IVIG - West Nile Encephalitis: Safety and Efficacy

NCT ID: NCT00068055

Last Updated: 2011-02-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 62 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-09-30
• Study Completion Date: 2006-12-31

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.

Conditions

West Nile Virus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

1

60 subjects to receive Omr-IgG-am.

Group Type: EXPERIMENTAL

Omr-lgG-am

Intervention Type: DRUG

Omr-IgG-am™ 5% is provided in 100 ml bottles (5.0 grams) as a sterile solution containing 5% protein, 10% maltose and water for injection. This product is licensed in Israel, but not in the US.

2

20 subjects to receive Polygam® S/D (IVIG).

Group Type: ACTIVE_COMPARATOR

Polygam® S/D

Intervention Type: DRUG

Polygam® S/D is a solvent/detergent treated, sterile, freeze-dried preparation of highly purified immunoglobulin G (IgG) derived from large pools of human plasma. When reconstituted (5%) with the supplied diluent (sterile water for injection, USP) Polygam® S/D contains approximately 50mg of protein per ml (approximately 90% is gamma globulin); 3mg/ml human albumin, 22.5 mg/ml glycine, 20 mg/ml glucose, 2mlg/ml polyethylene glycol (PEG), 1 mcg/ml tri-nbutyl phosphate, 1 mcg/ml octoxynol 9, and 100 mcg/ml polysorbate 80.

3

20 subjects to receive normal saline.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Normal Saline.

Interventions

Omr-lgG-am

Omr-IgG-am™ 5% is provided in 100 ml bottles (5.0 grams) as a sterile solution containing 5% protein, 10% maltose and water for injection. This product is licensed in Israel, but not in the US.

Intervention Type: DRUG

Polygam® S/D

Polygam® S/D is a solvent/detergent treated, sterile, freeze-dried preparation of highly purified immunoglobulin G (IgG) derived from large pools of human plasma. When reconstituted (5%) with the supplied diluent (sterile water for injection, USP) Polygam® S/D contains approximately 50mg of protein per ml (approximately 90% is gamma globulin); 3mg/ml human albumin, 22.5 mg/ml glycine, 20 mg/ml glucose, 2mlg/ml polyethylene glycol (PEG), 1 mcg/ml tri-nbutyl phosphate, 1 mcg/ml octoxynol 9, and 100 mcg/ml polysorbate 80.

Intervention Type: DRUG

Placebo

Normal Saline.

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

HHS/NIAID/DMID

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

University of South Alabama Medical Center

Mobile, Alabama, United States

St. Joseph's Hospital and Medical Center

Phoenix, Arizona, United States

Mayo Clinic Hospital

Phoenix, Arizona, United States

University of Arizona Health Sciences Center

Tucson, Arizona, United States

University of Arkansas

Little Rock, Arkansas, United States

Enloe Medical Center

Chico, California, United States

Seton Medical Center

Daly City, California, United States

City of Hope National Medical Center

Duarte, California, United States

Kaiser Permanente South Bay Medical Center

Harbor City, California, United States

University of Southern California

Los Angeles, California, United States

University of California Irvine

Orange, California, United States

University of California Davis Medical Center

Sacramento, California, United States

University of California San Francisco

San Francisco, California, United States

California Pacific Medical Center

San Francisco, California, United States

Santa Rosa Kaiser Medical

Santa Rosa, California, United States

Exempla St. Joseph Hospital

Denver, Colorado, United States

University of Colorado

Denver, Colorado, United States

George Washington University Medical Center

Washington D.C., District of Columbia, United States

Idaho Falls Infectious Diseases, PLLC

Idaho Falls, Idaho, United States

Loyola University

Maywood, Illinois, United States

Indiana University

Indianapolis, Indiana, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Via Christi Regional Medical Center

Wichita, Kansas, United States

University of Kentucky

Lexington, Kentucky, United States

Tulane University

New Orleans, Louisiana, United States

Johns Hopkins University

Baltimore, Maryland, United States

National Institutes of Health

Bethesda, Maryland, United States

University of Michigan

Ann Arbor, Michigan, United States

Wayne State University

Detroit, Michigan, United States

Washington University in St. Louis

St Louis, Missouri, United States

Saint Louis University

St Louis, Missouri, United States

Mercury Street Medical Group

Butte, Montana, United States

Infectious Disease Specialists, PC

Missoula, Montana, United States

Central Nebraska Medical Clinic

Broken Bow, Nebraska, United States

McCook Clinic, PC

McCook, Nebraska, United States

Great Plains Regional Medical Center

North Platte, Nebraska, United States

VA Medical Center - Omaha

Omaha, Nebraska, United States

Creighton University

Omaha, Nebraska, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Clara Maass Medical Center

Belleville, New Jersey, United States

University of New Mexico

Albuquerque, New Mexico, United States

Flushing Hospital Medical Center

Flushing, New York, United States

St. Alexius Medical Center

Bismarck, North Dakota, United States

Dakota Clinic at Innovis

Fargo, North Dakota, United States

MeritCare Hospital

Fargo, North Dakota, United States

Trinity Health - Hospital

Minot, North Dakota, United States

University Hospital

Cincinnati, Ohio, United States

University Hospitals of Cleveland

Cleveland, Ohio, United States

University of Toledo

Toledo, Ohio, United States

Wright-Patterson Medical Center

Wright-Patterson AFB, Ohio, United States

Legacy Good Samaritan

Portland, Oregon, United States

Lehigh Valley Hospital

Allentown, Pennsylvania, United States

The Reading Hospital and Medical Center

West Reading, Pennsylvania, United States

Memorial Hospital of RI

Pawtucket, Rhode Island, United States

Rhode Island Hospital

Providence, Rhode Island, United States

Infectious Disease Consultations - Rapid City

Rapid City, South Dakota, United States

Avera Research Institute

Sioux Falls, South Dakota, United States

Vanderbilt University

Nashville, Tennessee, United States

The University of Texas Southwestern Medical Center

Dallas, Texas, United States

The University of Texas Medical Branch

Galveston, Texas, United States

The University of Texas Health Science Center at Houston

Houston, Texas, United States

The University of Texas Health Science Center

San Antonio, Texas, United States

Wilford Hall Medical Center

San Antonio, Texas, United States

The University of Texas Health Science Center at Tyler

Tyler, Texas, United States

University of Virginia

Charlottesville, Virginia, United States

University of Calgary

Calgary, Alberta, Canada

University of Alberta

Edmonton, Alberta, Canada

University of Manitoba

Winnipeg, Manitoba, Canada

Countries

United States; Canada

Other Identifiers

CASG 210

Identifier Type: -

Identifier Source: secondary_id

03-107

Identifier Type: -

Identifier Source: org_study_id