Clinical trial NCT06395662: Stratification of Risks of Conversion of Radiologically Isolated Syndromes (RIS) by Identifying Biomarkers in Serum and Cerebrospinal Fluid.
Official title: Improving the Stratification of Risks of Conversion of Radiologically Isolated Syndromes (RIS) by Identifying Biomarkers in Serum and Cerebrospinal Fluid. The ProBioRIS Study
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Radiologically Isolated Syndrome
Multiple Sclerosis
Keywords: Radiologically Isolated Syndrome
Multiple Sclerosis
Biomarkers
Lead sponsor: Centre Hospitalier Universitaire de Nīmes
Sponsor class: OTHER
Collaborators: name: International Center of Research in Infectiology, Lyon University
name: Universite Cote d'Azur
name: The University of Texas at Dallas
First posted: 2024-05-02
Enrollment: 320
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All patients registered in the ARISE, TERIS, OFSEP and SFSEP cohorts.

Brief summary: Radiologically isolated syndrome (RIS) often precedes Multiple Sclerosis (MS) but some patients have no symptoms. This study aims to use biological samples and magnetic resonance imaging (MRI) data from four large cohorts of patients with MS in the United States, Europe and France, to stratify the chances of RIS developing into MS. Identifying early biomarkers to predict greater disease severity would have a significant impact, not only on RIS but also on the entire clinical spectrum of multiple sclerosis.

Detailed description: Radiologically Isolated Syndrome (RIS) is defined as the presence of asymptomatic, idiopathic demyelinating-appearing white matter lesions in the central nervous system. RIS often precedes clinical multiple sclerosis. Data from the international RIS Consortium indicate that 34% of RIS patients will have their first multiple sclerosis symptom within 5 years, and 51% within 10 years, making RIS the earliest identifiable phase of MS. While most RIS patients will evolve to relapsing MS, \~10% directly evolve towards progressive multiple sclerosis. RIS is an informative cohort for studying the earliest pathophysiologic changes, but remains a significant challenge for MS clinicians, as not all RIS patients will develop clinical symptoms. There is a need to distinguish RIS patients at high risk of clinical MS from those who will remain asymptomatic. Stratification would be invaluable to inform treatment/monitoring recommendations and counsel patients.

In the RIS Consortium cohort, age at diagnosis, positive CSF oligoclonal bands (OCBs) or elevated IgG index, infratentorial or spinal cord lesions, and gadolinium-enhancing (Gd+) lesions during follow-up independently predicted a first clinical event at 10 years. Additional serum and CSF biomarkers may further refine the risk stratification for clinical MS and may predict more severe tissue injury measured by MRI.

Serum and cerebrospinal fluid biomarkers can refine risk stratification of the progression from risk to clinical multiple sclerosis and predict more severe tissue damage as measured by magnetic resonance imaging. Identifying early biomarkers to predict greater disease severity would have a significant impact, not only on RIS, but also on the entire clinical spectrum of multiple sclerosis. However, RIS remains a rare disease and large cohorts are needed to validate potential prognostic biomarkers.

The international RIS Consortium has had a unique opportunity to apply for a research grant from the National Multiple Sclerosis Society to combine biomarker expertise, advanced magnetic resonance imaging analysis, and collaborative networks and cohorts to refine the prognosis of multiple sclerosis. Here, the proposal is to use biological samples and magnetic resonance imaging data from four large cohorts of patients with multiple sclerosis in the United States, Europe and France. In fact, this proposal is based on existing clinical and magnetic resonance imaging data and stored serum and cerebrospinal fluid samples from the ARISE (clinicaltrials. gov NCT02739542) and TERIS (NCT03122652) trials, which are randomized, double-blind, placebo-controlled trials on multiple sclerosis, as well as two prospective, real-world cohorts of multiple sclerosis patients from the French multiple sclerosis observatory (OFSEP = Observatoire Français de la Sclérose en Plaques) and the French multiple sclerosis society (SFSEP = Société Francophone de la Sclérose En Plaques).

The French observatory for multiple sclerosis, coordinated by Professor Sandra Vukusic in Lyon, brings together neurologists from all over France and 61 centers that use the European Database for Multiple Sclerosis, including 31 French hospitals and expert centers, and more than 45,000 people with multiple sclerosis or related diseases (half the population with multiple sclerosis in France). This includes a priority effort involving at least 85 RIS patients validated by the central supervision of the RIS consortium (Prof. Christine Lebrun-Frenay, Nice), with longitudinal follow-up and systematic association of clinical data with biological samples and neuro-imaging.

Standardized biological samples obtained from RIS patients and banked in certified biological resource centers guarantee the high quality of biological samples associated with clinical and medical imaging data collected prospectively in the EDMUS database. This biocollection offers a unique opportunity to identify and validate potential biomarkers of disease activity and clinical conversion in RIS patients, notably in association with those of randomized clinical trials and the SFSEP, which relies on the same French network of experts in multiple sclerosis (CRC-SEP = Centres de Ressources et de Compétences sur la Sclérose en Plaques) and biological research centers.

The hypothesis is that increases in the serum Neurofilament Light (sNfl) chain and serum Glial Fibrillary Astrocytic Protein (sGFAP) will be associated with higher numbers of new gadolinium-enhancing (Gd+) lesions, higher T2 lesion volume, higher rates of clinical relapse, and faster thalamic volume decline over 96 weeks.

Eligibility criteria: Inclusion Criteria:

* Patients from the OFSEP, SFSEP, RISE and TERIS cohorts with centralized validated radiologoically isolated syndrome and a standardized magnetic resonance imaging from the OFSEP or Randomized Clinical Trials database.
* at least one cerebro-spinal fluid and/or serum sample at baseline available at a local or centralized biological resource center.
* if present, serum sample collected at the time of clinical conversion.

Exclusion Criteria:

* patients with no biocollection, or with non-standardized magnetic resonance imaging acquisitions

Primary outcomes:
measure: Aim 1a : Association between Serum Neurofilament Light chain (sNfL) and RIS in all groups of patients
timeFrame: Week 0
measure: Aim 1a : Association between Serum Neurofilament Light chain (sNfL) and RIS in all groups of patients
timeFrame: Week 96
measure: Aim 1a : Association between Serum Glial Fibrillary Astrocytic Protein (sGFAP) and RIS in all groups of patients
timeFrame: Week 0
measure: Aim 1a : Association between Serum Glial Fibrillary Astrocytic Protein (sGFAP) and RIS in all groups of patients
timeFrame: Week 96
measure: Aim 1b: Association between Serum Neurofilament Light chain (sNfL) and RIS in placebo-treated patients
timeFrame: Week 0
measure: Aim 1b: Association between Serum Neurofilament Light chain (sNfL) and RIS in placebo-treated patients
timeFrame: Week 96
measure: Aim 1b : Association between Serum Glial Fibrillary Astrocytic Protein (sGFAP)and RIS in placebo-treated patients
timeFrame: Week 0
measure: Aim 1b: Association between Serum Glial Fibrillary Astrocytic Protein (sGFAP)and RIS in placebo-treated patients
timeFrame: Week 96
Secondary outcomes:
measure: Aim 2a: Kappa free light chain (KFLC) index in RIS patients in the SFSEP, OFSEP and ARISE cohorts, n=121
timeFrame: Week 0
measure: Aim 2a: Kappa free light chain (KFLC) index in RIS patients in the SFSEP, OFSEP and ARISE cohorts, n=121
timeFrame: Week 96
measure: Aim 2a: Cerebrospinal fluid neurofilament light chain as a potential biomarker of RIS.
timeFrame: Week 0
measure: Aim 2a: Cerebrospinal fluid neurofilament light chain as a potential biomarker of RIS.
timeFrame: Week 96
measure: Aim 2a: Chitinase-3-like protein 1 as a potential biomarker of RIS.
timeFrame: Week 0
measure: Aim 2a: Chitinase-3-like protein 1 as a potential biomarker of RIS.
timeFrame: Week 96
measure: Aim 2a: Oligoclonal bands as a potential biomarker of RIS.
timeFrame: Week 0
measure: Aim 2a: Oligoclonal bands as a potential biomarker of RIS.
timeFrame: Week 96
measure: Aim 2b: Validation of cerebrospinal fluid neurofilament light chain as a potential biomarker of RIS.
timeFrame: Week 0
measure: Aim 2b: Validation of cerebrospinal fluid neurofilament light chain as a potential biomarker of RIS.
timeFrame: Week 96
measure: Aim 2b: Validation of chitinase-3-like protein 1 as a potential biomarker of RIS.
timeFrame: Week 0
measure: Aim 2b: Validation of chitinase-3-like protein 1 as a potential biomarker of RIS.
timeFrame: Week 96
measure: Aim 2b: Validation of oligoclonal bands as a potential biomarker of RIS.
timeFrame: Week 0
measure: Aim 2b: Validation of oligoclonal bands as a potential biomarker of RIS.
timeFrame: Week 96
measure: Aim 3: Improving prediction of clinical disease activity of RIS
timeFrame: Week 0
measure: Aim 3: Improving prediction of clinical disease activity of RIS
timeFrame: Week 96
Other outcomes:
measure: Age of patients who provided serum and cerebrospinal fluid samples
timeFrame: Week 0
measure: Sex of patients who provided serum and cerebrospinal fluid samples
timeFrame: Week 0
measure: Disease-Modifying Therapy exposure in patients who provided serum and cerebrospinal fluid samples
timeFrame: Week 0
Locations:
city: Dallas
country: United States
facility: University of Texas, Southwestern
state: Texas
city: Nice
country: France
facility: COTE D'AZUR UNIVERSITY, URRIS-UR2CA. Hôpital Pasteur 2, 30, Voie Romaine
state: Alpes-Maritimes
city: Lyon
country: France
facility: INTERNATIONAL CENTER OF RESEARCH IN INFECTIOLOGY, LYON UNIVERSITY, INSERM U1111, CNRS UMR 5308, ENS, UCBL 46 Allée d'Italie
state: Rhône
Study officials:
References: