NCT02221037 - Study of GSK2862277 in Subjects Undergoing Oesophagectomy Surgery | Crick

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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).

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

Secondary Outcomes

Baseline Adjusted Change in EVLWI on Completion of Surgery

EVLW refers to the fluid within the lung but outside the vascular compartment. It includes extravasated plasma, intracellular water, lymphatic fluid, and surfactant. EVLWI was measured by trans-pulmonary thermodilution via a PiCCO hemodynamic monitor. 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. Only those participants with data available at the specified time points were analyzed.

Time frame: 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)

AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with use of a medicinal product (MP), whether or not considered related to MP. AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with use of MP. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or all events of possible drug induced liver injury with hyperbilirubinemia. Safety Population comprised of all participants who received at least one complete dose of study treatment.

Time frame: Up to Day 31

Number of Participants With Hematology Abnormalities of Potential Clinical Importance

Hematology parameters included basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, monocytes, neutrophils, neutrophil bands, platelets, red blood cell (RBC) count, segmented neutrophils and white blood cell (WBC) count. The potential clinical concern values were: hematocrit (low: \<0.3 fraction and high: \>0.54 fraction), Hemoglobin (low: \<90 gram per Liter and high: \>180 gram per Liter), lymphocytes (low: \<0.6 x 10\^9 cells/Liter and high: \>3.0 x 10\^9 cells/Liter), neutrophils: (low: \<1.5 x 10\^9 cells/Liter and high: \>20 x 10\^9 cells/Liter), platelets: (low: \<100 x 10\^9 cells/Liter and high: \>600 x 10\^9 cells/Liter) and WBC: (low: \<3 x 10\^9 cells/Liter and high: \>20 x 10\^9 cells/Liter). Only those participants for which at least one value of potential clinical concern was reported are summarized.

Time frame: Up to Day 8

Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance

Clinical chemistry parameters and their potential clinical concern values were: albumin (low: \<25 millimole \[mmol\]/L and high: \>60 mmol/L), calcium (low: \<1.8 mmoL/L and high: \>2.75 mmol/L), creatinine (low: \<30 mmol/L and high: \>160 mmol/L), glucose (low: \<3 mmol/L and high: \>9 mmol/L), potassium (low: \<2.5 mmol/L and high: \>5.5 mmol/L), sodium (low: \<120 mmol/L and high: \>160 mmol/L), total carbon dioxide content (low: \<16 mmol/L and high: \>35 mmol/L) and blood urea nitrogen (low: \<3 mmol/L and high: \>15 mmol/L). Number of participants with clinical chemistry abnormalities of potential clinical importance are presented.

Time frame: Up to Day 8

Number of Participants With Abnormal Urinalysis Parameters

Urinalysis included dipstick urine test which was used to screen for glucose, ketones, occult blood and protein on Day 1 (pre-dose) and Day 8. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters of urine glucose, ketones, occult blood and protein can be read as Trace, 1+, 2+ and 3+, indicating proportional concentrations in the urine sample.

Time frame: Day 1 (pre-dose) and Day 8

Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Importance

Single 12-lead ECGs were obtained thereafter during the study, using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, RR and corrected QT (QTc) intervals. Number of participants with ECG values of potential clinical importance are presented.

Time frame: Days 1, 2, 4 and 8

Number of Participants With Vital Signs of Potential Clinical Importance

Vital sign measurements included systolic and diastolic blood pressure, pulse rate, temperature and respiratory rate. Vital sign measurements were measured in a semi-recumbent or supine position after 5 minutes rest. The potential clinical concern range for systolic blood pressure: \<85 and \>160 millimeters of mercury, for diastolic: \<45 and \>100 millimeters of mercury and heart rate: \<40 and \>110 beats per minute. Number of participants with vital signs of potential clinical importance are presented.

Time frame: Up to Day 31

Baseline Adjusted Change in PaO2/FiO2 on Completion of Surgery

Oxygenation and function of gas exchange was assessed by the comparison of partial pressure of oxygen arterially (PaO2) divided by the fraction of oxygen that is being inspired (FiO2), sometimes referred to simply as the 'P to F ratio'. The P to F ratio was assessed at time points during the period of intubation and mechanical ventilation. An arterial blood sample was required for determination of the partial pressure of oxygen and the percentage of O2 which is being inspired was recorded at the corresponding time point. 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.

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

Levels of BAL Biomarkers on Completion of Surgery

Samples were collected to determine concentrations of biomarkers in BAL using an appropriately validated assay on Day 1 after completion of surgery. BAL biomarkers included soluble tumor necrosis factor receptor (STNFR) type I, free, STNFR type I, total, tumor necrosis factor alpha, interleukin 6, interleukin 8, interleukin 1 beta, monocyte chemotactic protein-1, macrophage inflammatory protein 1 alpha, macrophage inflammatory protein 1 beta, interleukin 10 and soluble receptor for advanced glycation end (sRAGE) products. Any value below limit of quantification was replaced with half the lower limit of quantification (LLQ) prior to deriving the summary measures. Mean levels of BAL biomarkers on completion of surgery are presented. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

Time frame: Day 1 (on completion of surgery)

Levels of BAL Biomarkers (C-reactive Protein and Total Proteins) on Completion of Surgery

Samples were collected to determine concentrations of biomarkers in BAL using an appropriately validated assay. BAL biomarkers included C-reactive protein and total proteins. Any value below limit of quantification was replaced with half the LLQ prior to deriving the summary measures. All BAL C-reactive protein samples were below limit of quantification and all were assigned to half the LLQ prior to deriving the summary measures. Mean levels of BAL biomarkers on completion of surgery are presented. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

Time frame: Day 1 (on completion of surgery)

Levels of BAL Biomarkers (Surfactant Protein and Clara Cell Secretory Protein) on Completion of Surgery

Samples were collected to determine concentrations of biomarkers in BAL using an appropriately validated assay. BAL biomarkers included surfactant protein D and clara cell secretory protein. Any value below limit of quantification was replaced with half the LLQ prior to deriving the summary measures. Mean levels of BAL biomarkers on completion of surgery are presented. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

Time frame: Day 1 (on completion of surgery)

Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4

Oxygenation and function of gas exchange was assessed by the comparison of PaO2 divided by the FiO2, sometimes referred to simply as the 'P to F ratio'. The P to F ratio was assessed at time points during the period of intubation and mechanical ventilation. An arterial blood sample was required for determination of the partial pressure of oxygen and the percentage of O2 which is being inspired was recorded at the corresponding time point. 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. PP1 Population was analyzed. Only those participants available at the specified time points were analyzed represented by n=X,X in the category titles.

Time frame: Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4

Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4

PVPI is a derived value from EVLW, and is considered to be less variable than EVLWI. PVPI was measured via single-indicator transpulmonary thermodilution as long as the participant remained in the ICU with a patent indwelling PiCCO catheter. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value minus Baseline value. PP1 Population was analyzed. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

Time frame: Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4

Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4

EVLW refers to the fluid within the lung but outside the vascular compartment. It includes extravasated plasma, intracellular water, lymphatic fluid, and surfactant. EVLWI was measured by trans-pulmonary thermodilution via a PiCCO hemodynamic monitor. Change from Baseline value was the post-Baseline value minus Baseline value. PP1 Population was analyzed. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

Time frame: Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4

Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4

The SOFA score defines the presence and severity of dysfunction within 6 organ systems (cardiovascular, respiratory, coagulation, liver, renal, and nervous system) with a value of "0" for assigned to normal function to a maximum value of "4" for severe dysfunction in each of the organ systems. Each component of the SOFA score was added together, ranging from "0" indicating no organ dysfunction in any of the 6 organ systems, to "24" indicating maximal organ dysfunction across all 6 organ systems. Per-Protocol (PP) 2 Population comprised of all the participants in the Safety population for whom the study drug actually received was the same one they were randomized to (study drug).

Time frame: Day 2 to Day 4

Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0 to t])

Blood samples for pharmacokinetic analysis of GSK2862277 were collected at the indicated time points. Pharmacokinetic (PK) Population comprised of all participants in the Safety population for whom a pharmacokinetic sample (plasma and/or BAL) was obtained and analyzed.

Time frame: 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)

Maximum Observed Concentration (Cmax)

Blood samples for pharmacokinetic analysis of GSK2862277 were collected at the indicated time points.

Time frame: 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)

Derived Pharmacokinetic Parameter- Half-life (t1/2) and Time of Occurrence of Cmax (Tmax)

Half-life (t1⁄2) is the time required for a quantity to reduce to half its initial value. t1/2 was not determined in all cases due to insufficient data in the terminal phase. Blood samples for pharmacokinetic analysis of GSK2862277 were collected at the indicated time points. Only those participants available at the specified time points were analyzed represented by n=X,X in the category titles.

Time frame: 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)

Ratio of Total Protein Derived From BAL and Plasma Values

BAL sampling and plasma sampling was done on Day 1 (on completion of surgery). Raw summary statistics for the derived ratio were not produced. Only statistical modeling was performed that produced a posterior distribution for each treatment. Summary measure for the posterior distribution was the median. The quantity being modeled was the mean treatment effect (pooling data from BAL Collapsed and Ventilated Lungs). The standard deviation is capturing the dispersion of the estimate for the mean effect. Ratio of total protein (Ratio was derived from BAL and Plasma values) is presented.

Time frame: Day 1 (on completion of surgery)

Number of Participants With Positive Immunogenicity Results Post-dosing

Serum samples were obtained to determine incidence and titers of serum anti-GSK2862277 antibodies at the specified time points. The binding antibody detection assay was performed at the specified time points. Number of participants with positive immunogenicity results post-dosing is presented.

Time frame: Day 8 and Day 31

BAL Concentrations of GSK2862277

BAL samples were collected on Day 1 (on completion of surgery) and BAL concentrations of GSK2862277 and derived PK parameters were determined. Only those participants available at the specified time points were analyzed.

Time frame: Day 1 (on completion of surgery)

Study of GSK2862277 in Subjects Undergoing Oesophagectomy Surgery

Overview

Conditions

Interventions

Eligibility

Locations (6)

Outcomes

Primary Outcomes

Secondary Outcomes