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Open Access Research article

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

Peter E Morris1, Jay S Steingrub2, Bee Y Huang3, Shamay Tang3, Patrick M Liu4, Peter R Rhode3 and Hing C Wong3*

Author Affiliations

1 Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest University School of Medicine, Winston Salem, NC, USA

2 Division of Pulmonary and Critical Care Medicine, Baystate Medical Center, Springfield, MA, USA

3 Altor BioScience Corp., Miramar, FL, USA

4 Development Sciences, Genentech, Inc., South San Francisco, CA, USA

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BMC Pulmonary Medicine 2012, 12:5  doi:10.1186/1471-2466-12-5

Published: 16 February 2012

Abstract

Background

The tissue factor (TF)-dependent extrinsic pathway has been suggested to be a central mechanism by which the coagulation cascade is locally activated in the lungs of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS) and thus represents an attractive target for therapeutic intervention. This study was designed to determine the pharmacokinetic and safety profiles of ALT-836, an anti-TF antibody, in patients with ALI/ARDS.

Methods

This was a prospective, randomized, placebo-controlled, dose-escalation Phase I clinical trial in adult patients who had suspected or proven infection, were receiving mechanical ventilation and had ALI/ARDS (PaO2/FiO2 ≤ 300 mm). Eighteen patients (6 per cohort) were randomized in a 5:1 ratio to receive ALT-836 or placebo, and were treated within 48 hours after meeting screening criteria. Cohorts of patients were administered a single intravenously dose of 0.06, 0.08 or 0.1 mg/kg ALT-836 or placebo. Blood samples were taken for pharmacokinetic and immunogenicity measurements. Safety was assessed by adverse events, vital signs, ECGs, laboratory, coagulation and pulmonary function parameters.

Results

Pharmacokinetic analysis showed a dose dependent exposure to ALT-836 across the infusion range of 0.06 to 0.1 mg/kg. No anti-ALT-836 antibody response was observed in the study population during the trial. No major bleeding episodes were reported in the ALT-836 treated patients. The most frequent adverse events were anemia, observed in both placebo and ALT-836 treated patients, and ALT-836 dose dependent, self-resolved hematuria, which suggested 0.08 mg/kg as an acceptable dose level of ALT-836 in this patient population.

Conclusions

Overall, this study showed that ALT-836 could be safely administered to patients with sepsis-induced ALI/ARDS.

Trial registration

ClinicalTrials.gov: NCT01438853

Keywords:
Tissue Factor; Acute Lung Injury; Acute Respiratory Distress Syndrome; Clinical Trial; Phase I