From Genetics to Transcriptomics to Unravel the Mechanisms Behind a Poor Outcome in Multiple Sclerosis (OUTCOMS)

• ClinicalTrials.gov Identifier: NCT04873492
• Recruitment Status: Recruiting
• First Posted: May 5, 2021
• Last Update Posted: January 30, 2023
• Sponsor: Nantes University Hospital
• Information provided by (Responsible Party): Nantes University Hospital

Tracking Information

• First Submitted Date: April 30, 2021
• First Posted Date: May 5, 2021
• Last Update Posted Date: January 30, 2023
• Actual Study Start Date: January 24, 2022
• Estimated Primary Completion Date: July 24, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 30, 2021)

Bulk RNA-sequencing [ Time Frame: Blood sample collection within 6 months after first inflammatory event for MS patients and at inclusion for healthy volunteers. ]

Transcriptional profile of T and B cells in aggressive and non-aggressive MS and healthy volunteers. Measurement of gene expression of naïve and memory CD4+ and CD8+ T and B cell. Comparison of these expression level between MS patients with aggressive and non-aggressive form and healthy volunteers.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 30, 2021)

• Single RNA sequencing [ Time Frame: Blood sample collection within 6 months after first inflammatory event. ]
  Single cell transcriptomics of T and B cells in order to identify by clustering, sub populations within these cells based on gene expression and associated to poor pronostic.
• Association of genetic sequence variation from whole genome sequencing with gene expression profile via Bulk RNA-seq [ Time Frame: Blood sample collection within 6 months after first inflammatory event. ]
  Add genetic variant analyzes to RNA seq analyses related to MS 1) Identify eQTL. 2 Impute SNPs result to calculate MS Genetic Burden (MSGB) a polygenic risk score of MS computed based on a weighted scoring algorithm using independent MS-SNPs.
• Association of transcriptomic variation with DNA methylation [ Time Frame: Blood sample collection within 6 months after first inflammatory event. ]
  Add Analyzes of gene expression regulation throughout DNA methylation of CpG sites to RNA seq analyses related to MS.
• OMIC integration [ Time Frame: Blood sample collection within 6 months after first inflammatory event. ]
  Developing machine learning method to combine genomic, epigenomic transcriptomic and clinical data to pinpoint genes of interest particularly involved in aggressive MS outcomes.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: From Genetics to Transcriptomics to Unravel the Mechanisms Behind a Poor Outcome in Multiple Sclerosis
• Official Title: From Genetics to Transcriptomics to Unravel the Mechanisms Behind a Poor Outcome in Multiple Sclerosis
• Brief Summary: MS is a heterogeneous disease either in its response to treatment or clinical manifestation. Indeed, the natural history of MS is varying from a benign condition to a devastating and rapidly incapacitating disease. Clinical heterogeneity could also be cellular and / or molecular. The aim is to identify from OMIC analyses, at the early stage of the disease, differentially expressed molecules and / or cell subpopulations derived from CD8 + T lymphocytes and / or CD4 + T lymphocytes and / or B lymphocytes and monocytes from patients with aggressive versus non-aggressive, compared to a cohort of healthy controls
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The study model consists of two cohorts, the first one or "learning cohort" includes a group of health volunteers and 2 groups of MS patients from who clinical outcome (aggressive vs non-aggressive) is already known based on clinical follow up since first event. Clinical data and blood sample have been already collected and are available from OFSEP (Observatoire français de la Sclérose en plaques). Blood will be analyzed to characterize transcriptomic, epigenomic, genomic immune cells features to discover predictive markers of clinical outcome. The second cohort or "validation cohort" consists of MS patients enrolled after their first event and followed for maximum 2-years until the determination of their clinical outcome. Blood will be collected after their first event and used in FACS to classified the patients based on molecule of interest discover thanks to learning cohort and predict clinical outcome.

Masking: None (Open Label)
Masking Description:

NA/NO

Primary Purpose: Basic Science

• Condition: Multiple Sclerosis

Intervention

Other: Biological sample collection

Venous blood sample will be collected from patients belonging to validation cohort and healthy volunteers at baseline resulting in 90 Ml EDTA tube and 10 ml serum tube. Approximately 100 ml will be collected. optional saliva and stool collection will be performed.

Study Arms

• Retrospective Aggressive MS patients
  Patients from who the clinical outcome is already known and classified as poor based on study definition detailed in inclusion criteria (retrospective arm). Blood sample collected after first event is available and used to characterize OMIC profile of T and B cells involve in MS.
  Intervention: Other: Biological sample collection
• Retrospective Non Aggressive MS patient
  Patient from who the clinical outcome is already known and classified as non-aggressive based on study definition detailed in inclusion criteria (retrospective arm). Blood sample collected after first event is available and used to characterize OMIC profile of T and B cells involve in MS.
  Intervention: Other: Biological sample collection
• Healthy volunteers
  Prospective arm use as comparator.
  Intervention: Other: Biological sample collection
• Prospective MS patients
  MS patients from who the clinical outcome will be established at the end of the follow up. Blood sample will be collected after the first event to validate molecules of interest from OMIC results by using FACS a different technology and classify MS patient.
  Intervention: Other: Biological sample collection

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 30, 2021): 130
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: July 24, 2025
• Estimated Primary Completion Date: July 24, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria :

Common criteria for retrospective MS patients:

• Patients aged 18 years or older
• Clinical isolated syndrome (CIS) with or without dissemination in space
• Patients affiliated to an appropriate health insurance

Criteria for Aggressive MS group

• Start of a 2nd line therapy within the two years following the CIS

Criteria for Non aggressive MS group

• No conversion according to McDonald criteria from clinical isolated syndrome to multiple sclerosis within 2 years or
• Conversion based to McDonald criteria treated or not with first line disease modifying therapy within 2 years.
• Have a minimum of least 2 years of follow-up.

Healthy volunteers

• Aged 18 years or older
• No history of clinically isolated syndrome or MS

Pairing criteria :

• Age +/- 5 years
• Sex

Prospective MS Patients

• Patients aged 18 years or older
• Clinical isolated syndrome (CIS) with or without dissemination in space
• Patients affiliated to an appropriate health insurance

Exclusion Criteria :

• Ongoing participation to a another study
• Refusal to genetic analyses
• Immunosuppressive drug at the time of blood collection
• Adults under a legal protection regime (guardianship, trusteeship, judicial safeguard)
• Pregnancy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: David LAPLAUD, PhD; 33 2 40 16 52 00; david.laplaud@chu-nantes.fr

• Listed Location Countries: France

Administrative Information

• NCT Number: NCT04873492
• Other Study ID Numbers: RC20_0404
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Nantes University Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Nantes University Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Nantes University Hospital
• Verification Date: January 2023