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

GlaxoSmithKline44 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Lung Injury, Acute

Interventions

Dose 1 GSK2586881DRUG

Low dose GSK2586881 administered intravenously

Dose 2 GSK2586881DRUG

Medium dose GSK2586881 administered intravenously

Dose 3 GSK2586881DRUG

Medium-High dose GSK2586881 administered intravenously

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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.

Locations (19)

GSK Investigational Site

Sacramento, California, United States

GSK Investigational Site

Chicago, Illinois, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Up to Day 7

Hematology Parameter Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Assessment Upto Day 7 (Part B)

Data from ClinicalTrials.gov

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Secondary Outcomes

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

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)

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.

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)

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.

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

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

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.

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).

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.

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).

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.

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.

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.

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.

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.

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 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.

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 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.

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

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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)

Time frame: Follow-up (Day 14 )and follow-up (Day 28)