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

NCT00996840 | Completed Phase 2 Results DMC

• 1 other identifier: 111592
• Study Type: interventional
• Target: 77
• Locations: 1 country
• Sites: 6

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.

Conditions

Lung Injury, Acute

Keywords

dilmapimod; p38; SB-681323; Acute Lung Injury (ALI); Acute Respiratory Distress Syndrome (ARDS)

Outcome Measures

Primary Outcomes (20)

• 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 Outcomes (8)

• Mean Serum Interleukin-6 Levels

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

• Mean Serum CXCL8 (Interleuin-8) Levels

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

• Mean Serum C-Reactive Protein (CRP) Levels

  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

  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

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

Study Arms (5)

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

Interventions

SB-681323 Intravenous 3mg DRUG

3 mg SB-681323 Intravenous administration infused over 4 hours

Cohort 1 - SB-681323 Intravenous 3mg

SB-681323 Intravenous 7.5 mg DRUG

7.5 mg SB-681323 Intravenous administration infused over 24 hours

Cohort 2 - SB-681323 Intravenous 7.5 mg

SB-681323 Intravenous 7.5mg DRUG

7.5 mg SB-681323 Intravenous administration infused over 4 hours

Cohort 3 - SB-681323 Intravenous 7.5mg

SB-681323 Intravenous 10mg DRUG

10 mg SB-681323 Intravenous administration infused over 24 hours

Cohort 4 - SB-681323 Intravenous 10mg

Placebo OTHER

Placebo to match intervention

Combined Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (6)

GSK Investigational Site

Lexington, Kentucky, 40536-0293, United States

Location

GSK Investigational Site

Durham, North Carolina, 27710, United States

Location

GSK Investigational Site

Winston-Salem, North Carolina, 27157, United States

Location

GSK Investigational Site

Philadelphia, Pennsylvania, 19104, United States

Location

GSK Investigational Site

Pittsburgh, Pennsylvania, 15213, United States

Location

GSK Investigational Site

Nashville, Tennessee, 37232-7110, United States

Location

Related Publications (1)

• 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.

  PMID: 26102252 DERIVED

Related Links

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

MeSH Terms

Conditions

Acute Lung Injury; Respiratory Distress Syndrome

Condition Hierarchy (Ancestors)

Lung Injury; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 15, 2009
• First Posted: October 16, 2009
• Study Start: October 16, 2009
• Primary Completion: February 9, 2013
• Study Completion: February 9, 2013
• Last Updated: October 18, 2017
• Results First Posted: October 18, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will share

Locations

US (6)