- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01438853
Effects of TNX-832 (Sunol cH36) in Subjects With Acute Lung Injury/Acute Respiratory Distress Syndrome
The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-832 (Sunol cH36) in Subjects With Acute Lung Injury/Acute Respiratory Distress Syndrome
Study Overview
Status
Intervention / Treatment
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
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Nova Scotia
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Halifax, Nova Scotia, Canada, B3H 1V7
- Capital Health
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Florida
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Miami, Florida, United States, 33125
- University of Miami
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Massachusetts
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Boston, Massachusetts, United States, 02215
- Beth Israel Deconess Medical Center
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Missouri
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St. Louis, Missouri, United States, 63130
- Washington University
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North Carolina
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Winston-Salem, North Carolina, United States, 27157
- Wake Forest University
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Ohio
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Akron, Ohio, United States, 44307
- Akron General Medical Center
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Texas
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Houston, Texas, United States, 77030
- Baylor School of Medicine
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
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 |
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Experimental: TNX-832
Anti-tissue factor antibody
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Single intravenous dose of TNX-832 at 0.06, 0.08 or 0.10 mg/kg
Other Names:
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Placebo Comparator: Drug Placebo
Placebo control
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Single intravenous dose of saline control
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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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
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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.
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Throughout the 4 weeks following treatment
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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
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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.
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predose; 15 and 30 min; 1, 4, 6, 12 and 24 hrs; 2, 3, 4, 5, 6, and 7 days, 2, 3, 4 weeks
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Collaborators and Investigators
Sponsor
Investigators
- Study Director: Hing Wong, PhD, Altor BioScience
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- TNX-832.201
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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