| GSK Investigational Site | Cologne | North Rhine-Westphalia | 50937 | Germany |
| GSK Investigational Site | Dresden | Saxony | 01307 | Germany |
| GSK Investigational Site | Berlin | 14050 | Germany |
| GSK Investigational Site | Barcelona | 08035 | Spain |
| GSK Investigational Site | Madrid | 28041 | Spain |
| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
|
| BG002 | GSK2586881 0.4 mg/kg | Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose. |
| BG003 | GSK2586881 0.8 mg/kg | Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose. |
| BG004 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
Participants received a single IV dose of 0.1 mg/kg GSK2586881 and were followed up till 28 days post-dose.
| OG001 | GSK2586881 0.2 mg/kg | Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose. |
| OG002 | GSK2586881 0.4 mg/kg | Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose. |
| OG003 | GSK2586881 0.8 mg/kg | Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose. |
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| Primary | Change From Baseline in Cardiac Output (CO) | 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. | Evaluable Population. Only those participants with data available at the specified time points were analyzed. | Posted | Geometric Mean | 95% Confidence Interval | Ratio | Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1) |
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| Primary | Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) | 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. | Evaluable Population. Only those participants with data available at the specified time points were analyzed. | Posted | Geometric Mean | 95% Confidence Interval | Ratio | Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1) |
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| Secondary | Number of Participants With Non-serious Adverse Events (AEs) | 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. | Safety Population comprised of all participants who took at least 1 dose of study treatment. | Posted | Count of Participants | Participants | Up to Day 28 |
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| Secondary | Number of Participants With Serious Adverse Events (SAEs) | 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. | Safety Population | Posted | Count of Participants | Participants | Up to Day 28 |
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| Secondary | Change From Baseline in Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Amino Transferase and Aspartate Amino Transferase | 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. | Safety Population | Posted | Mean | Standard Deviation | International units per liter | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
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| Secondary | Change From Baseline in Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Creatinine | 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. | Safety Population | Posted | Mean | Standard Deviation | Micromoles per liter | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
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| Secondary | Change From Baseline in Clinical Chemistry Parameters: Calcium, Glucose, Potassium, Sodium and Blood Urea Nitrogen (BUN) | 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. | Safety Population | Posted | Mean | Standard Deviation | Millimoles per liter | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
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| Secondary | Change From Baseline in Clinical Chemistry Parameter: Total Protein | 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. | Safety Population | Posted | Mean | Standard Deviation | Grams per liter | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
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| Secondary | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell (WBC) Count | 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. | Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Mean | Standard Deviation | Giga cells per liter | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
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| Secondary | Change From Baseline in Hematology Parameter: Hemoglobin | 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. | Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Mean | Standard Deviation | Grams per liter | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
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| Secondary | Change From Baseline in Hematology Parameter: Hematocrit | 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. | Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Mean | Standard Deviation | Proportion of red blood cells in blood | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
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| Secondary | Change From Baseline in Hematology Parameter: Mean Corpuscle Hemoglobin | 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. | Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Mean | Standard Deviation | Picograms | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
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| Secondary | Change From Baseline in Hematology Parameter: Mean Corpuscle Volume | 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. | Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Mean | Standard Deviation | Femtoliters | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
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| Secondary | Change From Baseline in Hematology Parameter: Red Blood Cell (RBC) Count | 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. | Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Mean | Standard Deviation | Trillion cells per liter | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
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| Secondary | Change From Baseline in Hematology Parameter: Reticulocytes | 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. | Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Mean | Standard Deviation | Percentage of reticulocytes in blood | Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
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| Secondary | Number of Participants With Urinalysis Results by Dipstick Method | 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. | Safety Population | Posted | Count of Participants | Participants | 24 hours post-dose (Day 1) |
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| Secondary | Change From Baseline in Pulse Rate | 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. | Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Mean | Standard Deviation | Beats per minute | 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) |
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| Secondary | Change From Baseline in Respiratory Rate | 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. | Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Mean | Standard Deviation | Breaths per minute | 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) |
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| Secondary | Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) | 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. | Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Mean | Standard Deviation | Millimeters of mercury | 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) |
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| Secondary | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | 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. | Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Count of Participants | Participants | 4 hours and 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit) |
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| Secondary | Change From Baseline in Pulse Oximetry Parameter: Percent Oxygen in Blood | 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. | Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Mean | Standard Deviation | Percentage of 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) |
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| Secondary | Number of Participants With Positive Immunogenicity Results | 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. | Safety Population | Posted | Count of Participants | Participants | Up to Day 28 |
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| Secondary | Change From Baseline in Systemic Renin-Angiotensin System (RAS) Peptides: Angiotensin II, Angiotensin (1-5) and Angiotensin (1-7) | 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. | Evaluable Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Geometric Mean | 95% Confidence Interval | Ratio | 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) |
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| Secondary | Change From Baseline in Pulmonary Wedge RAS Peptides: Angiotensin II, Angiotensin (1-5) and Angiotensin (1-7) | 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. | Evaluable Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Geometric Mean | 95% Confidence Interval | Ratio | Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1) |
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| Secondary | Systemic RAS Peptide: Angiotensin II/Angiotensin (1-7) Ratio at Indicated Time Points | 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. | Evaluable Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Geometric Mean | 95% Confidence Interval | Ratio | 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) |
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| Secondary | Pulmonary Wedge RAS Peptide: Angiotensin II/Angiotensin (1-7) Ratio at Indicated Time Points | 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. | Evaluable Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Geometric Mean | 95% Confidence Interval | Ratio | 1 hour, 2 hours and 4 hours post-dose (Day 1) |
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| Secondary | Change From Baseline in Disease Biomarkers: N-terminal Pro B-type Natriuretic Peptide (NT Pro-BNP) | 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. | Evaluable Population. Only those participants with data available at the specified time points were analyzed. | Posted | Geometric Mean | 95% Confidence Interval | Ratio | Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1) |
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| Secondary | Change From Baseline in Nitrite, Nitrate and Endogenous Nitrite (Biomarkers of Nitric Oxide [NO]) | 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. | Evaluable Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). | Posted | Geometric Mean | 95% Confidence Interval | Ratio | Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1) |
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| Secondary | Change From Baseline in Disease Biomarker: Cardiac Troponin-I | 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. | Evaluable Population. Only those participants with data available at the specified time points were analyzed. | Posted | Geometric Mean | 95% Confidence Interval | Ratio | Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1) |
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| Secondary | Maximum Observed Plasma Concentration (Cmax) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of Cmax. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pharmacokinetic population comprised of participants in the Safety Population for whom a pharmacokinetic sample was obtained and analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | Micrograms per milliliter | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
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| Secondary | Time to Cmax (Tmax) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of tmax. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pharmacokinetic Population | Posted | Median | Full Range | Hours | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
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| Secondary | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-t]) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of AUC(0-t). Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pharmacokinetic Population | Posted | Geometric Mean | Geometric Coefficient of Variation | Hours*micrograms per milliliter | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
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| Secondary | Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of AUC(0-inf). Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pharmacokinetic Population. Only those participants with data available at the specified time points were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | Hours*micrograms per milliliter | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
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| Secondary | Last Observed Quantifiable Concentration (Ct) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of Ct. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pharmacokinetic Population | Posted | Geometric Mean | Geometric Coefficient of Variation | Micrograms per milliliter | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
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| Secondary | Time of the Last Quantifiable Concentration (Tlast) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of tlast. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pharmacokinetic Population | Posted | Median | Full Range | Hours | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
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| Secondary | Plasma Clearance (CL) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of CL. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pharmacokinetic Population. Only those participants with data available at the specified time points were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liters per hour | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
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| Secondary | Apparent Volume of Distribution of GSK2586881 | Blood samples were collected at indicated time points for evaluation of apparent volume of distribution. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pharmacokinetic Population. Only those participants with data available at the specified time points were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liters | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
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| Secondary | Apparent Terminal Phase Half-life (t1/2) of GSK2586881 | Blood samples were collected at indicated time points for evaluation of t1/2. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. | Pharmacokinetic Population. Only those participants with data available at the specified time points were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | Hours | Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1) |
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| Other Pre-specified | Change From Baseline in Cardiac Index (CI) | 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. | Evaluable Population. Only those participants with data available at the specified time points were analyzed. | Posted | Geometric Mean | 95% Confidence Interval | Ratio | Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1) |
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| 0 |
| 4 |
| 0 |
| 4 |
| 1 |
| 4 |
| EG001 | GSK2586881 0.2 mg/kg | Participants received a single IV dose of 0.2 mg/kg GSK2586881 and were followed up till 28 days post-dose. | 0 | 5 | 0 | 5 | 3 | 5 |
| EG002 | GSK2586881 0.4 mg/kg | Participants received a single IV dose of 0.4 mg/kg GSK2586881 and were followed up till 28 days post-dose. | 0 | 6 | 0 | 6 | 5 | 6 |
| EG003 | GSK2586881 0.8 mg/kg | Participants received a single IV dose of 0.8 mg/kg GSK2586881 and were followed up till 28 days post-dose. | 0 | 8 | 0 | 8 | 2 | 8 |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
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| Pneumonia | Infections and infestations | MedDRA 22.0 | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA 22.0 | Systematic Assessment |
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| Viral upper respiratory tract infection | Infections and infestations | MedDRA 22.0 | Systematic Assessment |
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| Bradycardia | Cardiac disorders | MedDRA 22.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Erythema | Skin and subcutaneous tissue disorders | MedDRA 22.0 | Systematic Assessment |
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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.
| D002318 |
| Cardiovascular Diseases |
| 2 hours post-dose (Day 1) |
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| 4 hours post-dose (Day 1) |
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| 2 hours post-dose (Day 1) |
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| 4 hours post-dose (Day 1) |
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| Alkaline phosphatase, Day 7 to Day 14 |
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| ALT, 24 hours post-dose (Day 1) |
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| ALT, Day 7 to Day 14 |
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| AST, 24 hours post-dose (Day 1) |
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| AST, Day 7 to Day 14 |
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| Direct bilirubin, Day 7 to Day 14 |
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| Total bilirubin, 24 hours post-dose (Day 1) |
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| Total bilirubin, Day 7 to Day 14 |
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| Creatinine, 24 hours post-dose (Day 1) |
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| Creatinine, Day 7 to Day 14 |
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| Calcium, Day 7 to Day 14 |
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| Glucose, 24 hours post-dose (Day 1) |
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| Glucose, Day 7 to Day 14 |
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| Potassium, 24 hours post-dose (Day 1) |
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| Potassium, Day 7 to Day 14 |
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| Sodium, 24 hours post-dose (Day 1) |
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| Sodium, Day 7 to Day 14 |
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| BUN, 24 hours post-dose (Day 1) |
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| BUN, Day 7 to Day 14 |
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| Day 7 to Day 14 |
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| Basophils, Day 7 to Day 14, n=4,5,6,8 |
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| Eosinophils, 24 hours post-dose (Day 1), n=4,4,6,3 |
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| Eosinophils, Day 7 to Day 14, n=4,5,6,8 |
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| Lymphocytes, 24 hours post-dose (Day 1), n=4,4,6,3 |
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| Lymphocytes, Day 7 to Day 14, n=4,5,6,8 |
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| Monocytes, 24 hours post-dose (Day 1), n=4,4,6,3 |
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| Monocytes, Day 7 to Day 14, n=4,5,6,8 |
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| T.neutrophils, 24 hours post-dose(Day1),n=4,4,6,3 |
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| T.neutrophils, Day 7 to Day 14, n=4,5,6,8 |
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| Platelets, 24 hours post-dose (Day 1), n=4,4,6,5 |
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| Platelets, Day 7 to Day 14, n=4,5,6,8 |
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| WBC count, 24 hours post-dose (Day 1), n=4,4,6,5 |
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| WBC count, Day 7 to Day 14, n=4,5,6,8 |
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| Day 7 to Day 14, n=4,5,6,8 |
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| Day 7 to Day 14, n=4,5,6,8 |
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| Day 7 to Day 14, n=4,5,6,8 |
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| Day 7 to Day 14, n=4,5,6,8 |
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| Day 7 to Day 14, n=4,5,6,8 |
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| Day 7 to Day 14, n=4,5,6,8 |
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| Bilirubin, 24 hours post-dose (Day 1), trace |
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| Bilirubin, 24 hours post-dose (Day 1), 1+ |
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| Bilirubin, 24 hours post-dose (Day 1), 2+ |
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| Bilirubin, 24 hours post-dose (Day 1), 3+ |
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| Occult Blood, 24 hours post-dose (Day 1), negative |
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| Occult Blood, 24 hours post-dose (Day 1), trace |
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| Occult Blood, 24 hours post-dose (Day 1), 1+ |
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| Occult Blood, 24 hours post-dose (Day 1), 2+ |
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| Occult Blood, 24 hours post-dose (Day 1), 3+ |
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| Glucose, 24 hours post-dose (Day 1), negative |
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| Glucose, 24 hours post-dose (Day 1), trace |
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| Glucose, 24 hours post-dose (Day 1), 1+ |
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| Glucose, 24 hours post-dose (Day 1), 2+ |
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| Glucose, 24 hours post-dose (Day 1), 3+ |
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| Ketones, 24 hours post-dose (Day 1), negative |
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| Ketones, 24 hours post-dose (Day 1), trace |
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| Ketones, 24 hours post-dose (Day 1), 1+ |
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| Ketones, 24 hours post-dose (Day 1), 2+ |
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| Ketones, 24 hours post-dose (Day 1), 3+ |
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| Protein, 24 hours post-dose (Day 1), negative |
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| Protein, 24 hours post-dose (Day 1), trace |
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| Protein, 24 hours post-dose (Day 1), 1+ |
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| Protein, 24 hours post-dose (Day 1), 2+ |
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| Protein, 24 hours post-dose (Day 1), 3+ |
|
|
| 1 hour post-dose (Day 1), n=4,5,6,8 |
|
|
| 2 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| 4 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| 8 hours post-dose (Day 1), n=4,4,6,8 |
|
|
| 24 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| Day 7 to Day 14, n=4,5,6,8 |
|
|
|
| 1 hour post-dose (Day 1), n=4,5,6,8 |
|
|
| 2 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| 4 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| 8 hours post-dose (Day 1), n=4,4,6,8 |
|
|
| 24 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| Day 7 to Day 14, n=4,5,6,8 |
|
|
|
| DBP, 1 hour post-dose (Day 1), n=4,5,6,8 |
|
|
| DBP, 2 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| DBP, 4 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| DBP, 8 hours post-dose (Day 1), n=4,4,6,8 |
|
|
| DBP, 24 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| DBP, Day 7 to Day 14, n=4,5,6,8 |
|
|
| SBP, 0.5 hour post-dose (Day 1), n=4,5,6,8 |
|
|
| SBP, 1 hour post-dose (Day 1), n=4,5,6,8 |
|
|
| SBP, 2 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| SBP, 4 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| SBP, 8 hours post-dose (Day 1), n=4,4,6,8 |
|
|
| SBP, 24 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| SBP, Day 7 to Day 14, n=4,5,6,8 |
|
|
|
| Abnormal CS, 4 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| Abnormal NCS, 24 hours post-dose(Day 1), n=3,5,6,8 |
|
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| Abnormal CS, 24 hours post-dose (Day 1), n=3,5,6,8 |
|
|
| Abnormal NCS, Day 7 to Day 14, n=4,5,6,8 |
|
|
| Abnormal CS, Day 7 to Day 14, n=4,5,6,8 |
|
|
|
| 1 hour post-dose (Day 1), n=4,5,6,8 |
|
|
| 2 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| 4 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| 8 hours post-dose (Day 1), n=4,4,6,8 |
|
|
| 24 hours post-dose (Day 1), n=4,5,6,8 |
|
|
| Day 7 to Day 14, n=4,5,6,8 |
|
|
|
| Ang II, 0.5 hour post-dose (Day 1), n=4,5,5,8 |
|
|
| Ang II, 1 hour post-dose (Day 1), n=4,5,5,8 |
|
|
| Ang II, 2 hours post-dose (Day 1), n=4,5,5,8 |
|
|
| Ang II, 4 hours post-dose (Day 1), n=4,5,5,8 |
|
|
| Ang II, 8 hours post-dose (Day 1), n=4,5,5,8 |
|
|
| Ang II, 24 hours post-dose (Day 1), n=4,5,5,8 |
|
|
| Ang II, Day 7 to Day 14, n=4,5,5,7 |
|
|
| Ang (1-5), 0.08 hour post-dose (Day 1), n=4,5,4,6 |
|
|
| Ang (1-5), 0.5 hour post-dose (Day 1), n=4,5,4,6 |
|
|
| Ang (1-5), 1 hour post-dose (Day 1), n=4,5,4,6 |
|
|
| Ang (1-5), 2 hours post-dose (Day 1), n=4,5,4,6 |
|
|
| Ang (1-5), 4 hours post-dose (Day 1), n=4,5,4,6 |
|
|
| Ang (1-5), 8 hours post-dose (Day 1), n=4,5,4,6 |
|
|
| Ang (1-5), 24 hours post-dose (Day 1), n=4,5,4,6 |
|
|
| Ang (1-5), Day 7 to Day 14, n=4,5,3,6 |
|
|
| Ang (1-7), 0.08 hour post-dose (Day 1), n=4,5,5,7 |
|
|
| Ang (1-7), 0.5 hour post-dose (Day 1), n=4,5,5,7 |
|
|
| Ang (1-7), 1 hour post-dose (Day 1), n=4,5,5,7 |
|
|
| Ang (1-7), 2 hours post-dose (Day 1), n=4,5,5,7 |
|
|
| Ang (1-7), 4 hours post-dose (Day 1), n=4,5,5,7 |
|
|
| Ang (1-7), 8 hours post-dose (Day 1), n=4,5,5,7 |
|
|
| Ang (1-7), 24 hours post-dose (Day 1), n=4,5,5,7 |
|
|
| Ang (1-7), Day 7 to Day 14, n=4,5,5,6 |
|
|
|
| Ang II, 2 hours post-dose (Day 1), n=4,4,4,8 |
|
|
| Ang II, 4 hours post-dose (Day 1), n=4,4,3,8 |
|
|
| Ang (1-5), 1 hour post-dose (Day 1), n=4,4,4,7 |
|
|
| Ang (1-5), 2 hours post-dose (Day 1), n=4,4,3,7 |
|
|
| Ang (1-5), 4 hours post-dose (Day 1), n=4,4,3,7 |
|
|
| Ang (1-7), 1 hour post-dose (Day 1), n=4,4,4,8 |
|
|
| Ang (1-7), 2 hours post-dose (Day 1), n=4,4,4,8 |
|
|
| Ang (1-7), 4 hours post-dose (Day 1), n=4,4,3,8 |
|
|
|
| 0.5 hour post-dose (Day 1), n=4,5,5,8 |
|
|
| 1 hour post-dose (Day 1), n=4,5,5,8 |
|
|
| 2 hours post-dose (Day 1), n=4,5,5,8 |
|
|
| 4 hours post-dose (Day 1), n=4,5,5,8 |
|
|
| 8 hours post-dose (Day 1), n=4,5,5,8 |
|
|
| 24 hours post-dose (Day 1), n=4,5,5,8 |
|
|
| Day 7 to Day 14, n=4,5,5,7 |
|
|
|
| 2 hours post-dose (Day 1), n=4,4,4,8 |
|
|
| 4 hours post-dose (Day 1), n=4,4,3,8 |
|
|
| 4 hours post-dose (Day 1) |
|
| 24 hours post-dose (Day 1) |
|
|
| Nitrite, 4 hours post-dose (Day 1), n=4,4,5,8 |
|
|
| Nitrite, 24 hours post-dose (Day 1), n=4,4,4,7 |
|
|
| Nitrate, 2 hours post-dose (Day 1), n=4,4,5,8 |
|
|
| Nitrate, 4 hours post-dose (Day 1), n=4,4,5,8 |
|
|
| Nitrate, 24 hours post-dose (Day 1), n=4,4,4,7 |
|
|
| En. nitrite, 2 hours post-dose (Day 1), n=4,4,5,8 |
|
|
| En. nitrite, 4 hours post-dose (Day 1), n=4,4,5,8 |
|
|
| En. nitrite, 24 hours post-dose (Day 1), n=4,4,4,7 |
|
|
| 4 hours post-dose (Day 1) |
|
| 24 hours post-dose (Day 1) |
|
| 2 hours post-dose (Day 1) |
|
| 4 hours post-dose (Day 1) |
|