Safety and Effectiveness of Switching Relapsing MS Patients Treated With Natalizumab at Risk for PML to Teriflunomide

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by Multiple Sclerosis Center of Northeastern New York
Sponsor:
Collaborator:
Providence Multiple Sclerosis Center
Information provided by (Responsible Party):
Multiple Sclerosis Center of Northeastern New York
ClinicalTrials.gov Identifier:
NCT01970410
First received: October 22, 2013
Last updated: November 4, 2013
Last verified: November 2013
  Purpose

The purpose of this study is to determine if teriflunomide will be safe and effective to prevent relapses in patients with relapsing types of MS when switching from natalizumab to teriflunomide in patients at risk for PML. This is a two center interventional study of patients who have had 12 or more continuous infusions of natalizumab , who are anti-JCV-ab positive, and who had been free of clinical relapses during prior 12 months of natalizumab therapy who will be switching to teriflunomide.


Condition Intervention Phase
Multiple Sclerosis
Drug: teriflunomide
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Switching Relapsing Multiple Sclerosis Patients Treated With Natalizumab at Risk for Progressive Multifocal Leukoencephalopathy to Teriflunomide: Is This Safe and Effective?

Resource links provided by NLM:


Further study details as provided by Multiple Sclerosis Center of Northeastern New York:

Primary Outcome Measures:
  • Proportion of patients relapse free at 12 months [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Time to return of radiological evidence of MS activity with new Gd+ lesions on cranial MRI. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • EDSS sustained progression for 3 months as measured by at least 0.5 increase from baseline or 1 in any EDSS set score [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Number of new T2 or enlarging T2 hyperintensities on monthly sentinel brain MRIs [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 70
Study Start Date: October 2013
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Teriflunomide
Teriflunomide 14 mg oral teriflunomide daily
Drug: teriflunomide
14 mg oral teriflunomide daily
Other Name: Aubagio

Detailed Description:

Teriflunomide is the primary metabolite of leflunomide, which is marketed worldwide for the treatment of rheumatoid arthritis. Teriflunomide inhibits dihydroorotate dehydrogenase( DHODH), the forth enzyme in the de novo synthesis pathway of pyrimidines.Activated T-lymphocytes utilize both the de novo pyrimidine and salvage pathways of pyrimidines ribonucleotide synthesis.After mitogen stimulation, teriflunomide inhibits in vitro T cell proliferation, DNA and RNA synthesis and expression of cell surface and nuclear antigens that are directly involved in T-cell activation and proliferation.

Natalizumab (NTZ) is a FDA approved treatment for relapsing-forms of multiple sclerosis (MS) with pivotal studies showing an annualized relapse-rate (ARR) reduction of 68%, a reduction of new gadolinium (Gd+) lesions by 92% and a reduction of disability of 42% compared to placebo.NTZ is highly effective in controlling MS but the risk of developing progressive multifocal leukoencephalopathy (PML) increases with the duration of the use of natalizumab. It can have a serious and life threatening complication in about 1 in 500 to 1 in 250 patients who have had more that 18 infusions due PML and who have a detected antibody (Ab) for the JC virus. The risk of PML is much greater in patients who have had prior immunosuppressive (IS) treatment. The combination of detected anti-JCV Ab , duration of NTZ treatment of greater than 24 months and prior IS increases the risk of development PML to an incidence of 11 per 1000 treated patients. So there is a need to have an alternative MS disease modifying treatment (DMT) to use for patients at risk to develop PML from NTZ treatment that might be sufficiently effective for MS so as not to have the patients' MS worsen while lowering or eliminating the risk of PML.

  Eligibility

Ages Eligible for Study:   21 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male and female patients, age 21 to 60 with relapsing forms of MS, treated with natalizumab for 12 consecutive months or longer with anti-JCV Ab positive during that time period.
  • Able to understand and sign Informed Consent Document.
  • Stable disease during treatment with natalizumab. No clinical relapses for at least 12 months.
  • Stable MRI on follow-up MRI scans for prior 12 months without evidence of new or enlarging T-2 hyperintensities or Gd+ lesions.
  • No clinical evidence by imaging or CSF for PML.
  • No evidence of significant cognitive limitation or psychiatric disorder.
  • EDSS of 1.0 to 6.0 inclusive.

Exclusion Criteria:

  • Any mental condition of such that patient is unable to understand the nature, scope and possible consequences of the study.
  • Patients that are known HIV positive.
  • Patients with a known history of hepatitis.
  • Known history of active tuberculosis not adequately treated, or a positive ppd skin test or positive quantiferon gold.
  • Any persistent or severe infection.
  • Any malignancy within 5 years, except for Basal or Squamous cell skin lesions, which have been surgically excised, with no evidence of metastasis.
  • Clinically relevant or unstable cardiovascular, neurological (i.e. progressive weakness, increasing hypesthesia), endocrine, or other major systemic diseases.
  • History of drug or alcohol abuse within the past year.
  • Any significant depression or psychiatric disease (BDI II greater than 25) within the past year.
  • Any significant lab abnormality as deemed by the investigator including but not limited to the following:

    1. Hypoproteinemia with serum albumin < 3.0g/dl.
    2. Serum creatinine >133umol/L (or >1.5 mg/dl)
    3. Hematocrit <24% and/or
    4. Absolute white blood cell count < 4,000 cells/mm3 (µl) and/or
    5. Platelet Count <150,000 cells/mm3 (µl) and /or
    6. Absolute neutrophil < 1,500 cells/mm3 (µl)
    7. Liver function impairment or persisting elevations of SGPT/ALT, SGOT/AST, or direct bilirubin greater than 1.5 fold the upper limit of normal.
  • Any confounding illness or other diseases of the spine or bone that would impair evaluation of the patient or treatment effects.
  • Any clinical, CSF or MRI evidence for PML.
  • Prior treatment with immunosuppressive drugs except for past use of intravenous steroids to treat MS relapses.
  • Pregnant or breast feeding women.
  • Women of childbearing potential not protected by effective contraceptive method of birth control and/or are unwilling or unable to be tested for pregnancy.
  • In the conception of a child during the course of the trial.
  • Known history of hypersensitivity to teriflunomide or leflunomide.
  • Persisting elevations (confirmed by retest) of serum amylase or lipase greater than 2-fold the upper limit of normal.
  • Known history of chronic pancreatic disease or pancreatitis.
  • Prior use within 4 weeks before randomization or concomitant use of phenytoin, warfarin, tolbutamide, cholestyramine, or products containing St. John's Wort
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01970410

Contacts
Contact: Carol Gorman, LPN, CRC 518-785-1000 cgorman@tristateneuro.com

Locations
United States, New York
Multiple Sclerosis Center of Northeastern New York Recruiting
Latham, New York, United States, 12110
Contact: Judy Button, BS, CRC    518-785-1000    jbutton@tristateneuro.com   
Principal Investigator: Keith R Edwards, MD         
United States, Oregon
Providence Multiple Sclerosis Center Recruiting
Portland, Oregon, United States, 97225
Principal Investigator: Stanley Cohan, MD, Ph. D         
Sponsors and Collaborators
Multiple Sclerosis Center of Northeastern New York
Providence Multiple Sclerosis Center
Investigators
Study Director: Keith R Edwards, MD Multiple Sclerosis Center of Northeastern New York
Principal Investigator: Stanley Cohan, MD, Ph. D Providence Multiple Sclerosis Center
  More Information

Publications:

Responsible Party: Multiple Sclerosis Center of Northeastern New York
ClinicalTrials.gov Identifier: NCT01970410     History of Changes
Other Study ID Numbers: SWITCH-001
Study First Received: October 22, 2013
Last Updated: November 4, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Multiple Sclerosis Center of Northeastern New York:
teriflunomide
natalizumab
relapsing multiple sclerosis

Additional relevant MeSH terms:
Leukoencephalopathy, Progressive Multifocal
Leukoencephalopathies
Multiple Sclerosis
Sclerosis
Encephalitis, Viral
Encephalitis
Central Nervous System Viral Diseases
Virus Diseases
Polyomavirus Infections
DNA Virus Infections
Slow Virus Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Central Nervous System Infections
Demyelinating Diseases
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Autoimmune Diseases
Immune System Diseases
Pathologic Processes

ClinicalTrials.gov processed this record on July 23, 2014