Assessment of Tecfidera® in Radiologically Isolated Syndrome (RIS) (ARISE)

• ClinicalTrials.gov Identifier: NCT02739542
• Recruitment Status: Completed
• First Posted: April 15, 2016
• Results First Posted: May 11, 2022
• Last Update Posted: May 11, 2022
• Sponsor: University of Texas Southwestern Medical Center
• Collaborator: Biogen
• Information provided by (Responsible Party): Darin Okuda, University of Texas Southwestern Medical Center

Study Description

Brief Summary:

The purpose of this investigation is to systematically study the efficacy of Tecfidera in those individuals who possess incidental white matter anomalies within the brain following a MRI study that is performed for a reason other than for the evaluation of MS (multiple sclerosis).

Condition or disease	Intervention/treatment	Phase
Multiple Sclerosis (MS)	Drug: Tecfidera; Drug: Placebo	Phase 4

Detailed Description:

This is a multi-center, randomized, double-blinded study in which approximately 90 RIS (radiologically isolated syndrome) subjects will be treated with either Tecfidera or placebo for 2 years (1:1 randomization). Study participants, along with the treating and examining physicians, will be blinded to treatment assignment. Central Clinical and Imaging Units will screen all potential study subjects for inclusion/exclusion criteria. We expect to enroll all RIS subjects within the U.S.

Following informed consent and verification of entry criteria by the core units, study participants will be randomized 1:1 to either Tecfidera (120mg by mouth twice daily for 7 days with dose escalation to 240mg by mouth twice daily) or placebo. Clinical follow-up by the treating physician will occur at weeks 0, 48, 96, 144 and/or End of Study and during or immediately following clinical exacerbations. During clinical visits, comprehensive medical history data will be obtained by the treating physician. All reported acute or progressive clinical events will be adjudicated by the Central Clinical Unit. Clinical visits due to suspected exacerbations associated with CNS (central nervous system) demyelination, and associated diagnostic studies and treatments, will be covered under the medical standard of care by third party payers. A recommendation to re-evaluate the patient within 3 months following the clinical event to assess for extent of recovery will be made. In addition to the face-to-face visits described above, study participants will be contacted over the telephone at weeks 4, 8, 36, 60, 84, 108, and 132 to assess for medical or treatment difficulties and for study medication compliance. Standardized MRI studies of the brain will be performed at weeks 0, 96, 144 or End of Study. Clinical imaging studies of the brain and/or spinal cord performed during or immediately following the onset of a clinical exacerbation will be performed at the discretion of the site PI with scan costs covered under the medical standard of care. An end of study clinical MRI of the cervical spinal cord with and without contrast will be recommended to study participants at week 96 as medical standard of care.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 87 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Multi-center, Randomized, Double-blinded Assessment of Tecfidera® in Extending the Time to a First Attack in Radiologically Isolated Syndrome (RIS) (ARISE)
• Actual Study Start Date: March 19, 2016
• Actual Primary Completion Date: March 31, 2021
• Actual Study Completion Date: March 31, 2021

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Tecfidera; Tecfidera (120mg by mouth twice daily for 7 days with dose escalation to 240mg by mouth twice daily)	Drug: Tecfidera; Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs.; Other Name: Dimethyl fumarate
Placebo Comparator: Placebo; Placebo by mouth twice daily.	Drug: Placebo; Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs.

Outcome Measures

Primary Outcome Measures :

1. The Time From Randomization to the First Demyelinating Event (Acute or Development of an Initial Symptom Resulting in a Progressive Clinical Course) [ Time Frame: 96 weeks ]
   The primary outcome measure for this trial is the time to the first acute or progressive neurological event resulting from CNS demyelination from randomization into the trial.

Secondary Outcome Measures :

1. Change in Lesion Volume on T2-weighted MRI [ Time Frame: Baseline, 96 weeks ]
   Change in lesion volume on T2-weighted MRI is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.
2. Number of Newly Enlarging T2 Lesions [ Time Frame: 96 weeks ]
   Number of newly enlarging T2 lesions is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.
3. Number of New T2 Lesions [ Time Frame: 96 weeks ]
   Number of new T2 lesions as measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.
4. Newly Enlarging T2 Lesions and New T2 Lesions Combined [ Time Frame: 96 weeks ]
   Newly enlarging T2 lesions and new T2 lesions combined is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.
5. Number of Contrast Enhancing Lesions [ Time Frame: 96 weeks ]
   Number of contrast enhancing lesions is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.
6. Change in the Number of Participants With Brain Atrophy [ Time Frame: Baseline, 96 weeks ]
   Change in the number of participants with brain atrophy is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria

1. Males and females meeting 2009 RIS criteria
2. Identified RIS cases with the initial MRI demonstrating anomalies suggestive of demyelinating disease dated > 2009
3. Incidental anomalies identified on MRI of the brain or spinal cord with the primary reason for the acquired MRI resulting from an evaluation of a process other than MS

4. CNS white matter anomalies meeting the following MRI criteria:

   • Ovoid, well-circumscribed, and homogeneous foci with or without involvement of the corpus callosum
   • T2-hyperintensities measuring > 3mm2 and fulfilling 3 of 4 Barkhof-Tintoré criteria for dissemination in space
   • CNS anomalies not consistent with a vascular pattern
   • Qualitative determination that CNS anomalies have a characteristic appearance of demyelinating lesions
5. MRI anomalies do not account for clinically apparent neurological impairments in patients

Exclusion criteria

1. Women who are pregnant or nursing
2. Incomplete medical history or radiological data
3. History of remitting clinical symptoms consistent with multiple sclerosis lasting > 24 hours prior to CNS imaging revealing anomalies suggestive of MS
4. History of paroxysmal symptoms associated with MS (i.e. Lhermitte's or Uhthoff's phenomena)
5. CNS MRI anomalies are better accounted for by another disease process
6. The subject is unwilling or unable to comply with the requirements of the study protocol
7. Exposure to a disease modifying therapy for MS/RIS within the past 3 months
8. Exposure to high-dose glucocorticosteroid treatment within the past 30 days
9. Participation in other clinical trials involving treatment with a disease-modifying agent

Contacts and Locations

Locations

United States, California

Keck School of Medicine - USC - Department of Neurology

Los Angeles, California, United States, 90089

United States, Maryland

Johns Hopkins University - Neurology

Baltimore, Maryland, United States, 21287

United States, Minnesota

Mayo Clinic Department of Neurology

Rochester, Minnesota, United States, 55905

United States, Missouri

Washington University Department of Neurology

Saint Louis, Missouri, United States, 63110

United States, Nevada

Cleveland Clinic - Lou Ruvo Center for Brain Health

Las Vegas, Nevada, United States, 89106

United States, New York

MS Clinical Care and Research Center, Dept of Neurology, Columbia University

New York, New York, United States, 10032

United States, Oklahoma

Oklahoma Medical Research Foundation, MS Center of Excellence

Oklahoma City, Oklahoma, United States, 73104

United States, Texas

MS Treatment Center of Dallas

Dallas, Texas, United States, 75246

UT Southwestern Medical Center

Dallas, Texas, United States, 75390-8806

United States, Washington

Swedish Medical Center

Seattle, Washington, United States, 98122

MultiCare Institute for Research and Innovation

Tacoma, Washington, United States, 98405

Sponsors and Collaborators

University of Texas Southwestern Medical Center

Biogen

Investigators

• Principal Investigator: Darin T Okuda, MD; UT Southwestern Medical Center

  Study Documents (Full-Text)

Documents provided by Darin Okuda, University of Texas Southwestern Medical Center:

Study Protocol  [PDF] December 5, 2018

Statistical Analysis Plan  [PDF] July 9, 2021

Informed Consent Form  [PDF] December 5, 2018

More Information

Additional Information:

Tecfidera USPI 

Publications of Results:

Okuda DT, Mowry EM, Beheshtian A, Waubant E, Baranzini SE, Goodin DS, Hauser SL, Pelletier D. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology. 2009 Mar 3;72(9):800-5. doi: 10.1212/01.wnl.0000335764.14513.1a. Epub 2008 Dec 10. Erratum In: Neurology. 2009 Apr 7;72(14):1284.

Other Publications:

Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O'Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 2005 Dec;58(6):840-6. doi: 10.1002/ana.20703.

Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011 Feb;69(2):292-302. doi: 10.1002/ana.22366.

Lebrun C, Bensa C, Debouverie M, De Seze J, Wiertlievski S, Brochet B, Clavelou P, Brassat D, Labauge P, Roullet E; CFSEP. Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical conversion profile. J Neurol Neurosurg Psychiatry. 2008 Feb;79(2):195-8. doi: 10.1136/jnnp.2006.108274.

Siva A, Saip S, Altintas A, Jacob A, Keegan BM, Kantarci OH. Multiple sclerosis risk in radiologically uncovered asymptomatic possible inflammatory-demyelinating disease. Mult Scler. 2009 Aug;15(8):918-27. doi: 10.1177/1352458509106214.

Lebrun C, Blanc F, Brassat D, Zephir H, de Seze J; CFSEP. Cognitive function in radiologically isolated syndrome. Mult Scler. 2010 Aug;16(8):919-25. doi: 10.1177/1352458510375707. Epub 2010 Jul 7.

De Stefano N, Stromillo ML, Rossi F, Battaglini M, Giorgio A, Portaccio E, Hakiki B, Malentacchi G, Gasperini C, Santangelo M, Bartolozzi ML, Sormani MP, Federico A, Amato MP. Improving the characterization of radiologically isolated syndrome suggestive of multiple sclerosis. PLoS One. 2011 Apr 29;6(4):e19452. doi: 10.1371/journal.pone.0019452.

Gabelic T, Radmilovic M, Posavec V, Skvorc A, Boskovic M, Adamec I, Milivojevic I, Barun B, Habek M. Differences in oligoclonal bands and visual evoked potentials in patients with radiologically and clinically isolated syndrome. Acta Neurol Belg. 2013 Mar;113(1):13-7. doi: 10.1007/s13760-012-0106-1. Epub 2012 Jun 28.

Giorgio A, Stromillo ML, Rossi F, Battaglini M, Hakiki B, Portaccio E, Federico A, Amato MP, De Stefano N. Cortical lesions in radiologically isolated syndrome. Neurology. 2011 Nov 22;77(21):1896-9. doi: 10.1212/WNL.0b013e318238ee9b. Epub 2011 Nov 9.

Lebrun C, Le Page E, Kantarci O, Siva A, Pelletier D, Okuda DT; Club Francophone de Sclerose en Plaques (CFSEP); Radiologically Isolated Syndrome Consortium (RISC) Group. Impact of pregnancy on conversion to clinically isolated syndrome in a radiologically isolated syndrome cohort. Mult Scler. 2012 Sep;18(9):1297-302. doi: 10.1177/1352458511435931. Epub 2012 Feb 2.

Okuda DT, Mowry EM, Cree BA, Crabtree EC, Goodin DS, Waubant E, Pelletier D. Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome. Neurology. 2011 Feb 22;76(8):686-92. doi: 10.1212/WNL.0b013e31820d8b1d. Epub 2011 Jan 26.

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

Okuda DT, Kantarci O, Lebrun-Frenay C, Sormani MP, Azevedo CJ, Bovis F, Hua LH, Amezcua L, Mowry EM, Hotermans C, Mendoza J, Walsh JS, von Hehn C, Vargas WS, Donlon S, Naismith RT, Okai A, Pardo G, Repovic P, Stuve O, Siva A, Pelletier D. Dimethyl Fumarate Delays Multiple Sclerosis in Radiologically Isolated Syndrome. Ann Neurol. 2023 Mar;93(3):604-614. doi: 10.1002/ana.26555. Epub 2022 Dec 10.

• Responsible Party: Darin Okuda, PROFESSOR, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT02739542
• Other Study ID Numbers: 102014-019
• First Posted: April 15, 2016
• Results First Posted: May 11, 2022
• Last Update Posted: May 11, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Darin Okuda, University of Texas Southwestern Medical Center:

Radiologically Isolated Syndrome (RIS)

Additional relevant MeSH terms:

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Dimethyl Fumarate; Dermatologic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs