IVIG - West Nile Encephalitis: Safety and Efficacy
IVIG - West Nile Encephalitis: Safety and Efficacy
This study will look at the safety and effectiveness of an experimental medication containing
 antibodies (Omr-IgG-am™) in people with West Nile Virus (WNV) who already have brain and/or
 spinal cord inflammation or who are at high risk of developing these problems because they
 have weak immune systems. WNV can cause problems such as headaches, fever, muscle weakness,
 coma, and death. Study investigators believe people who are not able to fight infection well
 may be at risk for developing neurologic problems (having to do with the brain, spinal cord,
 nerves, and muscles) if they get WNV infection. Up to 110 subjects, 18 years or older, will
 participate for about 3 months and will receive either Omr-IgG-am™, Polygam® S/D, or placebo
 given through a small tube placed in a blood vessel in the arm. Hospitalization, up to 5
 additional study visits, blood sample collection, MRI pictures of the brain and spinal cord,
 and neurological, muscle, and heart activity tests are also required.
The purpose of this study is to assess whether Omr-IgG-am™, an intravenous immunoglobulin
 (IVIg) containing antibodies specific for West Nile virus (WNV), is safe and well-tolerated
 in patients with suspected or laboratory diagnosed WNV disease. An initial estimation of
 efficacy will also be made. This Phase I/II study will enroll hospitalized adults with a
 presumptive diagnosis of West Nile encephalitis and/or myelitis or those with a positive
 laboratory test for diagnosis of WNV infection who are at high risk for progressing to severe
 neurologic disease based on age or immunosuppression. Patients will be randomized in blocks
 of five to receive either Omr-IgGam ™, Polygam® S/D (IVIG containing minimal anti-WNV
 antibodies) or normal saline in a ratio of 3:1:1. Patients and investigators will be blinded
 to treatment assignments. Patients will receive a single intravenous dose of study medication
 or one of two placebos. The study participants will receive 0.5 grams/kg of Omr-IgG-am™ or
 Polygam® S/D or a comparable volume of normal saline. All patients will be followed for
 safety, natural history endpoints, and efficacy. A subset of patients will have
 pharmacokinetic measurements of specific anti-WNV antibodies assessed following treatment.
 The primary endpoints are safety and tolerability following Omr-IgG-am™ administration.
 Secondary endpoints include pharmacokinetics of specific anti-WNV antibodies, mortality in
 confirmed WNV positive patients, and the combination of mortality and functional status at
 three months in both confirmed WNV-infected patients and all patients by intention to treat.
 This combined endpoint will be measured using four standardized measures of cognitive and
 functional status: the Barthel Index; the Modified Rankin Scale; the Glasgow Outcome Score;
 and the Modified Mini-Mental Status Examination. A comparison of outcomes will be made for
 the group receiving Omr-IgG-am™ versus those receiving either placebo, and between the two
 placebo groups. Other secondary endpoints include the proportion of patients in each group
 returning to pre-morbid baseline and each subject's improvement at 3 months as compared to
 that subject's worst (of any previous) evaluation. Natural history endpoints will also be
 assessed. They will include the duration of intensive care unit and hospital stay,
 development and persistence of WNV-specific IgG and IgM antibodies, combined functional score
 and mortality at 3 months between the group with encephalitis and/or myelitis at baseline
 versus the group with a positive WNV test only, outcomes in patients treated late in coma and
 correlation of outcome with time-to-treatment following symptom onset.
Inclusion Criteria:

 In order to participate in this clinical trial, all subjects (or legal representative) must
 provide written informed consent. Only patients meeting entry criteria will be enrolled.
 Eligible subjects must fall into one of two categories:

 A. Hospitalized patients greater than or equal to 18 years of age with encephalitis and/or
 myelitis as defined below:

 New neurologic abnormality:

 -  Asymmetric extremity weakness without sensory abnormality; or

 -  Other neurologic abnormality (including altered level of consciousness, dysarthria and
 dysphagia) plus fever (subjective or objective) within the previous 4 days AND

 CSF examination within the previous 96 hours showing:

 -  Absence of organism on gram or fungal stain

 -  White blood cell count greater than or equal to 4 per cubic mm corrected for
 significant red blood cell contamination.

 -  Ratio of CSF: plasma glucose of greater than or equal to 40% (CSF glucose / plasma
 glucose greater than or equal to 0.4) Serum and CSF glucose levels should be obtained
 within 8 hours of each other for this calculation.

 OR

 B. Hospitalized patients, without encephalitis and/or myelitis as defined below, who meet
 the following criteria:

 A positive IgM serology or PCR test for WNV in blood or cerebrospinal fluid, AND

 Clinical illness compatible with WNV infection as described by occurrence of greater than
 or equal to 3 of the following findings during the preceding less than or equal to 10 days:

 -  Diarrhea

 -  Headache

 -  Fever > 38º C

 -  Nausea and/or vomiting

 -  Myalgias and/or arthralgias

 -  Nuchal rigidity

 -  Macular or papular rash

 -  New neurological abnormality AND

 A risk factor for the development of WNV neurologic disease as defined by:

 -  Age greater than or equal to 40 years, or

 -  Age greater than or equal to 18 years plus immunosuppression, as defined by any of the
 following:

 Hematologic malignancy; previous diagnosis of diabetes mellitus; chemotherapy within
 previous 4 weeks; stem cell transplant recipient or solid organ transplant recipient;
 taking immunosuppressive medications, including prednisone greater than or equal to 7.5
 mg/day within the previous 4 weeks; history of human immunodeficiency virus (HIV)
 infection, congenital immunodeficiency syndrome (including common variable
 immunodeficiency)

 Exclusion Criteria:

 Unable to obtain valid informed consent History of intolerance (including anaphylaxis) to
 IVIg or related compounds Known history of IgA deficiency Known history of hypersensitivity
 to maltose

 History of (or at time of study entry) hyperviscosity syndrome, such as but not limited to:

 -  Waldenstrom's macroglobulinemia

 -  Multiple myeloma

 -  Total white blood cell count > 80,000/cubic mm

 -  Hematocrit > 55%

 -  Platelet count > 700,000/cubic mm Meets criteria of Class III or IV of the New York
 Heart Association Classification for congestive heart failure patients Serum
 creatinine > 2.5 mg/dL or requires dialysis Alternate explanation (as determined by
 the investigator) for clinical findings (such as structural brain lesion,
 cerebrovascular accident, or other infectious disease, including confirmed infections
 with other flaviviruses) Pregnant or breastfeeding (negative serum or urine pregnancy
 test within previous 72 hours if woman is not postmenopausal or has not been
 surgically sterilized) Investigator's opinion that patient would be unable to adhere
 to protocol requirements Receipt of ribavirin, interferon alpha, intravenous
 immunoglobulin, or any investigational drug for treatment of WNV or hepatitis within
 15 days prior to study entry