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

NCT ID: NCT00879606

Last Updated: 2015-04-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 150 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-04-30
• Study Completion Date: 2013-01-31

Brief Summary

This is a prospective, randomized (1:1), double-blind, multi-center, Phase II clinical study to test the safety and efficacy of a recombinant chimeric anti-tissue factor antibody (ALT-836) versus placebo in patients with sepsis and acute lung injury/acute respiratory distress syndrome (ALI/ARDS). This study was divided into two parts and the first part of the study has been completed. In the first part of the study, sixty patients were randomized at a 1:1 ratio to receive one dose of the study drug or placebo. In the second part of the study, ninety patients will be randomized at a 1:1 ratio to receive a multi-dose treatment regimen of single doses every 72 hours up to a maximum of 4 doses of the study drug or placebo, provided there are no safety concerns.

Detailed Description

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.

Conditions

Sepsis; Acute Lung Injury; Acute Respiratory Distress Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

1

Participants will be randomized to receive ALT-836.

Group Type: EXPERIMENTAL

ALT-836

Intervention Type: DRUG

In the first part of this study, recombinant chimeric anti-tissue factor antibody ALT-836 was administered as a single dose (0.06 mg/Kg) via intravenous infusion over 15 minutes. In the second part of this study, up to four doses (0.06 mg/Kg) of ALT-836 will be administered via intravenous infusion over 15 minutes.

2

Patients will be randomized to receive placebo.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

In the first part of this study, a single dose of Placebo was administered via intravenous infusion over 15 minutes. In the second part of this study, up to four doses of Placebo will be administered via intravenous infusion over 15 minutes.

Interventions

ALT-836

In the first part of this study, recombinant chimeric anti-tissue factor antibody ALT-836 was administered as a single dose (0.06 mg/Kg) via intravenous infusion over 15 minutes. In the second part of this study, up to four doses (0.06 mg/Kg) of ALT-836 will be administered via intravenous infusion over 15 minutes.

Intervention Type: DRUG

Placebo

In the first part of this study, a single dose of Placebo was administered via intravenous infusion over 15 minutes. In the second part of this study, up to four doses of Placebo will be administered via intravenous infusion over 15 minutes.

Intervention Type: DRUG

Other Intervention Names

Formerly TNX-832; Sunol-cH36

Eligibility Criteria

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.

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.

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Altor BioScience

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hing C Wong, PhD

Role: STUDY_CHAIR

Altor BioScience

Locations

Los Angeles County and USC Medical Center

Los Angeles, California, United States

UC Davis Medical Center

Sacramento, California, United States

Stanford University

Stanford, California, United States

Yale University

New Haven, Connecticut, United States

Northwestern University

Chicago, Illinois, United States

West Suburban Hospital Medical Center

Oak Park, Illinois, United States

Illinois Lung and Critical Care Institute

Peoria, Illinois, United States

University of Iowa

Iowa City, Iowa, United States

Kentucky Lung Clinic

Hazard, Kentucky, United States

University of Louisville-Division of Pulmonary and Critical Care

Louisville, Kentucky, United States

Baystate Medical Center

Springfield, Massachusetts, United States

Saint Luke's Hospital

Kansas City, Missouri, United States

Saint Louis University

St Louis, Missouri, United States

Mercy Hospital St. Louis

St Louis, Missouri, United States

Mount Sinai Medical Center

New York, New York, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Carolinas Medical Center

Charlotte, North Carolina, United States

Piedmont Respiratory Research Foundation

Greensboro, North Carolina, United States

Wake Forest University

Winston-Salem, North Carolina, United States

University of Oklahoma

Oklahoma City, Oklahoma, United States

Countries

United States

References

Morris PE, Steingrub JS, Huang BY, Tang S, Liu PM, Rhode PR, Wong HC. A phase I study evaluating the pharmacokinetics, safety and tolerability of an antibody-based tissue factor antagonist in subjects with acute lung injury or acute respiratory distress syndrome. BMC Pulm Med. 2012 Feb 16;12:5. doi: 10.1186/1471-2466-12-5.

Reference Type: DERIVED

PMID: 22340260 (View on PubMed)

Related Links

http://www.altorbioscience.com

Altor Bioscience Corporation, Miramar, Florida, US

Other Identifiers

NHLBI/NIH-5R44HL082397-03

Identifier Type: -

Identifier Source: secondary_id

CA-ALT-836-01-08

Identifier Type: -

Identifier Source: org_study_id