Disease Modifying Therapies Withdrawal in Inactive Secondary Progressive Multiple Sclerosis Patients Older Than 50 Years (STOP-I-SEP)

NCT ID: NCT03653273

Last Updated: 2023-10-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 250 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-24
• Study Completion Date: 2028-01-31

Brief Summary

Further controlled and randomized prospective studies in Multiple sclerosis, analyzing the potential impact of treatment discontinuation on disability progression, focal disease activity and quality of life are needed. The optimum patient age and duration of inactive SPMS before treatment withdrawal and the monitoring procedures also need to be specified, the ultimate goal being to provide evidence-based recommendations for clinical practice. Following the previous retrospective experience, we decided to drive a multicenter prospective study in France based on the hypothesis that stopping disease modifying therapy will not induce an increased risk of disability progression and relapse in selected SPMS patients (older patients without lesion activity) but will improve the quality of life and may reduce treatment-related costs.

Detailed Description

Multiple sclerosis (MS) usually evolves over decades and can present several phenotypes. Approximately 85% of newly diagnosed Multiple Sclerosis (MS) patients present the Relapsing-Remitting MS (RRMS) phenotype. After a mean time of approximatively 20 years, a large majority of these patients evolve to the so-called "Secondary Progressive MS" (SPMS) phase. SPMS is characterized by an irreversible disability progression not related to relapses, although relapses could be superimposed. Nevertheless, the shift in-between RRMS and SPMS is not clear. Different subtypes of SPMS have been recently defined by F Lublin et al. This classification takes into account persistent focal inflammatory activity (active vs inactive SPMS) along with disease progression (progressing vs non-progressing SPMS). In clinical routine, it is important to identify these stages of MS as they differently respond to the disease modifying therapies (DMTs).

Introducing DMTs during the RRMS phase had consistently demonstrated a significant impact on the annual relapse rate (ARR) and on the short-term disability progression. Conversely, during the SPMS phase, the impact of DMTs remained uncertain on disability progression, especially in older patients, with "inactive" disease. As a matter of fact, the DMTs are considered to be anti-inflammatory by nature, but the focal inflammation reduces with age and disease duration.

In addition, the DMTs have side effects and cost approximately 10,000 euros per year and per patient. In this context, the usefulness of continuing DMTs in "inactive" SPMS patients older than 50 years is questionable.

In a preliminary retrospective study conducted at our Institute which enrolled 100 SPMS patients, the ARR remained stable 3 years after treatment withdrawal (0.07, 95% CI [0.05, 0.11]), relative to the 3 years prior to treatment withdrawal (0.12, [0.09, 0.16]). EDSS scores were available for 94 patients The percentage of patients experiencing a significant increase of their EDSS score during the 3 years after treatment withdrawal also remained stable compared to the 3 years prior treatment withdrawal. These preliminary data support the safety of DMTs withdrawal in selected SPMS patients. However, further prospective studies are needed to provide evidence-based guidelines for daily practice.

This randomized controlled clinical trial thus aims to compare SPMS patients older than 50 years without evidence of focal inflammatory activity for 3 years, stopping DMTs versus patients with the same criteria still receiving treatment. We hypothesize that stopping DMTs will not induce an increased risk of disability progression or relapse in SPMS patients but will improve their quality of life and have an impact on treatment-related costs.

So far, the impact of DMTs withdrawal in a selected SPMS population has not been explored. Having evidence-based recommendations on the treatment management of these patients is essential, considering the consequences in terms of disability, relapses, side effects, quality of life and costs. DMTs in MS are now available since 20 years, with an increasing number of approved molecules. As a matter of fact, this question concerns a large number of patients: a retrospective analysis of patients included in the Rennes EDMUS database allowed to identify 71 SPMS patients older than 50 years and without evidence of focal inflammatory activity for 3 years actually undergoing a DMT.

For evident conflict of interests, the pharmaceutical firms will not promote or fund clinical trials on treatment withdrawal. A randomized controlled study initiated by academia and financed by public funding should be performed to explore these questions. We will evaluate the impact of these changes from the patient and the health system's points of view. The results of this clinical trial will lead to a concrete change in clinical practice.

Conditions

Multiple Sclerosis

Study Design

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

Study Groups

DMT withdrawal

DMT will be immediately stopped after randomization.These patients will be followed for 2 years.

Group Type: EXPERIMENTAL

DMT withdrawal

Intervention Type: OTHER

Group 1 (DMT withdrawal) will not undergo any disease modifying treatments (DMT).

DMT continuation

The previously established therapy will be continued at the same dose during two years.

