Anti-TF Antibody (ALT-836) to Treat Septic Patients With Acute Lung Injury or Acute Respiratory Distress Syndrome

Tissue factor (TF)-dependent procoagulant activity and associated inflammatory processes may
play a role in the severity and progression of ALI/ARDS. Recent studies demonstrated that
TF levels were elevated in plasma and pulmonary edema fluid of ARDS/ALI patients compared to
control patients with hydrostatic pulmonary edema. These higher plasma TF levels were
correlated with increased mortality, fewer ventilation-free days, the presence of
disseminated intravascular coagulation and the presence of sepsis in patients with ALI/ARDS,
suggesting that systemic activation of coagulation may be clinically important in ALI/ARDS.
Moreover, the pulmonary TF levels in patients with ALI/ARDS were found to range between 0.5
and 2 nM, approximately 100-fold higher than simultaneous plasma levels, suggesting an
intra-alveolar source of TF. Thus, anti-TF antibody blockage of TF activity may therefore
provide an effective therapeutic mechanism for the treatment of inflammatory disorders such
as ALI and ARDS. This study will test the hypothesis that administration of anti-TF
antibody (ALT-836) to septic patients with ALI/ARDS will improve the clinical outcome by
shortening the duration of mechanical ventilation for these patients.

INCLUSION CRITERIA:

1. Suspected or proven infection

2. Hypoxemia: PaO2/FiO2is ≤300 mm Hg

3. Bilateral infiltrates consistent with pulmonary edema

4. Positive-pressure mechanical ventilation through an endotracheal tube

5. No clinical evidence of left atrial hypertension to explain bilateral infiltrates

6. Presence of at least three of the four SIRS criteria. If only two criteria are
evidenced, one must be temperature or WBC

Criteria 2 and 3 must occur within a 24-hour interval. The 48-hour enrollment time window
begins when criteria 2, 3, and 4 are met.

EXCLUSION CRITERIA:

1. <18 years

2. Inability to obtain consent

3. Patient, surrogate, or physician not committed to full support

4. Moribund state in which death was perceived to be imminent

5. Morbid obesity

6. Malignancy or other irreversible disease or condition for which 6-month mortality is
estimated to be >50%

7. Known HIV positive with known end stage processes

8. Prior cardiac arrest requiring CPR without fully demonstrated neurological recovery;
or New York Heart Association Class IV

9. Pregnant or nursing

10. ALI/ARDS induced by mechanical or chemical injury directly to the lung (including
burns, trauma, and near drowning)

11. >48 hours since all inclusion criteria are met

12. Neuromuscular disease that impairs ability to ventilate without assistance

13. Severe chronic respiratory disease, severe pulmonary hypertension, or ventilator
dependency

14. Chest wall deformity resulting in severe exercise restriction, secondary
polycythemia, or respirator dependent

15. History of organ transplant (including bone marrow)

16. Severe chronic liver disease, as determined by a Child-Pugh Score >10

17. Hemoglobin persistently < 7.0 g/dL

18. Platelet count <50,000/mm3

19. Prolonged INR >3

20. Bleeding disorders unless corrective surgery has been performed

21. Active internal bleeding

22. Major surgery within 24 hours before study drug infusion, or evidence of active
bleeding postoperatively, or plan for any major surgery within 3 days after study
drug infusion.

23. Diffuse alveolar hemorrhage from vasculitis

24. Known bleeding diathesis

25. Presence of an epidural catheter or lumbar puncture within 48 hours before study drug
infusion or anticipation of receiving an epidural catheter or a lumbar puncture
within 48 hours after study drug infusion

26. Stroke within 3 months of study entry

27. Trauma with an increased risk of life-threatening bleeding

28. A history of severe head trauma that required hospitalization, or intracranial
surgery within two months of study entry

29. Any history of intracerebral arteriovenous malformation, cerebral aneurysm, or
central nervous system mass lesion

30. Uses of certain medications or treatment regimens such as chemotherapy,
unfractionated heparin, low-molecular-weight heparin, Warfarin, antithrombin III,
acetylsalicylic acid, glycoprotein IIb/IIIa antagonists, thrombolytic therapy, and
activated Protein C are restricted.

31. Participation in another experimental medication study within 30 days of study entry.