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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Assessment of the Anti-Inflammatory Activity, Efficacy and Safety of Intravenous SB-681323 in Subjects at Risk for Development of Acute Lung Injury (ALI) or Acute Respiratory Distress Syndrome (ARDS).

Conditions
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Lung Injury, Acute

Intervention / Treatment
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* Drug: SB-681323 Intravenous 3mg
* Drug: SB-681323 Intravenous 7.5 mg
* Drug: SB-681323 Intravenous 7.5mg
* Drug: SB-681323 Intravenous 10mg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - SB-681323 Intravenous 3mg<br>3mg SB-681323 Intravenous administration, infused over 4 hours | Drug: SB-681323 Intravenous 3mg<br>* 3 mg SB-681323 Intravenous administration infused over 4 hours<br>|
| Experimental: Cohort 2 - SB-681323 Intravenous 7.5 mg<br>7.5 mg SB-681323 Intravenous administration infused over 24 hours | Drug: SB-681323 Intravenous 7.5 mg<br>* 7.5 mg SB-681323 Intravenous administration infused over 24 hours<br>|
| Experimental: Cohort 3 - SB-681323 Intravenous 7.5mg<br>7.5 mg SB-681323 Intravenous administration infused over 4 hours | Drug: SB-681323 Intravenous 7.5mg<br>* 7.5 mg SB-681323 Intravenous administration infused over 4 hours<br>|
| Experimental: Cohort 4 - SB-681323 Intravenous 10mg<br>10 mg SB-681323 Intravenous administration infused over 24 hours | Drug: SB-681323 Intravenous 10mg<br>* 10 mg SB-681323 Intravenous administration infused over 24 hours<br>|
| Experimental: Combined Placebo<br>Placebo to match intervention | Other: Placebo<br>* Placebo to match intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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. | Day 2, pre-dose, Day 3, pre-dose, Day 3, 24 h and Follow up (Day 7) | 
| 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. | Day 2, pre-dose, Day 3, pre-dose, Day 3, 24 h and Follow up (Day 7) | 
| 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. | Day 2, pre-dose, Day 3, pre-dose, Day 3, 24 h and Follow up (Day 7) | 
| 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. | Day 2, pre-dose, Day 3, pre-dose, Day 3, 24 h and Follow up (Day 7) | 
| 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. | Day 2, pre-dose, Day 3, pre-dose, Day 3, 24 h and Follow up (Day 7) | 
| 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. | Day 1 (pre-dose) and Day 3 (24 h) | 
| Mean Clinical Chemistry Parameters-Blood pH at Screening | Absolute values of Blood pH at screening were reported as clinical chemistry parameter. | Screening | 
| Vital Parameter- Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Absolute values of SBP and DBP were reported. | 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) | 
| Vital Parameter: Mean Heart Rate | Absolute values of mean heart rate were reported. | 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) | 
| Vital Sign: Mean Percent Oxygen (O2) in Blood | Absolute values of mean percent O2 in blood were reported. | 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) | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | Day 2, pre-dose, Day 3, pre-dose, Day 3, 24 h and Follow-up (Day 7) | 
| 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. | Up to Follow-up (Day 7) | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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. | 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1 | 
| 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. | 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1 | 
| 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. | 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1 | 
| 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. | 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1 | 
| 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). | 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) | 
| 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). | 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) | 
| 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). | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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p38, dilmapimod, SB-681323, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS)