Assessment of Tecfidera® in Radiologically Isolated Syndrome (RIS)

Multiple Sclerosis (MS) Clinical Trial

— ARISE  

Official title:

Multi-center, Randomized, Double-blinded Assessment of Tecfidera® in Extending the Time to a First Attack in Radiologically Isolated Syndrome (RIS) (ARISE)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02739542
• Other study ID #: 102014-019
• Status: Completed
• Phase: Phase 4
• Start date: March 19, 2016
• Est. completion date: March 31, 2021

Study information

• Verified date: April 2022
• Source: University of Texas Southwestern Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 87
• Est. completion date: March 31, 2021
• Est. primary completion date: March 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis (MS)

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Johns Hopkins University - Neurology	Baltimore	Maryland
United States	MS Treatment Center of Dallas	Dallas	Texas
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Cleveland Clinic - Lou Ruvo Center for Brain Health	Las Vegas	Nevada
United States	Keck School of Medicine - USC - Department of Neurology	Los Angeles	California
United States	MS Clinical Care and Research Center, Dept of Neurology, Columbia University	New York	New York
United States	Oklahoma Medical Research Foundation, MS Center of Excellence	Oklahoma City	Oklahoma
United States	Mayo Clinic Department of Neurology	Rochester	Minnesota
United States	Washington University Department of Neurology	Saint Louis	Missouri
United States	Swedish Medical Center	Seattle	Washington
United States	MultiCare Institute for Research and Innovation	Tacoma	Washington

Sponsors (2)

Lead Sponsor	Collaborator
University of Texas Southwestern Medical Center	Biogen

Country where clinical trial is conducted

United States, 

References & Publications (11)

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. — View Citation

Gabelic T, Radmilovic M, Posavec V, Skvorc A, Boškovic 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Epub 2012 Feb 2. — View Citation

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.000033576 — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Time From Randomization to the First Demyelinating Event (Acute or Development of an Initial Symptom Resulting in a Progressive Clinical Course)	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.	96 weeks
Secondary	Change in Lesion Volume on T2-weighted MRI	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.	Baseline, 96 weeks
Secondary	Number of Newly Enlarging T2 Lesions	Number of newly enlarging T2 lesions is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.	96 weeks
Secondary	Number of New T2 Lesions	Number of new T2 lesions as measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.	96 weeks
Secondary	Newly Enlarging T2 Lesions and New T2 Lesions Combined	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.	96 weeks
Secondary	Number of Contrast Enhancing Lesions	Number of contrast enhancing lesions is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.	96 weeks
Secondary	Change in the Number of Participants With Brain Atrophy	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.	Baseline, 96 weeks

External Links

•   Tecfidera USPI