Acute Lung Injury, Acute Respiratory Distress Syndrome, Sepsis
Conditions
Keywords
Sepsis, Acute Lung Injury, Acute Respiratory Distress Syndrome, ALI/ARDS, Lung Disease
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.
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.
Interventions
BIOLOGICALTNX-832
Single intravenous dose of TNX-832 at 0.06, 0.08 or 0.10 mg/kg
DRUGPlacebo
Single intravenous dose of saline control
Sponsors
Genentech, Inc.
Tanox
Altor BioScience
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | Up to 4 weeks | 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. |
| Cmax | predose; 15 and 30 min; 1, 4, 6, 12 and 24 hrs; 2, 3, 4, 5, 6, and 7 days, 2, 3, 4 weeks | maximum observed concentration (Cmax) |
| AUCinf and AUClast | Up 163.3 hours | Area under the plasma concentration curve from time 0 extrapolated to infinite time (AUC0-inf). AUClast (area under the serum concentration-time curve from the time of dosing to the time of the last observed concentration). |
| Terminal t1/2 and Tmax | predose; 15 and 30 min; 1, 4, 6, 12 and 24 hrs; 2, 3, 4, 5, 6, and 7 days, 2, 3, 4 weeks | t1/2 (terminal elimination phase half life). Tmax (time to maximum serum concentration). |
| Vd and Vss | predose; 15 and 30 min; 1, 4, 6, 12 and 24 hrs; 2, 3, 4, 5, 6, and 7 days, 2, 3, 4 weeks | Volume of distribution (Vd) based on the terminal elimination phase, also referred to as VZ; in mL/kg. Volume of distribution at steady state (Vss), calculated as the Mean residence Time times Clearance; in mL/kg. |
| Cl | up to 1 week | Total body clearance, CL=Dose/AUC; in mL/hr/kg |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo TNX-832 | 3 |
| 0.06 MG/KG Dose TNX-832 | 5 |
| 0.1 MG/KG Dose TNX-832 | 5 |
| 0.08 MG/KG Dose TNX-832 | 5 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | 0.08 MG/KG Dose | 0.1 MG/KG Dose | 0.06 MG/KG Dose |
|---|---|---|---|---|---|
| Age, Continuous | 49.67 years STANDARD_DEVIATION 24.3 | 49.53 years STANDARD_DEVIATION 17.26 | 54.00 years STANDARD_DEVIATION 16.9 | 54.60 years STANDARD_DEVIATION 13.7 | 40.40 years STANDARD_DEVIATION 18.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 5 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 1 Participants | 10 Participants | 2 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Female | 2 Participants | 14 Participants | 3 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 2 Participants | 0 Participants | 1 Participants |
| Subjects with Acute Lung Injury/Acute Respiratory Distress Syndrome | 3 Participants | 18 Participants | 5 Participants | 5 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 5 | 0 / 5 | 1 / 5 |
| other Total, other adverse events | 3 / 3 | 4 / 5 | 5 / 5 | 4 / 5 |
| serious Total, serious adverse events | 0 / 3 | 1 / 5 | 2 / 5 | 2 / 5 |
Outcome results
Primary
AUCinf and AUClast
Area under the plasma concentration curve from time 0 extrapolated to infinite time (AUC0-inf). AUClast (area under the serum concentration-time curve from the time of dosing to the time of the last observed concentration).
