SB-681323 IV for Subjects at Risk of Acute Lung Injury or ARDS

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.

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.