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.
Acute Lung Injury
Acute Respiratory Distress Syndrome
|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|
- 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.
|Study Start Date:||December 2004|
|Study Completion Date:||February 2008|
|Primary Completion Date:||July 2006 (Final data collection date for primary outcome measure)|
Anti-tissue factor antibody
Single intravenous dose of TNX-832 at 0.06, 0.08 or 0.10 mg/kg
Placebo Comparator: Drug Placebo
Single intravenous dose of saline control
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.
|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|
|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|
|Halifax, Nova Scotia, Canada, B3H 1V7|
|Study Director:||Hing Wong, PhD||Altor Bioscience|