Clinical trial NCT01438853
Conditions: Sepsis Acute Lung Injury Acute Respiratory Distress Syndrome
Keywords: Sepsis Acute Lung Injury Acute Respiratory Distress Syndrome ALI/ARDS Lung Disease
Sponsor: Altor BioScience
Start date: 2004-12-01; Completion date: 2008-02-01
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: Anti-tissue factor antibody arm 2: Placebo control
Interventions: intervention 1: TNX-832 intervention 2: Placebo
Intervention descriptions: intervention 1: Single intravenous dose of TNX-832 at 0.06, 0.08 or 0.10 mg/kg intervention 2: Single intravenous dose of saline control

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL
The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-
832 (Sunol-cH36) in Subjects with Acute Lung Injury/Acute 
Respiratory Distress Syndrome 
TNX-832 
Active Ingredient: TNX-832 (Sunol c-H36)
Indication: Acute Lung Injury/Acute Respiratory Distress Syndrome
Study TNX-832.201
Phase I/IIa
Study Initiation Date: December 16, 2004 
Date of Early Termination: July 26, 2006 
Abbreviated Clinical Study Report 
Prepared for Genentech, Inc. 
 by XTrials Research Services 
265 Davidson Ave, Suite 202 
Somerset, NJ 08873 
Report Issue Date:    11 February, 2008 
Sponsor Signatory: 
Alex Bajamonde 
Director, DATA Group, Genentech, Inc. 
Medical Director: 
Sean Bohen, M.D., Genentech, Inc. 
This study was performed in compliance with good clinical practice (GCP), including the 
archiving of essential documents.
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CONFIDENTIAL 
 
  
 
February 11, 2008                                                                                           
5
2. Synopsis 
Sponsor Name: 
Study Drug: 
Active Ingredient: 
Genentech 
TNX-832 
TNX-832 (Sunol-cH36) 
Title:  The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-832 
(Sunol-cH36) in Subjects with Acute Lung Injury/Acute Respiratory Distress Syndrome 
Investigators/Study Centers: This study was conducted at 12 sites in the United States 
and 5 sites in Canada. 
Publications: None 
Study Period:  16 Dec 2004 to 30 July 2006
Phase of development:  I/IIa 
Objectives: The objectives of this study were: 
x To evaluate the safety and pharmacokinetics of six dose levels of TNX-832 
(0.06 mg/kg, 0.08 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, and 0.4 mg/kg) in 
subjects with suspected or proven bacteria-induced ALI/ARDS.
x To evaluate the pharmacodynamic effects of six dose levels of TNX-832 
(0.06 mg/kg, 0.08 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, and 0.4 mg/kg) in 
subjects with suspected or proven bacteria-induced ALI/ARDS.
Methodology:  This multi-center, randomized, placebo-controlled, single-blinded 
dose-escalation study was to evaluate TNX-832 in subjects with suspected or proven 
bacteria-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).  
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.  In November, 2005, a Data Safety Monitoring 
Board (DSMB) review of adverse events in the 0.1 mg/kg in led to an observation of 
probably-related hematuria in all subjects who received TNX-832 at 0.1 mg/kg.  This 
review required the studying of TNX-832 at a lower dose cohort than previously 
planned.  One additional cohort (0.08 mg/kg) of at least 6 subjects was planned.  
Additionally, the DSMB recommended administering study drug through a slow IV 
infusion (over 2 hours; 50 cc/hr). In September, 2006, upon a subsequent DSMB review 
of adverse events in the 0.08 mg/kg dose group, a decision was made to prematurely 
discontinue the study.
Subject Population:  Eligible subjects were 18 years of age or older with a suspected or 
proven bacterial infection.  Subjects were also required to: 1). Have a diagnosis of acute 
lung injury/acute respiratory distress syndrome ALI/ARDS; 2). be receiving positive 
pressure ventilation through an endotracheal tube;  and  3). provide signed informed 
consent, authorization in accordance with the Health Inisurance Portability 
Accountability Act of 1996 (HIPAA) and agree to comply with all protocol-specified 
procedures and evaluations.
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CONFIDENTIAL 
 
  
 
