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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.
Full 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.
Enrollment
Sex
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Volunteers
Inclusion criteria
≥ 18 years
Suspected or proven bacterial infection
Receiving positive pressure ventilation through an endotracheal tube
Have ALI/ARDS, defined as having all of the following:
Provide signed informed consent
Exclusion criteria
Mechanically or chemically-induced ALI/ARDS (including burns, trauma, and near drowning)
End-stage lung disease
Decompensated congestive heart failure
Authorization to withdraw life support
Hemoglobin persistently <8.0 g/dL
Subjects who have any one of the following:
Subjects who have two or more of the following:
Subjects who have a history of one or more of the following:
Bleeding disorders within the past 6 weeks or vasculitis with diffused alveolar hemorrhage
Diagnosis of bleeding peptic ulcer disease within the previous 2 months
Congenital bleeding diatheses such as hemophilia
Treatment with anti-platelet, anti-coagulant agents, or non-steroidal anti-inflammatory drugs (NSAIDs)within 72 hours following infusion of study drug
Therapeutic heparin:
Prophylactic heparin:
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
Major trauma or trauma subjects at an increased risk of bleeding
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
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
Chronic renal failure, defined as a calculated glomerular filtration rate (GFR) ≤20 mL/min
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
History of organ transplant (including bone marrow)
Subjects with malignancy having a life expectancy <6 months
Known human immunodeficiency virus (HIV) positive with CD4+ T Cell count <200/uL
Women who are pregnant or nursing
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
Any prior treatment with a murine or chimeric antibody
Subjects who are moribund and where death is perceived to be imminent (within 72 hours after screening)
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
Primary purpose
Allocation
Interventional model
Masking
18 participants in 2 patient groups, including a placebo group
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Data sourced from clinicaltrials.gov
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