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

Sepsis Clinical Trial

Official title:

Efficacy and Safety Evaluation of ALT-836 in Patients With Sepsis and Acute Lung Injury/Acute Respiratory Distress Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00879606
• Other study ID #: CA-ALT-836-01-08
• Secondary ID: NHLBI/NIH-5R44HL
• Status: Completed
• Phase: Phase 2
• First received: April 8, 2009
• Last updated: March 20, 2015
• Start date: April 2009
• Est. completion date: January 2013

Study information

• Verified date: March 2015
• Source: Altor Bioscience Corporation
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 150
• Est. completion date: January 2013
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome
• Lung Injury
• Respiratory Distress Syndrome, Adult
• Respiratory Distress Syndrome, Newborn
• Sepsis
• Syndrome

Intervention

Drug:
• 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.
• 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.

Locations

Country	Name	City	State
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Piedmont Respiratory Research Foundation	Greensboro	North Carolina
United States	Kentucky Lung Clinic	Hazard	Kentucky
United States	University of Iowa	Iowa City	Iowa
United States	Saint Luke's Hospital	Kansas City	Missouri
United States	Los Angeles County and USC Medical Center	Los Angeles	California
United States	University of Louisville-Division of Pulmonary and Critical Care	Louisville	Kentucky
United States	Yale University	New Haven	Connecticut
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Mount Sinai Medical Center	New York City	New York
United States	West Suburban Hospital Medical Center	Oak Park	Illinois
United States	University of Oklahoma	Oklahoma City	Oklahoma
United States	Illinois Lung and Critical Care Institute	Peoria	Illinois
United States	UC Davis Medical Center	Sacramento	California
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Mercy Hospital St. Louis	St. Louis	Missouri
United States	Saint Louis University	St. Louis	Missouri
United States	Stanford University	Stanford	California
United States	Wake Forest University	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Altor Bioscience Corporation	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety profile of the study drug		Throughout the 28 days following treatment	Yes
Primary	Number of ventilator-free days at Day 28		Determined at Day 28	No
Secondary	Mortality at Day 7, 14, 21, 28 and 60		Determined at Day 7, 14, 21, 28 and 60	No
Secondary	Length of hospitalization at Day 28		Determined at Day 28	No
Secondary	Length of ICU stay at Day 28		Determined at Day 28	No
Secondary	Number of Non-pulmonary organ failure free days at Day 28		Determined at Day 28	No
Secondary	Changes in physiological variables of lung injury		Throughout the 28 days following treatment	No
Secondary	Changes in disease severity and lung injury scores		Throughout the 28 days following treatment	No
Secondary	Effects of the study drug and the etiology of the disease (i.e. pulmonary or extra-pulmonary origin)		Determined at Day 28	No
Secondary	Pharmacokinetics & Pharmacodynamics		Throughout the 28 days following treatment	No
Secondary	Immunogenicity		Throughout the 28 days following treatment	Yes

External Links

•   Altor Bioscience Corporation, Miramar, Florida, US