Clinical trial NCT03122652: Randomized, Double-blinded Study of Treatment:Teriflunomide, in Radiologically Isolated Syndrome
Official title: Multi-center, Randomized, Double-blinded Study of Teriflunomide® in Radiologically Isolated Syndrome (RIS) The TERIS Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Sclerosis
Keywords: Radiologically Isolated Syndrome
Lead sponsor: Centre Hospitalier Universitaire de Nice
Sponsor class: OTHER
Collaborators: name: Genzyme, a Sanofi Company
First posted: 2017-04-21
Enrollment: 125
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Time to the first acute or progressive neurological event resulting from CNS demyelination.
timeFrame: Week 96
Secondary outcomes:
measure: New or enlarging T2 lesions
timeFrame: Week 48
measure: New or enlarging T2 lesions
timeFrame: Week 96
measure: New contrast enhancing lesions
timeFrame: Week 48
measure: New contrast enhancing lesions
timeFrame: Week 96
measure: New T2-lesion volumes
timeFrame: Week 48
measure: New T2-lesion volumes
timeFrame: Week 96
measure: Brain atrophy
timeFrame: Week 96
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: CHU de Bordeaux
city: Caen
country: France
facility: CHU de Caen
city: Clermont-Ferrand
country: France
facility: CHU de Clermont-Ferrand
city: Grenoble
country: France
facility: CHU de Grenoble
city: Lille
country: France
facility: CHRU de Lille
city: Lyon
country: France
facility: Hospices Civils de Lyon
city: Montpellier
country: France
facility: CHRU de Montpellier
city: Nantes
country: France
facility: CHU de Nantes
city: Nice
country: France
facility: CHU de Nice
city: Nîmes
country: France
facility: CHU de Nîmes
city: Paris
country: France
facility: APHP - Hôpital La Pitié Salpêtrière
city: Rennes
country: France
facility: CHU de Rennes
city: Rouen
country: France
facility: CHU de Rouen
city: Strasbourg
country: France
facility: CHU de Strasbourg
city: Toulouse
country: France
facility: CHU de Toulouse
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Ankara
country: Turkey
facility: Hacettepe University
city: Antakya
country: Turkey
facility: Mustafa Kemal University
city: Bursa
country: Turkey
facility: Uludag University School of Medicine
city: Istanbul
country: Turkey
facility: Istanbul University
city: İzmir
country: Turkey
facility: Ege University Medical Faculty
city: Kocaeli
country: Turkey
facility: Kocaeli University School of Medicine
city: Samsun
country: Turkey
facility: Ondokuz Mayis University, Faculty of Medicine
Study officials:
affiliation: Centre Hospitalier Universitaire de Nice
name: Christine LEBRUN-FRENAY, MD
role: PRINCIPAL_INVESTIGATOR
References: