MAIN STUDY: SWITCH SUB-STUDY: SWITCH-JCV

Multiple Sclerosis Clinical Trial

Official title:

MAIN STUDY: Switching Relapsing Multiple Sclerosis Patients Treated With Natalizumab at Risk for Progressive Multifocal Leukoencephalopathy to Teriflunomide: Is This Safe and Effective? SUB-STUDY: Analysis of JCV Antibody Index in MS Patients Treated With Teriflunomide

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01970410
• Other study ID #: SWITCH-001
• Status: Completed
• Phase: Phase 4
• Start date: October 2013
• Est. completion date: February 14, 2022

Study information

• Verified date: January 2023
• Source: Providence Health & Services
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 55
• Est. completion date: February 14, 2022
• Est. primary completion date: April 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 60 Years

Eligibility

MAIN STUDY

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.

Related Conditions & MeSH terms

• Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• teriflunomide
14 mg oral teriflunomide daily

Locations

Country	Name	City	State
United States	Multiple Sclerosis Center of Northeastern New York	Latham	New York
United States	Phoenix Neurological Associates, Ltd	Phoenix	Arizona
United States	Providence Multiple Sclerosis Center	Portland	Oregon

Sponsors (2)

Lead Sponsor	Collaborator
Providence Health & Services	Multiple Sclerosis Center of Northeastern New York

Country where clinical trial is conducted

United States, 

References & Publications (11)

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. — View Citation

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 pr — View Citation

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 natalizuma — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MAIN STUDY: Number of Participants Relapse Free at 24 Months	Number of patients relapses free by month 24.	24 months
Secondary	MAIN STUDY: Time to Return of Radiological Evidence of Multiple Sclerosis Activity With New Gadolinium "Enhancing" (Gd+) Lesions on Cranial MRI.	Mean time to first Gadolinium "enhancing" (GAD+) lesion in months.	24 months
Secondary	MAIN STUDY: Expanded Disability Status Scale (EDSS) Sustained Progression for 3 Months as Measured by at Least 0.5 Increase From Baseline or 1 in Any EDSS Set Score	Mean time to 3-month sustained disability worsening (SDW) in months. SDW is defined as an increase of = 1 point for patients with EDSS of 1.0-5.0, and = 0.5 points for patients with an EDSS of 5.5-6.0, sustained for 3 months. Patients with = 1 point increase in EDSS in whom a second measure was not obtained 3 months later were not included as SDW.	24 months
Secondary	MAIN STUDY: Mean Time to New T2 or Enlarging T2 Hyperintensities on Monthly Sentinel Brain MRIs	Mean time of new T2 or enlarging T2 Lesions	24 months