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

Condition(s) studied

Investigational drug(s) / intervention(s)

treatment withdrawal: Patients will STOP their DMT

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

MRI: Cerebral+spinal cord enhanced MRI (M0) Cerebral enhanced MRI (M6, Relapse early visit) Unenhanced cerebral MRI (M12, M18, M24, Relapse distant visit

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

Disability evaluation tests: EDSS: Expanded Disability Status Scale 25Foot/Walk 9-HPT:Nine Hole Peg Test

Study 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.

Eligibility

Primary outcome measure(s)

• Time to first clinical and/or radiological disease activity during a period of 2 years. — 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.

Trial sites (22)

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