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

• ClinicalTrials.gov Identifier: NCT01970410
• Recruitment Status: Active, not recruiting
• First Posted: October 28, 2013
• Last Update Posted: March 22, 2018
• Sponsor: Multiple Sclerosis Center of Northeastern New York
• Collaborator: Providence Multiple Sclerosis Center
• Information provided by (Responsible Party): Multiple Sclerosis Center of Northeastern New York

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Multiple Sclerosis	Drug: teriflunomide	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 70 participants
• Intervention Model: Single Group Assignment
• Masking: None (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?
• Study Start Date: October 2013
• Estimated Primary Completion Date: June 2018
• Estimated Study Completion Date: June 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Teriflunomide; Teriflunomide 14 mg oral teriflunomide daily	Drug: teriflunomide; 14 mg oral teriflunomide daily; Other Name: Aubagio

Outcome Measures

Primary Outcome Measures :

1. Proportion of patients relapse free at 12 months [ Time Frame: 12 months ]

Secondary Outcome Measures :

1. Time to return of radiological evidence of MS activity with new Gd+ lesions on cranial MRI. [ Time Frame: 12 months ]
2. 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 ]
3. Number of new T2 or enlarging T2 hyperintensities on monthly sentinel brain MRIs [ Time Frame: 12 months ]

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• 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

Locations

United States, Arizona

Phoenix Neurological Associates, Ltd

Phoenix, Arizona, United States, 85018

United States, New York

Multiple Sclerosis Center of Northeastern New York

Latham, New York, United States, 12110

United States, Oregon

Providence Multiple Sclerosis Center

Portland, Oregon, United States, 97225

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 of Results:

Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2;354(9):899-910.

Gorelik L, Lerner M, Bixler S, Crossman M, Schlain B, Simon K, Pace A, Cheung A, Chen LL, Berman M, Zein F, Wilson E, Yednock T, Sandrock A, Goelz SE, Subramanyam M. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol. 2010 Sep;68(3):295-303. doi: 10.1002/ana.22128.

Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012 May 17;366(20):1870-80. doi: 10.1056/NEJMoa1107829.

Miravalle A, Jensen R, Kinkel RP. Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Arch Neurol. 2011 Feb;68(2):186-91. doi: 10.1001/archneurol.2010.257. Epub 2010 Oct 11.

Stüve O, Cravens PD, Frohman EM, Phillips JT, Remington GM, von Geldern G, Cepok S, Singh MP, Tervaert JW, De Baets M, MacManus D, Miller DH, Radü EW, Cameron EM, Monson NL, Zhang S, Kim R, Hemmer B, Racke MK. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology. 2009 Feb 3;72(5):396-401. doi: 10.1212/01.wnl.0000327341.89587.76. Epub 2008 Nov 5.

Other Publications:

Gold R, Wolinsky JS. Pathophysiology of multiple sclerosis and the place of teriflunomide. Acta Neurol Scand. 2011 Aug;124(2):75-84. doi: 10.1111/j.1600-0404.2010.01444.x. Epub 2010 Sep 29. Review.

Fox RI, Herrmann ML, Frangou CG, Wahl GM, Morris RE, Strand V, Kirschbaum BJ. Mechanism of action for leflunomide in rheumatoid arthritis. Clin Immunol. 1999 Dec;93(3):198-208. Review.

Rückemann K, Fairbanks LD, Carrey EA, Hawrylowicz CM, Richards DF, Kirschbaum B, Simmonds HA. Leflunomide inhibits pyrimidine de novo synthesis in mitogen-stimulated T-lymphocytes from healthy humans. J Biol Chem. 1998 Aug 21;273(34):21682-91.

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983 Nov;33(11):1444-52.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Cohan SL, Edwards K, Lucas L, Gervasi-Follmar T, O'Connor J, Siuta J, Kamath V, Garten L, Chen C, Thomas J, Smoot K, Kresa-Reahl K, Spinelli KJ. Reducing return of disease activity in patients with relapsing multiple sclerosis transitioned from natalizumab to teriflunomide: 12-month interim results of teriflunomide therapy. Mult Scler J Exp Transl Clin. 2019 Jan 16;5(1):2055217318824618. doi: 10.1177/2055217318824618. eCollection 2019 Jan-Mar.

• Responsible Party: Multiple Sclerosis Center of Northeastern New York
• ClinicalTrials.gov Identifier: NCT01970410 History of Changes
• Other Study ID Numbers: SWITCH-001
• First Posted: October 28, 2013
• Last Update Posted: March 22, 2018
• Last Verified: March 2018

Keywords provided by Multiple Sclerosis Center of Northeastern New York:

teriflunomide; natalizumab; relapsing multiple sclerosis

Additional relevant MeSH terms:

Multiple Sclerosis; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Natalizumab; Immunologic Factors; Physiological Effects of Drugs