SB-681323 IV for Subjects at Risk of Acute Lung Injury or... | NCT00996840

NCT00996840

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Detailed Description

The acute respiratory distress syndrome (ARDS) is a form of severe lung injury (ALI) characterized by hypoxemic respiratory failure (the lungs are unable to absorb oxygen to the arterial blood) and non-cardiogenic pulmonary edema (accumulation of fluid in the lungs). The syndrome may be caused by direct or indirect injury to the lungs. It is associated with a mortality rate of up to 40-50%. There are no marketed pharmacologic therapies for this devastating syndrome.

This study aims to assess the safety and tolerability of SB-681323, which is a potent, selective inhibitor of p38 alpha mitogen-activated protein kinase.

The rationale behind the development of this drug is that there are elevated levels of circulating pro-inflammatory agents, such as cytokines which are biological agents that increase levels of inflammation in the lungs. These agents are part of an 'inflammatory loop' and it may be beneficial to the condition to dampen this loop.

p38 mitogen activated protein kinase (MAPK) plays a major role in the regulation and activation of intracellular proteins which are subsequently involved in the regulation of the cytokines. The pathway is activated by 'stress', such as injury, causing the inflammation. Therefore, 'dampening' this system should reduce the level of inflammation.

This study will investigate the anti-inflammatory activity, efficacy (effectiveness at achieving the desired effect) and safety of SB-681323.

To measure the efficacy of the drug, biomarkers will be measured. Biomarkers are biological agents in the body that are effected by the presence of specific injury or inflammation and are directly or indirectly linked to a regulatory system of event in the body. They are used to measure for the presence and severity of the condition in question. This study will investigate biomarkers linked directly or indirectly to the p38 alpha regulatory mechanism/system. We will be measuring biomarkers such as serum inflammatory biomarkers, coagulation (blood clotting) system biomarkers, biomarkers of endothelial cell / neutrophil interaction and biomarkers of lung epithelial cell injury.

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Cohort 1 - SB-681323 Intravenous 3mg	Experimental	3mg SB-681323 Intravenous administration, infused over 4 hours	Drug: SB-681323 Intravenous 3mg
Cohort 2 - SB-681323 Intravenous 7.5 mg	Experimental	7.5 mg SB-681323 Intravenous administration infused over 24 hours	Drug: SB-681323 Intravenous 7.5 mg
Cohort 3 - SB-681323 Intravenous 7.5mg	Experimental	7.5 mg SB-681323 Intravenous administration infused over 4 hours	Drug: SB-681323 Intravenous 7.5mg
Cohort 4 - SB-681323 Intravenous 10mg	Experimental	10 mg SB-681323 Intravenous administration infused over 24 hours	Drug: SB-681323 Intravenous 10mg
Combined Placebo	Experimental	Placebo to match intervention	Other: Placebo

Name	Type	Description	Arm Group Labels	Other Names
SB-681323 Intravenous 3mg	Drug	3 mg SB-681323 Intravenous administration infused over 4 hours	Cohort 1 - SB-681323 Intravenous 3mg

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Mean Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, White Blood Cell Count	Mean hematology parameters including basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count, white blood cell count were reported. If sample for hematology test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.	"Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"
Mean Hematology Parameters- Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC)	Mean hematology parameters including hemoglobin, MCHC were reported. If sample for hematology test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.	"Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"
Mean Hematology Parameters- Mean Corpuscle Hemoglobin	Hematology parameter mean corpuscle hemoglobin was reported. If sample for hematology test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.	"Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"
Hematology Parameters-Mean Corpuscle Volume	Absolute values of mean corpuscle volume were reported. If sample for hematology test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.	"Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"
Mean Hematology Parameters-reticulocytes, Red Blood Cell Count	Absolute values of reticulocytes and red blood cell count were reported. If sample for hematology test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.

