Randomized, Double-blinded Study of Treatment:Teriflunomide, in Radiologically Isolated Syndrome

NCT ID: NCT03122652

Last Updated: 2023-03-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 125 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-25
• Study Completion Date: 2022-10-04

Brief Summary

Multiple sclerosis (MS) is a common cause of severe neurological disability in young adults, resulting from an autoimmune interruption of both myelin and axons within the central nervous system (CNS). The diagnosis is made by fulfilling both spatial criteria, by meeting the requisite number of lesions within the brain or spinal cord, along with criteria for time, by demonstrating a history of at least a second clinical attack or the development of a new MS lesion on MRI after the seminal neurological event. In the case of MS, healthy individuals who do not exhibit signs of neurological dysfunction commonly have brain MRI studies performed for a reason other than an evaluation for MS that reveal unexpected anomalies highly suggestive of demyelinating plaques given their size, location, and morphology. These healthy subjects lack symptomatology suggestive of MS and fulfill formal criteria for radiologically isolated syndrome (RIS), a recently described MS subtype that expands upon the phenotype of at-risk individuals for future demyelinating events. The discovery of such anomalies creates intersecting neuro-ethical, legal, social, and practical medical management quandaries and is, therefore, of both immediate and long-term clinical significance. Despite advancements in the characterization of RIS subjects, and in our understanding of risk factors for initial symptom development, the effect of treatment on such cases remain unclear.

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

RIS subjects are frequently exposed to disease modifying therapies despite the lack of scientific literature supporting the use of such treatments. Earlier treatment intervention may extend the time to the first acute or progressive clinical event resulting from CNS demyelination and reduce radiological progression. In addition, early treatment may result in more profound effects on reducing disability progression long-term.

The primary outcome measure for this trial is the time to the first acute or progressive neurological event resulting from CNS demyelination.

This study will include RIS subjects from the Europe who fulfill 2009 RIS Criteria.

Conditions

Multiple Sclerosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Terifunomide

Group Type: EXPERIMENTAL

Teriflunomide 14 MG Oral Tablet [Aubagio]

Intervention Type: DRUG

1 tablet once a day

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo Oral Tablet

Intervention Type: DRUG

1 tablet once a day

Interventions

Teriflunomide 14 MG Oral Tablet [Aubagio]

1 tablet once a day

Intervention Type: DRUG

Placebo Oral Tablet

1 tablet once a day

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Males and females of all ages(>18 years and <65 years) meeting 2009 RIS criteria:

A. The presence of incidentally identified CNS white matter anomalies meeting the following MRI criteria:

1. Ovoid, well-circumscribed, and homogeneous foci observed with or without involvement of the corpus callosum

2. T2 hyperintensities measuring ≥3 mm and fulfilling Barkhof criteria (at least three out of four) for dissemination in space

3. Anomalies not following a clear vascular pattern

4. Structural neuroimaging abnormalities identified not explained by another disease process B. No historical accounts of remitting clinical symptoms consistent with neurological dysfunction C. The MRI anomalies do not account for clinically apparent impairments in social, occupational, or generalized area of functioning D. The MRI anomalies are not due to the direct physiological effects of substances (recreational drug use, toxic exposure) or a medical condition E. Exclusion of individuals with MRI phenotypes suggestive of leukoaraiosis or extensive white matter changes lacking clear involvement of the corpus callosum F. The CNS MRI anomalies are not better accounted for by another disease process

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. Affiliation to the social security system

5. Subjects of reproductive potential are eligible only if the following applies:

• Women of childbearing potential (WOCBP):Must have a negative serum pregnancy test at Visit 1 (Screening) and negative urine pregnancy test at Visit 2 (Baseline);
• Must be agree to undertake 1 monthly urine pregnancy tests during the study and up to 6 weeks after the first of two tests showing teriflunomide plasma level <0.02 mg/L;
• Must agree to use reliable methods of contraception from Visit 1 until 6 weeks after the first oft wo tests showing teriflunomide plasma level <0.02 mg/L.

Fertile male subjects participating in the study who are sexually active with WOCBP:

• Must agree to use condom during the treatment period and for an additional 6 weeks after the first oft wo tests showing teriflunomide plasma level <0.02 mg/L.

Exclusion Criteria

1. Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of summary of product characteristics (SmPC).

2. Patients with severe hepatic impairment (Child-Pugh class C).

3. Patients with severe immunodeficiency states, e.g. AIDS.

4. Patients with significantly impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia.

5. Patients with severe active infection until resolution.

6. Patients with severe renal impairment undergoing dialysis.

7. Patients with severe hypoproteinaemia, e.g. in nephrotic syndrome.

8. Lactating or pregnant women

9. Subjects wishing to parent a child during the study

10. Incomplete medical history or radiological data

11. History of remitting clinical symptoms consistent with multiple sclerosis lasting > 24 hours prior to CNS imaging revealing anomalies suggestive of MS

12. History of paroxysmal symptoms associated with MS (i.e. Lhermitte's or Uhthoff's phenomena)

13. CNS MRI anomalies are better accounted for by another disease process

14. The subject is unwilling or unable to comply with the requirements of the study protocol

15. Exposure to a disease modifying therapy within the past 3 months

16. Exposure to high-dose glucocorticosteroid treatment within the past 30 days

17. Vulnerable subject (such as deprived from freedom) as defined in Section 1.61 of International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.)

18. Participation in another clinical trial of an investigational medicinal product

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genzyme, a Sanofi Company

INDUSTRY

Sponsor Role: collaborator

Centre Hospitalier Universitaire de Nice

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christine LEBRUN-FRENAY, MD

Role: PRINCIPAL_INVESTIGATOR

Centre Hospitalier Universitaire de Nice

Locations

CHU de Bordeaux

Bordeaux, , France

CHU de Caen

Caen, , France

CHU de Clermont-Ferrand

Clermont-Ferrand, , France

CHU de Grenoble

Grenoble, , France

CHRU de Lille

Lille, , France

Hospices Civils de Lyon

Lyon, , France

CHRU de Montpellier

Montpellier, , France

CHU de Nantes

Nantes, , France

CHU de Nice

Nice, , France

CHU de Nîmes

Nîmes, , France

APHP - Hôpital La Pitié Salpêtrière

Paris, , France

CHU de Rennes

Rennes, , France

CHU de Rouen

Rouen, , France

CHU de Strasbourg

Strasbourg, , France

CHU de Toulouse

Toulouse, , France

Inselspital Bern

Bern, , Switzerland

Hacettepe University

Ankara, , Turkey (Türkiye)

Mustafa Kemal University

Antakya, , Turkey (Türkiye)

Uludag University School of Medicine

Bursa, , Turkey (Türkiye)

Istanbul University

Istanbul, , Turkey (Türkiye)

Ege University Medical Faculty

Izmir, , Turkey (Türkiye)

Kocaeli University School of Medicine

Kocaeli, , Turkey (Türkiye)

Ondokuz Mayis University, Faculty of Medicine

Samsun, , Turkey (Türkiye)

Countries

France; Switzerland; Turkey (Türkiye)

References

Lebrun-Frenay C, Siva A, Sormani MP, Landes-Chateau C, Mondot L, Bovis F, Vermersch P, Papeix C, Thouvenot E, Labauge P, Durand-Dubief F, Efendi H, Le Page E, Terzi M, Derache N, Bourre B, Hoepner R, Karabudak R, De Seze J, Ciron J, Clavelou P, Wiertlewski S, Turan OF, Yucear N, Cohen M, Azevedo C, Kantarci OH, Okuda DT, Pelletier D; TERIS Study Group. Teriflunomide and Time to Clinical Multiple Sclerosis in Patients With Radiologically Isolated Syndrome: The TERIS Randomized Clinical Trial. JAMA Neurol. 2023 Oct 1;80(10):1080-1088. doi: 10.1001/jamaneurol.2023.2815.

Reference Type: DERIVED

PMID: 37603328 (View on PubMed)

Other Identifiers

14-PP-11

Identifier Type: -

Identifier Source: org_study_id