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

This study has been completed.
Sponsor:
Collaborators:
Genentech
Tanox
Information provided by (Responsible Party):
Altor Bioscience Corporation
ClinicalTrials.gov Identifier:
NCT01438853
First received: September 20, 2011
Last updated: September 21, 2011
Last verified: September 2011
  Purpose

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.


Condition Intervention Phase
Sepsis
Acute Lung Injury
Acute Respiratory Distress Syndrome
Biological: TNX-832
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Investigator)
Primary Purpose: Treatment
Official Title: The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-832 (Sunol cH36) in Subjects With Acute Lung Injury/Acute Respiratory Distress Syndrome

Resource links provided by NLM:


Further study details as provided by Altor Bioscience Corporation:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.


Enrollment: 18
Study Start Date: December 2004
Study Completion Date: February 2008
Primary Completion Date: July 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TNX-832
Anti-tissue factor antibody
Biological: TNX-832
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
Drug: Placebo
Single intravenous dose of saline control

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01438853

Locations
United States, Florida
University of Miami
Miami, Florida, United States, 33125
United States, Massachusetts
Beth Israel Deconess Medical Center
Boston, Massachusetts, United States, 02215
United States, Missouri
Washington University
St. Louis, Missouri, United States, 63130
United States, North Carolina
Wake Forest University
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
Akron General Medical Center
Akron, Ohio, United States, 44307
United States, Texas
Baylor School of Medicine
Houston, Texas, United States, 77030
Canada, Nova Scotia
Capital Health
Halifax, Nova Scotia, Canada, B3H 1V7
Sponsors and Collaborators
Altor Bioscience Corporation
Genentech
Tanox
Investigators
Study Director: Hing Wong, PhD Altor Bioscience
  More Information

No publications provided by Altor Bioscience Corporation

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Altor Bioscience Corporation
ClinicalTrials.gov Identifier: NCT01438853     History of Changes
Other Study ID Numbers: TNX-832.201
Study First Received: September 20, 2011
Last Updated: September 21, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Altor Bioscience Corporation:
Sepsis
Acute Lung Injury
Acute Respiratory Distress Syndrome
ALI/ARDS
Lung Disease

Additional relevant MeSH terms:
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Sepsis
Lung Injury
Wounds and Injuries
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Thoracic Injuries

ClinicalTrials.gov processed this record on April 21, 2014