Secondary Outcomes

Measure	Description	Time Frame
Mean Serum Interleukin-6 Levels	Serum samples were collected at 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1. Mean absolute values of Serum interleukin-6 levels at these specified time oints were reported.	6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1
Mean Serum CXCL8 (Interleuin-8) Levels

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

Male or female, 18 - 80 years of age (inclusive) with major trauma admitted to the Intensive Care Unit (ICU).
Injury Severity score (ISS) >16 to <70 (exclusive)
A female subject is eligible to participate if she is of non-child-bearing potential or of:
Child-bearing potential and agrees to use one of the approved contraception methods (oral contraceptive, either combined or progesterone alone, injectable progesterone, implants of levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, intrauterine device (IUD) or intrauterine system (IUS) with less than 1% non-effectiveness, documented male partner sterilization, double barrier method, i.e. condom and occlusive cap plus spermicidal agent) for an appropriate period of time (as determined by the product label or investigator, if applicable. Female subjects must agree to use contraception until one week post-last dose, if applicable.
Male subjects must agree to use one of the approved contraception methods (abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject, condom during non-vaginal intercourse with any partner (male or female), condom and occlusive cap plus spermicidal agent during sexual intercourse with a female) if applicable. This criterion must be followed from the time of the first dose of study medication until one week post-last dose, if applicable.
BMI within the range 19.0 - 35.0 kg/m2 inclusive (clinical estimate of height and weight is acceptable).
The subject or legal decision maker is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block.
The subject must be randomized into the study within 24-26 hours from the time of trauma.

Exclusion Criteria:

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

Known positive Hepatitis B surface antigen or Hepatitis C antibody.
Known positive test for HIV antibody.
A known history of substance abuse, alcohol abuse, or regular alcohol consumption within 6 months of the study defined as:
an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males), or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). One unit is equivalent to a half-pint (220mL) of beer or 1 (25ml) measure of spirits or 1 glass (125ml) of wine.
The subject has participated in a clinical trial and 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).
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.
Haemoglobin < 7g/dL.
Pregnant females as determined by positive serum or urine hCG test prior to dosing.
Lactating females.
Unwillingness or inability to follow the procedures outlined in the protocol.
History of sensitivity to heparin or heparin-induced thrombocytopenia.
Diagnosis of ALI at admission.
Head trauma (Abbreviated Injury Score [AIS]>3), liver trauma (AIS>2), or trauma that in the opinion of the Principle Investigator or GSK medical monitor is deemed unsurvivable.
Known history of neuromuscular disease or cord injury at C5 or above.
Elevated ALT or AST > 1.5 ULN.
History of bone marrow or solid organ transplant.
Known history of auto-immune disorder in which immunosuppressive agents, other than prednisone, were required within the last 6 weeks.
Known to be receiving oral or intravenous corticosteroids within 7 days of admission.
Subject with active tuberculosis or being treated for active tuberculosis.
Known history of malignancy within the past 5 years with the exception of successfully treated squamous cell or basal cell cancer of the skin.
Arterial blood pH less than 7.1 or serum HCO3 - <15 before infusion is started.
Persistent cardiovascular instability requiring therapy with more than one vasopressor.
A patient will be excluded if in the judgement of the Principle Investigator or GSK medical monitor their participation could jeopardize the health of the subject or the integrity of the study.

Contacts/Locations Module

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Lexington	Kentucky	40536-0293	United States
GSK Investigational Site

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
26102252	Derived	Christie JD, Vaslef S, Chang PK, May AK, Gunn SR, Yang S, Hardes K, Kahl L, Powley WM, Lipson DA, Bayliffe AI, Lazaar AL. A Randomized Dose-Escalation Study of the Safety and Anti-Inflammatory Activity of the p38 Mitogen-Activated Protein Kinase Inhibitor Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome. Crit Care Med. 2015 Sep;43(9):1859-69. doi: 10.1097/CCM.0000000000001132.

Label	URL
Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.	View source

ID	Type	URL	Comment
111592	Dataset Specification	View IPD

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Combined Placebo	Eligible participants received matching placebo intravenous (IV) infusion over 4 hours (h) or 24 h for 3 days
FG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 milligrams (mg), IV infusion over 4h for 3 days

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

No data available

No data is available for this block.

Masking Info

Type of Units Analyzed

Arm/Group Information

ID	Title	Description
BG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
BG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
BG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
BG003	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days
BG004	Cohort 4-SB-681323, 10 mg, 24 h	Eligible participants received SB-681323, 10 mg, IV infusion over 24h for 3 days
BG005	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

Years

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000 BG0010 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Mean Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, White Blood Cell Count

Mean hematology parameters including basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count, white blood cell count were reported. If sample for hematology test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.

