DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more



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

Information source: Multiple Sclerosis Center of Northeastern New York
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Multiple Sclerosis

Intervention: teriflunomide (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Multiple Sclerosis Center of Northeastern New York

Official(s) and/or principal investigator(s):
Keith R Edwards, MD, Study Director, Affiliation: Multiple Sclerosis Center of Northeastern New York
Stanley Cohan, MD, Ph. D, Principal Investigator, Affiliation: Providence Multiple Sclerosis Center

Overall contact:
Carol Gorman, LPN, CRC, Phone: 518-785-1000, Email: cgorman@tristateneuro.com

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.

Clinical Details

Official title: Switching Relapsing Multiple Sclerosis Patients Treated With Natalizumab at Risk for Progressive Multifocal Leukoencephalopathy to Teriflunomide: Is This Safe and Effective?

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Proportion of patients relapse free at 12 months

Secondary outcome:

Time to return of radiological evidence of MS activity with new Gd+ lesions on cranial MRI.

EDSS sustained progression for 3 months as measured by at least 0.5 increase from baseline or 1 in any EDSS set score

Number of new T2 or enlarging T2 hyperintensities on monthly sentinel brain MRIs

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

Minimum age: 21 Years. Maximum age: 60 Years. Gender(s): Both.

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

Locations and Contacts

Carol Gorman, LPN, CRC, Phone: 518-785-1000, Email: cgorman@tristateneuro.com

Multiple Sclerosis Center of Northeastern New York, Latham, New York 12110, United States; Recruiting
Judy Button, BS, CRC, Phone: 518-785-1000, Email: jbutton@tristateneuro.com
Keith R Edwards, MD, Principal Investigator

Providence Multiple Sclerosis Center, Portland, Oregon 97225, United States; Recruiting
Stanley Cohan, MD, Ph. D, Principal Investigator

Additional Information

Related 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.

Starting date: October 2013
Last updated: November 4, 2013

Page last updated: August 23, 2015

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017