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

Sponsor

Altor BioScience (Industry)

Overall Status

Completed

CT.gov ID

NCT01438853

Collaborator

Genentech, Inc. (Industry), Tanox (Industry)

Enrollment

Locations

Arms

Duration (Months)

2.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Sepsis Acute Lung Injury Acute Respiratory Distress Syndrome	Biological: TNX-832 Drug: Placebo	Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

18 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (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

Study Start Date :

Dec 1, 2004

Actual Primary Completion Date :

Jul 1, 2006

Actual Study Completion Date :

Feb 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
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

Arm

Intervention/Treatment

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

Outcome Measures

Primary Outcome Measures

Safety assessed by number of adverse events, and changes in vital signs, ECGs, laboratory, coagulation and pulmonary function parameters. [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.
Composite of pharmacokinetics [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy 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:

bilateral infiltrates consistent with pulmonary edema
Hypoxemia
no clinical evidence of left atrial hypertension

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:

platelet count <50,000/mm^3
prolonged prothrombin time (PT)
prolonged activated partial thromboplastin time (aPTT)
having significant potential for disseminated intravascular coagulation (DIC)

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

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)

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:
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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Miami	Miami	Florida	United States	33125
2	Beth Israel Deconess Medical Center	Boston	Massachusetts	United States	02215
3	Washington University	St. Louis	Missouri	United States	63130
4	Wake Forest University	Winston-Salem	North Carolina	United States	27157
5	Akron General Medical Center	Akron	Ohio	United States	44307
6	Baylor School of Medicine	Houston	Texas	United States	77030
7	Capital Health	Halifax	Nova Scotia	Canada	B3H 1V7