Hu Mik-Beta-1 to Treat HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis
|First Received Date ICMJE||July 12, 2006|
|Last Updated Date||March 17, 2015|
|Start Date ICMJE||January 2004|
|Estimated Primary Completion Date||May 2016 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE||Not Provided|
|Original Primary Outcome Measures ICMJE||Not Provided|
|Change History||Complete list of historical versions of study NCT00076843 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Hu Mik-Beta-1 to Treat HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis|
|Official Title ICMJE||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|
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:
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.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 1|
|Study Design ICMJE||Primary Purpose: Treatment|
|Intervention ICMJE||Drug: Hu MiK-Beta-1
|Study Arm (s)||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Suspended|
|Estimated Completion Date||May 2016|
|Estimated Primary Completion Date||May 2016 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Patients must be at least 18 years old.
Patients must have a diagnosis of HAM/TSP as defined by the WHO criteria, including a positive HTLV-I EIA and confirmatory pattern on Western Blot analysis. Other causes of chronic progressive myelopathy are excluded by tests for serum B12 level, Lyme disease serologies, RPR, anti-nuclear antibody (ANA), extractable nuclear antigen (ENA) screen and magnetic resonance images of brain and spinal cord.
At least 7% of each patient's peripheral blood mononuclear cell population must react with anti-CD122 immunofluorescent cell staining.
Spontaneous lymphoproliferation and HTLV-I specific cytotoxic T lymphocyte responses must be demonstrated by the patient's peripheral blood mononuclear cells in ex vivo culture.
Patients must be willing to comply with all aspects of the dosing and evaluation procedure including taking the required medications and should be willing to return for the follow-up visits.
Patients must be able to provide written, informed consent prior to any testing under this protocol, including screening and baseline investigations that are not considered part of routine patient care.
EDSS greater than or equal to 7 (unable to walk beyond approximately 5 meters even with aid, essentially restructed to wheelchair).
Any contraindication to monoclonal antibody therapy, including serious adverse events related to prior monoclonal antibody therapy. Patients who have received prior antibody therapy will have pertinent medical records reviewed by the study investigator. Subjects with prior monoclonal antibody use (especially murine MiK- Beta 1) and allergy/sensitivity to murine MiK- Beta 1 are excluded.
Any vaccination within 30 days prior to study entry.
Any chronic bacterial, mycobacterial, other viral (e.g. herpes virus), fungal, parasitic or protozoal infection.
History of malignancy (active or within the previous 5 years).
History or signs of immunodeficiency
Subjects with pre-existing cardiac disease, abnormal baseline echocardiogram or significantly abnormal ECG will undergo evaluation by a cardiologist, and will be excluded if, in the opinion of the cardiologist, participation in the study would compromise the safety of the patient.
Subjects with history or laboratory evidence of thrombosis or hypercoagulable state.
Concurrent medical condition that in the opinion of the investigator would compromise the safety of the patient.
HAM/TSP patients with co-existing HTLV-I associated medical conditions, such as uveitis, alveolitis or keratoconjunctivitis sicca are not excluded unless, in the opinion of the investigator, participation in the protocol would compromise the safety of the patient. However, patients with clinically significant co-morbid neuromuscular conditions such as inflammatory myopathies and neuropathies are excluded.
Patients with cognitive impairment who are unable to provide written, informed consent.
The patient has received an investigational drug for this condition within 6 months prior to entering the study.
Contraindication to prophylactic anticoagulation with low molecular weight heparin such as history of hypersensitivity to enoxaparin, haparin, pork products, or any component of the formulation (including benzyl alcohol in multiple-dose vials); thrombocytopenia associated with a positive in vitro test for antiplatelet antibodies in the presence of enoxaparin
The patient requires concurrent therapy with other immuno-modulating agents including interferons, corticosteroids and daclizumab.
Serious illness requiring systemic treatment and /or hospitalization until the subject either completes therapy or is clinically stable (in the opinion of the investigator) on therapy for at least 14 days prior to the first dose.
Abnormal screening/baseline tests exceeding any of the limits defined below:
Pregnant or lactating patients.
Women who are not using an acceptable method of contraception. Acceptability of various methods of contraception will be determined by the investigator. Post-menopausal or surgically sterile women must have documentation of post-menopausal status or surgical sterility available prior to enrollment.
Men who are not practicing adequate contraception. Acceptability of various methods of contraception will be determined by the investigator. Surgically sterile men must have documentation of surgical sterility available prior to enrollment.
Active drug or alcohol use or dependence that in the opinion of the investigator would interfere with adherence to study requirements.
Unwillingness or inability to comply with the requirements of this protocol including the presence of any condition (physical, mental or social) that is likely to affect the patient returning for follow-up visits on schedule.
Subjects who withdraw from this study may not re-enter. Patients who have received prior investigational therapy for HAM/TSP including daclizumab and interferon Beta must be off the investigational therapy for 6 months prior to enrollment.
|Ages||18 Years and older|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00076843|
|Other Study ID Numbers ICMJE||040071, 04-N-0071|
|Has Data Monitoring Committee||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||National Institute of Neurological Disorders and Stroke (NINDS)|
|Collaborators ICMJE||Not Provided|
|Information Provided By||National Institutes of Health Clinical Center (CC)|
|Verification Date||April 2014|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP