Chiron Study TFP008 A Phase 3, Multicenter, Randomized, Placebo-Controlled, Double-blind, Three-Arm Study to Evaluate the Safety and Efficacy of Tifacogin [Recombinant Tissue Factor Pathway Inhibitor] Administration in Subjects with Severe Community-Acquired Pneumonia

PI: Jane Dematte, MD

Pager 5-9816

Contact the PI or the Pulmonary Research pager (5-9285) for questions and enrollment

Indications: CAP

IRB Approval # 0555-020

Inclusion Criteria*

• Adults age 18 years old and older;
• A clinical diagnosis of community-acquired pneumonia documented or obtained within 24 hours preceding hospital admission through 24 hours following hospital admission:
• • Clinical Signs (at least two of the following):
  • • Fever or unexplained hypothermia
    • Tachypnea
    • Leukocytosis, or relative leukopenia not due to other causes
    • Hypoxemia (PaO2/FiO2 < 285 or SaO2 < 90%).
  • Radiographic Findings
  • • New pulmonary infiltrate(s) consistent with the diagnosis of CAP
  • Microbiological Criteria
• Pneumonia of sufficient severity to require ICU admission and management and meets one major or two minor severity criteria:
• • Major Criteria: one of the following:
  • • Receiving mechanical ventilatory support
    • Receiving treatment with vasopressors at therapeutic doses to maintain systolic blood pressure (SBP) > 90 mm Hg (or mean arterial pressure (MAP) > 70 mm Hg) despite adequate fluid resuscitation

OR

• • Minor Criteria: two of the following criteria documented within the previous 24 hours in subjects without evidence of rapid clinical improvement:
  • • Systolic blood pressure < 90 mm Hg or MAP < 70 mm Hg and received greater than or equal to 40 mL/kg of fluid resuscitation over a 6 hour period or vasopressors at therapeutic doses (see above) for at least 2 hours to maintain a SBP > 90 mm Hg or a MAP > 70 mm Hg
    • PaO2/FiO2 ratio < 250 or a respiratory rate greater than or equal to 30/min or the need for noninvasive mechanical ventilatory support
    • Blood urea nitrogen (BUN) > 7.0 mM (> 19.6 mg/dL)
    • New onset mental confusion (must be documented prior to the use of sedative or other new psychotropic medication)
    • Multi-lobar pneumonia
    • Platelet count < 100,000 cells/mm3 or a fall of > 25% during the previous 48 hours to a count of < 120,000 cells/mm3
    • Leukopenia
    • Hypothermia (core temperature< 36°C)
• Ability to initiate treatment within 36 hours of ICU admission and within 72 hours of hospitalization

Exclusion Criteria*

• Pregnancy
• Weight > 150 kg;
• Prior hospitalization within 14 days of current hospital admission;
• Non-ambulatory resident of a long-term care facility;
• Requires long-term mechanical ventilation;
• Known or suspected aspiration pneumonitis;
• Postobstructive pneumonia;
• History of bone marrow transplantation or solid organ transplantation requiring ongoing immunosuppressive therapy (subjects with stable renal transplantations may be enrolled) or with evidence of acute or chronic transplant rejection;
• Current diagnosis of acute leukemia, multiple myeloma, non-Hodgkin’s lymphoma or Hodgkin's disease;
• Severe neutropenia (absolute neutrophil count < 1,000 cells/mm3 due to causes other than CAP);
• Significant liver disease (Child-Pugh Grade C or known esophageal varices);
• Known or suspected helper/inducer T-lymphocytes (CD4+) count < 200, or a CD4+ T-lymphocyte percentage of total lymphocytes of < 14%;
• Known or suspected infective endocarditis;
• Cardio-pulmonary arrest within 72 hours preinfusion;
• Platelet count < 60,000
• History of intracranial bleeding within six months or closed head trauma or stroke within one month or other neurological condition with increased bleeding risk;
• Uncontrolled hemorrhage;
• Treatment with drotrecogin alfa within 24 hours prior to, or anticipated need for drotrecogin alfa within 24 hours after the start of study drug infusion;
• Treatment within 24 hours prior to the anticipated start of study drug infusion with Antithrombin III (AT-III), other systemic anticoagulants, antiplatelet drugs 
• Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion or any required drug/fluid therapy at time of consent. Refusal of chest compression is acceptable