Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03653273
Recruitment Status : Recruiting
First Posted : August 31, 2018
Last Update Posted : March 7, 2019
Sponsor:
Information provided by (Responsible Party):
Rennes University Hospital

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.

Condition or disease Intervention/treatment Phase
Multiple Sclerosis Other: DMT withdrawal Drug: DMT continuation Phase 3

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Disease Modifying Therapies Withdrawal in Inactive Secondary Progressive Multiple Sclerosis Patients Older Than 50 Years
Actual Study Start Date : January 24, 2019
Estimated Primary Completion Date : July 2024
Estimated Study Completion Date : January 2026

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. Disability progression measured by EDSS [ Time Frame: 24 months ]

    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.



Secondary Outcome Measures :
  1. Time of Disability progression [ Time Frame: 24 months ]
    Disability progression measured by Time from DMT withdrawal to disability progression

  2. Disability progression measured by composite score [ Time Frame: 24 months ]
    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

  3. Disability progression measured by SDMT [ Time Frame: 24 months ]
    Disability progression measured by Change in the SDMT score from baseline to 2-year

  4. Percentage of patients with Relapse [ Time Frame: 24 months ]
    Relapses measured by Percentage of patients with at least one relapse from baseline to 2-year

  5. Annualized relapse rate [ Time Frame: 24 months ]
    Relapses measured by Annualized relapse rate during 2-year

  6. Time of Relapses [ Time Frame: 24 months ]
    Relapses measured byTime from DMT withdrawal to first relapse;

  7. Percentage of patients with brain lesion [ Time Frame: 24 months ]
    Percentage of patients with one or more new or enlarging brain MRI (Magnetic Resonance Imaging) lesions from baseline to 2-year

  8. Percentage of patients with gadolinium enhancing lesion [ Time Frame: 24 months ]
    Percentage of patients with at least one gadolinium enhancing lesion(s) at 6 months, and/or 1 year,and/or 2-year

  9. Change in brain volume [ Time Frame: 24 months ]
    Change in brain volume from baseline to 2-year measured on MRI

  10. Percentage of patients with no evidence of disease activity [ Time Frame: 24 months ]
    Percentage of patients with no evidence of disease activity (NEDA 3: no clinical relapse, no MRI activity, no disability progression) at 2-year

  11. Percentage of patients who resume DMT in the treatment withdrawal group [ Time Frame: 24 months ]
    Percentage of patients who resume DMT in the treatment withdrawal group at 2-year

  12. Quality of life measured by SEP-59 score [ Time Frame: 24 months ]
    Change in the SEP-59 score from baseline to 2-year;

  13. Quality of life measured by EQ-5D score [ Time Frame: 24 months ]
    Change in the EuroQOL EQ-5D from baseline to 2-year;

  14. Medico economic impact [ Time Frame: 24 months ]
    Incremental Cost Effectiveness Ratio (ICER) defined as the cost for QALY gained in "treatment withdrawal group" versus "treatment continued group"



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients > 50 years old;
  • Secondary progressive phenotype for at least 3 years;
  • Disease modifying therapy of MS for at least 3 years (interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, fingolimod, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil); Both patients with the same DMT or with successive DMTs can be included;
  • 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 and/or Biotin are allowed throughout the study, provided they have been introduced at least 1 months before inclusion for Fampridine and 3 months before inclusion for Biotin.

Exclusion Criteria:

  • Patients treated with mitoxantrone or alemtuzumab, during the previous 3 years before inclusion;
  • Patients treated with rituximab, ocrelizumab or natalizumab 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, …).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03653273


Contacts
Layout table for location contacts
Contact: Anne KERBRAT, Dr 2 99 28 41 69 ext +33 anne.kerbrat@chu-rennes.fr
Contact: Gilles EDAN, Pr 2 99 28 41 22 ext +33 gilles.edan@chu-rennes.fr

Locations
Show Show 22 study locations
Sponsors and Collaborators
Rennes University Hospital
Investigators
Layout table for investigator information
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: François ROUHART, Dr CHU Brest
Principal Investigator: Pierre CLAVELOU, Pr University Hospital, Clermont-Ferrand
Principal Investigator: Thibault MOREAU, Pr CHU Dijon
Principal Investigator: Eric MANCHON, Dr CH de Gonesse
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: David LAPLAUD, Pr CHU Nantes
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: Ayman TOURBAH, Pr CHU Reims
Principal Investigator: Rasha WARDI, Dr CH Saint Brieuc
Principal Investigator: Jérôme DE SEZE, Pr CHU Strasbourg
Principal Investigator: Anne-Marie GUENNOC, Dr CHU Tours

Layout table for additonal information
Responsible Party: Rennes University Hospital
ClinicalTrials.gov Identifier: NCT03653273    
Other Study ID Numbers: 35RC17_8842_STOP-I-SEP
First Posted: August 31, 2018    Key Record Dates
Last Update Posted: March 7, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Rennes University Hospital:
multiple sclerosis
secondary progressive
disease modifying treatment
medico economic impact
treatment withdrawal
Additional relevant MeSH terms:
Layout table for MeSH terms
Multiple Sclerosis
Multiple Sclerosis, Chronic Progressive
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases