Last updated: 11/07/2018 03:35:46

SB-681323 IV for subjects at risk of acute lung injury or ARDS

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GSK study ID
111592
See study documents
Clinicaltrials.gov ID
NCT00996840
See results summary
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Completed
Completed
Overview
Eligibility
Locations
Study documents
Results summary
Plain language summaries
Additional information

Trial overview

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).
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Allocation:
Randomized
Primary outcomes:

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)"

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)"

Mean hematology parameters- Mean Corpuscle Hemoglobin

Timeframe: “Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"

Hematology parameters-Mean Corpuscle Volume

Timeframe: “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

Timeframe: “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

Timeframe: “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

Timeframe: “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

Timeframe: “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)

Timeframe: “Day 2, pre-dose", "Day 3, pre-dose", "Day 3, 24 h" and "Follow up (Day 7)"

Mean clinical chemistry parameters-estradiol

Timeframe: Day 1 (pre-dose) and Day 3 (24 h)

Mean clinical chemistry parameters-Blood pH at screening

Timeframe: Screening

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)"

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)"

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)"

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”

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”

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”

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”

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)

Number of participants with any adverse events (AE) and serious adverse events (SAE)

Timeframe: Up to Follow-up (Day 7)

Secondary outcomes:

Mean Serum interleukin-6 levels

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

Mean Serum CXCL8 (Interleuin-8) levels

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

Mean Serum C-Reactive Protein (CRP) levels

Timeframe: 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

Timeframe: 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

Timeframe: 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)

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)

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)

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)

Interventions:
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
Enrollment:
77
Observational study model:
Not applicable
Primary completion date:
2013-09-02
Time perspective:
Not applicable
Clinical publications:
William Powley, Aili Lazaar, Dave Lipson, Shuying Yang, Phillip Chang, Jason Christie, Scott Gunn, May Addison, and Steven Vaslef. Safety of the p38 inhibitor dilmapimod (SB-681323) in trauma patients at risk for developing ARDS. Crit Care Med. 2015;43(9):1859-1869
Medical condition
Lung Injury, Acute
Product
dilmapimod
Collaborators
GSK
Study date(s)
October 2009 to February 2013
Type
Interventional
Phase
2

Participation criteria

Sex
Female & Male
Age
18 - 80 years
Accepts healthy volunteers
No
  • A subject will be eligible for inclusion in this study only if all of the following criteria
  • apply:
  • A subject will not be eligible for inclusion in this study if any of the following criteria
  • apply:
Inclusion and exclusion 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.

Trial location(s)

Location
Status
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Location
GSK Investigational Site
Philadelphia, Pennsylvania, United States, 19104
Status
Study Complete
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Location
GSK Investigational Site
Lexington, Kentucky, United States, 40536-0293
Status
Study Complete
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Location
GSK Investigational Site
Winston-Salem, North Carolina, United States, 27157
Status
Study Complete
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Location
GSK Investigational Site
Durham, North Carolina, United States, 27710
Status
Study Complete
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Location
GSK Investigational Site
Nashville, Tennessee, United States, 37232-7110
Status
Study Complete
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Location
GSK Investigational Site
Pittsburgh, Pennsylvania, United States, 15213
Status
Study Complete
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Study documents

Clinical study report
Available language(s): English
Download document(s)
Scientific result summary
Available language(s): English
Download document(s)

If you wish to request for full study report, please contact - [email protected]

Results overview

Results posted on ClinicalTrials.gov

Recruitment status
Completed
Actual primary completion date
2013-09-02
Actual study completion date
2013-09-02

Plain language summaries

Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.

Additional information about the trial

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