All subject Population comprised of as all participant who received at least one dose of study medication. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Giga cells per liter

"Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days
OG004	Cohort 4-SB-681323, 10 mg, 24 h	Eligible participants received SB-681323, 10 mg, IV infusion over 24h for 3 days

Units	Counts
Participants	OG00020 OG0019 OG00212 OG003

Title	Denominators	Categories
Basophils: Day 2, pre-dose	ParticipantsOG00019 ParticipantsOG0018 ParticipantsOG00212 ParticipantsOG003

Primary

Mean Hematology Parameters- Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC)

Mean hematology parameters including hemoglobin, MCHC were reported. If sample for hematology test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.

All subject population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Grams per liter (g/L)

"Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h

Primary

Mean Hematology Parameters- Mean Corpuscle Hemoglobin

Hematology parameter mean corpuscle hemoglobin was reported. If sample for hematology test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.

All subject population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Picogram (pg)

"Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days

Primary

Hematology Parameters-Mean Corpuscle Volume

Absolute values of mean corpuscle volume were reported. If sample for hematology test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.

All subject population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Femtoliter

"Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days

Primary

Mean Hematology Parameters-reticulocytes, Red Blood Cell Count

Absolute values of reticulocytes and red blood cell count were reported. If sample for hematology test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.

All subject population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Trillion cells per liter (TI/L)

"Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h

Primary

Mean Clinical Chemistry Parameters- Albumin and Total Protein

Absolute values of albumin and total protein were reported. If sample for clinical chemistry test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.

All subject population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

g/L

"Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days

Primary

Mean Clinical Chemistry Parameters-alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Creatine Kinase and Gamma Glutamyl Transferase

Absolute values of alkaline phosphatase, alanine amino transferase, aspartate amino transferase, creatine kinase and gamma glutamyl transferase were reported. If sample for clinical chemistry test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.

All subject population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

International units per liter (IU/L)

"Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days

Primary

Mean Clinical Chemistry Parameters- Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid

Absolute values of direct bilirubin, total bilirubin, creatinine and uric acid were reported. If sample for clinical chemistry test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.

All subject population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Micromol per liter

"Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h

Primary

Mean Clinical Chemistry Parameters- Calcium, Chloride, Glucose, Bicarbonate, Potassium, Sodium and Ratio of Urea to Blood Urea Nitrogen (Urea/BUN)

Absolute values of calcium, chloride, glucose, bicarbonate, potassium, sodium and Urea/BUN were reported. If sample for clinical chemistry test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.

All subject population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Millimole per liter

"Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h

Primary

Mean Clinical Chemistry Parameters-estradiol

Absolute values of Estradiol were reported. If sample for clinical chemistry test had been obtained for standard of care within ± 4 h of the planned assessment then it was not collected at the planned assessment time point.

All subject population. Only those participants available at the specified time points were analyzed. Data were not collected from participants in Cohort 2-SB-681323, 7.5 mg, 24 h, Cohort 3-SB-681323, 7.5 mg, 4 h, and Cohort 4-SB-681323, 10 mg, 24 h.

Posted

Mean

Standard Deviation

Picomole per liter

Day 1 (pre-dose) and Day 3 (24 h)

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h

Primary

Mean Clinical Chemistry Parameters-Blood pH at Screening

Absolute values of Blood pH at screening were reported as clinical chemistry parameter.

All subject population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

pH Units

Screening

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days
OG004

Primary

Vital Parameter- Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

Absolute values of SBP and DBP were reported.

All subject population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Millimeter of Mercury (mmHg)

For Cohort 1 and 3: "Day 1, 4 h", "Day 2, pre-dose", "Day 3, pre-dose and 24 h" and "Follow up (Day 7)"; for Cohort 2 and 4: "Day 2, pre-dose", "Day 3, pre-dose and 24 h", and "Follow up (Day 7)"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days

Primary

Vital Parameter: Mean Heart Rate

Absolute values of mean heart rate were reported.

All subject population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Beats per minute

For Cohort 1 and 3: "Day 1, 4 h", "Day 2, pre-dose", "Day 3, pre-dose and 24 h" and "Follow up (Day 7)"; for Cohort 2 and 4: "Day 2, pre-dose", "Day 3, pre-dose and 24 h", and "Follow up (Day 7)"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days

Primary

Vital Sign: Mean Percent Oxygen (O2) in Blood

Absolute values of mean percent O2 in blood were reported.

All subject population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Percent O2

For Cohort 1 and 3: "Day 1, 4 h", "Day 2, pre-dose", "Day 3, pre-dose and 24 h" and "Follow up (Day 7)"; for Cohort 2 and 4: "Day 2, pre-dose", "Day 3, pre-dose and 24 h", and "Follow up (Day 7)"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days

Primary

Vital Signs: Mean Oxygen Saturation (SaO2) Via Pulse Oximetry

Assessment of SaO2 via pulse oximetry was planned for cohort 1 and 3 at Day 1 (4 h), Day 2 (pre-dose) and Day 3 (pre-dose and 24 h) and for cohort 2 and 4: Day 2 (pre-dose) and Day 3 (pre-dose and 24 h). However, the analyzable data was not collected for this parameter.

All subject population. Data was not collected for this parameter.

Posted

For Cohort 1 and 3: "Day 1, 4 h", "Day 2, pre-dose", "Day 3, pre-dose and 24 h"; for Cohort 2 and 4: "Day 2, pre-dose", and "Day 3, pre-dose and 24 h"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h

Primary

Vital Signs: Mean Level of Positive End Expiratory Pressure

Assessment of level of positive end expiratory pressure was planned for cohort 1 and 3 at Day 1 (4 h), Day 2 (pre-dose) and Day 3 (pre-dose and 24 h) and for cohort 2 and 4: Day 2 (pre-dose) and Day 3 (pre-dose and 24 h). However, the analyzable data was not collected for this parameter.

All subject population. Data was not collected for this parameter.

Posted

For Cohort 1 and 3: "Day 1, 4 h", "Day 2, pre-dose", "Day 3, pre-dose and 24 h"; for Cohort 2 and 4: "Day 2, pre-dose", and "Day 3, pre-dose and 24 h"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h

Primary

Vital Signs: Mean Level of Peak and Plateau Ventilator Pressures

Assessment of mean level of peak and plateau ventilator pressures was planned for cohort 1 and 3 at Day 1 (4 h), Day 2 (pre-dose) and Day 3 (pre-dose and 24 h) and for cohort 2 and 4: Day 2 (pre-dose) and Day 3 (pre-dose and 24 h). However, the analyzable data was not collected for this parameter.

All subject population. Data was not collected for this parameter.

Posted

For Cohort 1 and 3: "Day 1, 4 h", "Day 2, pre-dose", "Day 3, pre-dose and 24 h"; for Cohort 2 and 4: "Day 2, pre-dose", and "Day 3, pre-dose and 24 h"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h

Primary

Vital Signs: Mean Oxygen Requirement (FiO2) Via Pulse Oximetry

Assessment of mean FiO2 via pulse oximetry was planned for cohort 1 and 3 at Day 1 (4 h), Day 2 (pre-dose) and Day 3 (pre-dose and 24 h) and for cohort 2 and 4: Day 2 (pre-dose) and Day 3 (pre-dose and 24 h). However, the analyzable data was not collected for this parameter.

All subject population. Data was not collected for this parameter.

Posted

For Cohort 1 and 3: "Day 1, 4 h", "Day 2, pre-dose", "Day 3, pre-dose and 24 h"; for Cohort 2 and 4: "Day 2, pre-dose", and "Day 3, pre-dose and 24 h"

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h

Primary

Mean Electrocardiogram (ECG) Parameters Including PR, QRS, QT, and QTcB, QTcF, RR Intervals

12-lead ECGs were obtained at each timepoint during the study using an ECG machine that automatically calculated the heart rate and measures RR, PR, QRS, QT, and QTc intervals. Absolute mean values of PR, QRS, QT, and QTcB, QTcF, RR intervals were reported.

All subject population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Milliseconds

Day 2, pre-dose, Day 3, pre-dose, Day 3, 24 h and Follow-up (Day 7)

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h

Primary

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

AE was defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE include AEs those result in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

All subject population.

Posted

Count of Participants

Participants

Up to Follow-up (Day 7)

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h

Secondary

Mean Serum Interleukin-6 Levels

Serum samples were collected at 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1. Mean absolute values of Serum interleukin-6 levels at these specified time oints were reported.

Pharmacodynamic (PD) Population was defined as patients in the 'All Subjects' population for whom a pharmacodynamic sample was obtained and analysed (Flow Cytometry data were excluded from the definition of pharmacodynamic sample). Only those participants available at the specified time points were analyzed.

Posted

Geometric Mean

95% Confidence Interval

Picogram per milliliter (pg/mL)

6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003

Secondary

Mean Serum CXCL8 (Interleuin-8) Levels

Serum samples were collected at 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1. Mean absolute values of Serum CXCL8 (Interleuin-8) levels at these specified time points were reported.

PD Population. Only those participants available at the specified time points were analyzed.

Posted

Geometric Mean

95% Confidence Interval

pg/ml

6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days

Secondary

Mean Serum C-Reactive Protein (CRP) Levels

Serum samples were collected at 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1. Mean absolute values of serum CRP levels at these specified time points were reported.

PD Population. Only those participants available at the specified time points were analyzed.

Posted

Geometric Mean

95% Confidence Interval

mg/L

6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days

Secondary

Markers of Endothelial Cell/Neutrophil Interaction: Mean Soluble Tumor Necrosis Factor Receptors-I

Samples were collected at 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1. Mean absolute values of soluble tumor necrosis factor receptors-I levels at these specified time points were reported.

PD Population. Only those participants available at the specified time points were analyzed.

Posted

Geometric Mean

95% Confidence Interval

pg/mL

6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days

Secondary

Markers of Lung Epithelial Cell Injury: Mean Myeloperoxidase (MPO) Levels

Serum samples were collected at 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1. Mean absolute values of MPO levels at these specified time points were reported.

PD Population. Only those participants available at the specified time points were analyzed.

Posted

Geometric Mean

95% Confidence Interval

pg/mL

6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1

ID	Title	Description
OG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days
OG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG003	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days

Secondary

Mean Area Under the Concentration-time Curve From Zero (Pre-dose) to 24 Hours (AUC0-24)

Absolute values of the mean AUC 0-24 of SB-681323 were reported. PK samples were collected for cohort 1 and 3 at Day 1 (pre-dose, 4, 4.25, 5, 6, 8, 12, 18h), Day 2 (pre-dose and 4h), Day 3 (0, 4, 24, 48h) and for cohort 2 and 4 at Day 1 (pre-dose), Day (pre-dose), Day 3 (pre-dose, 24h10minutes [min], 24h45min, 27, 34, 40, 80 h since doing on Day 3).

Pharmacokinetic (PK) population was defined as patients in the 'All Subjects' population for whom a pharmacokinetic sample was obtained and analyzed. Note: Due to some placebo patients PK samples being assayed in error, the above PK population definition was adjusted to also exclude any patient receiving Placebo.

Posted

Geometric Mean

95% Confidence Interval

h*ng/mL

For cohort 1 and 3: Day 1 (pre-dose, 4, 4.25, 5, 6, 8, 12, 18h), Day 2 (pre-dose and 4h), Day 3 (0, 4, 24, 48h). For cohort 2 and 4: Day 1 (pre-dose), Day (pre-dose), Day 3 (pre-dose)

ID	Title	Description
OG000	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG001	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG002	Cohort 3-SB-681323, 7.5 mg, 4 h

Secondary

Mean Average Concentration (Cavg) of SB-681323

Absolute values of mean Cavg of SB-681323 were reported. PK samples were collected for cohort 1 and 3 at Day 1 (pre-dose, 4, 4.25, 5, 6, 8, 12, 18h), Day 2 (pre-dose and 4h), Day 3 (0, 4, 24, 48h) and for cohort 2 and 4 at Day 1 (pre-dose), Day (pre-dose), Day 3 (pre-dose, 24h 10 min, 24h 45min, 27, 34, 40, 80 h since doing on Day 3).

PK Population. Only those participants available at the specified time points were analyzed.

Posted

Geometric Mean

95% Confidence Interval

ng/mL

For cohort 1 and 3: Day 1 (pre-dose, 4, 4.25, 5, 6, 8, 12, 18h), Day 2 (pre-dose and 4h), Day 3 (0, 4, 24, 48h). For cohort 2 and 4: Day 1 (pre-dose), Day (pre-dose), Day 3 (pre-dose, 24h 10minutes [min], 24h 45min, 27, 34, 40, 80 h since doing on Day 3)

ID	Title	Description
OG000	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG001	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG002	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days

Secondary

Maximum Observed Concentration (Cmax) of SB-681323

Absolute values of the Cmax of SB-681323 were reported. PK samples were collected for cohort 1 and 3 at Day 1 (pre-dose, 4, 4.25, 5, 6, 8, 12, 18h), Day 2 (pre-dose and 4h), Day 3 (0, 4, 24, 48h) and for cohort 2 and 4 at Day 1 (pre-dose), Day (pre-dose), Day 3 (pre-dose, 24h 10 min, 24h 45min, 27, 34, 40, 80 h since doing on Day 3).

PK population. Only those participants available at the specified time points were analyzed.

Posted

Geometric Mean

95% Confidence Interval

ng/mL

For cohort 1 and 3: Day 1 (pre-dose, 4, 4.25, 5, 6, 8, 12, 18h), Day 2 (pre-dose and 4h), Day 3 (0, 4, 24, 48h). For cohort 2 and 4: Day 1 (pre-dose), Day (pre-dose), Day 3 (pre-dose, 24h 10 min, 24h 45min, 27, 34, 40, 80 h since doing on Day 3)

ID	Title	Description
OG000	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days
OG001	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days
OG002	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Combined Placebo	Eligible participants received matching placebo IV infusion over 4 h or 24 h for 3 days	20	1	20	18	20
EG001	Cohort 1-SB-681323, 3 mg, 4 h	Eligible participants received SB-681323, 3 mg, IV infusion over 4h for 3 days	9	1	9	7	9
EG002	Cohort 2-SB-681323, 7.5 mg, 24 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 24h for 3 days	12	1	12	10	12
EG003	Cohort 3-SB-681323, 7.5 mg, 4 h	Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days	18	4	18	16	18
EG004	Cohort 4-SB-681323, 10 mg, 24 h	Eligible participants received SB-681323, 10 mg, IV infusion over 24h for 3 days	18	0	18	14	18

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Gastrointestinal anastomotic leak	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG0031 affected18 at risk EG004
Wound dehiscence	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003
Mental impairment	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Quadriplegia	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Acute respiratory distress syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Aspiration	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Mental status changes	Psychiatric disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Feeding disorder	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0004 affected20 at risk EG0011 affected9 at risk EG0021 affected12 at risk EG0030 affected18 at risk EG0040 affected18 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0012 affected9 at risk EG0020 affected12 at risk EG003
Hypophosphataemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0022 affected12 at risk EG003
Hypovolaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0002 affected20 at risk EG0010 affected9 at risk EG0022 affected12 at risk EG003
Hypomagnesaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003
Hypocalcaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0006 affected20 at risk EG0014 affected9 at risk EG0024 affected12 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0004 affected20 at risk EG0014 affected9 at risk EG0020 affected12 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0004 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003
Ileus	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003
Pyrexia	General disorders	MedDRA	Systematic Assessment	EG0008 affected20 at risk EG0011 affected9 at risk EG0026 affected12 at risk EG003
Oedema peripheral	General disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Asthenia	General disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Infusion site bruising	General disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Infusion site extravasation	General disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Hypertension	Vascular disorders	MedDRA	Systematic Assessment	EG0007 affected20 at risk EG0012 affected9 at risk EG0023 affected12 at risk EG003
Hypotension	Vascular disorders	MedDRA	Systematic Assessment	EG0003 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Deep vein thrombosis	Vascular disorders	MedDRA	Systematic Assessment	EG0002 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Bacterial test positive	Investigations	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Blood potassium decreased	Investigations	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Hepatic enzyme increased	Investigations	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0011 affected9 at risk EG0021 affected12 at risk EG003
Blood creatine phosphokinase increased	Investigations	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003
Blood pressure increased	Investigations	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Haemoglobin decreased	Investigations	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Blood alkaline phosphatase increased	Investigations	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Blood glucose increased	Investigations	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Blood phosphorus decreased	Investigations	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Blood potassium increased	Investigations	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Electrocardiogram QT prolonged	Investigations	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Electrocardiogram ST segment depression	Investigations	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Oxygen saturation decreased	Investigations	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Prothrombin time prolonged	Investigations	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Sputum culture positive	Investigations	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Urine output decreased	Investigations	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
White blood cell count increased	Investigations	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Pulmonary oedema	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0002 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Hypoxia	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Acute respiratory distress syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Bronchial secretion retention	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Respiratory arrest	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Sinus congestion	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Wheezing	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Agitation	Psychiatric disorders	MedDRA	Systematic Assessment	EG0004 affected20 at risk EG0010 affected9 at risk EG0022 affected12 at risk EG003
Anxiety	Psychiatric disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003
Delirium	Psychiatric disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Atrial fibrillation	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0011 affected9 at risk EG0021 affected12 at risk EG003
Tachycardia	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Bradycardia	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Cardiac failure	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Pericardial effusion	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Sinus tachycardia	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Supraventricular tachycardia	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Ventricular extrasystoles	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Oliguria	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0002 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Renal failure acute	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003
Urinary retention	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Myoglobinuria	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Urinary incontinence	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Anaemia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0011 affected9 at risk EG0021 affected12 at risk EG003
Coagulopathy	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003
Leukopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG0002 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Pneumonia	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Bacteraemia	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Pneumococcal sepsis	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Pneumonia staphylococcal	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Pruritus	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Rash	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Hypoaesthesia	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Convulsion	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Headache	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Lethargy	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0011 affected9 at risk EG0020 affected12 at risk EG003
Paraesthesia	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Postoperative respiratory distress	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003
Hypernatraemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Metabolic alkalosis	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0020 affected12 at risk EG003
Vitamin B complex deficiency	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0000 affected20 at risk EG0010 affected9 at risk EG0021 affected12 at risk EG003

