Teriflunomide in HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis

• ClinicalTrials.gov Identifier: NCT04799288
• Recruitment Status: Recruiting
• First Posted: March 16, 2021
• Last Update Posted: March 16, 2023
• Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )

Study Description

Brief Summary:

Background:

HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare, progressive disease. It occurs in some people infected with the HTLV-1 virus. It leads to weakness in the lower limbs and other serious problems. It has no treatment. Teriflunomide is a drug used to treat multiple sclerosis. It reduces immune cells that make the disease worse. Researchers want to learn if this drug can help people with HAM/TSP.

Objective:

To learn the effects, immune response, safety, and tolerability of teriflunomide in people with HAM/TSP.

Eligibility:

Adults ages 18 and older with HAM/TSP.

Design:

Participants will be screened under protocol 98-N-0047.

Participants will have a medical history. They will have physical and neurological exams. They will have blood and urine tests.

Participants will take 1 tablet of the study drug once a day for 9 months. They will keep a drug diary.

Participants will have lymphapheresis. For this, blood is drawn from a needle in one arm. A machine divides the blood into red cells, plasma, and white cells. The white cells are removed. The plasma and red cells are returned to the participant through a needle in the other arm.

Participants will have lumbar punctures ( spinal taps ). For this, a thin needle is inserted into the spinal canal in the lower back. Spinal fluid is removed.

Participants will have magnetic resonance imaging (MRI) of the brain and spine. The MRI scanner is a metal cylinder surrounded by a strong magnetic field. During the MRI, participants will lie on a table that can slide in and out of the scanner.

Participation will last for 15 months.

Condition or disease	Intervention/treatment	Phase
HAM/TSP	Drug: Teriflunomide	Phase 1; Phase 2

Detailed Description:

Study Description:

In this single center, single arm, open label, baseline versus treatment pilot clinical trial, sixteen subjects with HAM/TSP will receive teriflunomide 14mg by mouth once a day in an initial 9 month treatment phase, followed by a 3 month post treatment follow-up phase. Outcome measures will be collected every 3 months for the duration of the study.

Objectives:

We will determine the effects of teriflunomide, an FDA approved drug for the treatment of relapsing remitting multiple sclerosis that inhibits de novo pyrimidine synthesis, on immune activation markers in patients with HAM/TSP and the correlation of these with virological, radiological and clinical measures of disease burden .

Endpoints:

The primary outcome measure is ex vivo spontaneous lymphoproliferation in HAM/TSP patients receiving teriflunomide. Secondary outcome measures will include determination of immune activation patterns of PBMC and CSF using multicolor flow cytometric analysis and HTLV-I proviral load in blood and CSF. Safety and tolerability of teriflunomide will be assessed by tabulation of adverse events, clinical exam, standardized neurological disability scales (EDSS, IPEC, HAQ-DI), MR imaging of brain and spinal cord and clinical laboratory studies.

Study Population:

Up to 24 adults with HAM/TSP, targeting at least 16 participants who complete 9 months of treatment with teriflunomide

Phase:

I/II

Description of Sites/Facilities Enrolling Participants:

NIH Clinical Center

Description of Study Intervention:

Administration of teriflunomide 14mg daily for 9 months

Study Duration:

48 months

Participant Duration:

15 months

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of Teriflunomide in HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis
• Actual Study Start Date: September 24, 2021
• Estimated Primary Completion Date: August 31, 2025
• Estimated Study Completion Date: August 31, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Teriflunomide; Teriflunomide 14 mg daily	Drug: Teriflunomide; Teriflunomide 14mg will be administered orally as 1 tablet once daily during the 9-month treatment phase of the study.

Outcome Measures

Primary Outcome Measures :

1. ex vivo spontaneous lymphoproliferation in HAM/TSP patients receiving teriflunomide [ Time Frame: Percent change between Day 0 and month 9 of spontaneous proliferation. ]
   ex vivo spontaneous lymphoproliferation of HAM/TSP patients receiving teriflunomide and multicolor flow cytometric analysis of immune activation markers in both PBMCs and CSF

Secondary Outcome Measures :

1. Tabulation of adverse events [ Time Frame: at each visit ]
   This is a first in HAM/TSP pilot study using teriflunomide thus important to monitor for any unexpected events related to worsening of disease laboratory and clinical measures.
2. Percent change between CD8+ and CD4+ cells in the CSF [ Time Frame: between month -3 and month 9 ]
   CD8 cells are thought to be immunopathogenic and drive the immune response. In vitro studies have shown a reduction of CD8+ and CD4+ cells in the presences of teriflunomide.
3. HTLV-1 proviral load in the peripheral blood mononuclear cells (PBMCs) [ Time Frame: at month 9 and compared to Day 0 ]
   HTLV-1 proviral load is a measure of the percent of infected cells and previous data suggests a correlation with disease activity.
4. HTLV-1 proviral load in the CSF cells [ Time Frame: at month 9 and compared to month -3 ]
   HTLV-1 proviral load is a measure of the percent of infected cells and previous data suggests a correlation with disease activity.
5. Change in IPEC score [ Time Frame: at month 9 and compared to Day 0 ]
   This is a first in HAM/TSP pilot study using teriflunomide thus important to monitor for any unexpected events related to worsening of clinical measures.
6. Change in EDSS score [ Time Frame: at month 9 and compared to Day 0 ]
   This is a first in HAM/TSP pilot study using teriflunomide thus important to monitor for any unexpected events related to worsening of clinical measures.
7. Change in 25-foot timed walk [ Time Frame: at month 9 and compared to Day 0 ]
   This is a first in HAM/TSP pilot study using teriflunomide thus important to monitor for any unexpected events related to worsening of clinical measures.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• 18 years or older
• Diagnosis of HAM/TSP as defined by WHO criteria, including a positive HTLV-1 EIA and confirmatory Western Blot.
• Enrolled in 98-N-0047
• Patient must be willing and able to comply with all the aspects of trial design and follow-up.
• Negative QuantiFERON-TB gold, or completion of latent tuberculosis infection treatment, per CDC and National TB Controllers Association recommendations
• Ability to take oral medication and be willing to adhere to the protocol regimen
• Patients must be able to provide informed consent
• If able to become pregnant or to father a child, patient must agree to commit to the use of a reliable/accepted method of birth control (i.e. hormonal contraception (birth control pills, injected hormones, vaginal ring), intrauterine device, barrier methods with spermicide (diaphragm with spermicide, condom with spermicide) or surgical sterilization (hysterectomy, tubal ligation, or vasectomy) for the duration of the treatment arm of the study and for two years following cessation of treatment with teriflunomide.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

• Alternative diagnoses that can explain neurological disability
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial or interfere with participation for the full duration of the trial; or not in the best interest of the subject to participate, in the opinion of the treating investigator
• Severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections.
• Liver dysfunction, as indicated by baseline aspartate aminotransferase (AST) or alanine or alanine aminotransferase (ALT) greater than 2 times the upper limit of normal
• Positive serological evidence of HIV, HTLV II, Hepatitis B or C
• Treatment with immunomodulatory/immunosuppressive therapy (aside from topical steroids) in the preceding 6 months.
• Pregnant or lactating women.
• Treatment with other investigational drugs within 6 months before enrollment
• Known hypersensitivity to teriflunomide or leflunomide
• Concomitant treatment with leflunomide

Contacts and Locations

Contacts

Contact: Anita M Fletcher, M.D.; (301) 496-1801; anita.fletcher@nih.gov

Contact: Steven Jacobson, Ph.D.; (301) 496-0519; jacobsons@ninds.nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 prpl@cc.nih.gov

Sponsors and Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Steven Jacobson, Ph.D.; National Institute of Neurological Disorders and Stroke (NINDS)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

• Responsible Party: National Institute of Neurological Disorders and Stroke (NINDS)
• ClinicalTrials.gov Identifier: NCT04799288
• Other Study ID Numbers: 210016; 21-N-0016
• First Posted: March 16, 2021
• Last Update Posted: March 16, 2023
• Last Verified: March 13, 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: .All IPD that results in a publication
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: 6 months after publication
• Access Criteria: IPD will be shared under tech transfer agreements.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) ):

Aubagio; Single center; Open Label

Additional relevant MeSH terms:

Paraparesis, Tropical Spastic; Spinal Cord Diseases; Paraparesis; Paraparesis, Spastic; Neurologic Manifestations; Nervous System Diseases; Central Nervous System Diseases; Paresis; Myelitis; Central Nervous System Infections; Infections; HTLV-I Infections; Deltaretrovirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Teriflunomide; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors