SB-681323 IV for Subjects at Risk of Acute Lung Injury or ARDS
Condition: Lung Injury, Acute
MeSH terms: Respiratory Distress Syndrome; Acute Lung Injury; Lung Injury; Wounds and Injuries
Intervention: SB-681323 Intravenous 3mg; SB-681323 Intravenous 7.5 mg; SB-681323 Intravenous 7.5mg; SB-681323 Intravenous 10mg; Placebo
Intervention description: 3 mg SB-681323 Intravenous administration infused over 4 hours; 7.5 mg SB-681323 Intravenous administration infused over 24 hours; 7.5 mg SB-681323 Intravenous administration infused over 4 hours; 10 mg SB-681323 Intravenous administration infused over 24 hours; Placebo to match intervention
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 77.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: dilmapimod; p38; SB-681323; Acute Lung Injury (ALI); Acute Respiratory Distress Syndrome (ARDS)

Summary:

      This is an early phase (Phase IIa), randomized, double-blind, parallel group, multi-centre
      study for subjects with trauma (physical injury) who are at risk for developing Acute Lung
      Injury (ALI) or Acute Respiratory Distress Syndrome (ARDS). The primary purpose of the study
      is to evaluate the safety and tolerability of SB-681323, which is a potent, selective
      inhibitor of p38 alpha (MAPK) (prevents inflammation of tissue), in comparison to a placebo.
    

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.