ID	Term
D055371	Acute Lung Injury
D012128	Respiratory Distress Syndrome

Eligible participants received SB-681323, 7.5 mg, IV infusion over 4h for 3 days

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0042 affected18 at risk

EG0040 affected18 at risk

EG0043 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0043 affected18 at risk

EG0040 affected18 at risk

EG0042 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0042 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0042 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

EG0041 affected18 at risk

EG0040 affected18 at risk

OG0040.0279± 0.03191

OG0040.0315± 0.04240

OG0040.0240± 0.02501

OG0040.0724± 0.07411

OG0040.0664± 0.04955

OG0040.1142± 0.07005

OG0040.1998± 0.14855

OG0041.5365± 0.83119

OG0041.1593± 0.55383

OG0041.4288± 0.62231

OG0041.2835± 0.41700

OG0040.7246± 0.24992

OG0040.6957± 0.22589

OG0040.6712± 0.29185

OG0040.7591± 0.23030

OG0048.2319± 2.78227

OG0048.1779± 2.36852

OG0046.9604± 3.51501

OG0048.4943± 4.71139

OG0040.0513± 0.02192

OG0041.9655± 0.13867

OG004395.09(311.51 to 501.11)

OG00421.85(17.38 to 27.46)

OG004110.88(97.49 to 126.10)

(1748.13 to 2394.72)

OG0042267.35(1961.10 to 2621.42)

(32839.83 to 60756.75)

OG00462108.1(46378.91 to 83171.68)

(182.558 to 259.993)

Title	Measurements
	OG000112.199(92.339 to 136.331) OG001207.050(172.749 to 248.163) OG002182.590(156.946 to 212.425) OG003237.549(197.345 to 285.943)

Title	Measurements
	OG000106.037(81.444 to 138.057) OG001211.282(177.858 to 250.988) OG002188.895(160.977 to 221.654) OG003230.891(189.316 to 281.598)

Title	Measurements
	OG0004.675(3.847 to 5.680) OG0018.627(7.198 to 10.340) OG0027.608(6.539 to 8.851) OG0039.898(8.223 to 11.914)

Title	Measurements
	OG0004.418(3.393 to 5.752) OG0018.803(7.411 to 10.458) OG0027.871(6.707 to 9.236) OG0039.620(7.888 to 11.733)

Title	Measurements
	OG00022.830(19.533 to 26.683) OG0018.842(7.377 to 10.599) OG00238.697(33.996 to 44.048) OG00310.382(8.647 to 12.466)

Title	Measurements
	OG00021.888(18.670 to 25.661) OG0018.990(7.515 to 10.755) OG00239.180(34.157 to 44.943) OG00310.131(8.273 to 12.407)

ID	Term
D055370	Lung Injury
D008171	Lung Diseases
D012140	Respiratory Tract Diseases
D012120	Respiration Disorders