Study of GSK2862277 in Subjects Undergoing Oesophagectomy Surgery
Condition: Lung Injury, Acute and Respiratory Distress Syndrome, Adult
MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Lung Injury; Acute Lung Injury
Intervention: GSK2862277; Placebo
Intervention description: It is available as 26 milligrams (mg) white to off-white, uniform lyophilized cake that will be reconstituted (using reconstitution fluid formulated with polysorbate 80 in Water for Injection) to 40 mg/vial of Lyophile for reconstitution for inhalation with duration of nebulisation as approximately 3-5 min and will be administered using "Pari eFlow with s30 mesh" device.; It is a clear, colorless to pale yellow liquid, will be administered in volume to match active dose as solution for inhalation with duration of nebulisation as approximately 3-5 min and will be administered using "Pari eFlow with s30 mesh" device.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 35.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: PaO2/FiO2; Peri-operative lung injury; EVLWI; ARDS; PVPI; SOFA scores; GSK2862277; Oesophagectomy

Summary:

      Lung injury in patients undergoing oesophagectomy may occur during surgery (peri-operatively)
      as a result of One Lung Ventilation (OLV) and/or during the immediate post-operative period
      when patients receive intensive care. This is reinforced by the observation that
      physiological markers of lung injury are most elevated immediately after completion of
      surgery, and the development of clinical Acute Respiratory Distress Syndrome (ARDS)occurs
      immediately post-operatively (within 72 hours of surgery), with the majority of cases
      reported 24-48 hours after completion of surgery. This study is designed to investigate the
      impact of pre-operative administration of GSK2862277 on biological and physiological markers
      of lung injury in patients undergoing surgical resection of oesophageal cancer in order to
      achieve optimal exposure at the site of injury following OLV and lung deflation. This study
      is a randomized placebo controlled, double-blind, multi-centre, single dose parallel group,
      design. There will be two treatment groups comprising one active and one placebo arm with
      approximately 40 patients per group. Patients enrolled in the study will be scheduled to
      undergo planned/elective trans-thoracic surgery for oesophagectomy. The primary endpoint for
      this study is the change in pulmonary vascular permeability index (PVPI) from pre-surgical
      levels to the end of surgery. GSK2862277 will be administered as an orally inhaled aerosol
      (single nebulized dose) over approximately 3 to 5 minutes (min) 1-3 hours prior to surgery.
      Subject will be monitored daily until discharge and followed up till day 28.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject has a planned elective transthoracic oesophagectomy

          -  Male or female between 18 and 80 years of age inclusive, at the time of signing the
             informed consent.

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form.

          -  A female subject is eligible to participate if she is of:

          -  Non-childbearing potential defined as pre-menopausal females with a documented tubal
             ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous
             amenorrhea [in questionable cases a blood sample with simultaneous follicle
             stimulating hormone (FSH) > 40 milli-International Units per milliliter and estradiol
             < 40 picograms per milliliter (<147 picomoles per liter) is confirmatory]. Females on
             hormone replacement therapy (HRT) and whose menopausal status is in doubt will be
             required to use contraception methods if they wish to continue their HRT during the
             study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal
             status prior to study enrolment. For most forms of HRT, at least 2-4 weeks should
             elapse between the cessation of therapy and the blood draw; this interval depends on
             the type and dosage of HRT. Following confirmation of their post-menopausal status,
             they can resume use of HRT during the study without use of a contraceptive method.

          -  Liver parameters according to the thresholds below: Aspartate aminotransferase and
             Alanine aminotransferase < 5x Upper limit of normal (ULN); alkaline phosphatase and
             bilirubin <=1.5xULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is
             fractionated and direct bilirubin <35%).

          -  QT duration corrected for heart rate by Bazett's formula (QTcB) or QT duration
             corrected for heart rate by Fridericia's formula (QTcF) <= 480 milliseconds (msec) at
             screening

          -  Either QTcB or QTcF, machine or manual over-read can be used. This applies to both
             males and females. The QT correction formula used to determine inclusion and
             discontinuation for an individual subject should be the same throughout the study.

          -  Based on average QTc value of triplicate ECGs obtained over a brief recording period.

        Exclusion Criteria:

          -  Positive screening test for pre-existing antibodies that bind GSK2862277.

          -  Current evidence or history of pneumonia within 14 days before dosing.

          -  Diagnosis of chronic respiratory disease with a forced expiratory volume in one second
             (FEV1) less than 50% predicted or resting oxygen saturations of less 92%.

          -  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.

          -  The subject 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).

          -  Use of corticosteroids (Intravenous, oral or Intramuscular) at a dose of >= 10
             Milligrams per day (mg/day) prednisolone (or equivalent) within 14 days prior to
             dosing, or anti-Tumor Necrosis Factor (anti-TNF) or anti-IL1 within 60 days prior to
             dosing.

        Criteria Based Upon Medical Histories

          -  History or current evidence of clinically significant renal disease, diabetes
             mellitus/metabolic syndrome, hypertension, peripheral vascular disease or any other
             clinically significant respiratory, cardiovascular, neurological, endocrine, or
             hematological abnormalities that are uncontrolled on permitted therapy. Significant is
             defined as any disease that, in the opinion of the Investigator, would put the safety
             of the patients at risk through study participation, or which would affect the safety
             analysis or other analysis if the disease/condition exacerbated during the study.

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  History of regular alcohol consumption within 6 months of the study, defined as: an
             average weekly intake of >28 units for males or >14 units for females. One unit is
             equivalent to 8 grams of alcohol: a half-pint [~240 milliliter (ml)] of beer, 1 glass
             (125 ml) of wine or 1 (25 ml) measure of spirits Criteria Based Upon Diagnostic
             Assessments

          -  Screens positive for Hepatitis B surface antigen, Hepatitis C antibody

          -  Known Human Immunodeficiency Virus (HIV) positive; testing will be conducted in
             accordance with local procedures

          -  Tests positive for Mycobacterium tuberculosis using QuantiFERON Gold Test. Other
             Criteria

          -  Subject has received a live attenuated vaccine(s) within 3 weeks of randomisation or
             will require vaccination with a live attenuated vaccine prior to the end of the study
             (Day 28).

          -  Unwillingness or inability to follow the procedures outlined in the protocol.

          -  Subject is mentally or legally incapacitated.