Group Type: ACTIVE_COMPARATOR

DMT continuation

Intervention Type: DRUG

Group 2 (DMT continuation) may undergo the DMT . The therapy continued in this research is the one previously established, at the same dose, not implying additional precautions for use.

Interventions

DMT withdrawal

Group 1 (DMT withdrawal) will not undergo any disease modifying treatments (DMT).

Intervention Type: OTHER

DMT continuation

Group 2 (DMT continuation) may undergo the DMT . The therapy continued in this research is the one previously established, at the same dose, not implying additional precautions for use.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Patients > 50 years old;
• Secondary progressive phenotype for at least 3 years; The secondary progressive phenotype will be defined as progressive deterioration of disability not due to relapse, with an increase of at least 1 EDSS point since the beginning of the progressive phase (or 0.5 EDSS point if EDSS score ≥ 5.5).
• Disease modifying therapy of MS for at least 3 years (interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, rituximab, ocrelizumab); Both patients with the same DMT or with successive DMTs during 3 years can be included. It is important to note that patients could have been treated with fingolimod or natalizumab 2 or 3 years before inclusion, but not during the year before inclusion ;
• No evidence of focal inflammatory activity for at least 3 years (no clinical relapse and no gadolinium enhancement on an MRI scan);
• EDSS≥3.

Concomitant medications with Fampridine are allowed throughout the study, provided they have been introduced at least 1 months before inclusion.

Natalizumab and fingolimod during the year before inclusion were excluded because of the risk of recurrence of inflammatory activity or even rebound of inflammatory activity after withdrawal.

Both patients with the same DMT or with successive DMTs during 3 years can be included, as for example, cyclophosphamide is used for 1 or 2 years, sometimes followed by mycophenolate mofetil.

For Rituximab and Ocrelizumab, inclusion in STOP-I-SEP will be at 6 months from the last infusion to take into account the mode of action of these treatments and their specific administration scheme.

Exclusion Criteria

• Patients treated with mitoxantrone or alemtuzumab, during the previous 3 years before inclusion;
• Patients treated with natalizumab or fingolimod during the year before inclusion;
• Change of disease modifying therapy of MS for less than a year
• Other neurological or systemic disease ;
• Incapacity to understand or sign the consent form ;
• Contraindication to MRI ;
• Pregnancy or breast-feeding ;
• Patient in another clinical trial
• Persons referred to in Articles L. 1121-5 to L. 1121-8 and L. 1122-1-2 of the Public Health Code (eg minors, protected adults, …).

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Rennes University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Anne KERBRAT, Dr