February 11, 2008                                                                                           
6
Sponsor Name: 
Study Drug: 
Active Ingredient: 
Genentech 
TNX-832 
TNX-832 (Sunol-cH36) 
Title:  The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-832 
(Sunol-cH36) in Subjects with Acute Lung Injury/Acute Respiratory Distress Syndrome 
Study Medication: 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.  The 
TNX-832 dose for each cohort dosed was:
x Cohort 1: 
0.06 mg/kg TNX-832 
x Cohort 2: 
0.1 mg/kg TNX-832 
x Cohort 3: 
0.08 mg/kg TNX-832 
The original planned dose in Cohort 3 was .2 mg/kg. This was lowered to 0.08 mg/kg 
following a recommendation by the DSMB upon a review of adverse events in Cohort 2.
Criteria for Evaluation:
Pharmacokinetics:  The following PK parameters were to be determined: Cmax
(maximum serum concentration), Tmax (time to maximum serum concentration), AUClast
(area under the serum concentration-time curve from the time of dosing to the time of 
the last observed concentration), AUCf (area under the serum concentration-time curve 
from the time of dosing extrapolated to infinity), CL (serum clearance), Vd (apparent 
volume of distribution at elimination phase), Vss (apparent volume of distribution at 
steady state), t1/2 (terminal elimination phase half life). 
Pharmacodynamics: Sample for the following inflammatory markers were collected but 
not analyzed: C-reactive protein [CRP], IL-6, IL-8, IL-1ȕ, and TNF-Į.
Safety: Safety assessments performed during this study included adverse events, clinical 
laboratory parameters (hematology, chemistry, coagulation, urinalysis, hematoccult), 
vital signs measurements (body temperature, heart rate, respiratory rate, blood pressure), 
physical examinations and electrocardiograms.  Additional assessments included arterial 
blood gases, ventilation assessments, chest radiograph, hospital indices, and 
immunogenicity. 
Statistical Methods: Serum concentration and pharmacokinetic parameters were to be 
summarized by and compared among dosing cohorts using descriptive statistics. 
Parametric and/or non-parametric statistical comparisons were to be done if suggested 
by the data, but were not performed.  Continuous data variables were summarized by 
sample size, mean and its standard error, median, standard deviation , minimum, and 
maximum values.  PD samples were not analyzed as the data were not anticipated to 
provide any meaningful information about the action of the study drug.  Safety 
evaluations were based on the incidence, intensity and type of AEs and clinically 
significant changes in the subject’s physical examination findings, vital signs, and 
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CONFIDENTIAL 
 
  
 
February 11, 2008                                                                                           
7
Sponsor Name: 
Study Drug: 
Active Ingredient: 
Genentech 
TNX-832 
TNX-832 (Sunol-cH36) 
Title:  The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-832 
(Sunol-cH36) in Subjects with Acute Lung Injury/Acute Respiratory Distress Syndrome 
clinical laboratory results. Safety variables were tabulated and presented for all subjects 
who received TNX-832 or placebo. Subjects who received TNX-832 were grouped by 
cohort.  Subjects who received placebo were treated as one group. 
Summary: 
Number of Subjects: Eighteen subjects were assigned to study treatment.  Two subjects 
were withdrawn from the study following administration of study drug.  Subject 10-005 
died during the study.  The death occurred after removal of respiratory support for acute 
hypoxia; the death was determined by both the Investigator and the Sponsor to be not 
related to study drug administration.  Subject 08-002 withdrew consent 48 days after 
administration of 0.06 mg/kg TNX-832. 
Demographics:  Demographics and baseline characteristics are summarized in the table 
below.
 
Placebo 
N=3
0.06 mg/kg 
TNX-832
N=5
0.1 mg/kg 
TNX-832
N=5
0.08 mg/kg 
TNX-832
N=5
Age, [Mean (SD)] 
49.67 (24.3) 
40.40 (18.2) 
54.60 (13.7) 
54.00 (16.9) 
Gender, [N (%)] 
 
 
 
 
-Male 
1 (33.3) 
1 (20.0) 
0 (0.0) 
2 (40.0) 
-Female 
2 (66.7) 
4 (80.0) 
5 (100.0) 
3 (60.0) 
Race, [N (%)] 
 
 
 
 
-Caucasian 
1 (33.3) 
4 (80.0) 
3 (60.0) 
2 (40.0) 
-Black 
1 (33.3) 
0 (0) 
2 (40.0) 
2 (40.0) 
-Hispanic 
1 (33.3) 
1 (20.0) 
0 (0.0) 
1 (20.0) 
Pharmacokinetic:  Pharmacokinetic results are provided as an appendix to this report. 
Pharmacodynamic:  Pharmacodynamic samples were not analyzed. 
Safety Results:  There was one death during the study.  Subject 10005 died after 
removal of respiratory support for acute hypoxia.  The subject died 10 days after 
administration of 0.08 mg/kg TNX-832.  The death was considered unrelated to study 
medication by the Investigator.  Four subjects experienced non-fatal SAEs during the 
study, including bilateral pulmonary embolism, hypoxic respiratory failure secondary to 
hospital-acquired pneumonia, worsening acute renal failure, and worsening anemia and 
empyema.  Of these SAEs, the hypoxic respiratory failure secondary to hospital-
acquired pneumonia in one subject was considered possibly related to study medication. 
The worsening anemia and empyema in one subject were considered possibly related to 
study medication, with empyema considered unrelated at the time of resolution.  Of the 
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CONFIDENTIAL 
 
  
 
February 11, 2008                                                                                           
8
Sponsor Name: 
Study Drug: 
Active Ingredient: 
Genentech 
TNX-832 
TNX-832 (Sunol-cH36) 
Title:  The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-832 
(Sunol-cH36) in Subjects with Acute Lung Injury/Acute Respiratory Distress Syndrome 
18 subjects enrolled in this study, 16 subjects reported a total of 87 AEs during the 
study.  Of the 87 treatment-emergent AEs in this study, 48 (55%) AEs were moderate in 
intensity, 35 (40%) AEs were mild in intensity, and 4 (5%) AEs were severe in intensity.
Of the 87 treatment-emergent AEs, 16 AEs were considered by the Investigator to be 
related to study medication.  Two AEs were considered related to placebo 
administration; 3 AEs were considered related to 0.06 mg/kg TNX-832 administration; 5 
AEs were considered related to 0.1 mg/kg TNX-832 administration; 6 AEs were 
considered related to 0.08 mg/kg TNX-832 administration.  A summary of treatment-
emergent AEs is presented in the table below. 
Placebo 
0.06 mg/kg 
TNX-832
0.1 mg/kg 
TNX-832
0.08 mg/kg 
TNX-832
Total
Dosed 
3 
5 
5 
5 
18 
Number of AEs 
20 
18 
20 
29 
87 
Subjects with AEs 
3 
4 
5 
4 
16 
Subjects with SAEs 
0 
1 
2 
2 
5 
Subjects with severe 
AEs
2 
0 
1 
0 
3 
Subjects who 
discontinued due to 
AEs
0 
0 
0 
1 
1 
Seven subjects had 16 laboratory values that were reported as AEs.  None of these 
laboratory values reported as Aes were assessed as related to study medication by the 
Investigator, with the exception of decreased hemoglobin which resolved one day after 
onset with red blood cell transfusion.  There were no clinically significant trends in vital 
signs during the study.  Three subjects had changes in vital signs that were reported as 
AEs during the study.  None of these changes in vital signs reported as Aes were 
assessed as related to study medication by the Investigator.  Four subjects had ECG 
findings reported as Aes, none of which were assessed as related to study medication by 
the Investigator. There were no clinically significant trends in any ventilation evaluation 
during the study.  Two subjects had clinically significant findings on chest x-ray 
following administration of study medication.  One subject experienced pulmonary 
oedema, which resolved 22 days after onset.  One subject experienced empyema and 
right pleural effusion, which resolved 8 days and 2 days after onset, respectively. 
Conclusions:
This study was prematurely discontinued due to the high incidence of hematuria (nine 
occurrences) during the study.  All instances of hematuria were experienced by patients 
who received study drug. In this study, the most frequent AEs were hematuria (n=9) and 
anemia (n=6).  At the highest dose level of TNX-832 administered during this study (0.1 
mg/kg), all five subjects dosed had AEs of hematuria.  Hematuria was considered 
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CONFIDENTIAL 
 
  
 
February 11, 2008                                                                                           
9
Sponsor Name: 
Study Drug: 
Active Ingredient: 
Genentech 
TNX-832 
TNX-832 (Sunol-cH36) 
Title:  The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-832 
(Sunol-cH36) in Subjects with Acute Lung Injury/Acute Respiratory Distress Syndrome 
related to study medication by the Investigator in four of the five subjects.  After the 
dose level was reduced to 0.08 mg/kg in Cohort 3, 2 subjects experienced hematuria (1 
related to study medication).  Based upon the bleeding related AEs of hematuria, the 
DSMB decided to discontinue the study. In conclusion, the study was prematurely 
discontinued due to the high incidence of treatment-related hematuria reported during 
the study, and the continued observation of hematuria in spite of the lowered dose in the 
third cohort . 
x
Although there was one death during the study, the death was considered unrelated 
to study medication and was not the cause for discontinuation of the study. 
Date of Report: 11 February 2008 
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