The Safety, Tolerability, PK and PD of GSK2586881 in Patients With Acute Lung Injury

A Two Part Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2586881 in Patients With Acute Lung Injury

This is an early phase (phase IIa), randomized, multi-center study in subjects with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). The purpose of this study is to investigate the safety of GSK2586881 and to determine what effects it has on people with Acute Lung Injury (ALI) or Acute Respiratory Distress Syndrome (ARDS).

The study has two parts: Part A will be an open-label investigation in five subjects. Part B will be a double-blind, placebo controlled investigation and will involve approximately 60 subjects.

Study Overview

• Status: Completed
• Conditions: Lung Injury, Acute
• Intervention / Treatment: Drug: Dose 1 GSK2586881; Drug: Dose 2 GSK2586881; Drug: Dose 3 GSK2586881; Drug: Dose 4 GSK2586881; Drug: Placebo (saline)

Detailed Description

The acute respiratory distress syndrome (ARDS) is a form of severe acute lung injury (ALI) characterized by hypoxemic respiratory failure (the lungs are unable to absorb oxygen to the arterial blood) and non-cardiogenic pulmonary edema (accumulation of fluid in the lungs). The syndrome may be caused by direct or indirect injury to the lungs. It is associated with a mortality rate of up to 40-50%. There are no marketed pharmacologic therapies for this devastating syndrome.

This study aims to assess the safety, tolerability and pharmacodynamics of GSK2586881, a recombinant human angiotensin converting enzyme type 2 (rhACE2).

ACE2 is involved in the Renin-Angiotensin System (RAS), which controls blood pressure, electrolytes and intravascular fluid volume. A key function of rhACE2 is believed to be the cleavage of Angiotensin II (Ang II) to Ang (1-7), which have opposing physiological roles. Elevated levels of Ang II are associated with vasoconstriction, inflammation, fibrosis, vascular leak, and sodium absorption. Ang (1-7) appears to be a counterregulatory protein in the RAS; associated with vasodilation, anti-proliferation, antiinflammation, and reduced vascular leak. It has been observed that levels of Ang II are increased in humans with ALI/ ARDS. It is expected that the reduction of Ang II should have a positive impact on ALI and ARDS.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • GSK Investigational Site
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • GSK Investigational Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • GSK Investigational Site
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • GSK Investigational Site
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2H1
      • GSK Investigational Site
    • Sainte-Foy, Quebec, Canada, G1V 4G5
      • GSK Investigational Site
• United States
  • California
    • Sacramento, California, United States, 95817
      • GSK Investigational Site
  • Illinois
    • Chicago, Illinois, United States, 60611
      • GSK Investigational Site
  • Massachusetts
    • Springfield, Massachusetts, United States, 01199
      • GSK Investigational Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • GSK Investigational Site
  • New York
    • New York, New York, United States, 10003
      • GSK Investigational Site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • GSK Investigational Site
    • Greensboro, North Carolina, United States, 27403
      • GSK Investigational Site
    • Winston-Salem, North Carolina, United States, 27517
      • GSK Investigational Site
  • Ohio
    • Columbus, Ohio, United States, 43215
      • GSK Investigational Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • GSK Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • GSK Investigational Site
    • Philadelphia, Pennsylvania, United States, 19104
      • GSK Investigational Site
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female, 18 - 80 years of age (inclusive)
• Diagnosis of ALI with acute onset of PaO2/FiO2 ratio less than or equal to 300, and bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph. The infiltrates may be patchy, diffuse, homogeneous, or asymmetric, and requirement for positive pressure ventilation via an endotracheal tube, and no clinical evidence of left atrial hypertension
• Cause of ALI thought to be associated with infection, sepsis, pneumonia, aspiration, or similar as judged by the PI and/or medical monitor
• The subject must be randomized into the study within 48 hours from the time of diagnosis of ALI
• Period of hemodynamic stability (e.g. 4-6 hours) prior to the initiation of study treatment not requiring resuscitative measures with stable pressor requirements. In this study low-dose arginine vasopressin is not considered a pressor, and is permitted in Parts A and B.
• If mechanically ventilated, duration of mechanical ventilation must be less than 72 hours before dosing begins
• BMI within the range 19.0 - 38.0 kg/m2 inclusive
• The subject or legal decision maker is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• QTcB or QTcF less than 450 msec; or QTc less than 480 msec in subjects with Bundle Branch Block.
• Alanine aminotransferase (ALT) less than 5 x Upper Limit of Normal (ULN); bilirubin less than or equal to 1.5 x ULN.

Exclusion Criteria:

• Subjects whose clinical condition is deteriorating rapidly or any subject for whom the investigator does not consider there is a reasonable expectation that they will be able to complete the study.
• Known positive Hepatitis B surface antigen, Hepatitis C antibody or HIV antibody
• Current or chronic history of liver disease (Child Pugh score of greater than or equal to 10), or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Known history of substance abuse or alcohol abuse, within 6 months of the study causing chronic liver disease such as cirrhosis, chronic ascites or portal hypertension, or known evidence of withdrawal syndrome within the past 6 months.
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
• Inability to discontinue use of Angiotensin converting enzyme type 1 inhibitors or Angiotensin receptor blockers.
• Patients requiring high doses of loop diuretics with significant intravascular volume depletion, as assessed clinically
• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation
• Pregnant females as determined by positive serum or urine hCG test prior to dosing
• Lactating females
• Unwillingness or inability to follow the procedures outlined in the protocol
• Subject is legally incapacitated (e.g. a prisoner)
• History of sensitivity to heparin or heparin-induced thrombocytopenia
• Unstable Hemoglobin (Hb less than 7) at time of drug infusion
• Malignancy or other irreversible condition for which 6 month mortality is estimated to be greater than 50%
• Arterial blood pH less than 7.1 or serum HCO3 - less than 15 (if ABG not available) before infusion is started
• Known severe chronic respiratory disease:
• known Forced Expiratory Volume in 1 second (FEV1)/ Forced Vital Capacity (FVC) less than 45% predicted, or
• known chronic hypercapnia (PaCO2 greater than 45 mmHg) or chronic hypoxemia (PaO2 less than 55 mmHg) on FiO2 =0.21, or
• known FEV1 less than 15 ml/kg (e.g. 1L for 70 kg person), or
• known radiographic evidence of chronic interstitial infiltration, or
• known hospitalization within the past six months for respiratory failure (PaCO2 greater than 50 mmHg or PaO2 less than 55 mmHg, or oxygen saturation less than 88% on FiO2 = 0.21), or
• known chronic restrictive, obstructive, neuromuscular, chest wall, or pulmonary vascular disease resulting in severe exercise restriction
• Known history of neuromuscular disease that would affect time on mechanical ventilation or impairs ability to ventilate spontaneously
• Vasculitis with diffuse alveolar hemorrhage
• Lung transplantation
• Pre-existing renal failure on hemodialysis or peritoneal dialysis requiring renal replacement therapy
• A patient will be excluded if in the judgement of the Principle Investigator or GSK medical monitor their participation could jeopardize the health of the subject or the integrity of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Part A; 4 increasing doses of GSK2586881 given over 2 days	Drug: Dose 1 GSK2586881; Low dose GSK2586881 administered intravenously; Drug: Dose 2 GSK2586881; Medium dose GSK2586881 administered intravenously; Drug: Dose 3 GSK2586881; Medium-High dose GSK2586881 administered intravenously; Drug: Dose 4 GSK2586881; High dose GSK2586881 administered intravenously
EXPERIMENTAL: Part B; Repeat Medium-High dose of GSK2586881 (or placebo) over 3 days	Drug: Dose 3 GSK2586881; Medium-High dose GSK2586881 administered intravenously; Drug: Placebo (saline); Administered intravenously to match intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart Rate Assessments Upto Day 7 (Part B)	Vital sign included heart rate. Assessments were performed at Pre-dose, 0.5 hours, 2 hours, 6 hours and 12 hours on Day 1, 0 hours on Day 2 at 0 hours, 0.5 hours, 2 hours, 6 hours, 12 hours, 18 hours and 24 hours on Day 3 and at follow-up on Day 7.	Up to Day 7
Diastolic and Systolic Blood Pressure Assessments Upto Day 7 (Part B)	Vital sign included systolic blood pressure and diastolic blood pressure. Assessments were performed at Pre-dose, 0.5 hours, 2 hours, 6 hours and 12 hours on Day 1, 0 hours on Day 2 at 0 hours, 0.5 hours, 2 hours, 6 hours, 12 hours, 18 hours and 24 hours on Day 3 and at follow-up on Day 7.	Up to Day 7
