Disease Modifying Therapies Withdrawal in Inactive Relapsing-remitting Multiple Sclerosis Patients Aged 55 and Over (TWINS : Therapies Withdrawal IN Relapsing Multiple Sclerosis) (TWINS)

January 2, 2025 updated by: University Hospital, Strasbourg, France

Disease Modifying Therapies Withdrawal in Inactive Relapsing-remitting Multiple Sclerosis Patients Aged 55 and Over: A Multicentric, Randomized, Controlled, Open-label Clinical Trial (TWINS : Therapies Withdrawal IN Relapsing Multiple Sclerosis)

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by loss of motor and sensory function, that results from immune-mediated inflammation, demyelination and subsequent axonal damage. It is the most common cause of neurological disability in young adults, involving a long-term therapeutic follow-up. 85% of the patients are diagnosed with Relapsing-Remitting form of MS (RRMS). This form is characterized by clearly defined acute or subacute neurological symptoms (relapses) followed by periods of partial to complete recovery.

Disease-modifying therapies (DMT) used to treat RRMS are immunomodulatory or suppressor molecules which have proven efficacy in limiting disease activity (decreasing relapse rate and delaying time to disease progression).

However, the long-term safety of DMT is uncertain, as there is an increased risk of developing adverse events or infections (sometimes severe) such as observed in the last pandemic of COVID-19 (higher risk of infection), highlighting the need to reassess the benefit/risk ratio of maintaining immunomodulatory or suppressive therapy in the MS population. In elderly patients with comorbidity, this risk is further increased. To date, few studies on the discontinuation of treatment in elderly RRMS patients have been conducted. However, those available demonstrate that there was no difference in relapse rates between patients who continued or discontinued treatment. These results are consistent with immunosenescence studies in RRMS that suggested a negative correlation between relapse rate/inflammatory processes and age. On the contrary, there is evidence indicating a positive correlation between age and the number of infections.

In addition, in the current context in France, it is important to take into account the medico-social cost associated with long-term treatments. In France, the average estimated annual cost per patient is 12,000€, more than half of which is attributed to medications.Furthermore, with age progression, an inversion of the benefit/cost assessment has been observed in treated patients.

Considering these medical and medico-social factors, it is reasonable to question the value of continuing treatment in stable patients with RRMS over 55 years.

This is a randomized, controlled, multicentric, open-label, parallel groups, 1:1 ratio non-inferiority clinical trial, comparing (1) a group that will stop treatment, to (2) a group that will continue treatment, over the course of 2 years, to determine the survival rate without MS activity defined clinically or by imaging.

The patients in both arms will be followed over 2 years after randomization. 5 visits will be performed for all patients: inclusion/randomization visit (M0) and 4 follow-up visits every 6 months (M6, M12, M18, and M24). An additional phone call at M3 is planned.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

200

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • France
      • Bordeaux, France, 33076
        • CHU de Bordeaux-Hopital Pellegrin
        • Contact:
        • Principal Investigator:
          • Aurélie RUET, MD
      • Caen, France, 14033
        • CHU de Caen-Hôpital Côte de Nacre
        • Principal Investigator:
          • Pierre BRANGER
        • Contact:
      • Clermont Ferrand, France, 63003
        • CHU de Clermont-Ferrand-Hôpital Gabriel Montpied
        • Principal Investigator:
          • Pierre CLAVELOU
        • Contact:
      • Créteil, France, 94010
        • Assistance Publique des Hôpitaux de Paris (APHP)-Hôpital Henri Mondor
        • Contact:
        • Principal Investigator:
          • Alain CREANGE, MD PhD
      • Dijon, France, 21079
        • CHU de Dijon-Hôpital du Bocage
        • Principal Investigator:
          • Thibault MOREAU
        • Contact:
      • Gonesse, France, 95500
        • CH de Gonesse
        • Principal Investigator:
          • Eric MANCHON
        • Contact:
      • La Tronche, France, 38700
        • CHU de Grenoble Alpes
        • Contact:
        • Principal Investigator:
          • Catalina COCLITU, MD
      • Lille, France, 59020
        • Groupement des Hôpitaux de l'Institut Catholique de Lille Hôpital Saint Vincent de Paul
        • Principal Investigator:
          • Arnaud KWIATKOWSKI, MD
        • Contact:
      • Lille, France, 59037
        • CHU de Lille-Hôpital Roger Salengro
        • Contact:
        • Principal Investigator:
          • Hélène ZEPHIR THI
      • Limoges, France, 87042
        • CHU de Limoges-Hopital Dupuytren
        • Contact:
        • Principal Investigator:
          • Maxime MERINDOL
      • Marseille, France, 13005
        • Assistance Publique des Hôpitaux de Marseille (APHM)-Hôpital La Timone Adultes
        • Contact:
        • Principal Investigator:
          • Bertrand AUDOIN
      • Montpellier, France, 34295
        • CHU de Montpellier-Hôpital G. De Chauliac
        • Contact:
        • Principal Investigator:
          • Xavier AYRIGNAC
      • Nancy, France, 54035
        • CHU de Nancy -Hôpital Central
        • Principal Investigator:
          • Guillaume MATHEY, MD
        • Contact:
      • Nice, France, 06002
        • CHU de Nice-Hôpital Pasteur
        • Principal Investigator:
          • Mikaël COHEN
        • Contact:
      • Nimes, France, 30029
        • CHU de Nîmes
        • Contact:
        • Principal Investigator:
          • Eric THOUVENOT, MD PhD
      • Paris, France, 75019
        • Fondation Ophtalmologique Rothschild
        • Contact:
        • Principal Investigator:
          • Caroline BENSA
      • Paris, France, 75013
        • Assistance Publique des Hôpitaux de Paris (APHP)-Hôpital Pitié-Salpêtrière
        • Principal Investigator:
          • Elisabeth MAILLART
        • Contact:
      • Rennes, France, 35033
        • CHU de Rennes-C.H.R. Pontchaillou
        • Contact:
        • Principal Investigator:
          • Laure MICHEL
      • Rouen, France, 76038
        • CHU de Rouen-Hôpital Charles Nicolle
        • Principal Investigator:
          • Bertrand BOURRE
        • Contact:
      • Saint Herblain, France, 44 093
        • CHU Nantes -CIC de Neurologie
        • Contact:
        • Principal Investigator:
          • David-Axel LAPLAUD
      • Strasbourg, France, 67000
      • Tours, France, 37044
        • CHU de Tours
        • Contact:
        • Principal Investigator:
          • Ines DOGHRI, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Patient (male or female) aged 55 and over
  2. RRMS diagnosis according to revised McDonald 2017 criteria
  3. First MS symptom >5 years ago. If the date is unknown, RRMS diagnosis >5 years ago

  4. Stable disease in the last 5 years according to the revised Lublin and Reingold classification characterized by :

    Stable T2 lesions documented by MRI performed at least 5 years prior to inclusion versus MRI performed within 6 months prior to the inclusion visit, AND Stable EDSS documented at least 5 years prior to inclusion versus EDSS documented within 6 months prior to inclusion visit, according to the investigator's judgment, AND The absence of relapses within 5 years prior to the inclusion visit

  5. Treated with a Moderate Efficacy Therapy (MET) for at least 5 consecutive years (IFN-β, glatiramer acetate, dimethyl fumarate, teriflunomide, diroximel fumarate); switching from one first-line treatment to another is accepted if the reason for the change is related to personal convenience or intolerance to the first treatment.
  6. Patient with affiliation to a social security regimen
  7. Patient able to understand the objectives and risks associated with the research and to give informed consent to the study
  8. Patient willing and able to comply with study procedures for the duration of the study

Exclusion Criteria:

  1. Primary progressive or secondary progressive with or without relapse as defined by the revised Lublin and Reingold classification
  2. Previous or ongoing treatment with a High Efficacy therapy (HET), with the exception of induction therapy (mitoxantrone, stem cell transplantation, alemtuzumab) provided that the last administration took place at least 10 years prior to inclusion.

  3. Contraindication to MRI (claustrophobia, weight ≥ 140 kg, pacemaker, cochlear implants, foreign body in eye, intracranial vascular clips, surgery in the 6 weeks prior to the beginning of the study, coronary stent implanted in the 8 weeks prior to the beginning of the study,…).

    NB : Gadolinium contraindication will not prevent recruitment of the patient; in this case MRI will be carried out without contrast product injection

  4. History of neurological disease affecting the central nervous system: hereditary degenerative CNS disease, degenerative cognitive disease, systemic autoimmune disease, sarcoidosis, Lyme disease…
  5. Chronic disease which requires chronic treatment with corticoids or immunosuppressors
  6. Uncontrolled cardiac, renal or hepatic disease
  7. Patient participating in another interventional trial (drug or a medical device) or patient who are still within an exclusion period
  8. Patient wishing to discontinue background therapy, whether or not they are experiencing adverse effects.
  9. Patient not considering discontinuing background therapy, whether or not they are experiencing adverse effects.
  10. Pregnant or breastfeeding woman
  11. Patient with difficulty to read or understand French,
  12. Patient subject to a legal protection measure

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Experimental
Treatment withdrawal; patients will stop their Disease Modifying Treatment (DMT)
Drug: treatment withdrawal
Patients will STOP their DMT
Other: MRI
Cerebral+spinal cord enhanced MRI (M0) Cerebral enhanced MRI (M6, Relapse early visit) Unenhanced cerebral MRI (M12, M18, M24, Relapse distant visit
Behavioral: Quality of Life questionnaires
EQ-5D5L: EuroQol-5-Dimension 5 levels Burden of Treatment Questionnaire (BTQ self-administered questionnaires) Hospital Anxiety and Depression (HAD) questionnaire
Other: Disability evaluation tests
EDSS: Expanded Disability Status Scale 25Foot/Walk 9-HPT:Nine Hole Peg Test
Active Comparator: Control arm
Patients will continue their DMT as per routine pratice
Other: MRI
Cerebral+spinal cord enhanced MRI (M0) Cerebral enhanced MRI (M6, Relapse early visit) Unenhanced cerebral MRI (M12, M18, M24, Relapse distant visit
Behavioral: Quality of Life questionnaires
EQ-5D5L: EuroQol-5-Dimension 5 levels Burden of Treatment Questionnaire (BTQ self-administered questionnaires) Hospital Anxiety and Depression (HAD) questionnaire
Other: Disability evaluation tests
EDSS: Expanded Disability Status Scale 25Foot/Walk 9-HPT:Nine Hole Peg Test
Drug: Usual DMT continuation
Patients will continue their DMT during the trial as usual : Interferon-β (IFN-β), glatiramer acetate, dimethyl fumarate, teriflunomide or diroximel fumarate

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to first clinical and/or radiological disease activity during a period of 2 years.
Time Frame: From enrollment to the end of study visit at 24 months

A clinical activity (relapse) is defined by the occurrence of new or worsening of neurological symptoms linked to MS. Relapses must meet the following criteria:

  • Symptoms must last at least 24 hours, without other clinical factors leading to confusion (fever, infection, lesion, drug adverse events)
  • Must be followed by improvement or resolution of the neurological state within 30 days
  • New symptoms or worsening of neurological state must be accompanied by an objective neurologic state aggravation
  • The neurological symptom must be linked to the modified FSS (pyramidal, cerebellar, brainstem, sphincter, mental, sensory or visual functions)

A radiological activity is defined if MRI shows either:

  • at least 3 new or enlarged T2 ≥ 3 mm on the same exam or
  • at least 3 cumulative new or enlarged T2 lesions ≥ 3 mm during follow up or
  • one enhanced gadolinium lesion compared to the previous MRI.
From enrollment to the end of study visit at 24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Strasbourg, France

Collaborators

Ministry of Health, France

Investigators

  • Principal Investigator: Nicolas COLLONGUES, MD, PhD, University Hospital, Strasbourg, france

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

January 1, 2025

Primary Completion (Estimated)

January 1, 2027

Study Completion (Estimated)

June 1, 2029

Study Registration Dates

First Submitted

October 22, 2024

First Submitted That Met QC Criteria

October 25, 2024

First Posted (Actual)

October 29, 2024

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

January 2, 2025

Last Verified

January 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 8670
  • 2024-513475-41-00 (Ctis)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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