Clinical trial NCT02221037: Study of GSK2862277 in Subjects Undergoing Oesophagectomy Surgery
Official title: A Placebo Controlled, Double-blind, Multi-centre, Single Dose, Parallel Group, Randomised Clinical Trial of GSK2862277 in Patients Undergoing Oesophagectomy Surgery
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Lung Injury, Acute and Respiratory Distress Syndrome, Adult
Keywords: PaO2/FiO2
Peri-operative lung injury
EVLWI
ARDS
PVPI
SOFA scores
GSK2862277
Oesophagectomy
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-08-20
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Baseline Adjusted Change in Pulmonary Vascular Permeability Index (PVPI) on Completion of Surgery
timeFrame: Baseline (Day 1 [immediately prior to start of surgery]) and Day 1 (on completion of surgery)
Secondary outcomes:
measure: Baseline Adjusted Change in EVLWI on Completion of Surgery
timeFrame: Baseline (Day 1 [immediately prior to start of surgery]) and Day 1 (on completion of surgery)
measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to Day 31
measure: Number of Participants With Hematology Abnormalities of Potential Clinical Importance
timeFrame: Up to Day 8
measure: Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance
timeFrame: Up to Day 8
measure: Number of Participants With Abnormal Urinalysis Parameters
timeFrame: Day 1 (pre-dose) and Day 8
measure: Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Importance
timeFrame: Days 1, 2, 4 and 8
measure: Number of Participants With Vital Signs of Potential Clinical Importance
timeFrame: Up to Day 31
measure: Baseline Adjusted Change in PaO2/FiO2 on Completion of Surgery
timeFrame: Baseline (Day 1 [immediately prior to start of surgery]) and Day 1 (on completion of surgery)
measure: Levels of BAL Biomarkers on Completion of Surgery
timeFrame: Day 1 (on completion of surgery)
measure: Levels of BAL Biomarkers (C-reactive Protein and Total Proteins) on Completion of Surgery
timeFrame: Day 1 (on completion of surgery)
measure: Levels of BAL Biomarkers (Surfactant Protein and Clara Cell Secretory Protein) on Completion of Surgery
timeFrame: Day 1 (on completion of surgery)
measure: Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4
timeFrame: Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4
measure: Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4
timeFrame: Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4
measure: Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4
timeFrame: Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4
measure: Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4
timeFrame: Day 2 to Day 4
measure: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0 to t])
timeFrame: Day 1 (pre-dose, 1 hour post-dose and on completion of surgery), Day 2 (24 to 26 hours post-dose) and Day 3 (46 to 50 hours post-dose)
measure: Maximum Observed Concentration (Cmax)
timeFrame: Day 1 (pre-dose, 1 hour post-dose and on completion of surgery), Day 2 (24 to 26 hours post-dose) and Day 3 (46 to 50 hours post-dose)
measure: Derived Pharmacokinetic Parameter- Half-life (t1/2) and Time of Occurrence of Cmax (Tmax)
timeFrame: Day 1 (pre-dose, 1 hour post-dose and on completion of surgery), Day 2 (24 to 26 hours post-dose) and Day 3 (46 to 50 hours post-dose)
measure: Ratio of Total Protein Derived From BAL and Plasma Values
timeFrame: Day 1 (on completion of surgery)
measure: Number of Participants With Positive Immunogenicity Results Post-dosing
timeFrame: Day 8 and Day 31
measure: BAL Concentrations of GSK2862277
timeFrame: Day 1 (on completion of surgery)
Other outcomes:
Locations:
city: Cottingham
country: United Kingdom
facility: GSK Investigational Site
state: Yorkshire
city: Belfast
country: United Kingdom
facility: GSK Investigational Site
city: Birmingham
country: United Kingdom
facility: GSK Investigational Site
city: Birmingham
country: United Kingdom
facility: GSK Investigational Site
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
city: Middlesborough
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Ryan J, Bayliffe AI, McAuley DF, Yeung J, Thickett DR, Howells PA, O'Donnell C, Vassallo AM, Wright TJ, McKie E, Hardes K, Summers C, Shields MO, Powley W, Wilson R, Lazaar AL, Fowler A, Perkins GD. A nebulised antitumour necrosis factor receptor-1 domain antibody in patients at risk of postoperative lung injury: A randomised, placebo-controlled pilot study. Eur J Anaesthesiol. 2020 Nov;37(11):1014-1024. doi: 10.1097/EJA.0000000000001245.