The Safety, Tolerability, PK and PD of GSK2586881 in Patients With Acute Lung Injury
Condition: Lung Injury, Acute
MeSH terms: Lung Injury; Acute Lung Injury; Wounds and Injuries
Intervention: Dose 1 GSK2586881; Dose 2 GSK2586881; Dose 3 GSK2586881; Dose 4 GSK2586881; Placebo (saline)
Intervention description: Low dose GSK2586881 administered intravenously; Medium dose GSK2586881 administered intravenously; Medium-High dose GSK2586881 administered intravenously; High dose GSK2586881 administered intravenously; Administered intravenously to match intervention
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 44.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: rhACE2; Acute Respiratory Distress Syndrome (ARDS); Acute Lung Injury; GSK2586881; critical care

Summary:

      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.
    

Eligibility 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.