IVIG - West Nile Encephalitis: Safety and Efficacy

West Nile Virus Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00068055
• Other study ID #: 03-107
• Secondary ID: CASG 210
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: September 4, 2003
• Last updated: February 3, 2011
• Start date: September 2003
• Est. completion date: December 2006

Study information

• Verified date: July 2009
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Ethics Review CommitteeUnited States: Institutional Review BoardUnited States: Federal GovernmentUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 62
• Est. completion date: December 2006
• Est. primary completion date: December 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Encephalitis
• West Nile Virus

Intervention

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.
• 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
Normal Saline.

Locations

Country	Name	City	State
Canada	University of Calgary	Calgary	Alberta
Canada	University of Alberta	Edmonton	Alberta
Canada	University of Manitoba	Winnipeg	Manitoba
United States	University of New Mexico	Albuquerque	New Mexico
United States	Lehigh Valley Hospital	Allentown	Pennsylvania
United States	University of Michigan	Ann Arbor	Michigan
United States	Johns Hopkins University	Baltimore	Maryland
United States	Clara Maass Medical Center	Belleville	New Jersey
United States	National Institutes of Health	Bethesda	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	St. Alexius Medical Center	Bismarck	North Dakota
United States	Central Nebraska Medical Clinic	Broken Bow	Nebraska
United States	Mercury Street Medical Group	Butte	Montana
United States	University of Virginia	Charlottesville	Virginia
United States	Enloe Medical Center	Chico	California
United States	University Hospital	Cincinnati	Ohio
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	The University of Texas Southwestern Medical Center	Dallas	Texas
United States	Seton Medical Center	Daly City	California
United States	Exempla St. Joseph Hospital	Denver	Colorado
United States	University of Colorado	Denver	Colorado
United States	Wayne State University	Detroit	Michigan
United States	City of Hope National Medical Center	Duarte	California
United States	Dakota Clinic at Innovis	Fargo	North Dakota
United States	MeritCare Hospital	Fargo	North Dakota
United States	Flushing Hospital Medical Center	Flushing	New York
United States	The University of Texas Medical Branch	Galveston	Texas
United States	Kaiser Permanente South Bay Medical Center	Harbor City	California
United States	The University of Texas Health Science Center at Houston	Houston	Texas
United States	Idaho Falls Infectious Diseases, PLLC	Idaho Falls	Idaho
United States	Indiana University	Indianapolis	Indiana
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of Kentucky	Lexington	Kentucky
United States	University of Arkansas	Little Rock	Arkansas
United States	University of Southern California	Los Angeles	California
United States	Loyola University	Maywood	Illinois
United States	McCook Clinic, PC	McCook	Nebraska
United States	Trinity Health - Hospital	Minot	North Dakota
United States	Infectious Disease Specialists, PC	Missoula	Montana
United States	University of South Alabama Medical Center	Mobile	Alabama
United States	Vanderbilt University	Nashville	Tennessee
United States	Tulane University	New Orleans	Louisiana
United States	Great Plains Regional Medical Center	North Platte	Nebraska
United States	Creighton University	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	VA Medical Center - Omaha	Omaha	Nebraska
United States	University of California Irvine	Orange	California
United States	Memorial Hospital of RI	Pawtucket	Rhode Island
United States	Mayo Clinic Hospital	Phoenix	Arizona
United States	St. Joseph's Hospital and Medical Center	Phoenix	Arizona
United States	Legacy Good Samaritan	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Infectious Disease Consultations - Rapid City	Rapid City	South Dakota
United States	University of California Davis Medical Center	Sacramento	California
United States	Washington University in St. Louis	Saint Louis	Missouri
United States	The University of Texas Health Science Center	San Antonio	Texas
United States	Wilford Hall Medical Center	San Antonio	Texas
United States	California Pacific Medical Center	San Francisco	California
United States	University of California San Francisco	San Francisco	California
United States	Santa Rosa Kaiser Medical	Santa Rosa	California
United States	Avera Research Institute	Sioux Falls	South Dakota
United States	Saint Louis University	St. Louis	Missouri
United States	University of Toledo	Toledo	Ohio
United States	University of Arizona Health Sciences Center	Tucson	Arizona
United States	The University of Texas Health Science Center at Tyler	Tyler	Texas
United States	George Washington University Medical Center	Washington	District of Columbia
United States	The Reading Hospital and Medical Center	West Reading	Pennsylvania
United States	Via Christi Regional Medical Center	Wichita	Kansas
United States	Wright-Patterson Medical Center	Wright-Patterson AFB	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.		Duration of study.	Yes
Secondary	Pharmacokinetics of specific anti-WNV antibodies as measured by ELISA and PRNT methods.		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.	No
Secondary	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.		At 3 months.	No
Secondary	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.		At 3 months.	No
Secondary	Mortality alone among confirmed WNV patients.		At 3 months.	No
Secondary	Combined morbidity and mortality in treatment versus placebo groups for all (including those without WNV infection) subjects by intention to treat analysis.		At 3 months.	No
Secondary	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.		At 3 months.	No