Clinical trial NCT00996840: SB-681323 IV for Subjects at Risk of Acute Lung Injury or ARDS
Official title: 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).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lung Injury, Acute
Keywords: dilmapimod
p38
SB-681323
Acute Lung Injury (ALI)
Acute Respiratory Distress Syndrome (ARDS)
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-10-16
Enrollment: 77
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

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.

Primary outcomes:
measure: Mean Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, White Blood Cell Count
timeFrame: "Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"
measure: Mean Hematology Parameters- Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC)
timeFrame: "Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"
measure: Mean Hematology Parameters- Mean Corpuscle Hemoglobin
timeFrame: "Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"
measure: Hematology Parameters-Mean Corpuscle Volume
timeFrame: "Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"
measure: Mean Hematology Parameters-reticulocytes, Red Blood Cell Count
timeFrame: "Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"
measure: Mean Clinical Chemistry Parameters- Albumin and Total Protein
timeFrame: "Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"
measure: Mean Clinical Chemistry Parameters-alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Creatine Kinase and Gamma Glutamyl Transferase
timeFrame: "Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"
measure: Mean Clinical Chemistry Parameters- Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid
timeFrame: "Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"
measure: Mean Clinical Chemistry Parameters- Calcium, Chloride, Glucose, Bicarbonate, Potassium, Sodium and Ratio of Urea to Blood Urea Nitrogen (Urea/BUN)
timeFrame: "Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"
measure: Mean Clinical Chemistry Parameters-estradiol
timeFrame: Day 1 (pre-dose) and Day 3 (24 h)
measure: Mean Clinical Chemistry Parameters-Blood pH at Screening
timeFrame: Screening
measure: Vital Parameter- Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: 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)"
measure: Vital Parameter: Mean Heart Rate
timeFrame: 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)"
measure: Vital Sign: Mean Percent Oxygen (O2) in Blood
timeFrame: 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)"
measure: Vital Signs: Mean Oxygen Saturation (SaO2) Via Pulse Oximetry
timeFrame: 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"
measure: Vital Signs: Mean Level of Positive End Expiratory Pressure
timeFrame: 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"
measure: Vital Signs: Mean Level of Peak and Plateau Ventilator Pressures
timeFrame: 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"
measure: Vital Signs: Mean Oxygen Requirement (FiO2) Via Pulse Oximetry
timeFrame: 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"
measure: Mean Electrocardiogram (ECG) Parameters Including PR, QRS, QT, and QTcB, QTcF, RR Intervals
timeFrame: Day 2, pre-dose, Day 3, pre-dose, Day 3, 24 h and Follow-up (Day 7)
measure: Number of Participants With Any Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to Follow-up (Day 7)
Secondary outcomes:
measure: Mean Serum Interleukin-6 Levels
timeFrame: 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1
measure: Mean Serum CXCL8 (Interleuin-8) Levels
timeFrame: 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1
measure: Mean Serum C-Reactive Protein (CRP) Levels
timeFrame: 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1
measure: Markers of Endothelial Cell/Neutrophil Interaction: Mean Soluble Tumor Necrosis Factor Receptors-I
timeFrame: 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1
measure: Markers of Lung Epithelial Cell Injury: Mean Myeloperoxidase (MPO) Levels
timeFrame: 6, 12, 18, 24, 48, 72 and 96 h since first dose on Day 1
measure: Mean Area Under the Concentration-time Curve From Zero (Pre-dose) to 24 Hours (AUC0-24)
timeFrame: 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)
measure: Mean Average Concentration (Cavg) of SB-681323
timeFrame: 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)
measure: Maximum Observed Concentration (Cmax) of SB-681323
timeFrame: 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)
Other outcomes:
Locations:
city: Lexington
country: United States
facility: GSK Investigational Site
state: Kentucky
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Winston-Salem
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.