Time frame: Up 163.3 hours
Population: 0 participants were analyzed in the placebo AUCinf. Two participants in the 0.06 mg/kg and 1participant in the 0.1 mg/kg cohort did not meet the criteria for reliable estimation of PK parameters and are not included in calculation of Cohort mean values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.06 MG/KG Dose | AUCinf and AUClast | AUCinf | 39031 mcg*hr/mL | Standard Deviation 24178 |
| 0.06 MG/KG Dose | AUCinf and AUClast | AUClast | 35868 mcg*hr/mL | Standard Deviation 22950 |
| 0.1 MG/KG Dose | AUCinf and AUClast | AUCinf | 59921 mcg*hr/mL | Standard Deviation 16629 |
| 0.1 MG/KG Dose | AUCinf and AUClast | AUClast | 53973 mcg*hr/mL | Standard Deviation 17289 |
| 0.08 MG/KG Dose | AUCinf and AUClast | AUCinf | 59851 mcg*hr/mL | Standard Deviation 20459 |
| 0.08 MG/KG Dose | AUCinf and AUClast | AUClast | 56860 mcg*hr/mL | Standard Deviation 21705 |
Primary
Cl
Total body clearance, CL=Dose/AUC; in mL/hr/kg
Time frame: up to 1 week
Population: 0 participants were analyzed in placebo Cl
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.06 MG/KG Dose | Cl | 1.9 mL/hr/kg | Standard Deviation 1 |
| 0.1 MG/KG Dose | Cl | 1.8 mL/hr/kg | Standard Deviation 0.4 |
| 0.08 MG/KG Dose | Cl | 1.5 mL/hr/kg | Standard Deviation 0.7 |
Primary
Cmax
maximum observed concentration (Cmax)
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
Population: O participants were analyzed for placebo pk
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.06 MG/KG Dose | Cmax | 1297 ng/mL | Standard Deviation 560 |
| 0.1 MG/KG Dose | Cmax | 1800 ng/mL | Standard Deviation 253 |
| 0.08 MG/KG Dose | Cmax | 1492 ng/mL | Standard Deviation 344 |
Primary
Number of Participants With Adverse Events
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.
Time frame: Up to 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Adverse Events | 3 Participants |
| 0.06 MG/KG Dose | Number of Participants With Adverse Events | 4 Participants |
| 0.1 MG/KG Dose | Number of Participants With Adverse Events | 5 Participants |
| 0.08 MG/KG Dose | Number of Participants With Adverse Events | 4 Participants |
Primary
Terminal t1/2 and Tmax
t1/2 (terminal elimination phase half life). Tmax (time to maximum serum concentration).
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
Population: 0 participants were analyzed in placebo Terminal t1/2
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.06 MG/KG Dose | Terminal t1/2 and Tmax | T1/2 | 18.5 hr | Standard Deviation 5.9 |
| 0.06 MG/KG Dose | Terminal t1/2 and Tmax | Tmax | 1.0 hr | Standard Deviation 0 |
| 0.1 MG/KG Dose | Terminal t1/2 and Tmax | T1/2 | 22.6 hr | Standard Deviation 6.2 |
| 0.1 MG/KG Dose | Terminal t1/2 and Tmax | Tmax | 0.9 hr | Standard Deviation 0.4 |
| 0.08 MG/KG Dose | Terminal t1/2 and Tmax | T1/2 | 22.6 hr | Standard Deviation 3.1 |
| 0.08 MG/KG Dose | Terminal t1/2 and Tmax | Tmax | 4.2 hr | Standard Deviation 0.6 |
Primary
Vd and Vss
Volume of distribution (Vd) based on the terminal elimination phase, also referred to as VZ; in mL/kg. Volume of distribution at steady state (Vss), calculated as the Mean residence Time times Clearance; in mL/kg.
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
Population: 0 participants were analyzed in placebo Vd and Vss
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.06 MG/KG Dose | Vd and Vss | Vd | 46.1 mL/kg | Standard Deviation 13.1 |
| 0.06 MG/KG Dose | Vd and Vss | Vss | 44.9 mL/kg | Standard Deviation 12.29 |
| 0.1 MG/KG Dose | Vd and Vss | Vd | 54.5 mL/kg | Standard Deviation 6.6 |
| 0.1 MG/KG Dose | Vd and Vss | Vss | 53.0 mL/kg | Standard Deviation 5.3 |
| 0.08 MG/KG Dose | Vd and Vss | Vd | 47.7 mL/kg | Standard Deviation 16 |
| 0.08 MG/KG Dose | Vd and Vss | Vss | 46.7 mL/kg | Standard Deviation 14.7 |