title: 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.
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 (PaO(2)/FiO(2) ≤ 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.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT01438853.
authors.affiliation: Altor BioScience Corp., Miramar, FL, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Morris
authors.forename: Jay S
authors.initials: JS
authors.lastname: Steingrub
authors.forename: Bee Y
authors.initials: BY
authors.lastname: Huang
authors.forename: Shamay
authors.initials: S
authors.lastname: Tang
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Liu
authors.forename: Peter R
authors.initials: PR
authors.lastname: Rhode
authors.forename: Hing C
authors.initials: HC
authors.lastname: Wong
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000906:Antibodies / Q000494:pharmacology* / Q000633:toxicity; D001688:Biological Products / Q000493:pharmacokinetics* / Q000633:toxicity; D015331:Cohort Studies; D005260:Female; D006417:Hematuria / Q000139:chemically induced; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics* / Q000633:toxicity; D011994:Recombinant Proteins / Q000493:pharmacokinetics* / Q000633:toxicity; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome / Q000188:drug therapy*; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
chemical_list: C572574:ALT-836; D000906:Antibodies; D001688:Biological Products; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D013925:Thromboplastin