Study of GSK2862277 in Subjects Undergoing Oesophagectomy Surgery

NCT02221037 | Terminated Phase 2 Results

• 2 other identifiers: 1163412014-000643-33
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 6

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.

Conditions

Lung Injury, Acute and Respiratory Distress Syndrome, Adult

Keywords

PaO2/FiO2; Peri-operative lung injury; EVLWI; ARDS; PVPI; SOFA scores; GSK2862277; Oesophagectomy

Outcome Measures

Primary Outcomes (1)

• Baseline Adjusted Change in Pulmonary Vascular Permeability Index (PVPI) on Completion of Surgery

  PVPI is a derived value from extra vascular lung water (EVLW), and is considered to be less variable than extra vascular lung water Index (EVLWI). PVPI was measured via single-indicator transpulmonary thermodilution with a patent indwelling Pulse Contour Cardiac Output (PiCCO) catheter. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value (on completion of surgery on Day 1) minus Baseline value. Per-Protocol 1 (PP1) Population comprised of all the participants in the Safety population for whom the treatment actually received was the same one when they were randomized to (both study drug and BAL sampling location).

  Baseline (Day 1 [immediately prior to start of surgery]) and Day 1 (on completion of surgery)

Secondary Outcomes (21)

• Baseline Adjusted Change in EVLWI on Completion of Surgery

  Baseline (Day 1 [immediately prior to start of surgery]) and Day 1 (on completion of surgery)

• Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

  Up to Day 31

• Number of Participants With Hematology Abnormalities of Potential Clinical Importance

  Up to Day 8

• Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance

  Up to Day 8

• Number of Participants With Abnormal Urinalysis Parameters

  Day 1 (pre-dose) and Day 8

Study Arms (2)

GSK2862277

EXPERIMENTAL

GSK2862277 will be administered as single orally inhaled aerosol over approximately 3 to 5 minutes; approximately 1-3 hours prior to the subjects scheduled surgery, before the initiation of pre-operative procedures. After surgery subject will undergo either ventilated or collapsed lung BAL procedure. Regular assessments will be conducted until the time of patient discharge. Subjects will be followed up as outpatients at Day 28

Drug: GSK2862277

Placebo

PLACEBO COMPARATOR

Placebo will be administered as single orally inhaled aerosol over approximately 3 to 5 minutes; approximately 1-3 hours prior to the subjects scheduled surgery, before the initiation of pre-operative procedures. After surgery subject will be undergo either ventilated or collapsed lung BAL procedure. Regular assessments will conducted until the time of patient discharge. Subjects will be followed up as outpatients at Day 28

Drug: Placebo

Interventions

GSK2862277 DRUG

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.

GSK2862277

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Based on average QTc value of triplicate ECGs obtained over a brief recording period.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (6)

GSK Investigational Site

Cottingham, Yorkshire, HU16 5JQ, United Kingdom

Location

GSK Investigational Site

Belfast, BT9 7AB, United Kingdom

Location

GSK Investigational Site

Birmingham, B15 2TH, United Kingdom

Location

GSK Investigational Site

Birmingham, B9 5SS, United Kingdom

Location

GSK Investigational Site

Cambridge, CB2 0QQ, United Kingdom

Location

GSK Investigational Site

Middlesbrough, TS4 3BU, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 32467417 BACKGROUND

MeSH Terms

Conditions

Lung Injury; Respiratory Distress Syndrome

Interventions

GSK2862277

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Thoracic Injuries; Wounds and Injuries; Respiration Disorders

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 18, 2014
• First Posted: August 20, 2014
• Study Start: April 28, 2015
• Primary Completion: June 28, 2017
• Study Completion: June 28, 2017
• Last Updated: October 27, 2020
• Results First Posted: January 11, 2019

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (copy the URL below to your browser)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

GB (6)