Hu Mik-Beta-1 to Treat HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis
This study will examine the use of the humanized Mik-Beta-1 (Hu Mik-(SqrRoot) 1) monoclonal antibody in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Some patients infected with the human T-lymphotropic virus type 1 (HTLV-1) virus develop HAM/TSP, a disease in which the immune response to HTLV-1 becomes directed against the person's own body in what is called an autoimmune response. Hu-Mik-Beta-1 is a genetically engineered antibody that blocks the action of a chemical produced by the body during infection or inflammation called interleukin 15 (IL-15). Blocking IL-15 may prevent the autoimmune response that results in HAM/TSP.
Patients 18 years of age and older with HAM/TSP may be eligible for this study. Candidates are screened with a medical history and physical examination, blood and urine tests, and an electrocardiogram. Participants undergo the following procedures:
Baseline visit(s): Repeat physical examination and blood and urine tests, as well as the following:
- Lumbar puncture: A local anesthetic is injected to numb the skin of the lower back. A needle is inserted in the space between the bones where the cerebrospinal fluid that bathes the brain and spinal cord circulates below the spinal cord. About 4 tablespoons of fluid is collected through the needle.
- Magnetic resonance imaging (MRI): This test uses radio waves and magnets to produce images of body tissues and organs. The patient lies on a table that slides into a metal cylinder surrounded by a strong magnetic field. During part of the scan, a contrast agent is injected to brighten the images.
- Apheresis: This procedure is used to collect large quantities of white blood cells. Whole blood is collected through a needle in an arm vein and directed into a machine that separates it into its components by spinning. The white cells and plasma are removed and the rest of the blood (red cells and platelets) is returned to the body through the same needle.
- Hu Mik-Beta-1 treatment: Infusions of Hu Mik-Beta-1 are given through a vein every 3 weeks for nine doses. The first treatment requires at least an overnight hospital stay; subsequent infusions are given in the outpatient clinic.
- Blood and urine tests and a physical examination at every treatment visit and a skin test at one treatment visit.
- Research tests at the end of the 24-week treatment period, including lumbar puncture (spinal tap), MRI scan, and apheresis.
- After completing treatment, patients have three follow-up clinic visits for blood and urine tests, and a skin test at one follow-up visit.
|Study Design:||Primary Purpose: Treatment|
|Official Title:||Phase I/II Study of HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) Using the Humanized MiK-Beta-1 Monoclonal Antibody Directed Toward the IL-2/IL-15R-Beta Subunit (CD122) That Blocks IL-15 Action|
|Study Start Date:||January 2004|
|Estimated Study Completion Date:||May 2017|
|Estimated Primary Completion Date:||December 2016 (Final data collection date for primary outcome measure)|
In a phase I/II trial we wish to determine the toxicity and provide preliminary clinical response information following the administration of humanized MiK-beta-1 (Hu MiK-Beta1), a monoclonal antibody directed toward IL-2/IL-15R Beta (CD122), in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This antibody blocks the action of IL-15, a cytokine involved in the pathogenesis of HTLV-I associated diseases and autoimmune disorders such as rheumatoid arthritis and multiple sclerosis.
HAM/TSP affects about 1% of patients infected with the human T lymphotropic virus type 1 (HTLV-I), manifesting as progressive myelopathy. Several features of the immune response in HAM/TSP indicate that IL-15 may be critical to its pathogenesis. HTLV-I transactivates IL-15 and IL-15 R alpha expression through its tax protein, and supports the activation of lymphocytes in HAM/TSP, as evidenced by their spontaneous proliferation in ex vivo culture. We showed that the antibody HuMiK-Beta1 could inhibit this spontaneous lymphoproliferation. In addition, IL-15 has been shown to have a preferential positive effect on the survival of CD8+ T-cells, especially those of the memory phenotype. In HAM/TSP, an extraordinarily high frequency of tax specific CD8+ T-cells in the peripheral blood and cerebrospinal fluid is postulated to participate in the damage to the central nervous system. We have demonstrated that the addition of Hu MiK-Beta1 to ex vivo cells from HAM/TSP patients led to a marked decline in tax specific CD8+ T-cells.
Design of the Study and Outcome Parameters
In this single center, open label trial, four subjects with HAM/TSP will receive 0.5 mg/kg Hu MiK-beta1 dosed every three weeks for a total of five doses, and two subjects with HAM/TSP will receive placebo (normal saline) under the same dosing schedule. In addition, following the completion of the 0.5 mg/kg dose administration in four subjects with HAM/TSP, a dose escalation study will be performed with three subjects with HAM/TSP receiving 1.0 mg/kg of Hu MiK-beta1 at three week intervals for a total of five doses per subject, and three subjects with HAM/TSP receiving 1.5 mg/kg of Hu MiK-beta1 at three week intervals for a total of five doses per subject A Total of 10 subjects will receive study drug/placebo. We anticipate consenting up to eighteen subjects to allow for up to eight dropouts. Participants who withdraw voluntarily (not due to toxicity) after initiation of the study are considered dropouts. If this occurs prior to receiving three doses of the study medication the subjects can be replaced and should have three follow-up evaluations at four-week intervals following the last dose of the study drug. Patients who voluntarily drop out after receiving at least 3 doses of the study drug will remain in the study and continue the protocol-specific evaluations. Toxicity will be assessed using standard criteria. The clinical response will be evaluated using standardized scales including expanded disability status scale, Scripps neurologic rating scale and ambulation index. In addition, viral and immunologic outcome measures will include assays of spontaneous lymphoproliferation analysis of HTLV-I tax tetramer specific CD8+ cells, HTLV-I proviral load determination and T-cell phenotype analysis.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00076843
|Contact: Steven Jacobson, Ph.D.||(301) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL) 800-411-1222 ext TTY8664111010 email@example.com|
|Principal Investigator:||Steven Jacobson, Ph.D.||National Institute of Neurological Disorders and Stroke (NINDS)|