IVIG - West Nile Encephalitis: Safety and Efficacy

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00068055

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

0.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

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

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

62 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, 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

Study Start Date :

Sep 1, 2003

Actual Primary Completion Date :

Dec 1, 2006

Actual Study Completion Date :

Dec 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
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.

Arm

Intervention/Treatment

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.

Outcome Measures

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. [Duration of study.]

Secondary Outcome Measures

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.]
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.]
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.]
Mortality alone among confirmed WNV patients. [At 3 months.]
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.]
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.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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.

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

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294-2050
2	University of South Alabama Medical Center	Mobile	Alabama	United States	36617
3	St. Joseph's Hospital and Medical Center	Phoenix	Arizona	United States	85013
4	Mayo Clinic Hospital	Phoenix	Arizona	United States	85054
5	University of Arizona Health Sciences Center	Tucson	Arizona	United States	85724
6	University of Arkansas	Little Rock	Arkansas	United States	72205
7	Enloe Medical Center	Chico	California	United States	95926
8	Seton Medical Center	Daly City	California	United States	94015
9	City of Hope National Medical Center	Duarte	California	United States	91010
10	Kaiser Permanente South Bay Medical Center	Harbor City	California	United States	90710
11	University of Southern California	Los Angeles	California	United States	90033
12	University of California Irvine	Orange	California	United States	92868-3298
13	University of California Davis Medical Center	Sacramento	California	United States	95817
14	University of California San Francisco	San Francisco	California	United States	94114
15	California Pacific Medical Center	San Francisco	California	United States	94115
16	Santa Rosa Kaiser Medical	Santa Rosa	California	United States	95403
17	Exempla St. Joseph Hospital	Denver	Colorado	United States	80218
18	University of Colorado	Denver	Colorado	United States	80262
19	George Washington University Medical Center	Washington	District of Columbia	United States	20037
20	Idaho Falls Infectious Diseases, PLLC	Idaho Falls	Idaho	United States	83404
21	Loyola University	Maywood	Illinois	United States	60153
22	Indiana University	Indianapolis	Indiana	United States	46202-5124
23	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
24	Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
25	University of Kentucky	Lexington	Kentucky	United States	40536-0084
26	Tulane University	New Orleans	Louisiana	United States	70112
27	Johns Hopkins University	Baltimore	Maryland	United States	21287
28	National Institutes of Health	Bethesda	Maryland	United States	20892-1662
29	University of Michigan	Ann Arbor	Michigan	United States	48105
30	Wayne State University	Detroit	Michigan	United States	48201
31	Washington University in St. Louis	Saint Louis	Missouri	United States	63110-1093
32	Saint Louis University	St. Louis	Missouri	United States	63110
33	Mercury Street Medical Group	Butte	Montana	United States	59701
34	Infectious Disease Specialists, PC	Missoula	Montana	United States	59802
35	Central Nebraska Medical Clinic	Broken Bow	Nebraska	United States	68822
36	McCook Clinic, PC	McCook	Nebraska	United States	69001
37	Great Plains Regional Medical Center	North Platte	Nebraska	United States	69101
38	VA Medical Center - Omaha	Omaha	Nebraska	United States	68105
39	Creighton University	Omaha	Nebraska	United States	68131
40	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-7630
41	Clara Maass Medical Center	Belleville	New Jersey	United States	07109
42	University of New Mexico	Albuquerque	New Mexico	United States	87106
43	Flushing Hospital Medical Center	Flushing	New York	United States	11355
44	St. Alexius Medical Center	Bismarck	North Dakota	United States	58506
45	Dakota Clinic at Innovis	Fargo	North Dakota	United States	58103
46	MeritCare Hospital	Fargo	North Dakota	United States	58122
47	Trinity Health - Hospital	Minot	North Dakota	United States	58701
48	University Hospital	Cincinnati	Ohio	United States	45219
49	University Hospitals of Cleveland	Cleveland	Ohio	United States	44106
50	University of Toledo	Toledo	Ohio	United States	43614
51	Wright-Patterson Medical Center	Wright-Patterson AFB	Ohio	United States	45433
52	Legacy Good Samaritan	Portland	Oregon	United States	97210
53	Lehigh Valley Hospital	Allentown	Pennsylvania	United States	18103
54	The Reading Hospital and Medical Center	West Reading	Pennsylvania	United States	19611
55	Memorial Hospital of RI	Pawtucket	Rhode Island	United States	02860
56	Rhode Island Hospital	Providence	Rhode Island	United States	02903
57	Infectious Disease Consultations - Rapid City	Rapid City	South Dakota	United States	57701
58	Avera Research Institute	Sioux Falls	South Dakota	United States	57105
59	Vanderbilt University	Nashville	Tennessee	United States	37205
60	The University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390-8884
61	The University of Texas Medical Branch	Galveston	Texas	United States	77555-0167
62	The University of Texas Health Science Center at Houston	Houston	Texas	United States	77030
63	The University of Texas Health Science Center	San Antonio	Texas	United States	78229-3900
64	Wilford Hall Medical Center	San Antonio	Texas	United States	78236
65	The University of Texas Health Science Center at Tyler	Tyler	Texas	United States	75708
66	University of Virginia	Charlottesville	Virginia	United States	22908
67	University of Calgary	Calgary	Alberta	Canada	T2N4N
68	University of Alberta	Edmonton	Alberta	Canada	T6G 2B7
69	University of Manitoba	Winnipeg	Manitoba	Canada	R3E 0W3