Clinical trial NCT06663189: Disease Modifying Therapies Withdrawal in Inactive Relapsing-remitting Multiple Sclerosis Patients Aged 55 and Over (TWINS : Therapies Withdrawal IN Relapsing Multiple Sclerosis)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Relapsing-remitting Multiple Sclerosis (RRMS)
Lead sponsor: University Hospital, Strasbourg, France
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2024-10-29
Enrollment: 200
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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 criteria: 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

Primary outcomes:
measure: Time to first clinical and/or radiological disease activity during a period of 2 years.
timeFrame: From enrollment to the end of study visit at 24 months
Secondary outcomes:
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: CHU de Bordeaux-Hôpital Pellegrin
city: Caen
country: France
facility: CHU de Caen-Hôpital Côte de Nacre
city: Clermont Ferrand
country: France
facility: CHU de Clermont-Ferrand-Hôpital Gabriel Montpied
city: Créteil
country: France
facility: Assistance Publique des Hôpitaux de Paris (APHP)-Hôpital Henri Mondor
city: Dijon
country: France
facility: CHU de Dijon-Hôpital du Bocage
city: Gonesse
country: France
facility: CH de Gonesse
city: La Tronche
country: France
facility: CHU de Grenoble Alpes
city: Lille
country: France
facility: Groupement des Hôpitaux de l'Institut Catholique de Lille Hôpital Saint Vincent de Paul
city: Lille
country: France
facility: CHU de Lille-Hôpital Roger Salengro
city: Limoges
country: France
facility: CHU de Limoges-Hôpital Dupuytren
city: Marseille
country: France
facility: Assistance Publique des Hôpitaux de Marseille (APHM)-Hôpital La Timone Adultes
city: Montpellier
country: France
facility: CHU de Montpellier-Hôpital G. De Chauliac
city: Nancy
country: France
facility: CHU de Nancy -Hôpital Central
city: Nice
country: France
facility: CHU de Nice-Hôpital Pasteur
city: Nimes
country: France
facility: CHU de Nîmes
city: Paris
country: France
facility: Assistance Publique des Hôpitaux de Paris (APHP)-Hôpital Pitié-Salpêtrière
city: Paris
country: France
facility: Fondation Ophtalmologique Rothschild
city: Rennes
country: France
facility: CHU de Rennes-C.H.R. Pontchaillou
city: Rouen
country: France
facility: CHU de Rouen-Hôpital Charles Nicolle
city: Saint Herblain
country: France
facility: CHU Nantes -CIC de Neurologie
city: Strasbourg
country: France
facility: Les Hôpitaux Universitaires de Strasbourg
city: Tours
country: France
facility: CHU de Tours
Study officials:
affiliation: University Hospital, Strasbourg, France
name: Nicolas COLLONGUES, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: