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

NCT03122652 | Completed Phase 3

• 1 other identifier: 14-PP-11
• Study Type: interventional
• Target: 125
• Locations: 3 countries
• Sites: 23

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

Keywords

Radiologically Isolated Syndrome

Outcome Measures

Primary Outcomes (1)

• Time to the first acute or progressive neurological event resulting from CNS demyelination.

  Acute neurological event: The development of an acute neurological episode localized to the optic nerve, brainstem, cerebellum, spinal cord, or long sensory or motor tracts, lasting \> 24 hours followed by a period of symptom improvement. Progressive event: The onset of a clinical symptom (e.g. leg weakness) with the temporal profile revealing at least a 12-month progression of neurological deficits.

  Week 96

Secondary Outcomes (7)

• New or enlarging T2 lesions

  Week 48

• New or enlarging T2 lesions

  Week 96

• New contrast enhancing lesions

  Week 48

• New contrast enhancing lesions

  Week 96

• New T2-lesion volumes

  Week 48

Study Arms (2)

Terifunomide

EXPERIMENTAL

Drug: Teriflunomide 14 MG Oral Tablet [Aubagio]

Placebo

PLACEBO COMPARATOR

Drug: Placebo Oral Tablet

Interventions

Teriflunomide 14 MG Oral Tablet [Aubagio] DRUG

1 tablet once a day

Terifunomide

Placebo Oral Tablet DRUG

1 tablet once a day

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Ovoid, well-circumscribed, and homogeneous foci observed with or without involvement of the corpus callosum
• T2 hyperintensities measuring ≥3 mm and fulfilling Barkhof criteria (at least three out of four) for dissemination in space
• Anomalies not following a clear vascular pattern
• Identified RIS cases with the initial MRI demonstrating anomalies suggestive of demyelinating disease dated ≥ 2009
• 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
• Affiliation to the social security system
• 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.

You may not qualify if:

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of summary of product characteristics (SmPC).
• Patients with severe hepatic impairment (Child-Pugh class C).
• Patients with severe immunodeficiency states, e.g. AIDS.
• Patients with significantly impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia.
• Patients with severe active infection until resolution.
• Patients with severe renal impairment undergoing dialysis.
• Patients with severe hypoproteinaemia, e.g. in nephrotic syndrome.
• Lactating or pregnant women
• Subjects wishing to parent a child during the study
• Incomplete medical history or radiological data
• History of remitting clinical symptoms consistent with multiple sclerosis lasting \> 24 hours prior to CNS imaging revealing anomalies suggestive of MS
• History of paroxysmal symptoms associated with MS (i.e. Lhermitte's or Uhthoff's phenomena)
• CNS MRI anomalies are better accounted for by another disease process
• The subject is unwilling or unable to comply with the requirements of the study protocol
• Exposure to a disease modifying therapy within the past 3 months

Sponsors & Collaborators

• Centre Hospitalier Universitaire de Nice: lead
• Genzyme, a Sanofi Company: collaborator

Study Sites (23)

CHU de Bordeaux

Bordeaux, 33000, France

Location

CHU de Caen

Caen, France

Location

CHU de Clermont-Ferrand

Clermont-Ferrand, France

Location

CHU de Grenoble

Grenoble, France

Location

CHRU de Lille

Lille, 59000, France

Location

Hospices Civils de Lyon

Lyon, 69677, France

Location

CHRU de Montpellier

Montpellier, 34000, France

Location

CHU de Nantes

Nantes, France

Location

CHU de Nice

Nice, 06000, France

Location

CHU de Nîmes

Nîmes, France

Location

APHP - Hôpital La Pitié Salpêtrière

Paris, 75013, France

Location

CHU de Rennes

Rennes, 35000, France

Location

CHU de Rouen

Rouen, France

Location

CHU de Strasbourg

Strasbourg, 67000, France

Location

CHU de Toulouse

Toulouse, 31000, France

Location

Inselspital Bern

Bern, 3010, Switzerland

Location

Hacettepe University

Ankara, Turkey (Türkiye)

Location

Mustafa Kemal University

Antakya, Turkey (Türkiye)

Location

Uludag University School of Medicine

Bursa, Turkey (Türkiye)

Location

Istanbul University

Istanbul, Turkey (Türkiye)

Location

Ege University Medical Faculty

Izmir, 35100, Turkey (Türkiye)

Location

Kocaeli University School of Medicine

Kocaeli, Turkey (Türkiye)

Location

Ondokuz Mayis University, Faculty of Medicine

Samsun, Turkey (Türkiye)

Location

Related Publications (1)

• 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.

  PMID: 37603328 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis

Interventions

teriflunomide; Tablets

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations

Study Officials

• Christine LEBRUN-FRENAY, MD

  Centre Hospitalier Universitaire de Nice

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 12, 2017
• First Posted: April 21, 2017
• Study Start: September 25, 2017
• Primary Completion: February 5, 2019
• Study Completion: October 4, 2022
• Last Updated: March 17, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1); FR (15); TU (7)