Electrocardiogram (ECG) Parameters, Including PR, QRS, QT, and QTCU and RR Intervals Upto Day 7 (Part B)	Single 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QTCU and RR intervals. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.	Up to Day 7
Hematology Parameters Basophils, Eosinophil, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell Count Upto Day 7 (Part B)	Hematology parameters included basophils, eosinophil, lymphocytes, monocytes, total neutrophils, platelet count and white blood cell count. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.	Up to Day 7
Hematology Parameters Red Blood Cell Count and Reticulocyte Count Assessment Upto Day 7 (Part B)	Hematology parameters included red blood cell count and reticulocyte count. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.	Up to Day 7
Hematology Parameter Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Assessment Upto Day 7 (Part B)	Hematology parameters included hemoglobin and MCHC. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.	Up to Day 7
Hematology Parameter Mean Corpuscle Volume (MCV) Assessment Upto Day 7 (Part B)	Hematology parameter included MCV. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.	Up to Day 7
Hematology Parameter Mean Corpuscle Hemoglobin (MCH) Assessment Upto Day 7 (Part B)	Hematology parameter included MCH. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.	Up to Day 7
Hematology Parameter Hematocrit Assessment Upto Day 7 (Part B)	Hematology parameter included hematocrit. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.	Up to Day 7
Clinical Chemistry Parameters Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium, Urea/Blood Urea Nitrogen Assessment Upto Day 7 (Part B)	Clinical chemistry parameters included calcium, chloride, carbon dioxide, glucose, potassium, sodium, Urea/Blood urea nitrogen. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.	Up to Day 7
Clinical Chemistry Parameters Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Assessment Upto Day 7 (Part B)	Clinical chemistry parameters included direct bilirubin, total bilirubin, creatinine and uric acid. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.	Up to Day 7
Clinical Chemistry Parameters Alkaline Phosphatase, Asparatate Amino Transferase, Alanine Amino Transferase, Gamma Glutamyl Transferase Assessment Upto Day 7 (Part B)	Clinical chemistry parameters included alkaline phosphatase, asparatate amino transferase, alanine amino transferase, gamma glutamyl transferase. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.	Up to Day 7
Clinical Chemistry Parameters Albumin and Total Protein Assessment Upto Day 7 (Part B)	Clinical chemistry parameters included albumin and total protein. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.	Up to Day 7
Number of Participant With Adverse Event (AE) and Serious Adverse Event (SAE) Assessment Upto Day 7 (Part A)	An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury.	Up to Day 7
Number of Par With AE and Serious Adverse Event (SAE) Assessment Upto Day 7 (Part B)	An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury.	Up to Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of GSK2586881 Plasma Pharmacokinetic Concentration (Part A)	Blood samples for pharmacokinetic analysis of GSK2586881 were collected Pre-dose, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours (Day 1), 0 hours, 1 hour, 12 hours, 24 hours (Day 2). Data has been presented for GSK2586881 Plasma Pharmacokinetic Concentration versus time data for Part A	Pre-dose, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours (Day 1), 0 hours, 1 hour, 12 hours, 24 hours (Day 2)
Analysis of GSK2586881 Plasma Pharmacokinetic Concentration (Part B)	Blood samples for pharmacokinetic analysis of GSK2586881 were collected Pre-dose, 0.5 Hours, 2 hours, 6 hours, 12 hours (Day 1), 0 hours (Day 2), 0 hours, 0.5 hours, 2 hours, 6 hours, 12 hours, 18 hours and 24 hours (Day 3). Data has been presented for GSK2586881 Plasma Pharmacokinetic Concentration versus time data for Part B.	Pre-dose, 0.5 Hours, 2 hours, 6 hours, 12 hours (Day 1), 0 hours (Day 2), 0 hours, 0.5 hours, 2 hours, 6 hours, 12 hours, 18 hours and 24 hours (Day 3)
Analysis of Pharmacokinetic Parameter Clearance (CL) for GSK2586881 (Part A)	Blood samples for pharmacokinetic analysis of GSK2586881 were collected at Pre-dose, 0 hour, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours, 24 hours, 25 hours, 36 hours and 48 hours. CL was defined as the systemic clearance of parent drug. Clearance was calculated for individual participant and geometric mean of the values from all participants was reported.	Pre-dose, 0 hour, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours, 24 hours, 25 hours, 36 hours, 48 hours
Analysis Pharmacokinetic Parameter Clearance (CL) for GSK2586881 (Part B)	Blood samples for pharmacokinetic analysis of GSK2586881 were collected at Pre-dose, 0 hour, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours, 24 hours, 25 hours, 36 hours and 48 hours. CL was defined as the systemic clearance of parent drug. Clearance was calculated for individual participant and geometric mean of the values from all participants was reported.	Pre-dose, 0 hour, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours, 24 hours, 25 hours, 36 hours, 48 hours
Pharmacodynamic/Biomarker Analysis (Renin-angiotensin System Cascade Biomarkers) to Include Angiotensin (Ang) II and Ang (1-7) Upto Day 2 (Part A)	Renin-angiotensin system cascade biomarkers included Ang II and Ang (1-7). Blood samples for biomarker analyses were collected at Pre-dose, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours (Day 1) and 0 hours, 1 hour, 12 hours and 24 hours on Day 2.	Pre-dose, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours (Day 1) and 0 hours, 1 hour, 12 hours and 24 hours (Day 2).
Pharmacodynamic/Biomarker Analysis (Renin-angiotensin System Cascade Biomarkers) to Include Ang II/ Ang (1-7) Upto Day 2 (Part A)	Renin-angiotensin system cascade biomarkers included Ang II/Ang (1-7). Blood samples for biomarker analyses were collected at Pre-dose, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours on Day 1 and 0 hours, 1 hour, 12 hours and 24 hours on Day 2.	Pre-dose, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours (Day 1) and 0 hours, 1 hour, 12 hours and 24 hours (Day 2).
Pharmacodynamic/Biomarker Analysis (Renin-angiotensin System Cascade Biomarkers) to Include Ang II, Ang (1-7) and Ang (1-5) Upto Day 5(Part B)	Renin-angiotensin system cascade biomarkers included Ang II, Ang (1-7) and Ang (1-5). Blood samples for biomarker analyses were collected 0.5 hours, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 48.5 hours, 50 hours, 54 hours, 60 hours, 66 hours, 72 hours, 96 hours and 120 hours upto Day 5. Data has been presented for median along with the 95% credible interval.	0.5 hours, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 48.5 hours, 50 hours, 54 hours, 60 hours, 66 hours, 72 hours, 96 hours and 120 hours upto Day 5.
Pharmacodynamic/Biomarker Analysis (Renin-angiotensin System Cascade Biomarkers) to Include Ang II/Ang (1-5) and Ang II/Ang (1-7) Upto Day 5(Part B)	Renin-angiotensin system cascade biomarkers included Ang II/Ang (1-5) and Ang II/Ang (1-7) and). Blood samples for biomarker analyses were collected 0.5 hours, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 48.5 hours, 50 hours, 54 hours, 60 hours, 66 hours, 72 hours, 96 hours and 120 hours upto Day 5. Data has been presented for median along with the 95% credible interval.	0.5 hours, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 48.5 hours, 50 hours, 54 hours, 60 hours, 66 hours, 72 hours, 96 hours and 120 hours upto Day 5.
Measures of Oxygenation Including Level of Positive End Expiratory Pressure (PEEP), Peak Ventilatory Pressures and Plateau Ventilatory Pressures Upto Day 7 (Part B)	Measures of oxygenation included PEEP the pressure in the lungs (alveolar pressure) above atmospheric pressure (the pressure outside of the body) that exists at the end of expiration, peak ventilator pressure highest level of pressure applied to the lungs during inhalation and plateau ventilatory pressure the pressure applied to small airways and alveoli measured during an inspiratory pause on the ventilator. Assessments were performed at 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 24.5, 25, 26, 28, 30, 32, 36, 42, 48, 48.5, 49, 50, 52, 54, 56, 60, 66, 72 and 168 hours upto Day 7. Data has been presented for median along with the 95% credible interval.	0.5, 1, 2, 4, 6, 8, 12, 18, 24, 24.5, 25, 26, 28, 30, 32, 36, 42, 48, 48.5, 49, 50, 52, 54, 56, 60, 66, 72 and 168 hours upto Day 7
Measure of Oxygenation Including Fraction of Inspired Oxygen/ Partial Pressure of Oxygen in Arterial Blood (PaO2/FiO2) Ratio Via Pulse Oximetry Upto Day 7 (Part B)	Measure of oxygenation included PaO2/FiO2 ratio defined as the ratio of arterial oxygen partial pressure to fractional inspired oxygen by pulse oximeter a device that measured the oxygen saturation of arterial blood in a participant by utilizing a sensor attached typically to a finger, toe, or ear to determine the percentage of oxyhemoglobin in blood pulsating through a network of capillaries. Assessments were performed at 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 24.5, 25, 26, 28, 30, 32, 36, 42, 48, 48.5, 49, 50, 52, 54, 56, 60, 66, 72 and 168 hours upto Day 7. Data has been presented for median along with the 95% credible interval.	0.5, 1, 2, 4, 6, 8, 12, 18, 24, 24.5, 25, 26, 28, 30, 32, 36, 42, 48, 48.5, 49, 50, 52, 54, 56, 60, 66, 72 and 168 hours upto Day 7
Measure of Oxygenation Index Upto Day 7 (Part B)	Oxygenation index was defined as calculation used in intensive care medicine to measure the fraction of inspired oxygen (FiO2) and its usage within the body and was computed using the equation Oxygenation Index= FiO2 x Mean Airway Pressure/Pao2. Assessments were performed at 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 24.5, 25, 26, 28, 30, 32, 36, 42, 48, 48.5, 49, 50, 52, 54, 56, 60, 66, 72 and 168 hours upto Day 7. Data has been presented for median along with the 95% credible interval.	0.5, 1, 2, 4, 6, 8, 12, 18, 24, 24.5, 25, 26, 28, 30, 32, 36, 42, 48, 48.5, 49, 50, 52, 54, 56, 60, 66, 72 and 168 hours upto Day 7
Number of Participants With Acute Kidney Injury as Defined by Day 1 to Day 3 Change in Risk, Injury, Failure, Loss of Kidney Function, and End-stage Kidney Disease (RIFLE) Criteria Upto Day 3 (Part B)	The RIFLE score is made up of the glomerular filtration rate criteria (GFRC) and urine output criteria (UOC) and is defined as Risk (Serum Creatinine x 1.5 or GFR decrease > 25%-GFRC and < 0.5 milliliter/kilograms/hour [ml/kg/hour] x 6 hours-UOC), Injury (Serum Creatinine x 2 or GFR decrease > 50%-GFRC and < 0.5 ml/kg/hour x 12 hours), Failure (Serum Creatinine x 3, or GFR decrease > 75% [F=Failure] or Serum Creatinine >=4 milligrams/deciliter [mg/dl] with an acute rise > 0.5 mg/dl [Fc=Failure acute on chronic] and < 0.3 ml/kg/hour x 24 hours, or anuria x 12 hours [Fo=Failure oligouria]). Due to the duration of this study it was not possible to be calculate the designated RIFLE class Loss and RIFLE class End-stage kidney disease. Data has been presented for rifle score total, rifle score GFR and rifle score urine. Abbreviations NAKI= No acute kidney injury, R=risk, I=injury, MISS= Unable to derive score.	Upto Day 3
Evaluation of Sequential Organ Failure Assessment (SOFA) Score on Day 4 and Day 7 (Part B)	The SOFA score is a mortality prediction score that is based on the degree of dysfunction of 6 organ systems (respiratory, nervous, cardiovascular, liver, coagulation, and kidneys). The score ranges from 0-24. 0 (normal) to 4 (high degree of dysfunction) is given for each organ system, with a higher score indicating greater severity. A score of 0-6 is associated with a mortality rate of less than 10% while a score between 16 and 24 is associated with a greater than 90% mortality rate.	Day 4 and Day 7
