Recombinant Human Interferon Beta-1a (Avonex) for the Treatment of Patients With HTLV-1-Associated Myelopathy (HAM)

Brief Title

Recombinant Human Interferon Beta-1a (Avonex) for the Treatment of Patients With HTLV-1-Associated Myelopathy (HAM)

Official Title

Combined Virological and Immunological Evaluation of Treatment of Patients With Early HTLV-1-Associated Myelopathy With Recombinant Human Interferon Beta-1a

Brief Summary

      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.
    

Detailed Description

      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.
    

Study Phase

Phase 2

Study Type

Interventional




Condition

HTLV-I Infection

Intervention

Recombinant human interferon beta-1a


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

12

Start Date

September 1998

Completion Date

September 2004


Eligibility Criteria

        INCLUSION CRITERIA:

        patients entering this study will:

        be at least 16 years old;

        meet diagnostic criteria for HAM/TSP as defined by the WHO and current literature;

        have progression of the clinical symptoms during the past 12 months;

        have an EDSS of less than or equal to 7;

        have spontaneous in vitro lymphoproliferation;

        able to provide written informed consent;

        able to comply with protocol requirements;

        if a females, be not of a child bearing potential or if of child bearing potential
        documented to be non-pregnant by urine pregnancy test with adequate counseling and
        contraception.

        EXCLUSION CRITERIA:

        Patients entering this study will not:

        be pregnant or lactating;

        be HIV, HCV, or hepatitis B surface antigen positive;

        have a significant medical condition that in the opinion of the investigator would
        compromise the safety of the patient;

        have a history of suicidal ideations and no major depressive event (DSM-IV) within 3 months
        of enrollment;

        have used an investigational medication or steroids within 90 days of the enrollment visit;

        have a history of an allergic reaction to albumin;

        have metallic fragments, ferromagnetic surgical clips, and implanted electronic devices
        (cardiac pace makers, vagal nerve stimulators);

        drug abuse.
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00001785

Organization ID

980160

Secondary IDs

98-N-0160


Study Sponsor

National Institute of Neurological Disorders and Stroke (NINDS)


Study Sponsor

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Verification Date

September 2004