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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01597635
First Posted: May 14, 2012
Last Update Posted: September 28, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
GlaxoSmithKline
  Purpose

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.


Condition Intervention Phase
Lung Injury, Acute Drug: Dose 1 GSK2586881 Drug: Dose 2 GSK2586881 Drug: Dose 3 GSK2586881 Drug: Dose 4 GSK2586881 Drug: Placebo (saline) Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Two Part Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2586881 in Patients With Acute Lung Injury

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Heart Rate Assessments Upto Day 7 (Part B) [ Time Frame: Up to Day 7 ]
    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.

  • Diastolic and Systolic Blood Pressure Assessments Upto Day 7 (Part B) [ Time Frame: Up to Day 7 ]
    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.

  • Electrocardiogram (ECG) Parameters, Including PR, QRS, QT, and QTCU and RR Intervals Upto Day 7 (Part B) [ Time Frame: Up to Day 7 ]
    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.

  • Hematology Parameters Basophils, Eosinophil, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell Count Upto Day 7 (Part B) [ Time Frame: Up to Day 7 ]
    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.

  • Hematology Parameters Red Blood Cell Count and Reticulocyte Count Assessment Upto Day 7 (Part B) [ Time Frame: Up to Day 7 ]
    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.

  • Hematology Parameter Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Assessment Upto Day 7 (Part B) [ Time Frame: Up to Day 7 ]
    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.

  • Hematology Parameter Mean Corpuscle Volume (MCV) Assessment Upto Day 7 (Part B) [ Time Frame: Up to Day 7 ]
    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.

  • Hematology Parameter Mean Corpuscle Hemoglobin (MCH) Assessment Upto Day 7 (Part B) [ Time Frame: Up to Day 7 ]
    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.

  • Hematology Parameter Hematocrit Assessment Upto Day 7 (Part B) [ Time Frame: Up to Day 7 ]
    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.

  • Clinical Chemistry Parameters Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium, Urea/Blood Urea Nitrogen Assessment Upto Day 7 (Part B) [ Time Frame: Up to Day 7 ]
    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.

  • Clinical Chemistry Parameters Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Assessment Upto Day 7 (Part B) [ Time Frame: Up to Day 7 ]
    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.

  • Clinical Chemistry Parameters Alkaline Phosphatase, Asparatate Amino Transferase, Alanine Amino Transferase, Gamma Glutamyl Transferase Assessment Upto Day 7 (Part B) [ Time Frame: Up to Day 7 ]
    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.

  • Clinical Chemistry Parameters Albumin and Total Protein Assessment Upto Day 7 (Part B) [ Time Frame: Up to Day 7 ]
    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.

  • Number of Participant With Adverse Event (AE) and Serious Adverse Event (SAE) Assessment Upto Day 7 (Part A) [ Time Frame: Up to Day 7 ]
    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.

  • Number of Par With AE and Serious Adverse Event (SAE) Assessment Upto Day 7 (Part B) [ Time Frame: Up to Day 7 ]
    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.


Secondary Outcome Measures:
  • Analysis of GSK2586881 Plasma Pharmacokinetic Concentration (Part A) [ Time Frame: 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) ]
    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

  • Analysis of GSK2586881 Plasma Pharmacokinetic Concentration (Part B) [ Time Frame: 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) ]
    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.

  • Analysis of Pharmacokinetic Parameter Clearance (CL) for GSK2586881 (Part A) [ Time Frame: Pre-dose, 0 hour, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours, 24 hours, 25 hours, 36 hours, 48 hours ]
    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.

  • Analysis Pharmacokinetic Parameter Clearance (CL) for GSK2586881 (Part B) [ Time Frame: Pre-dose, 0 hour, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours, 24 hours, 25 hours, 36 hours, 48 hours ]
    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.

  • Pharmacodynamic/Biomarker Analysis (Renin-angiotensin System Cascade Biomarkers) to Include Angiotensin (Ang) II and Ang (1-7) Upto Day 2 (Part A) [ Time Frame: 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). ]
    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.

  • Pharmacodynamic/Biomarker Analysis (Renin-angiotensin System Cascade Biomarkers) to Include Ang II/ Ang (1-7) Upto Day 2 (Part A) [ Time Frame: 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). ]
    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.

  • Pharmacodynamic/Biomarker Analysis (Renin-angiotensin System Cascade Biomarkers) to Include Ang II, Ang (1-7) and Ang (1-5) Upto Day 5(Part B) [ Time Frame: 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. ]
    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.

  • 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) [ Time Frame: 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. ]
    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.

  • Measures of Oxygenation Including Level of Positive End Expiratory Pressure (PEEP), Peak Ventilatory Pressures and Plateau Ventilatory Pressures Upto Day 7 (Part B) [ Time Frame: 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 ]
    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.

  • 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) [ Time Frame: 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 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.


  • Measure of Oxygenation Index Upto Day 7 (Part B) [ Time Frame: 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 ]
    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.

  • 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) [ Time Frame: Upto Day 3 ]
    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.

  • Evaluation of Sequential Organ Failure Assessment (SOFA) Score on Day 4 and Day 7 (Part B) [ Time Frame: Day 4 and Day 7 ]
    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.

  • 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) [ Time Frame: 12 hours, 24 hours, 48 hours, 72 hours and 120 hours upto Day 5 ]
    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.

  • Biomarker Analysis for Serum Inflammatory Biomarker C-reactive Protein (CRP) Upto Day 5 (Part B) [ Time Frame: 12 hours, 24 hours, 48 hours, 72 hours and 120 hours upto Day 5 ]
    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.

  • 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) [ Time Frame: 12 hours, 24 hours, 48 hours, 72 hours and 120 hours upto Day 5 ]
    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.

  • Immunogenicity Assessment With Respect to Anti-Acetychollinesterase2 (ACE2) Binding Antibodies at Follow-up Day 14 and Follow-up Day 28 (Part A) [ Time Frame: Follow-up (Day 14) and follow-up (Day 28) ]
    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.

  • Immunogenicity Assessment With Respect to Anti-ACE2 Binding Antibodies at Follow-up Day 14 and Follow-up Day 28 (Part B) [ Time Frame: Follow-up (Day 14 )and follow-up (Day 28) ]
    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.


Enrollment: 44
Study Start Date: September 1, 2012
Study Completion Date: October 6, 2014
Primary Completion Date: October 1, 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01597635


Locations
United States, California
GSK Investigational Site
Sacramento, California, United States, 95817
United States, Illinois
GSK Investigational Site
Chicago, Illinois, United States, 60611
United States, Massachusetts
GSK Investigational Site
Springfield, Massachusetts, United States, 01199
United States, Michigan
GSK Investigational Site
Ann Arbor, Michigan, United States, 48109
United States, New York
GSK Investigational Site
New York, New York, United States, 10003
United States, North Carolina
GSK Investigational Site
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
United States, Ohio
GSK Investigational Site
Columbus, Ohio, United States, 43215
United States, Oregon
GSK Investigational Site
Portland, Oregon, United States, 97239
United States, Pennsylvania
GSK Investigational Site
Philadelphia, Pennsylvania, United States, 19104
GSK Investigational Site
Philadelphia, Pennsylvania, United States, 19107
United States, South Carolina
GSK Investigational Site
Charleston, South Carolina, United States, 29425
Canada, British Columbia
GSK Investigational Site
Vancouver, British Columbia, Canada, V5Z 1M9
GSK Investigational Site
Vancouver, British Columbia, Canada, V6Z 1Y6
Canada, Nova Scotia
GSK Investigational Site
Halifax, Nova Scotia, Canada, B3H 2Y9
Canada, Ontario
GSK Investigational Site
Kingston, Ontario, Canada, K7L 2V7
Canada, Quebec
GSK Investigational Site
Greenfield Park, Quebec, Canada, J4V 2H1
GSK Investigational Site
Sainte-Foy, Quebec, Canada, G1V 4G5
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01597635     History of Changes
Other Study ID Numbers: 114622
First Submitted: January 26, 2012
First Posted: May 14, 2012
Results First Submitted: July 23, 2017
Results First Posted: September 28, 2017
Last Update Posted: September 28, 2017
Last Verified: August 2017

Keywords provided by GlaxoSmithKline:
rhACE2
Acute Respiratory Distress Syndrome (ARDS)
Acute Lung Injury
GSK2586881
critical care

Additional relevant MeSH terms:
Wounds and Injuries
Lung Injury
Acute Lung Injury
Respiratory Distress Syndrome, Adult
Lung Diseases
Respiratory Tract Diseases
Thoracic Injuries
Respiration Disorders