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

Summary

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.

Conditions

• Relapsing-remitting Multiple Sclerosis (RRMS)

Interventions

DRUG

treatment withdrawal

Patients will STOP their DMT

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

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

Sponsors & Collaborators

• Ministry of Health, France

  collaborator OTHER_GOV

• University Hospital, Strasbourg, France

  lead OTHER

Principal Investigators

• Nicolas COLLONGUES, MD, PhD · University Hospital, Strasbourg, France

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

55 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-01-31

Primary Completion

2027-01-31

Completion

2029-06-30

Countries

• France

Study Locations