Clinical trial NCT00068055: IVIG - West Nile Encephalitis: Safety and Efficacy
Official title: A Phase I/II Randomized, Placebo-Controlled Trial to Assess the Safety and Efficacy of Intravenous Immunoglobulin G (OMR-IGG-AM) Containing High Anti-West Nile Virus Antibody Titers in Patients With, or at High Risk for Progression to West Nile Virus (WNV) Encephalitis and/or Myelitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: West Nile Virus
Keywords: West Nile Virus, encephalitis, myelitis, immunoglobulin G
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2003-09-08
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Safety (including all causes of mortality) in the test IVIg (Omr-IgG-am™) group versus the 2 placebo groups, as defined by the total number of serious adverse events regardless of relatedness to study drug administration.
timeFrame: Duration of study.
Secondary outcomes:
measure: Pharmacokinetics of specific anti-WNV antibodies as measured by ELISA and PRNT methods.
timeFrame: Baseline (pre-dose) blood sample collected immediately prior to the beginning of the infusion. After the infusion, additional blood samples collected at 1 hr, 6 hr, 12 hr, 24 hr, 72 hr, and then at Day 5, Day 7, Day 14, Day 30, Day 60 and Day 90.
measure: Proportion of patients returning to pre-morbid baseline at 3 months, between treated and untreated groups of patients with WNV infection, as assessed by two scoring systems the Barthel Index and the MRS.
timeFrame: At 3 months.
measure: Improvement as compared to subject's own worst (of any earlier) evaluation, for each subject as defined by the combined results of the 4 neurological functional tests.
timeFrame: At 3 months.
measure: Mortality alone among confirmed WNV patients.
timeFrame: At 3 months.
measure: Combined morbidity and mortality in treatment versus placebo groups for all (including those without WNV infection) subjects by intention to treat analysis.
timeFrame: At 3 months.
measure: Combined primary endpoint of mortality and morbidity among confirmed WNV patients as assessed by four scoring systems: the Barthel Index, the MRS, the GOS and the 3MS, in the experimental treatment group versus the control group.
timeFrame: At 3 months.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Mobile
country: United States
facility: University of South Alabama Medical Center
state: Alabama
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Health Sciences Center
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas
state: Arkansas
city: Chico
country: United States
facility: Enloe Medical Center
state: California
city: Daly City
country: United States
facility: Seton Medical Center
state: California
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Harbor City
country: United States
facility: Kaiser Permanente South Bay Medical Center
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Orange
country: United States
facility: University of California Irvine
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Santa Rosa
country: United States
facility: Santa Rosa Kaiser Medical
state: California
city: Denver
country: United States
facility: Exempla St. Joseph Hospital
state: Colorado
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Washington
country: United States
facility: George Washington University Medical Center
state: District of Columbia
city: Idaho Falls
country: United States
facility: Idaho Falls Infectious Diseases, PLLC
state: Idaho
city: Maywood
country: United States
facility: Loyola University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Wichita
country: United States
facility: Via Christi Regional Medical Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Bethesda
country: United States
facility: National Institutes of Health
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
city: St. Louis
country: United States
facility: Saint Louis University
state: Missouri
city: Butte
country: United States
facility: Mercury Street Medical Group
state: Montana
city: Missoula
country: United States
facility: Infectious Disease Specialists, PC
state: Montana
city: Broken Bow
country: United States
facility: Central Nebraska Medical Clinic
state: Nebraska
city: McCook
country: United States
facility: McCook Clinic, PC
state: Nebraska
city: North Platte
country: United States
facility: Great Plains Regional Medical Center
state: Nebraska
city: Omaha
country: United States
facility: VA Medical Center - Omaha
state: Nebraska
city: Omaha
country: United States
facility: Creighton University
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Belleville
country: United States
facility: Clara Maass Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Flushing
country: United States
facility: Flushing Hospital Medical Center
state: New York
city: Bismarck
country: United States
facility: St. Alexius Medical Center
state: North Dakota
city: Fargo
country: United States
facility: Dakota Clinic at Innovis
state: North Dakota
city: Fargo
country: United States
facility: MeritCare Hospital
state: North Dakota
city: Minot
country: United States
facility: Trinity Health - Hospital
state: North Dakota
city: Cincinnati
country: United States
facility: University Hospital
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
city: Toledo
country: United States
facility: University of Toledo
state: Ohio
city: Wright-Patterson AFB
country: United States
facility: Wright-Patterson Medical Center
state: Ohio
city: Portland
country: United States
facility: Legacy Good Samaritan
state: Oregon
city: Allentown
country: United States
facility: Lehigh Valley Hospital
state: Pennsylvania
city: West Reading
country: United States
facility: The Reading Hospital and Medical Center
state: Pennsylvania
city: Pawtucket
country: United States
facility: Memorial Hospital of RI
state: Rhode Island
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Rapid City
country: United States
facility: Infectious Disease Consultations - Rapid City
state: South Dakota
city: Sioux Falls
country: United States
facility: Avera Research Institute
state: South Dakota
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Galveston
country: United States
facility: The University of Texas Medical Branch
state: Texas
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston
state: Texas
city: San Antonio
country: United States
facility: The University of Texas Health Science Center
state: Texas
city: San Antonio
country: United States
facility: Wilford Hall Medical Center
state: Texas
city: Tyler
country: United States
facility: The University of Texas Health Science Center at Tyler
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
Study officials:
References: