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

Multiple Sclerosis Clinical Trial

— STOP-I-SEP  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03653273
• Other study ID #: 35RC17_8842_STOP-I-SEP
• Status: Recruiting
• Phase: Phase 3
• Start date: January 24, 2019
• Est. completion date: January 2028

Study information

• Verified date: October 2023
• Source: Rennes University Hospital
• Contact: Anne KERBRAT, Dr
• Phone: 2 99 28 41 69
• Email: anne.kerbrat[@]chu-rennes.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 250
• Est. completion date: January 2028
• Est. primary completion date: July 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

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, …).

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Chronic Progressive
• Sclerosis

Intervention

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

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.

Locations

Country	Name	City	State
France	CHU Angers	Angers
France	CHU de Bordeaux	Bordeaux
France	CHU Brest	Brest
France	CH de Chartres	Chartres
France	CHU Clermont-Ferrand	Clermont-Ferrand
France	Hôpital Henri Mondor	Créteil
France	CHU Dijon	Dijon
France	CHU Grenoble	Grenoble
France	CH de Libourne	Libourne
France	CHU Lille	Lille
France	Hôpital Saint Vincent de Paul	Lille
France	Hospices Civils Lyon	Lyon
France	AP-HM	Marseille
France	CHU Montpellier	Montpellier
France	CHU Nancy	Nancy
France	CHU Nantes	Nantes
France	CHU Nice	Nice
France	CHU de Nîmes	Nîmes
France	AP-HP (La Pitié Salpêtrière)	Paris
France	Fondation de Rothschild	Paris
France	CH Poissy	Poissy
France	CHU Poitiers	Poitiers
France	CH Quimper	Quimper
France	CHU Rennes	Rennes
France	CHU Strasbourg	Strasbourg
France	CH de Foch	Suresnes
France	CHU Tours	Tours

Sponsors (1)

Lead Sponsor	Collaborator
Rennes University Hospital

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Time of Disability progression	Disability progression measured by Time from DMT withdrawal to disability progression	24 months
Secondary	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
Secondary	Disability progression measured by SDMT	Disability progression measured by Change in the SDMT score from baseline to 2-year	24 months
Secondary	Percentage of patients with Relapse	Relapses measured by Percentage of patients with at least one relapse from baseline to 2-year	24 months
Secondary	Annualized relapse rate	Relapses measured by Annualized relapse rate during 2-year	24 months
Secondary	Time of Relapses	Relapses measured byTime from DMT withdrawal to first relapse;	24 months
Secondary	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
Secondary	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
Secondary	Change in brain volume	Change in brain volume from baseline to 2-year measured on MRI	24 months
Secondary	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
Secondary	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
Secondary	Quality of life measured by SEP-59 score	Change in the SEP-59 score from baseline to 2-year;	24 months
Secondary	Quality of life measured by EQ-5D score	Change in the EuroQOL EQ-5D from baseline to 2-year;	24 months
Secondary	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