OASIS: A Phase 2/3 Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of Talactoferrin Alfa in Patients with Severe Sepsis

1.Age * 18 years
2.Onset of severe sepsis within the previous 24 hours as defined by meeting all of the following criteria (A, B and C). Organ dysfunction must be present at the time of randomization. Randomization must occur within 24 hours of the first documented organ dysfunction (C) as defined below:
A.Objective evidence of confirmed or suspected infection. Suspected infection must be based on objective clinical evidence such as: (a) neutrophils in a normally sterile body fluid; (b) perforated viscus; (c) radiographic evidence of pneumonia; or (d) a syndrome associated with a high likelihood of infection (e.g., ascending cholangitis). and
B.the presence of at least three manifestations of a systemic inflammatory response syndrome (SIRS) due to infection (only two criteria if patient is on medication that controls heart rate or has a pacemaker):
*Body temperature: i) hyperthermia as indicated by a temperature of *38º C; or ii) hypothermia as indicated by a core temperature *36º C. For defining hypothermia, temperature must be obtained via a rectal temperature, central venous catheter monitor or urinary bladder thermistor, not by oral, tympanic or axillary measurement.
*Heart rate *90/min
*Respiratory rate *20/min or PaCO2 * 32 mmHg; or the use of mechanical ventilation for an acute respiratory process
*WBC *12,000/mm3 or *4,000/mm3, or >10% immature neutrophils (i.e., bands), and
C.at least one acute organ dysfunction due to sepsis, that is newly developed, and not explained by other disease processes or the effects of treatment and is ongoing at the time of randomization, defined as follows:
*Septic shock (Cardiovascular) * the requirement for vasopressors,* despite adequate fluid resuscitation,** to maintain a MAP >65 mm Hg or a systolic pressure >90 mm Hg.
* Vasopressors are defined as dopamine *5 *g/kg/min or any dose of norepinephrine, epinephrine, phenylephrine, or vasopressin, with the intent to support blood pressure. Dobutamine and dopexamine are not considered vasopressors.
**Adequate fluid resuscitation is defined as one of the following: i) a minimum of a 20 mL/kg (ideal body weight) intravenous fluid challenge (crystalloid or equivalent colloid); or ii) if measured, a central venous pressure (CVP) *8 mm Hg or *12 mm Hg if mechanically ventilated; or iii) a pulmonary artery occlusion pressure (PAOP) *12 mm Hg or *16 mm Hg if mechanically ventilated.
*Respiratory * must have mechanical ventilation and PaO2/FiO2 ratio *300 (SpO2/FiO2 *357) or if lung is the primary site of infection a PaO2/FiO2 ratio *200 (SpO2/FiO2 *214). Note: SpO2 may only be used if <97 (see Appendix E).
*Renal * i) an absolute increase in serum creatinine of *0.3 mg/dL within the preceding 48 hours, or ii) a relative increase in serum creatinine *50% within the preceding 48 hours, or iii) a urine output<0.5 mL/kg ideal body weight/hr for *2 hours in the absence of known or suspected urinary tract obstruction. In the presence of preexisting impairment of renal function (defined as a serum creatinine concentration >2 times the upper limit of the normal reference range prior to the onset of sepsis), the patient should meet another organ dysfunction criteria.
Meeting criteria i) or ii) requires *2 creatinine measurements within 48 hours. Criteria i), ii) or iii) must be met despite adequate fluid resuscitation.** (defined as above for septic shock)
*Hematologic * platelet count <80,000/mm3 or platelet count <120,000/mm3 in association with a PT INR *1.2
*Metabolic * serum lactate *2.0 mmol/L (or equivalent in other units) despite adequate fluid resuscitation** (defined as above for septic shock)
3.Must be receiving antimicrobial therapy
4.Informed-consent form signed by patient or authorized representatives, according to local rules and regulations
5.Able to take liquid medication by mouth or feeding tube

1. Receipt of any investigational medication or device within 4 weeks prior to randomization
2. Severe congestive heart failure (e.g., NYHA Class IV or pre-sepsis ejection fraction <30%)
3. Neutrophils <1,000/mm3 unless due to sepsis
4. Known HIV infection with CD4 <200 cells/mm3 or illnesses associated with end stage AIDS
(e.g., disseminated Mycobacterium Avium Complex, Cytomegalovirus and Progressive Multifocal
Leukoencephalopathy)
5. Presence of 3rd-degree burns involving >20% body surface area (unless burn occurred >7 days prior to randomization)
6. Receiving immunosuppressants, such as prednisone 20 mg/day or equivalent for *2 weeks immediately prior to evaluation for enrollment
7. Patient is moribund and whose death is considered imminent by the investigator
8. Life expectancy, due to pre-existing conditions such as cancer, is less than six months
9. Severe hypoxic encephalopathy (e.g., post cardiopulmonary resuscitation) or persistent vegetative state
10. Child-Pugh Class C liver disease pre-sepsis or known portal hypertension or esophageal varices
11. The patient or their legal representative, or the patient*s primary physician are not committed to providing full, aggressive, life support
12. Patients chronically bed-bound prior to the onset of sepsis
13. Pregnant or breast-feeding