A Phase 2 interventional study of GSK2862277 and Placebo in Lung Injury, Acute and Respiratory Distress Syndrome, Adult, sponsored by GlaxoSmithKline. Terminated at 6 sites in United Kingdom. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2020-10-27.
Sponsored by GlaxoSmithKline · Phase 2, Interventional, and Treatment
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.
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Exclusion Criteria:
Criteria Based Upon Medical Histories
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 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
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.
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)
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)
The study was conducted at 8 centers in the United Kingdom from 28-Apr-2015 to 28-Jun-2017.
| Milestone | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Started | 5 | 11 | 8 | 9 |
| Completed | 5 | 11 | 7 | 9 |
| Not completed | 0 | 0 | 1 | 0 |
| Withdrew: Physician decision | 0 | 0 | 1 | 0 |
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).
| Ratio | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Baseline Adjusted Change in Pulmonary Vascular Permeability Index (PVPI) on Completion of Surgery | 0.00 ± 0.367 | 0.11 ± 0.664 | -0.18 ± 0.536 | 0.21 ± 0.449 |
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.
| Milliliters per kilograms | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Baseline Adjusted Change in EVLWI on Completion of Surgery | 0.462 ± 1.4731 | -0.317 ± 1.3436 | 0.008 ± 1.2527 | -0.300 ± 3.8403 |
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.
| Participants | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| AE | 5 | 10 | 6 | 9 |
| SAE | 3 | 5 | 5 | 4 |
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.
| Participants | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Number of Participants With Hematology Abnormalities of Potential Clinical Importance | 5 | 10 | 5 | 8 |
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.
| Participants | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance | 4 | 5 | 4 | 4 |
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.
| Participants | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Urine glucose: Day 1 (pre-dose): Trace | 0 | 0 | 0 | 0 |
| Urine glucose: Day 1 (pre-dose): 1+ | 0 | 0 | 0 | 0 |
| Urine glucose: Day 1 (pre-dose): 2+ | 1 | 0 | 0 | 0 |
| Urine glucose: Day 1 (pre-dose): 3+ | 0 | 0 | 1 | 0 |
| Urine glucose: Day 8: Trace | 0 | 1 | 0 | 2 |
| Urine glucose: Day 8: 1+ | 0 | 0 | 0 | 0 |
| Urine glucose: Day 8: 2+ | 1 | 0 | 0 | 0 |
| Urine glucose: Day 8: 3+ | 0 | 0 | 0 | 0 |
| Urine ketones: Day 1 (pre-dose): Trace | 1 | 0 | 1 | 0 |
| Urine ketones: Day 1 (pre-dose): 1+ | 0 | 0 | 0 | 0 |
| Urine ketones: Day 1 (pre-dose): 2+ | 0 | 0 | 0 | 0 |
| Urine ketones: Day 1 (pre-dose): 3+ | 0 | 0 | 0 | 0 |
| Urine ketones: Day 8: Trace | 0 | 0 | 0 | 2 |
| Urine ketones: Day 8: 1+ | 0 | 0 | 1 | 0 |
| Urine ketones: Day 8: 2+ | 0 | 0 | 0 | 0 |
| Urine ketones: Day 8: 3+ | 0 | 0 | 0 | 0 |
| Urine occult blood: Day 1 (pre-dose): Trace | 0 | 0 | 1 | 0 |
| Urine occult blood: Day 1 (pre-dose): 1+ | 0 | 2 | 1 | 0 |
| Urine occult blood: Day 1 (pre-dose): 2+ | 0 | 0 | 0 | 0 |
| Urine occult blood: Day 1 (pre-dose): 3+ | 0 | 0 | 0 | 0 |
| Urine occult blood: Day 8: Trace | 0 | 0 | 0 | 0 |
| Urine occult blood: Day 8: 1+ | 1 | 1 | 0 | 0 |
| Urine occult blood: Day 8: 2+ | 0 | 0 | 0 | 2 |
| Urine occult blood: Day 8: 3+ | 0 | 1 | 0 | 0 |
| Urine protein: Day 1 (pre-dose): Trace | 0 | 0 | 0 | 2 |
| Urine protein: Day 1 (pre-dose): 1+ | 1 | 0 | 1 | 0 |
| Urine protein: Day 1 (pre-dose): 2+ | 0 | 1 | 0 | 1 |
| Urine protein: Day 1 (pre-dose): 3+ | 0 | 0 | 0 | 0 |
| Urine protein: Day 8: Trace | 1 | 5 | 0 | 3 |
| Urine protein: Day 8: 1+ | 2 | 4 | 2 | 2 |
| Urine protein: Day 8: 2+ | 0 | 0 | 1 | 2 |
| Urine protein: Day 8: 3+ | 0 | 0 | 0 | 0 |
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.
| Participants | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Importance | 5 | 7 | 4 | 8 |
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.
| Participants | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Number of Participants With Vital Signs of Potential Clinical Importance | 2 | 3 | 3 | 3 |
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.
| Millimiters of Mercury | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Baseline Adjusted Change in PaO2/FiO2 on Completion of Surgery | 8.9 ± 141.10 | 18.5 ± 160.82 | -47.5 ± 252.16 | 11.2 ± 98.12 |
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.
| Picograms per milliliter | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| STNFR type I, Free, n=5,9,5,8 | 645.5400 ± 398.14834 | 278.2529 ± 201.58668 | 106.1600 ± 168.39828 | 67.7713 ± 69.69634 |
| STNFR I, Total, n=5,9,5,8 | 299.4000 ± 168.92556 | 310.8136 ± 307.29751 | 175.5660 ± 167.67312 | 183.9000 ± 229.72939 |
| Tumor necrosis factor alpha, n=5,9,5,7 | 3.5110 ± 2.68376 | 24.3850 ± 33.67945 | 6.1040 ± 12.51974 | 3.7814 ± 5.33211 |
| Interleukin 6, n=5,9,5,8 | 63.580 ± 66.8285 | 138.917 ± 217.3948 | 15.844 ± 30.5243 | 43.828 ± 64.0092 |
| Interleukin 8, n=5,9,5,8 | 8041.600 ± 16369.4998 | 3822.170 ± 6270.8199 | 126.340 ± 145.1019 | 432.513 ± 731.0601 |
| Interleukin 1 beta, n=5,9,5,8 | 70.2376 ± 123.55622 | 66.3749 ± 99.46797 | 1.1674 ± 0.78732 | 18.6054 ± 38.61022 |
| Monocyte chemotactic protein-1, n=5,9,5,8 | 118.1600 ± 124.52553 | 122.2649 ± 170.65326 | 53.4260 ± 75.21106 | 51.5713 ± 59.72512 |
| Macrophage inflammatory protein 1 alpha, n=5,9,5,8 | 63.348 ± 54.8461 | 165.300 ± 203.2446 | 9.140 ± 0.0000 | 23.942 ± 32.7837 |
| Macrophage inflammatory protein 1 beta, n=5,9,5,8 | 142.040 ± 132.7086 | 219.891 ± 264.1694 | 28.292 ± 41.4424 | 48.413 ± 82.2684 |
| Interleukin 10, n=5,9,5,8 | 1.7098 ± 1.93498 | 5.2672 ± 8.39023 | 0.5130 ± 0.00000 | 1.8123 ± 3.23279 |
| sRAGE products, n=5,9,5,8 | 1440.2 ± 1144.89 | 2121.7 ± 2078.47 | 1966.0 ± 2734.60 | 1044.6 ± 1560.45 |
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.
| Milligrams per Liter | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| C-reactive protein, n=5,9,5,8 | 0.04650 ± 0.000000 | 0.04650 ± 0.000000 | 0.04650 ± 0.000000 | 0.04650 ± 0.000000 |
| Total proteins, n=5,10,5,8 | 423.6 ± 182.80 | 605.1 ± 670.60 | 136.8 ± 108.33 | 303.0 ± 274.85 |
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.
| Nanograms per milliliter | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Surfactant Protein D, n=5,9,5,8 | 411.92 ± 472.487 | 760.04 ± 898.224 | 872.88 ± 848.358 | 551.31 ± 943.640 |
| Clara cell secretory protein, n=5,7,5,7 | 3635.40 ± 2575.875 | 2131.66 ± 3217.852 | 1000.40 ± 1167.704 | 1409.21 ± 2358.501 |
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.
| Millimeters of Mercury | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Day 2, n=5,8,5,6 | -15.1 ± 171.84 | -103.3 ± 87.24 | 38.9 ± 312.28 | -79.3 ± 199.85 |
| Day 3, n=5,8,5,5 | -53.7 ± 120.35 | -43.0 ± 179.64 | -9.5 ± 325.46 | -119.0 ± 148.67 |
| Day 4, n=5,8,5,5 | -36.3 ± 139.18 | -123.6 ± 68.14 | -22.3 ± 342.46 | -56.5 ± 123.31 |
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.
| Ratio | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Day 2, n=5,6,3,5 | -0.22 ± 0.259 | -0.27 ± 0.427 | -0.50 ± 0.346 | -0.42 ± 0.630 |
| Day 3, n=4,6,3,5 | -0.20 ± 0.648 | -0.23 ± 0.516 | -0.30 ± 0.529 | -0.32 ± 0.756 |
| Day 4, n=3,5,2,4 | -0.40 ± 0.200 | -0.24 ± 0.666 | -0.20 ± 0.000 | -0.08 ± 0.850 |
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.
| Millimeters per kilograms | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Day 2, n=5,6,3,5 | -0.033 ± 1.1203 | -1.120 ± 2.4825 | -0.694 ± 0.8710 | 0.604 ± 1.3370 |
| Day 3, n=4,5,3,5 | 0.062 ± 1.2468 | -0.190 ± 1.4762 | -0.203 ± 2.3349 | 0.755 ± 1.4801 |
| Day 4, n=3,5,2,4 | -0.621 ± 0.2646 | 0.828 ± 4.1772 | 0.311 ± 1.9297 | 1.981 ± 2.8449 |
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).
| Scores on a Scale | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Day 2 | 1.0 ± 2.24 | 1.6 ± 1.39 | 1.5 ± 2.54 | 2.1 ± 1.92 |
| Day 3 | 3.4 ± 4.72 | 1.5 ± 1.80 | 1.8 ± 2.86 | 1.6 ± 1.43 |
| Day 4 | 2.2 ± 3.96 | 1.3 ± 0.90 | 1.3 ± 3.56 | 1.6 ± 1.69 |
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.
| Hours*picograms/milliliter | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|
| Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0 to t]) | 340505.15 ± 45.284 | 290102.64 ± 76.450 |
Blood samples for pharmacokinetic analysis of GSK2862277 were collected at the indicated time points.
| Picograms per milliliters | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|
| Maximum Observed Concentration (Cmax) | 31123.58 ± 64.452 | 25469.14 ± 93.307 |
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.
| Hours | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|
| Tmax, n=3,6 | 7.584 ± 11.4958 | 7.583 ± 11.4119 |
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.
| Ratio | Placebo (Pooling BAL Collapsed and Ventilated Lungs) | GSK2862277 26 mg (Pooling BAL Collapsed and Ventilated Lungs) |
|---|---|---|
| Ratio of Total Protein Derived From BAL and Plasma Values | 0.005 ± 0.0020 | 0.002 ± 0.0009 |
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.
| Participants | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Number of Participants With Positive Immunogenicity Results Post-dosing | 0 | 0 | 0 | 0 |
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.
| Nanograms per milliliter | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|
| BAL Concentrations of GSK2862277 | 11220.00 ± NA | 74155.37 ± 377 |
Collected over Serious adverse events and non-serious adverse events were collected from start of the study medication (Day 1) to Follow-up (Day 31). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo (BAL Collapsed Lung) | 0/5 (0%) | 3/5 (60%) | 5/5 (100%) |
| Placebo (BAL Ventilated Lung) | 0/11 (0%) | 5/11 (45.5%) | 10/11 (90.9%) |
| GSK2862277 26 mg (BAL Collapsed Lung) | 0/8 (0%) | 5/8 (62.5%) | 5/8 (62.5%) |
| GSK2862277 26 mg (BAL Ventilated Lung) | 0/9 (0%) | 4/9 (44.4%) | 8/9 (88.9%) |
| Event | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Pulmonary embolismRespiratory, thoracic and mediastinal disorders | 2/5 | 0/11 | 1/8 | 0/9 |
| PneumoniaInfections and infestations | 0/5 | 2/11 | 2/8 | 1/9 |
| Anastomotic leakInjury, poisoning and procedural complications | 0/5 | 1/11 | 0/8 | 2/9 |
| Atrial fibrillationCardiac disorders | 1/5 | 0/11 | 0/8 | 0/9 |
| Diaphragmatic herniaGastrointestinal disorders | 1/5 | 0/11 | 0/8 | 0/9 |
| Small intestinal obstructionGastrointestinal disorders | 1/5 | 0/11 | 0/8 | 0/9 |
| EmpyemaInfections and infestations | 1/5 | 0/11 | 0/8 | 0/9 |
| Failure to anastomoseInjury, poisoning and procedural complications | 1/5 | 0/11 | 0/8 | 0/9 |
| Iatrogenic injuryInjury, poisoning and procedural complications | 1/5 | 0/11 | 0/8 | 0/9 |
| NeutropeniaBlood and lymphatic system disorders | 0/5 | 0/11 | 1/8 | 0/9 |
| Event | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) |
|---|---|---|---|---|
| Atrial fibrillationCardiac disorders | 2/5 | 2/11 | 1/8 | 1/9 |
| ConstipationGastrointestinal disorders | 2/5 | 0/11 | 2/8 | 1/9 |
| Alanine aminotransferase increasedInvestigations | 2/5 | 2/11 | 2/8 | 2/9 |
| Musculoskeletal painMusculoskeletal and connective tissue disorders | 2/5 | 0/11 | 1/8 | 2/9 |
| HypotensionVascular disorders | 2/5 | 0/11 | 1/8 | 1/9 |
| Lower respiratory tract infectionInfections and infestations | 0/5 | 0/11 | 3/8 | 1/9 |
| Blood alkaline phosphatase increasedInvestigations | 0/5 | 4/11 | 1/8 | 0/9 |
| Blood phosphorus decreasedInvestigations | 0/5 | 0/11 | 0/8 | 3/9 |
| AnaemiaBlood and lymphatic system disorders | 1/5 | 3/11 | 0/8 | 0/9 |
| PyrexiaGeneral disorders | 1/5 | 3/11 | 2/8 | 1/9 |
Safety Population which comprised of all participants who received at least one complete dose of study treatment.
| Age, Continuous(Years) | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) | Total |
|---|---|---|---|---|---|
| Mean | 63.0 ± 9.70 | 63.5 ± 10.47 | 62.0 ± 4.69 | 59.3 ± 10.76 | 61.9 ± 9.09 |
| Sex: Female, Male(Participants) | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) | Total |
|---|---|---|---|---|---|
| Female | 0 | 4 | 0 | 2 | 6 |
| Male | 5 | 7 | 8 | 7 | 27 |
| Race/Ethnicity, Customized(Participants) | Placebo (BAL Collapsed Lung) | Placebo (BAL Ventilated Lung) | GSK2862277 26 mg (BAL Collapsed Lung) | GSK2862277 26 mg (BAL Ventilated Lung) | Total |
|---|---|---|---|---|---|
| White | 5 | 11 | 8 | 9 | 33 |
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Supporting information: Study protocol, Sap, Icf, Csr
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