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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00996840
First received: October 15, 2009
Last updated: April 11, 2013
Last verified: April 2013
  Purpose

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.


Condition Intervention Phase
Lung Injury, Acute
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
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
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).

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Safety and tolerability of intravenous SB-681323 repeated for three days in patients at risk for developing ALI or ARDS [ Time Frame: Days 1-3 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Evaluation of the pharmacokinetics of intravenous SB-681323, infused over 4 or 24 hours for three days in patients at risk for developing ALI or ARDS [ Time Frame: Days 1-3 ] [ Designated as safety issue: No ]
  • Evaluate the effects of intravenous SB-681323, infused over 4 or 24 hours for three days, compared with placebo in this population on biomarkers. [ Time Frame: Days 1-3 ] [ Designated as safety issue: No ]
  • Evaluate the effects of intravenous SB-681323, infused over 4 or 24 hours for three days, compared with placebo in this population on acute kidney injury scales. [ Time Frame: Days 1-3 ] [ Designated as safety issue: No ]

Enrollment: 90
Study Start Date: October 2009
Study Completion Date: February 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1 - SB-681323 Intravenous 3mg
3mg SB-681323 Intravenous administration, infused over 4 hours
Drug: SB-681323 Intravenous 3mg
3 mg SB-681323 Intravenous administration infused over 4 hours
Other: Placebo
Placebo to match intervention
Experimental: Cohort 2 - SB-681323 Intravenous 7.5 mg
7.5 mg SB-681323 Intravenous administration infused over 24 hours
Drug: SB-681323 Intravenous 7.5 mg
7.5 mg SB-681323 Intravenous administration infused over 24 hours
Other: Placebo
Placebo to match intervention
Experimental: Cohort 3 - SB-681323 Intravenous 7.5mg
7.5 mg SB-681323 Intravenous administration infused over 4 hours
Drug: SB-681323 Intravenous 7.5mg
7.5 mg SB-681323 Intravenous administration infused over 4 hours
Other: Placebo
Placebo to match intervention
Experimental: Cohort 4 - SB-681323 Intravenous 10mg
10 mg SB-681323 Intravenous administration infused over 24 hours
Drug: SB-681323 Intravenous 10mg
10 mg SB-681323 Intravenous administration infused over 24 hours
Other: Placebo
Placebo to match intervention

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

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00996840

Locations
United States, Kentucky
GSK Investigational Site
Lexington, Kentucky, United States, 40536-0293
United States, North Carolina
GSK Investigational Site
Durham, North Carolina, United States, 27710
GSK Investigational Site
Winston-Salem, North Carolina, United States, 27157
United States, Pennsylvania
GSK Investigational Site
Philadelphia, Pennsylvania, United States, 19104
GSK Investigational Site
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
GSK Investigational Site
Nashville, Tennessee, United States, 37232-7110
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00996840     History of Changes
Other Study ID Numbers: 111592
Study First Received: October 15, 2009
Last Updated: April 11, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
dilmapimod
p38
SB-681323
Acute Lung Injury (ALI)
Acute Respiratory Distress Syndrome (ARDS)

Additional relevant MeSH terms:
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Lung Injury
Wounds and Injuries
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Thoracic Injuries

ClinicalTrials.gov processed this record on July 29, 2014