Tropical Spastic Paraparesis Clinical Trial
Official title:
Combined Virological and Immunological Evaluation of Treatment of Patients With Early HTLV-1-Associated Myelopathy With Recombinant Human Interferon Beta-1a
HTLV stands for human T cell leukemia virus. HTLV-1 is a virus that attacks specific kinds
of white blood cells called T cells. T cells are part of the natural defense system of the
body. HTLV-1 has been associated with leukemia and lymphoma. In addition, approximately 1%
of all patients infected with HTLV-1 develops a condition known as HTLV-1 associated
myelopathy (HAM) / tropical spastic paraparesis (TSP).
Currently there is no clearly defined, effective treatment for patients with HAM/TSP.
Steroids have been used as therapy but have only been able to provide temporary relief of
symptoms. Human interferon is a small protein released from different kinds of cells in the
body. Interferon has been known to have antiviral and immunological effects and has been
used to treat hepatitis and multiple sclerosis. Interferon Beta is released from cells
called fibroblasts. These cells play a role in the production of connective tissue.
The purpose of this study is to evaluate the possible role of recombinant interferon beta
(Avonex) in treatment of HAM/TSP. The study is broken into three phases, a pre-treatment
phase, a treatment phase, and a post-treatment phase. The total duration of the study will
be 44 weeks.
Patients participating in this study will receive injections of Avonex 1 to 2 times a week.
Throughout the study patients will regularly submit blood samples and undergo diagnostic
tests such as MRI and measures of somatosensory evoked potentials.
HTLV-1 has been linked to a chronic, slowly progressive neurologic condition termed HTLV-1
associated spastic paraparesis or tropical spastic paraparesis (HAM/TSP) which affects about
1% of the infected individuals. The disease is thought to be due to a T cell viral induced
immunopathological process. A high frequency of HTLV-1 specific CD8 T cells are found in
patients with HAM/TSP. The immune system of patients infected with HTLV-1 appears to be
dysregulated, and increased spontaneous T cell proliferation can be demonstrated in vitro.
This is in part due to continuous antigenic stimulation and due to transactivation by the
HTLV-1 encoded Tax protein of host immunomodulatory genes such as CD80, CD86, IL-2 and its
receptor. In addition, an increased viral load has been demonstrated in symptomatic
individuals compared to asymptomatic HTLV-1 carriers. It is thought that the local immune
response to the virus within the central nervous system plays a role in the pathogenesis of
progressive spastic encephalomyeloneuropathy of HAM/TSP. Therefore, reduction of spontaneous
T cell proliferation and viral replication, as well as decrease of the compromise of the
blood brain barrier may ameliorate the immune-mediated component of the process which leads
to inflammatory destruction of nervous tissue in HAM/TSP.
Currently there is no clearly defined, effective treatment of patients with HAM/TSP.
Corticosteroids are the mainstay of therapy but provide mostly only transient symptomatic
relief. Treatment with human interferon has been shown to improve acute and chronic
hepatitis through its anti-viral and cytostatic effects. Further, patients with
relapsing-remitting multiple sclerosis, a disease thought to be at least in part a T cell
mediated, immunopathological process, exhibit a marked reduction of the frequency of new
lesion formation while on this medication. This latter effect may in part be explained by an
anti-inflammatory effect of interferon which allows repair of the blood brain barrier. To
evaluate possible role interferon beta in the treatment of HAM/TSP, we studied its effect on
induction on regulatory factors and spontaneous in vitro proliferation of peripheral blood
lymphocytes (PBLs) from HTLV-I infected individuals. Recombinant interferon beta-1b
inhibited spontaneous proliferation of PBLs from asymptomatic HTLV-1 carriers and patients
with HAM/TSP in a dose dependent manner and induced expression of interferon regulatory
factor-2 which is associated with down regulation of proinflammatory cytokines such as
interferon gamma. These preliminary results indicate that treatment with interferon-b may
ameliorate the immune dysregulation induced by HTLV-1 and may have therapeutic effect in the
treatment of HAM/TSP.
Twelve patients will be treated with administration of recombinant human interferon-beta1a.
Assessment of efficacy will be based on reduction of spontaneous proliferation and proviral
load. As a secondary measure the clinical response of patients will be evaluated. The study
will entail an 8-week pretreatment period, a 28-week treatment phase with escalation of the
interferon-beta1a dose, and a 12-week post-treatment phase. In cases where dose escalation
leads to intolerable side-effects, patients will be continued at the highest tolerated dose
of medication. Spontaneous proliferation, viral load, and clinical parameters will be
determined monthly.
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Endpoint Classification: Safety/Efficacy Study, Primary Purpose: Treatment
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