Clinical trial NCT03653273: Disease Modifying Therapies Withdrawal in Inactive Secondary Progressive Multiple Sclerosis Patients Older Than 50 Years (STOP-I-SEP)
Official title: Disease Modifying Therapies Withdrawal in Inactive Secondary Progressive Multiple Sclerosis Patients Older Than 50 Years
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Multiple Sclerosis
Keywords: multiple sclerosis
secondary progressive
disease modifying treatment
medico economic impact
treatment withdrawal
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
First posted: 2018-08-31
Enrollment: 250
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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, ...).

Primary outcomes:
measure: Disability progression measured by EDSS
timeFrame: 24 months
Secondary outcomes:
measure: Time of Disability progression
timeFrame: 24 months
measure: Disability progression measured by composite score
timeFrame: 24 months
measure: Disability progression measured by SDMT
timeFrame: 24 months
measure: Percentage of patients with Relapse
timeFrame: 24 months
measure: Annualized relapse rate
timeFrame: 24 months
measure: Time of Relapses
timeFrame: 24 months
measure: Percentage of patients with brain lesion
timeFrame: 24 months
measure: Percentage of patients with gadolinium enhancing lesion
timeFrame: 24 months
measure: Change in brain volume
timeFrame: 24 months
measure: Percentage of patients with no evidence of disease activity
timeFrame: 24 months
measure: Percentage of patients who resume DMT in the treatment withdrawal group
timeFrame: 24 months
measure: Quality of life measured by SEP-59 score
timeFrame: 24 months
measure: Quality of life measured by EQ-5D score
timeFrame: 24 months
measure: Medico economic impact
timeFrame: 24 months
Other outcomes:
Locations:
city: Angers
country: France
facility: CHU Angers
city: Bordeaux
country: France
facility: CHU de Bordeaux
city: Brest
country: France
facility: CHU Brest
city: Chartres
country: France
facility: CH de Chartres
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: Dijon
country: France
facility: CHU Dijon
city: Grenoble
country: France
facility: CHU Grenoble
city: Libourne
country: France
facility: CH de Libourne
city: Lille
country: France
facility: CHU Lille
city: Lille
country: France
facility: Hôpital Saint Vincent de Paul
city: Lyon
country: France
facility: Hospices Civils Lyon
city: Marseille
country: France
facility: AP-HM
city: Montpellier
country: France
facility: CHU Montpellier
city: Nancy
country: France
facility: CHU Nancy
city: Nantes
country: France
facility: CHU Nantes
city: Nice
country: France
facility: CHU Nice
city: Nîmes
country: France
facility: CHU de Nîmes
city: Paris
country: France
facility: AP-HP (La Pitié Salpêtrière)
city: Paris
country: France
facility: Fondation de Rothschild
city: Poissy
country: France
facility: CH Poissy
city: Poitiers
country: France
facility: CHU Poitiers
city: Quimper
country: France
facility: CH Quimper
city: Rennes
country: France
facility: CHU Rennes
city: Strasbourg
country: France
facility: CHU Strasbourg
city: Suresnes
country: France
facility: CH de Foch
city: Tours
country: France
facility: CHU Tours
Study officials:
affiliation: CHU Rennes - National Headache Center
name: Anne KERBRAT, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Angers
name: Clarisse SCHERER-GAGOU, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: AP-HM
name: Jean PELLETIER, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: AP-HP La pitié Salpêtrière
name: Céline LOUAPRE, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Brest
name: Aurore JOURDAIN, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Clermont-Ferrand
name: Pierre CLAVELOU, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Dijon
name: Thibault MOREAU, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Grenoble
name: Olivier CASEZ, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Lille
name: Hélène ZEPHIR, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospices Civils de Lyon
name: Sandra VUKUSIC, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Montpellier
name: Pierre LABAUGE, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU NANCY
name: Guillaume MATHEY, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Nantes University Hospital
name: David LAPLAUD, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU NICE
name: Christine LEBRUN-FRENAY, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CH Poissy
name: Olivier HEINZLEF, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Poitiers
name: Jean-Philippe NEAU, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CH Quimper
name: Marc COUSTANS, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Strasbourg
name: Jérôme DE SEZE, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Tours
name: Anne-Marie GUENNOC, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Fondation de Rothschild
name: Caroline BENSA-KOSCHER, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Hospitalier Universitaire de Nīmes
name: Eric THOUVENOT, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CH Henri Mondor
name: Alain CREANGE, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Saint Vincent de Paul
name: Arnaud KWIATKOWSKI, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Bordeaux
name: Aurelie RUET, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CH de Chartres
name: Jérôme GRIMAUD, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CH Foch
name: Maia TCHIKVILADZE, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CH de Libourne
name: Philippe CASENAVE, Dr
role: PRINCIPAL_INVESTIGATOR
References: