Evaluation of Disease-Modifying Therapy Discontinuation in Inactive Relapsing-Remitting Multiple Sclerosis Patients Aged 55+: A Randomized Controlled Trial
- Trial ID
- 2024-513475-41-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to demonstrate the **non-inferiority** in disease activity-free survival between the continuation and discontinuation of disease-modifying therapies in stable patients with relapsing-remitting **multiple sclerosis** (RRMS) aged 55 and over. This objective is clinically relevant as it may lead to a modification of the standard care protocol, potentially optimizing treatment strategies for older populations with RRMS.
Secondary objectives include comparing both groups (treatment discontinuation vs. treatment continuation) in terms of:
- Time to relapse
- Relapse rate
- Progression to secondary progressive multiple sclerosis forms
- Disability progression
- Cognitive impairment
- Quality of life
- Incidence of treatment-emergent adverse events, including side effects and infections
- Comorbidities
- Medico-economic impact of treatment discontinuation
Participants
The clinical trial focuses on **Relapsing-Remitting Multiple Sclerosis (RRMS)** and involves participants aged 55 and over. Both male and female subjects are included, with the study population being characterized by a stable disease status over the past five years. Participants have been diagnosed with RRMS according to the revised McDonald 2017 criteria and have experienced their first MS symptom more than five years ago. They have been treated with a Moderate Efficacy Therapy (MET) for at least five consecutive years, with allowances for switching treatments due to personal convenience or intolerance. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. The study aims to assess the non-inferiority in disease activity-free survival between continuation and discontinuation of treatment in stable RRMS patients, potentially influencing standard care protocols for older populations.
Plans and Procedures
The clinical trial is designed to evaluate the non-inferiority in **disease** activity-free survival between continuation and discontinuation of treatment in stable **relapsing-remitting multiple sclerosis** (RRMS) patients aged 55 and over. This is a multicentric, randomized, controlled, open-label trial. The trial aims to assess whether discontinuing disease-modifying therapies (DMTs) in this patient population is as effective as continuing them, potentially leading to a change in standard care protocols for older populations. The trial is expected to commence recruitment on September 16, 2024, and conclude by February 23, 2029, with a total duration of approximately 4.5 years.
Participants will be randomly assigned to either continue or discontinue their current moderate efficacy therapy (MET), which includes treatments such as **interferon beta-1a**, **dimethyl fumarate**, **teriflunomide**, **diroximel fumarate**, and **glatiramer acetate**. The trial will involve several study visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis according to the revised McDonald 2017 criteria, and stable disease status over the past five years. Follow-up visits will occur at six-month intervals (M6, M12, M18, and M24) to monitor primary and secondary endpoints, including time to first clinical and/or radiological disease activity, annual relapse rate, and transition to secondary progressive multiple sclerosis.
The expected length of participant involvement is up to 25 months, with conditions for early termination including the occurrence of significant adverse events or the participant's decision to withdraw. The end-of-study visit will assess the final outcomes and gather data on safety, efficacy, and cost-effectiveness. Throughout the trial, safety will be monitored through clinical examinations, patient questionnaires, and biological analyses in case of suspected infections. The trial's findings could significantly impact the management of RRMS in older adults, providing insights into the necessity of continued DMTs in this demographic.
Treatment
The clinical trial involves several **experimental medications** for the treatment of inactive relapsing-remitting multiple sclerosis in patients aged 55 and over. The first medication is **Tecfidera**, which contains the active substance **dimethyl fumarate**. It is administered orally in the form of 240 mg gastro-resistant hard capsules. The maximum daily dose is 480 mg, and the treatment period is up to 25 weeks.
Another medication used in the trial is **AVONEX**, which contains **interferon beta-1a**. This medication is provided as a 30 micrograms/0.5 ml solution for injection in a pre-filled pen. It is administered via intramuscular injection with a maximum daily dose of 4.3 micrograms over a treatment period of 25 weeks.
**AUBAGIO** is also included in the trial, containing the active substance **teriflunomide**. It is administered orally in the form of 14 mg film-coated tablets. The maximum daily dose is 14 mg, with a treatment duration of up to 25 weeks.
**Plegridy** is another medication in the study, containing **peginterferon beta-1a**. It is administered as a solution for injection in a pre-filled syringe, with doses of 63 micrograms and 94 micrograms. The route of administration is subcutaneous injection, with a maximum daily dose of 8.9 micrograms over a 25-week period.
**Betaferon** is included in the trial, containing **recombinant interferon beta-1b**. It is provided as a powder and solvent for solution for injection, administered via subcutaneous injection. The maximum daily dose is 125 micrograms, with a treatment period of 25 weeks.
**Copaxone** is another medication used, containing **glatiramer acetate**. It is administered as a 20 mg/ml solution for injection in a pre-filled syringe, with subcutaneous injection as the route of administration. The maximum daily dose is 20 mg, and the treatment period is up to 25 weeks.
**Rebif** is also part of the trial, containing **interferon beta-1a**. It is administered as a 44 micrograms solution for injection in a pre-filled syringe, with subcutaneous injection as the route. The maximum daily dose is 18.9 micrograms, with a treatment duration of 25 weeks.
**Vumerity** is included, containing **diroximel fumarate**. It is administered orally in the form of 231 mg gastro-resistant hard capsules. The maximum daily dose is 924 mg, with a treatment period of up to 25 weeks.
Lastly, **Extavia** is used in the trial, containing **recombinant interferon beta-1b**. It is provided as a powder and solvent for solution for injection, administered via subcutaneous injection. The maximum daily dose is 125 micrograms, with a treatment period of 25 weeks.
Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.
Efficacy
Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoint is the time to first clinical and/or radiological disease activity over a period of two years. This will be measured to evaluate the non-inferiority in disease activity-free survival between continuation and discontinuation of treatment in stable patients with **Relapsing-Remitting Multiple Sclerosis** (RRMS) aged 55 and over.
Secondary endpoints will involve a comprehensive set of evaluations comparing baseline scores at month 0 (M0) with those at months 6 (M6), 12 (M12), 18 (M18), and 24 (M24). These include:
- Kaplan Meier analysis of time to relapse
- Annual relapse rate (ARR)
- Transition to secondary progressive multiple sclerosis according to revised McDonald 2017 criteria
- Scores on the Expanded Disability Status Scale (EDSS), 25-Foot Walk, and 9-Hole Peg Test (9-HPT)
- Scores on the Cognitive and Symptom Checklist for Treatment (CSCT) questionnaire
- Scores on the SEP-59, EQ-5D, Hospital Anxiety and Depression (HAD), and Burden of Treatment (TBQ) questionnaires
- Safety assessments through the number and type of adverse or severe adverse events (AE/SAE), clinical examinations, patient questioning, and biological analysis in case of suspected infection
- Multiple sclerosis comorbidities questionnaire
- Economic evaluations including average annual cost, incremental cost-effectiveness ratio, and cost-utility ratios
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient (male or female) aged 55 and over
- RRMS (Relapsing-Remitting Multiple Sclerosis) diagnosis according to revised McDonald 2017 criteria
- First MS symptom > 5 years ago. If the date is unknown, RRMS diagnosis > 5 years ago
- Stable disease in the last 5 years according to the revised Lublin and Reingold classification 19 characterized by : a) Stable T2 lesions related to MS documented by brain MRI performed at least 5 years prior to inclusion versus MRI performed within 6 months prior to the inclusion visit, AND b) Non-worsened EDSS documented at least 5 years prior to inclusion versus EDSS documented within 6 months prior to inclusion visit, according to the investigator's judgment, AND c) The absence of relapses within 5 years prior to the inclusion visit
- Treated with a Moderate Efficacy Therapy (MET) for at least 5 consecutive years (IFN-β, glatiramer acetate, dimethyl fumarate, teriflunomide, diroximel fumarate) strictly used in accordance with their marketing authorization; switching from one first-line treatment to another is accepted if the reason for the change is related to personal convenience or intolerance to the first treatment.
Exclusion Criteria
- Primary progressive or secondary progressive with or without relapse as defined by the revised Lublin and Reingold classification
- Previous or ongoing treatment with a High Efficacy therapy (HET), with the exception of induction therapy (mitoxantrone, stem cell transplantation, alemtuzumab) provided that the last administration took place at least 10 years prior to inclusion
- Contraindication to MRI (claustrophobia, weight ≥ 140 kg, pacemaker, cochlear implants, foreign body in eye, intracranial vascular clips, surgery in the 6 weeks prior to the beginning of the study, coronary stent implanted in the 8 weeks prior to the beginning of the study,…). NB: Gadolinium contraindication will not prevent recruitment of the patient; in this case MRI will be carried out without contrast product injection
- History of neurological disease affecting the central nervous system: hereditary degenerative CNS disease, degenerative cognitive disease, clinical or radiological history of a clinically significant cerebral arteriovenous malformation, or one that has bled, systemic autoimmune disease, sarcoidosis, Lyme disease…
- Chronic disease which requires chronic treatment with corticoids or immunosuppressors
- Uncontrolled cardiac, renal or hepatic disease
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 16 Sept 2024 | 200 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Betaferon 250 microgram/ml, powder and solvent for solution for injection | Test | POWDER AND SOLVENT FOR SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 125 | 25 | PRD3219992 |
Vumerity 231 mg gastro-resistant hard capsules | Test | GASTRO-RESISTANT HARD CAPSULES | ORAL | 924 | 25 | PRD10194646 |
Tecfidera 240 mg gastro-resistant hard capsules | Test | GASTRO-RESISTANT HARD CAPSULES | ORAL | 480 | 25 | PRD10191509 |
Plegridy 63 micrograms + 94 micrograms solution for injection in pre-filled syringe | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS INJECTION | 8.9 | 25 | PRD10191315 |
Rebif 44 micrograms solution for injection in pre-filled syringe | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS INJECTION | 18.9 | 25 | PRD3307057 |
AUBAGIO 14 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 14 | 25 | PRD2675141 |
Copaxone 20 mg/ml, solution injectable en seringue préremplie | Test | SOLUTION INJECTABLE EN SERINGUE PRÉREMPLIE | SUBCUTANEOUS INJECTION | 20 | 25 | PRD5234063 |
AVONEX 30 micrograms/0.5ml solution for injection in pre-filled pen. | Test | SOLUTION FOR INJECTION IN PRE-FILLED PEN | INTRAMUSCULAR INJECTION | 4.3 | 25 | PRD10189209 |