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

Disease Modifying Therapies Withdrawal in Inactive Secondary Progressive Multiple Sclerosis Patients Older Than 50 Years

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.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Other: DMT withdrawal; Drug: DMT continuation

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.

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anne KERBRAT, Dr; Phone Number: +33 2 99 28 41 69; Email: anne.kerbrat@chu-rennes.fr
• Study Contact Backup: Name: Gilles EDAN, Pr; Phone Number: +33 2 99 28 41 22; Email: gilles.edan@chu-rennes.fr

Study Locations

• France
  • Angers, France
    • Recruiting
    • CHU Angers
    • Contact: Clarisse SCHERER-GAGOU, Dr
  • Bordeaux, France
    • Active, not recruiting
    • CHU de Bordeaux
  • Brest, France
    • Recruiting
    • CHU Brest
    • Contact: François ROUHART, Dr
  • Chartres, France
    • Active, not recruiting
    • CH de Chartres
  • Clermont-Ferrand, France
    • Recruiting
    • CHU Clermont-Ferrand
    • Contact: Pierre CLAVELOU, Pr
  • Créteil, France
    • Active, not recruiting
    • Hôpital Henri Mondor
  • Dijon, France
    • Active, not recruiting
    • CHU Dijon
  • Grenoble, France
    • Recruiting
    • CHU Grenoble
    • Contact: Olivier CASEZ, Dr
  • Libourne, France
    • Active, not recruiting
    • CH de Libourne
  • Lille, France
    • Recruiting
    • CHU Lille
    • Contact: Hélène ZEPHIR, Pr
  • Lille, France
    • Recruiting
    • Hôpital Saint Vincent de Paul
    • Contact: Arnaud KWIATKOWSKI, Dr
    • Principal Investigator: Arnaud KWIATKOWSKI, Dr
  • Lyon, France
    • Recruiting
    • Hospices Civils Lyon
    • Contact: Sandra Vukusic, Pr
  • Marseille, France
    • Active, not recruiting
    • AP-HM
  • Montpellier, France
    • Recruiting
    • CHU Montpellier
    • Contact: Pierre LABAUGE, Pr
  • Nancy, France
    • Terminated
    • CHU Nancy
  • Nantes, France
    • Recruiting
    • CHU Nantes
    • Contact: David LAPLAUD, Pr
  • Nice, France
    • Recruiting
    • CHU Nice
    • Contact: Christine LEBRUN-FRENAY, Pr
  • Nîmes, France
    • Not yet recruiting
    • CHU de Nîmes
    • Contact: Eric THOUVENOT, Pr
  • Paris, France
    • Recruiting
    • AP-HP (La Pitié Salpêtrière)
    • Contact: Céline LOUAPRE, Dr
  • Paris, France
    • Terminated
    • Fondation de Rothschild
  • Poissy, France
    • Recruiting
    • CH Poissy
    • Contact: Olivier HEINZLEF, Dr
  • Poitiers, France
    • Terminated
    • CHU Poitiers
  • Quimper, France
    • Recruiting
    • CH Quimper
    • Contact: Marc COUSTANS, Dr
  • Rennes, France
    • Recruiting
    • CHU Rennes
    • Contact: Anne Kerbrat, Dr
  • Strasbourg, France
    • Recruiting
    • CHU Strasbourg
    • Contact: Jérôme De Seze, Pr
  • Suresnes, France
    • Active, not recruiting
    • CH de Foch
  • Tours, France
    • Recruiting
    • Chu Tours
    • Contact: Anne-Marie GUENNOC, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 48 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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, …).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DMT withdrawal; DMT will be immediately stopped after randomization.These patients will be followed for 2 years.	Other: DMT withdrawal; Group 1 (DMT withdrawal) will not undergo any disease modifying treatments (DMT).
Active Comparator: DMT continuation; The previously established therapy will be continued at the same dose during two years.	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disability progression measured by EDSS	Disability progression measured by the Percentage of patients experiencing disability progression (confirmed at 6 months) at 2 years. Disability progression will be defined as an increase in the EDSS of at least 1 point if the baseline EDSS was 5.5 or less, or 0.5 point if the Baseline EDSS was more than 5.5.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time of Disability progression	Disability progression measured by Time from DMT withdrawal to disability progression	24 months
Disability progression measured by composite score	Disability progression measured by Change in a composite disability progression score (increase in the EDSS score, or an increase in the time to perform the timed 25-foot walk ≥ 20%, or an increase in the time to complete the 9-hole peg test ≥ 20%) confirmed at 6 months	24 months
Disability progression measured by SDMT	Disability progression measured by Change in the SDMT score from baseline to 2-year	24 months
Percentage of patients with Relapse	Relapses measured by Percentage of patients with at least one relapse from baseline to 2-year	24 months
Annualized relapse rate	Relapses measured by Annualized relapse rate during 2-year	24 months
Time of Relapses	Relapses measured byTime from DMT withdrawal to first relapse;	24 months
Percentage of patients with brain lesion	Percentage of patients with one or more new or enlarging brain MRI (Magnetic Resonance Imaging) lesions from baseline to 2-year	24 months
Percentage of patients with gadolinium enhancing lesion	Percentage of patients with at least one gadolinium enhancing lesion(s) at 6 months, and/or 1 year,and/or 2-year	24 months
Change in brain volume	Change in brain volume from baseline to 2-year measured on MRI	24 months
Percentage of patients with no evidence of disease activity	Percentage of patients with no evidence of disease activity (NEDA 3: no clinical relapse, no MRI activity, no disability progression) at 2-year	24 months
Percentage of patients who resume DMT in the treatment withdrawal group	Percentage of patients who resume DMT in the treatment withdrawal group at 2-year	24 months
Quality of life measured by SEP-59 score	Change in the SEP-59 score from baseline to 2-year;	24 months
Quality of life measured by EQ-5D score	Change in the EuroQOL EQ-5D from baseline to 2-year;	24 months
Medico economic impact	Incremental Cost Effectiveness Ratio (ICER) defined as the cost for QALY gained in "treatment withdrawal group" versus "treatment continued group"	24 months

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Investigators: Principal Investigator: Anne KERBRAT, Dr, CHU Rennes - National Headache Center; Principal Investigator: Clarisse SCHERER-GAGOU, Dr, University Hospital, Angers; Principal Investigator: Jean PELLETIER, Pr, AP-HM; Principal Investigator: Céline LOUAPRE, Dr, AP-HP La Pitié Salpêtrière; Principal Investigator: Pierre CLAVELOU, Pr, University Hospital, Clermont-Ferrand; Principal Investigator: Thibault MOREAU, Pr, CHU Dijon; Principal Investigator: Olivier CASEZ, Dr, University Hospital, Grenoble; Principal Investigator: Hélène ZEPHIR, Pr, CHU Lille; Principal Investigator: Sandra VUKUSIC, Pr, Hospices Civils de Lyon; Principal Investigator: Pierre LABAUGE, Pr, University Hospital, Montpellier; Principal Investigator: Guillaume MATHEY, Dr, CHU Nancy; Principal Investigator: Christine LEBRUN-FRENAY, Pr, CHU Nice; Principal Investigator: Olivier HEINZLEF, Dr, CH Poissy; Principal Investigator: Jean-Philippe NEAU, Pr, CHU Poitiers; Principal Investigator: Marc COUSTANS, Dr, CH Quimper; Principal Investigator: Jérôme DE SEZE, Pr, CHU Strasbourg; Principal Investigator: Anne-Marie GUENNOC, Dr, Chu Tours; Principal Investigator: Caroline BENSA-KOSCHER, Dr, Fondation de Rothschild; Principal Investigator: Eric THOUVENOT, Pr, Centre Hospitalier Universitaire de Nimes; Principal Investigator: Alain CREANGE, Pr, CH Henri Mondor; Principal Investigator: Arnaud KWIATKOWSKI, Dr, Hôpital Saint Vincent de Paul; Principal Investigator: Aurore JOURDAIN, Dr, CHU Brest; Principal Investigator: David LAPLAUD, Pr, Nantes University Hospital; Principal Investigator: Aurelie RUET, Pr, University Hospital, Bordeaux; Principal Investigator: Jérôme GRIMAUD, Dr, CH de Chartres; Principal Investigator: Maia TCHIKVILADZE, Dr, CH Foch; Principal Investigator: Philippe CASENAVE, Dr, CH de Libourne

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2019
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: August 28, 2018
• First Submitted That Met QC Criteria: August 28, 2018
• First Posted (Actual): August 31, 2018

Study Record Updates

• Last Update Posted (Actual): October 24, 2023
• Last Update Submitted That Met QC Criteria: October 23, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: multiple sclerosis; medico economic impact; treatment withdrawal; secondary progressive; disease modifying treatment
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Disease Attributes; Chronic Disease; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis
• Other Study ID Numbers: 35RC17_8842_STOP-I-SEP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No