Role: PRINCIPAL_INVESTIGATOR

CHU Rennes - National Headache Center

Clarisse SCHERER-GAGOU, Dr

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Angers

Jean PELLETIER, Pr

Role: PRINCIPAL_INVESTIGATOR

AP-HM

Céline LOUAPRE, Dr

Role: PRINCIPAL_INVESTIGATOR

AP-HP La pitié Salpêtrière

Aurore JOURDAIN, Dr

Role: PRINCIPAL_INVESTIGATOR

CHU Brest

Pierre CLAVELOU, Pr

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Clermont-Ferrand

Thibault MOREAU, Pr

Role: PRINCIPAL_INVESTIGATOR

CHU Dijon

Olivier CASEZ, Dr

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Grenoble

Hélène ZEPHIR, Pr

Role: PRINCIPAL_INVESTIGATOR

CHU Lille

Sandra VUKUSIC, Pr

Role: PRINCIPAL_INVESTIGATOR

Hospices Civils de Lyon

Pierre LABAUGE, Pr

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Montpellier

Guillaume MATHEY, Dr

Role: PRINCIPAL_INVESTIGATOR

CHU NANCY

David LAPLAUD, Pr

Role: PRINCIPAL_INVESTIGATOR

Nantes University Hospital

Christine LEBRUN-FRENAY, Pr

Role: PRINCIPAL_INVESTIGATOR

CHU NICE

Olivier HEINZLEF, Dr

Role: PRINCIPAL_INVESTIGATOR

CH Poissy

Jean-Philippe NEAU, Pr

Role: PRINCIPAL_INVESTIGATOR

CHU Poitiers

Marc COUSTANS, Dr

Role: PRINCIPAL_INVESTIGATOR

CH Quimper

Jérôme DE SEZE, Pr

Role: PRINCIPAL_INVESTIGATOR

CHU Strasbourg

Anne-Marie GUENNOC, Dr

Role: PRINCIPAL_INVESTIGATOR

CHU Tours

Caroline BENSA-KOSCHER, Dr

Role: PRINCIPAL_INVESTIGATOR

Fondation de Rothschild

Eric THOUVENOT, Pr

Role: PRINCIPAL_INVESTIGATOR

Centre Hospitalier Universitaire de Nīmes

Alain CREANGE, Pr

Role: PRINCIPAL_INVESTIGATOR

CH HENRI MONDOR

Arnaud KWIATKOWSKI, Dr

Role: PRINCIPAL_INVESTIGATOR

Hôpital Saint Vincent de Paul

Aurelie RUET, Pr

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Bordeaux

Jérôme GRIMAUD, Dr

Role: PRINCIPAL_INVESTIGATOR

CH de Chartres

Maia TCHIKVILADZE, Dr

Role: PRINCIPAL_INVESTIGATOR

CH Foch

Philippe CASENAVE, Dr

Role: PRINCIPAL_INVESTIGATOR

CH de Libourne

Locations

CHU Angers

Angers, , France

Site Status: RECRUITING

CHU de Bordeaux

Bordeaux, , France

Site Status: ACTIVE_NOT_RECRUITING

CHU Brest

Brest, , France

Site Status: RECRUITING

CH de Chartres

Chartres, , France

Site Status: ACTIVE_NOT_RECRUITING

CHU Clermont-Ferrand

Clermont-Ferrand, , France

Site Status: RECRUITING

Hôpital Henri Mondor

Créteil, , France

Site Status: ACTIVE_NOT_RECRUITING

CHU Dijon

Dijon, , France

Site Status: ACTIVE_NOT_RECRUITING

CHU Grenoble

Grenoble, , France

Site Status: RECRUITING

CH de Libourne

Libourne, , France

Site Status: ACTIVE_NOT_RECRUITING

CHU Lille

Lille, , France

Site Status: RECRUITING

Hôpital Saint Vincent de Paul

Lille, , France

Site Status: RECRUITING

Hospices Civils Lyon

Lyon, , France

Site Status: RECRUITING

AP-HM

Marseille, , France

Site Status: ACTIVE_NOT_RECRUITING

CHU Montpellier

Montpellier, , France

Site Status: RECRUITING

CHU Nancy

Nancy, , France

Site Status: TERMINATED

CHU Nantes

Nantes, , France

Site Status: RECRUITING

CHU Nice

Nice, , France

Site Status: RECRUITING

CHU de Nîmes

Nîmes, , France

Site Status: NOT_YET_RECRUITING

AP-HP (La Pitié Salpêtrière)

Paris, , France

Site Status: RECRUITING

Fondation de Rothschild

Paris, , France

Site Status: TERMINATED

CH Poissy

Poissy, , France

Site Status: RECRUITING

CHU Poitiers

Poitiers, , France

Site Status: TERMINATED

CH Quimper

Quimper, , France

Site Status: RECRUITING

CHU Rennes

Rennes, , France

Site Status: RECRUITING

CHU Strasbourg

Strasbourg, , France

Site Status: RECRUITING

CH de Foch

Suresnes, , France

Site Status: ACTIVE_NOT_RECRUITING

CHU Tours

Tours, , France

Site Status: RECRUITING

Countries

France

Central Contacts

Anne KERBRAT, Dr

Role: CONTACT

anne.kerbrat@chu-rennes.fr

2 99 28 41 69 ext. +33

Gilles EDAN, Pr

Role: CONTACT

gilles.edan@chu-rennes.fr

2 99 28 41 22 ext. +33

Facility Contacts

Clarisse SCHERER-GAGOU, Dr

Role: primary

François ROUHART, Dr

Role: primary

Pierre CLAVELOU, Pr

Role: primary

Olivier CASEZ, Dr

Role: primary

Hélène ZEPHIR, Pr

Role: primary

Arnaud KWIATKOWSKI, Dr

Role: primary

Sandra VUKUSIC, Pr

Role: primary

Pierre LABAUGE, Pr

Role: primary

David LAPLAUD, Pr

Role: primary

Christine LEBRUN-FRENAY, Pr

Role: primary

Eric THOUVENOT, Pr

Role: primary

Céline LOUAPRE, Dr

Role: primary

Olivier HEINZLEF, Dr

Role: primary

Marc COUSTANS, Dr

Role: primary

Anne KERBRAT, Dr

Role: primary

Jérôme DE SEZE, Pr

Role: primary

Anne-Marie GUENNOC, Dr

Role: primary

Other Identifiers

35RC17_8842_STOP-I-SEP

Identifier Type: -

Identifier Source: org_study_id