IVIG - West Nile Encephalitis: Safety and Efficacy

This study has been completed.
Sponsor:
Information provided by:
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00068055
First received: September 4, 2003
Last updated: February 3, 2011
Last verified: July 2009
  Purpose

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.


Condition Intervention Phase
West Nile Virus
Drug: Omr-lgG-am
Drug: Polygam® S/D
Drug: Placebo
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • 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. [ Time Frame: Duration of study. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Pharmacokinetics of specific anti-WNV antibodies as measured by ELISA and PRNT methods. [ Time Frame: 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. ] [ Designated as safety issue: No ]
  • 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. [ Time Frame: At 3 months. ] [ Designated as safety issue: No ]
  • 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. [ Time Frame: At 3 months. ] [ Designated as safety issue: No ]
  • Mortality alone among confirmed WNV patients. [ Time Frame: At 3 months. ] [ Designated as safety issue: No ]
  • Combined morbidity and mortality in treatment versus placebo groups for all (including those without WNV infection) subjects by intention to treat analysis. [ Time Frame: At 3 months. ] [ Designated as safety issue: No ]
  • 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. [ Time Frame: At 3 months. ] [ Designated as safety issue: No ]

Enrollment: 62
Study Start Date: September 2003
Study Completion Date: December 2006
Primary Completion Date: December 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
60 subjects to receive Omr-IgG-am.
Drug: 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.
Active Comparator: 2
20 subjects to receive Polygam® S/D (IVIG).
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.
Placebo Comparator: 3
20 subjects to receive normal saline.
Drug: Placebo
Normal Saline.

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00068055

  Hide Study Locations
Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294-2050
University of South Alabama Medical Center
Mobile, Alabama, United States, 36617
United States, Arizona
Mayo Clinic Hospital
Phoenix, Arizona, United States, 85054
St. Joseph's Hospital and Medical Center
Phoenix, Arizona, United States, 85013
University of Arizona Health Sciences Center
Tucson, Arizona, United States, 85724
United States, Arkansas
University of Arkansas
Little Rock, Arkansas, United States, 72205
United States, California
Enloe Medical Center
Chico, California, United States, 95926
Seton Medical Center
Daly City, California, United States, 94015
City of Hope National Medical Center
Duarte, California, United States, 91010
Kaiser Permanente South Bay Medical Center
Harbor City, California, United States, 90710
University of Southern California
Los Angeles, California, United States, 90033
University of California Irvine
Orange, California, United States, 92868-3298
University of California Davis Medical Center
Sacramento, California, United States, 95817
University of California San Francisco
San Francisco, California, United States, 94114
California Pacific Medical Center
San Francisco, California, United States, 94115
Santa Rosa Kaiser Medical
Santa Rosa, California, United States, 95403
United States, Colorado
Exempla St. Joseph Hospital
Denver, Colorado, United States, 80218
University of Colorado
Denver, Colorado, United States, 80262
United States, District of Columbia
George Washington University Medical Center
Washington, District of Columbia, United States, 20037
United States, Idaho
Idaho Falls Infectious Diseases, PLLC
Idaho Falls, Idaho, United States, 83404
United States, Illinois
Loyola University
Maywood, Illinois, United States, 60153
United States, Indiana
Indiana University
Indianapolis, Indiana, United States, 46202-5124
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
Via Christi Regional Medical Center
Wichita, Kansas, United States, 67214
United States, Kentucky
University of Kentucky
Lexington, Kentucky, United States, 40536-0084
United States, Louisiana
Tulane University
New Orleans, Louisiana, United States, 70112
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
National Institutes of Health
Bethesda, Maryland, United States, 20892-1662
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48105
Wayne State University
Detroit, Michigan, United States, 48201
United States, Missouri
Washington University in St. Louis
Saint Louis, Missouri, United States, 63110-1093
Saint Louis University
St. Louis, Missouri, United States, 63110
United States, Montana
Mercury Street Medical Group
Butte, Montana, United States, 59701
Infectious Disease Specialists, PC
Missoula, Montana, United States, 59802
United States, Nebraska
Central Nebraska Medical Clinic
Broken Bow, Nebraska, United States, 68822
McCook Clinic, PC
McCook, Nebraska, United States, 69001
Great Plains Regional Medical Center
North Platte, Nebraska, United States, 69101
Creighton University
Omaha, Nebraska, United States, 68131
University of Nebraska Medical Center
Omaha, Nebraska, United States, 68198-7630
VA Medical Center - Omaha
Omaha, Nebraska, United States, 68105
United States, New Jersey
Clara Maass Medical Center
Belleville, New Jersey, United States, 07109
United States, New Mexico
University of New Mexico
Albuquerque, New Mexico, United States, 87106
United States, New York
Flushing Hospital Medical Center
Flushing, New York, United States, 11355
United States, North Dakota
St. Alexius Medical Center
Bismarck, North Dakota, United States, 58506
MeritCare Hospital
Fargo, North Dakota, United States, 58122
Dakota Clinic at Innovis
Fargo, North Dakota, United States, 58103
Trinity Health - Hospital
Minot, North Dakota, United States, 58701
United States, Ohio
University Hospital
Cincinnati, Ohio, United States, 45219
University Hospitals of Cleveland
Cleveland, Ohio, United States, 44106
University of Toledo
Toledo, Ohio, United States, 43614
Wright-Patterson Medical Center
Wright-Patterson AFB, Ohio, United States, 45433
United States, Oregon
Legacy Good Samaritan
Portland, Oregon, United States, 97210
United States, Pennsylvania
Lehigh Valley Hospital
Allentown, Pennsylvania, United States, 18103
The Reading Hospital and Medical Center
West Reading, Pennsylvania, United States, 19611
United States, Rhode Island
Memorial Hospital of RI
Pawtucket, Rhode Island, United States, 02860
Rhode Island Hospital
Providence, Rhode Island, United States, 02903
United States, South Dakota
Infectious Disease Consultations - Rapid City
Rapid City, South Dakota, United States, 57701
Avera Research Institute
Sioux Falls, South Dakota, United States, 57105
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37205
United States, Texas
The University of Texas Southwestern Medical Center
Dallas, Texas, United States, 75390-8884
The University of Texas Medical Branch
Galveston, Texas, United States, 77555-0167
The University of Texas Health Science Center at Houston
Houston, Texas, United States, 77030
The University of Texas Health Science Center
San Antonio, Texas, United States, 78229-3900
Wilford Hall Medical Center
San Antonio, Texas, United States, 78236
The University of Texas Health Science Center at Tyler
Tyler, Texas, United States, 75708
United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22908
Canada, Alberta
University of Calgary
Calgary, Alberta, Canada, T2N4N
University of Alberta
Edmonton, Alberta, Canada, T6G 2B7
Canada, Manitoba
University of Manitoba
Winnipeg, Manitoba, Canada, R3E 0W3
Sponsors and Collaborators
  More Information

No publications provided

Responsible Party: Robert Johnson, HHS/NIAID/DMID
ClinicalTrials.gov Identifier: NCT00068055     History of Changes
Other Study ID Numbers: 03-107, CASG 210
Study First Received: September 4, 2003
Last Updated: February 3, 2011
Health Authority: Canada: Ethics Review Committee
United States: Institutional Review Board
United States: Federal Government
United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
West Nile Virus, encephalitis, myelitis, immunoglobulin G

Additional relevant MeSH terms:
Encephalitis
Virus Diseases
Central Nervous System Viral Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Central Nervous System Infections
Immunoglobulin G
Immunoglobulins
Antibodies
Immunoglobulins, Intravenous
Rho(D) Immune Globulin
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 31, 2014