Effects of TNX-832 (Sunol cH36) in Subjects With Acute Lung Injury/Acute Respiratory Distress Syndrome

September 21, 2011 updated by: Altor BioScience

The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-832 (Sunol cH36) in Subjects With Acute Lung Injury/Acute Respiratory Distress Syndrome

This Phase I/IIa, multi-center, randomized, placebo-controlled, single-blinded dose-escalation study evaluated TNX-832 (also referred to as ALT-836 and Sunol cH36) in subjects with suspected or proven bacteria-induced ALI/ARDS. Up to five cohorts of at least six subjects each were originally planned. Subjects were to be randomized in a 5:1 ratio to receive TNX-832 or placebo,respectively, administered as a single bolus infusion over 15 minutes. Three cohorts of subjects were enrolled to the study and safety and pharmacokinetics of the study treatment were evaluated.

Study Overview

Detailed Description

Tissue factor (TF) is a transmembrane glycoprotein that acts as the principal initiator of the extrinsic coagulation pathway. TF is a key mediator between the immune system and coagulation and is the principal activator of coagulation. The TF-FVIIa complex activates FX and FIX, resulting in the cleavage of prothrombin to thrombin. Normally, localized activation of the coagulation cascade associated with inflammatory responses plays a role in controlling the spread of infectious agents; however, aberrant TF expression often leads to serious thrombotic disorders. TF-dependent thrombosis has been associated with many diseases including septic shock, coronary artery disease (CAD), cancer, and many inflammatory and autoimmune disorders such as lupus, rheumatoid arthritis, psoriasis, and inflammatory bowel disease.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are forms of acute respiratory failure characterized by diffuse pulmonary infiltrates, pulmonary hypertension, refractory hypoxemia, loss of pulmonary compliance and normal hydrostatic pressures. ALI and ARDS commonly occur in patients with acute catastrophic events such as sepsis, trauma and severe pulmonary infections. The incidence of ALI and ARDS is extremely high in patients with sepsis. By blocking the initiating events of extrinsic coagulation activation, their effects on pro-inflammatory events in the lungs and disordered fibrin deposition may be corrected and the evolution of severe structural and functional injury may be averted during ALI/ARDS. TNX-832 (formerly known as Sunol-cH36), directed against human TF, which can block the pathological complications of TF-dependent thrombus formation. The blockage by TNX-832 of initiating events in the extrinsic coagulation pathway may attenuate the effects on pro-inflammatory events in ALI/ARDS patients, thereby averting or decreasing disordered fibrin deposition and averting the evolution of severe structural and functional injury.

Study Type

Interventional

Enrollment (Actual)

18

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Nova Scotia
      • Halifax, Nova Scotia, Canada, B3H 1V7
        • Capital Health
    • Florida
      • Miami, Florida, United States, 33125
        • University of Miami
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Beth Israel Deconess Medical Center
    • Missouri
      • St. Louis, Missouri, United States, 63130
        • Washington University
    • North Carolina
      • Winston-Salem, North Carolina, United States, 27157
        • Wake Forest University
    • Ohio
      • Akron, Ohio, United States, 44307
        • Akron General Medical Center
    • Texas
      • Houston, Texas, United States, 77030
        • Baylor School of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. ≥ 18 years
  2. Suspected or proven bacterial infection
  3. Receiving positive pressure ventilation through an endotracheal tube
  4. Have ALI/ARDS, defined as having all of the following:

    • bilateral infiltrates consistent with pulmonary edema
    • Hypoxemia
    • no clinical evidence of left atrial hypertension
  5. Provide signed informed consent

Exclusion Criteria:

  1. Mechanically or chemically-induced ALI/ARDS (including burns, trauma, and near drowning)
  2. End-stage lung disease
  3. Decompensated congestive heart failure
  4. Authorization to withdraw life support
  5. Hemoglobin persistently <8.0 g/dL
  6. Subjects who have any one of the following:

    • platelet count <50,000/mm^3
    • prolonged prothrombin time (PT)
    • prolonged activated partial thromboplastin time (aPTT)
    • having significant potential for disseminated intravascular coagulation (DIC)
  7. Subjects who have two or more of the following:

    • prolonged aPTT
    • fibrinogen level below the lower limit of normal
    • presence of petechiae, ecchymoses, or other evidence of coagulopathy
  8. Subjects who have a history of one or more of the following:

    • hematuria (microscopic or gross)
    • urinary tract neoplasia
    • nephrolithiasis
    • glomerulonephritis
    • active urinary tract infection (UTI)
  9. Bleeding disorders within the past 6 weeks or vasculitis with diffused alveolar hemorrhage
  10. Diagnosis of bleeding peptic ulcer disease within the previous 2 months
  11. Congenital bleeding diatheses such as hemophilia
  12. Treatment with anti-platelet, anti-coagulant agents, or non-steroidal anti-inflammatory drugs (NSAIDs)within 72 hours following infusion of study drug

    • Therapeutic heparin:

      • Unfractionated heparin within eight hours prior to study drug infusion
      • Low molecular weight heparins within the 12 hours prior to study drug infusion
    • Prophylactic heparin:

      • Unfractionated heparin >15,000 units/day
      • Low molecular weight heparins
    • Warfarin if used within 7 days prior to study drug infusion
    • Thrombolytic treatment within 3 days prior to study drug infusion
    • 8Glycoprotein IIb/IIIa antagonists within 7 days prior to study drug infusion
    • Aspirin or any aspirin containing compound within 3 days prior to study drug infusion
    • APC infusion within 72 hours prior to study drug infusion
  13. Major trauma or trauma subjects at an increased risk of bleeding
  14. History of severe head trauma that required hospitalization, intracranial surgery, or stroke or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or central nervous system mass lesion with an epidural catheter or who anticipate receiving an epidural catheter during study drug infusion
  15. Major surgery within the previous 3 days, any postoperative subject with evidence of active bleeding, or any subject with planned or anticipated surgery within 72 hours after study drug infusion. History of abnormal bleeding during surgical procedures
  16. Chronic renal failure, defined as a calculated glomerular filtration rate (GFR) ≤20 mL/min
  17. Subjects with baseline aspartate transaminase (AST) or alanine transaminase (ALT) level >5 times the upper limit of normal. Subjects with known esophageal varices, chronic jaundice, biopsy proven cirrhosis, or chronic ascites
  18. History of organ transplant (including bone marrow)
  19. Subjects with malignancy having a life expectancy <6 months
  20. Known human immunodeficiency virus (HIV) positive with CD4+ T Cell count <200/uL
  21. Women who are pregnant or nursing
  22. Participation in another clinical research study within 30 days before administration of study drug, with the exception of participation in studies involving noninvasive monitoring medical devices
  23. Any prior treatment with a murine or chimeric antibody
  24. Subjects who are moribund and where death is perceived to be imminent (within 72 hours after screening)
  25. Subjects who have persistent hypotension not responding to fluid or vasopressor administration; subjects who require more than two vasopressors 26. Any medical condition which in the opinion of the investigator would interfere with optimal participation in the study or that would produce a significant risk to a subject

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: TNX-832
Anti-tissue factor antibody
Single intravenous dose of TNX-832 at 0.06, 0.08 or 0.10 mg/kg
Other Names:
  • ALT-836
  • Sunol cH36
Placebo Comparator: Drug Placebo
Placebo control
Single intravenous dose of saline control

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety assessed by number of adverse events, and changes in vital signs, ECGs, laboratory, coagulation and pulmonary function parameters.
Time Frame: Throughout the 4 weeks following treatment
To evaluate the safety of escalating dose levels of TNX-832 in subjects with suspected or proven bacteria-induced ALI/ARDS. Safety was assessed by number of treatment emergent adverse events, and changes in vital signs, ECGs, laboratory, coagulation and pulmonary function parameters from baseline. Immunogenicity (serum anti-TNX-832 antibody response) was evalutated.
Throughout the 4 weeks following treatment
Composite of pharmacokinetics
Time Frame: predose; 15 and 30 min; 1, 4, 6, 12 and 24 hrs; 2, 3, 4, 5, 6, and 7 days, 2, 3, 4 weeks
To evaluate the pharmacokinetics of escalating dose levels of TNX-832 in subjects with suspected or proven bacteria-induced ALI/ARDS. Pharmacokinetic parameters assessed are terminal half life, maximum serum concentration, volume of distribution, total body clearance, area under the drug concentration versus time curve extrapolated to infinity.
predose; 15 and 30 min; 1, 4, 6, 12 and 24 hrs; 2, 3, 4, 5, 6, and 7 days, 2, 3, 4 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Investigators

  • Study Director: Hing Wong, PhD, Altor BioScience

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2004

Primary Completion (Actual)

July 1, 2006

Study Completion (Actual)

February 1, 2008

Study Registration Dates

First Submitted

September 20, 2011

First Submitted That Met QC Criteria

September 21, 2011

First Posted (Estimate)

September 22, 2011

Study Record Updates

Last Update Posted (Estimate)

September 22, 2011

Last Update Submitted That Met QC Criteria

September 21, 2011

Last Verified

September 1, 2011

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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