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

NCT ID: NCT06663189

Last Updated: 2025-01-03

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-01-31
• Study Completion Date: 2029-06-30

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.

Conditions

Relapsing-remitting Multiple Sclerosis (RRMS)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Experimental

Treatment withdrawal; patients will stop their Disease Modifying Treatment (DMT)

Group Type: EXPERIMENTAL

treatment withdrawal

Intervention Type: DRUG

Patients will STOP their DMT

MRI

Intervention Type: OTHER

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

Intervention Type: BEHAVIORAL

EQ-5D5L: EuroQol-5-Dimension 5 levels Burden of Treatment Questionnaire (BTQ self-administered questionnaires) Hospital Anxiety and Depression (HAD) questionnaire

Disability evaluation tests

Intervention Type: OTHER

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

Control arm

Patients will continue their DMT as per routine pratice

Group Type: ACTIVE_COMPARATOR

Usual DMT continuation

Intervention Type: DRUG

Patients will continue their DMT during the trial as usual : Interferon-β (IFN-β), glatiramer acetate, dimethyl fumarate, teriflunomide or diroximel fumarate

MRI

Intervention Type: OTHER

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

Intervention Type: BEHAVIORAL

EQ-5D5L: EuroQol-5-Dimension 5 levels Burden of Treatment Questionnaire (BTQ self-administered questionnaires) Hospital Anxiety and Depression (HAD) questionnaire

Disability evaluation tests

Intervention Type: OTHER

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

Interventions

treatment withdrawal

Patients will STOP their DMT

Intervention Type: 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

Intervention Type: DRUG

MRI

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

Intervention Type: OTHER

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

Intervention Type: BEHAVIORAL

Disability evaluation tests

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

Intervention Type: OTHER

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

• Minimum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ministry of Health, France

OTHER_GOV

Sponsor Role: collaborator

University Hospital, Strasbourg, France

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nicolas COLLONGUES, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Strasbourg, France

Locations

CHU de Bordeaux-Hôpital Pellegrin

Bordeaux, , France

CHU de Caen-Hôpital Côte de Nacre

Caen, , France

CHU de Clermont-Ferrand-Hôpital Gabriel Montpied

Clermont-Ferrand, , France

Assistance Publique des Hôpitaux de Paris (APHP)-Hôpital Henri Mondor

Créteil, , France

CHU de Dijon-Hôpital du Bocage

Dijon, , France

CH de Gonesse

Gonesse, , France

CHU de Grenoble Alpes

La Tronche, , France

Groupement des Hôpitaux de l'Institut Catholique de Lille Hôpital Saint Vincent de Paul

Lille, , France

CHU de Lille-Hôpital Roger Salengro

Lille, , France

CHU de Limoges-Hôpital Dupuytren

Limoges, , France

Assistance Publique des Hôpitaux de Marseille (APHM)-Hôpital La Timone Adultes

Marseille, , France

CHU de Montpellier-Hôpital G. De Chauliac

Montpellier, , France

CHU de Nancy -Hôpital Central

Nancy, , France

CHU de Nice-Hôpital Pasteur

Nice, , France

CHU de Nîmes

Nîmes, , France

Assistance Publique des Hôpitaux de Paris (APHP)-Hôpital Pitié-Salpêtrière

Paris, , France

Fondation Ophtalmologique Rothschild

Paris, , France

CHU de Rennes-C.H.R. Pontchaillou

Rennes, , France

CHU de Rouen-Hôpital Charles Nicolle

Rouen, , France

CHU Nantes -CIC de Neurologie

Saint-Herblain, , France

Les Hôpitaux Universitaires de Strasbourg

Strasbourg, , France

CHU de Tours

Tours, , France

Countries

France

Central Contacts

Sarah HUSTACHE

Role: CONTACT

dpidrci@chru-strasbourg.fr

03 3 88 11 54 15 ext. 00 33

Facility Contacts

Aurélie RUET, MD

Role: primary

aurelie.ruet@chu-bordeaux.fr

05 56 79 55 21 ext. +33 (0)

Pierre BRANGER

Role: primary

branger-p@chu-caen.fr

(0) 2 31 06 46 17 ext. 00 33

Pierre CLAVELOU

Role: primary

pclavelou@chu-clermontferrand.fr

(0)4 73 75 07 50 ext. 00 33

Alain CREANGE, MD PhD

Role: primary

alain.creange@aphp.fr

01 49 81 23 15 ext. +33 (0)

Thibault MOREAU

Role: primary

thibault.moreau@chu-dijon.fr

(0)3 80 29 55 84 ext. 00 33

Eric MANCHON

Role: primary

eric.manchon@ch-gonesse.fr

(0)1 34 53 21 21 ext. 00 33

Catalina COCLITU, MD

Role: primary

cicoclitu@chu-grenoble.fr

04 76 76 58 71 ext. +33 (0)

Arnaud KWIATKOWSKI, MD

Role: primary

kwiatkowski.arnaud@ghicl.net

03 20 87 49 01 ext. +33 (0)

Hélène ZEPHIR THI

Role: primary

h-zephir@chru-lille.fr

(0)3 20 44 68 46 ext. 33

Maxime MERINDOL

Role: primary

maxime.merindol@chu-limoges.fr

(0)5 55 05 65 68 ext. 00 33

Bertrand AUDOIN

Role: primary

bertrand.AUDOIN@ap-hm.fr

(0)4 91 38 59 34 ext. 00 33

Xavier AYRIGNAC

Role: primary

x-ayrignac@chu-montpellier.fr

(0)467337413 ext. 00 33

Guillaume MATHEY, MD

Role: primary

G.MATHEY@chru-nancy.fr

03 83 85 16 88 ext. +33 (0)

Mikaël COHEN

Role: primary

Cohen.m@chu-nice.fr

04 92 03 79 01 ext. 00 33

Eric THOUVENOT, MD PhD

Role: primary

eric.thouvenot@chu-nimes.fr

04 66 68 32 61 ext. +33 (0)

Elisabeth MAILLART

Role: primary

elisabeth.maillart@ahp.fr

01 42 17 62 05 ext. 00 33

Caroline BENSA

Role: primary

cbensa@for.paris

(0)1 48 03 68 52 ext. 00 33

Laure MICHEL

Role: primary

laure.michel@chu-rennes.fr

(0)299284266 ext. 00 33

Bertrand BOURRE

Role: primary

bertrand.bourre@chu-rouen.fr

(0)2 32 88 58 11 ext. 00 33

David-Axel LAPLAUD

Role: primary

david.laplaud@chu-nantes.fr

(0)2 40 16 52 12 ext. 00 33

Laura DROCTOVE

Role: primary

laura.droctove@chru-strasbourg.fr

Ines DOGHRI, MD

Role: primary

I.DOGHRI@chu-tours.fr

02 47 47 37 22 ext. +33 (0)

Other Identifiers

2024-513475-41-00

Identifier Type: CTIS

Identifier Source: secondary_id

8670

Identifier Type: -

Identifier Source: org_study_id