MAIN STUDY: SWITCH SUB-STUDY: SWITCH-JCV

NCT ID: NCT01970410

Last Updated: 2023-01-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 55 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-10-31
• Study Completion Date: 2022-02-14

Brief Summary

MAIN STUDY: 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.

SUB-STUDY: To study the number of patients experiencing a reduction in the anti-JCV antibody Index value in patients who had received at least one dose of teriflunomide during participation in the SWITCH protocol (main study).

Detailed Description

MAIN STUDY: Teriflunomide (TFM) 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 "enhancing" (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.

SUB-STUDY: John Cunningham virus (JCV) is the responsible organism for the development of progressive multifocal encephalopathy (PML). Multiple sclerosis (MS) patients treated with natalizumab (NTZ), who have evidence of exposure to JCV have a significantly elevated risk, as high as 12/1000 patients, of developing PML, necessitating the elective transition of patients off NTZ.

JCV is a member of the polyoma virus family, and closely related to BK virus. BK virus has been found to be a significant threat to destroy transplanted kidneys and there is growing evidence that treatment with leflunomide, the pro-drug of teriflunomide (TFM) clears BKV from the kidney.

Main study assessed the clinical efficacy of TFM in MS patients transitioned off NTZ solely because they have evidence of exposure to JCV, as determined by the presence of serum anti-JCV immunoglobulin G (IgG). Previous work by other investigators has demonstrated a close correlation between positive anti-JCV antibody titers and the presence of active JCV infection.

There is evidence that JCV is closely related to its fellow polyoma virus BKV, and that BKV is cleared by treatment with the TFM pro-drug leflunomide, we propose to determine if treatment of the JCV antibody positive patients currently enrolled in the approved protocol results in reduction in, or reversion to negative, of the anti-JCV antibody titer as measured by the JCV antibody Index, a commercially available assay which is used internationally as the standard for evidence of JCV exposure in NTZ-treated patients.

Conditions

Multiple Sclerosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Teriflunomide

Teriflunomide 14 mg oral teriflunomide daily

Group Type: EXPERIMENTAL

teriflunomide

Intervention Type: DRUG

14 mg oral teriflunomide daily

Interventions

teriflunomide

14 mg oral teriflunomide daily

Intervention Type: DRUG

Other Intervention Names

Aubagio

Eligibility 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 cerebrospinal fluid (CSF) for PML.
• No evidence of significant cognitive limitation or psychiatric disorder.
• Expanded Disability Status Scale (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 serum glutamate pyruvate transaminase (SGPT)/ Alanine transaminase (ALT), serum glutamate oxaloacetate transaminase (SGOT)/ aspartate aminotransferase (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

SUB-STUDY

Eligibility Criteria for JCV sub-study:

• Must have been enrolled in the SWITCH protocol and received at least 1 dose of 14mg TFM during the study period.
• Must be willing to sign written, informed consent for this JCV sub-study and follow protocol requirements.

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Multiple Sclerosis Center of Northeastern New York

OTHER

Sponsor Role: collaborator

Providence Health & Services

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Keith R Edwards, MD

Role: STUDY_DIRECTOR

Multiple Sclerosis Center of Northeastern New York

Stanley Cohan, MD, Ph. D

Role: PRINCIPAL_INVESTIGATOR

Providence Multiple Sclerosis Center

Locations

Phoenix Neurological Associates, Ltd

Phoenix, Arizona, United States

Multiple Sclerosis Center of Northeastern New York

Latham, New York, United States

Providence Multiple Sclerosis Center

Portland, Oregon, United States

Countries

United States

References

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Reference Type: BACKGROUND

PMID: 20880295 (View on PubMed)

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. doi: 10.1006/clim.1999.4777.

Reference Type: BACKGROUND

PMID: 10600330 (View on PubMed)

Ruckemann 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. doi: 10.1074/jbc.273.34.21682.

Reference Type: BACKGROUND

PMID: 9705303 (View on PubMed)

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. doi: 10.1056/NEJMoa044397.

Reference Type: BACKGROUND

PMID: 16510744 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20737510 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22591293 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20937940 (View on PubMed)

Stuve 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, Radu 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.

Reference Type: BACKGROUND

PMID: 18987352 (View on PubMed)

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983 Nov;33(11):1444-52. doi: 10.1212/wnl.33.11.1444.

Reference Type: BACKGROUND

PMID: 6685237 (View on PubMed)

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.

Reference Type: RESULT

PMID: 30729028 (View on PubMed)

Cohan S, Gervasi-Follmar T, Kamath A, Kamath V, Chen C, Smoot K, Baraban E, Edwards K. The results of a 24-month controlled, prospective study of relapsing multiple sclerosis patients at risk for progressive multifocal encephalopathy, who switched from prolonged use of natalizumab to teriflunomide. Mult Scler J Exp Transl Clin. 2021 Dec 16;7(4):20552173211066588. doi: 10.1177/20552173211066588. eCollection 2021 Oct.

Reference Type: RESULT

PMID: 34950502 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan: Sub Study

View Document

Document Type: Study Protocol and Statistical Analysis Plan: Main Study

View Document

Document Type: Informed Consent Form: Sub Study

View Document

Document Type: Informed Consent Form: Main study

View Document

Other Identifiers

SWITCH-001

Identifier Type: -

Identifier Source: org_study_id