Biomarker Analysis for Serum Inflammatory Biomarkers, Markers of Neutrophil Activation, Markers of Lung Epithelial Cell Injury, Renin Levels and Aldosterone Levels Upto Day 5 (Part B)	Serum inflammatory biomarkers included CXCL-8 [IL-8], IL-6, markers of neutrophil activation included (e.g. myeloperoxidase [MPO]), markers of lung epithelial cell injury included receptor for advanced glycation end-products [RAGE], Angiopoietin 2, along with rennin, aldosterone levels. Blood samples for biomarker analyses were collected 12 hours, 24 hours, 48 hours, 72 hours and 120 hours upto Day 5. Data has been presented for median along with the 95% credible interval.	12 hours, 24 hours, 48 hours, 72 hours and 120 hours upto Day 5
Biomarker Analysis for Serum Inflammatory Biomarker C-reactive Protein (CRP) Upto Day 5 (Part B)	Serum inflammatory biomarker included CRP. Blood samples for biomarker analyses were collected 12 hours, 24 hours, 48 hours, 72 hours and 120 hours upto Day 5. Data has been presented for median along with the 95% credible interval.	12 hours, 24 hours, 48 hours, 72 hours and 120 hours upto Day 5
Biomarker Analysis for Markers of Lung Epithelial Cell Injury Clara Cell Protein 16 [CCP16]) and Surfactant Protein D [SP-D] Upto Day 5 (Part B)	Markers of lung epithelial cell injury included CCP16 and SP-D. Blood samples for biomarker analyses were collected 12 hours, 24 hours, 48 hours, 72 hours and 120 hours upto Day 5. Data has been presented for median along with the 95% credible interval.	12 hours, 24 hours, 48 hours, 72 hours and 120 hours upto Day 5
Immunogenicity Assessment With Respect to Anti-Acetychollinesterase2 (ACE2) Binding Antibodies at Follow-up Day 14 and Follow-up Day 28 (Part A)	Blood samples for immunogenicity analysis were collected at follow-up (Day 14) and follow-up (Day 28). Antibodies to GSK2586881 were measured using a validated electrochemiluminescence bridging assay. All pre-dose and post-dose samples were first tested for Anti-ACE2 binding antibodies by screening and confirmation assay steps. The post-dose samples tested positive for anti-ACE2 binding antibodies were further characterized for anti-ACE2 neutralizing antibodies. Testing was conducted using a tiered approach; samples were first tested in a screening assay, only samples found positive in this assay were tested in the confirmation assay.	Follow-up (Day 14) and follow-up (Day 28)
Immunogenicity Assessment With Respect to Anti-ACE2 Binding Antibodies at Follow-up Day 14 and Follow-up Day 28 (Part B)	Blood samples for immunogenicity analysis were collected at follow-up (Day 14) and follow-up (Day 28). Antibodies to GSK2586881 were measured using a validated electrochemiluminescence bridging assay. All pre-dose and post-dose samples were first tested for Anti-ACE2 binding antibodies by screening and confirmation assay steps. The post-dose samples tested positive for anti-ACE2 binding antibodies were further characterized for anti-ACE2 neutralizing antibodies. Testing was conducted using a tiered approach; samples were first tested in a screening assay, only samples found positive in this assay were tested in the confirmation assay.	Follow-up (Day 14 )and follow-up (Day 28)

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Khan A, Benthin C, Zeno B, Albertson TE, Boyd J, Christie JD, Hall R, Poirier G, Ronco JJ, Tidswell M, Hardes K, Powley WM, Wright TJ, Siederer SK, Fairman DA, Lipson DA, Bayliffe AI, Lazaar AL. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017 Sep 7;21(1):234. doi: 10.1186/s13054-017-1823-x.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (ACTUAL): October 1, 2014
• Study Completion (ACTUAL): October 6, 2014

Study Registration Dates

• First Submitted: January 26, 2012
• First Submitted That Met QC Criteria: May 10, 2012
• First Posted (ESTIMATE): May 14, 2012

Study Record Updates

• Last Update Posted (ACTUAL): September 28, 2017
• Last Update Submitted That Met QC Criteria: August 31, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: critical care; Acute Respiratory Distress Syndrome (ARDS); Acute Lung Injury; rhACE2; GSK2586881
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Thoracic Injuries; Wounds and Injuries; Acute Lung Injury; Lung Injury
• Other Study ID Numbers: 114622