RItuximab Versus Ocrelizumab in Relapsing-remitting Multiple Sclerosis. (TRIO)

April 15, 2024 updated by: Rennes University Hospital

A Prospective Randomized Trial of Non-inferiority Comparing RItuximab Versus Ocrelizumab in Relapsing-remitting Multiple Sclerosis

The goal of this randomized clinical trial is to compare relapse remitting multiple sclerosis (RRMS) patients treated by ocrelizumab or by rituximab followed for 2 years. The main question it aims to answer is : • to demonstrate the non-inferiority of rituximab versus ocrelizumab in active relapsing MS patients on the % of patients without disease activity at 2 years.

During the 2 years, the study includes 6 follow-up visits and the completion of various health and quality of life questionnaires. The protocol visits follow the usual schedule of treatment infusions for the disease (at initiation of treatment, 15 days after, and then every 6 months).

Two comparison groups: Researchers will compare rituximab treated patients versus ocrelizumab treated patients to see the % of patients without disease activity at 2 years.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). This disease is the leading cause of non-traumatic disability in young adults and France is characterized by a high prevalence (currently 1/1000 inhabitants) of MS.

Clinical trials with B cell depleting therapies have shown efficacy in relapsing-remitting MS (RRMS) and are increasingly perceived as an important addition to the existing panel of Disease-modifying treatments (DMTs). Rituximab, a mouse chimeric anti CD20, is approved for non-Hodgkin's lymphoma, chronic lymphocytic leukemia, certain forms of vasculitis and Rheumatoid Arthritis with first marketing approval in 1998. Rituximab has undergone clinical testing in RRMS in 2008 in a phase II placebo-controlled trial, demonstrating the clinico-radiological efficacy in 104 patients. Despite these promising results and the absence of adverse events, its clinical development was interrupted by the manufacturer (Roche). However, for several years, rituximab has been increasingly prescribed (off-label) in Europe and USA in patients refractory to first-line therapies, with a very good safety and efficacy. Thus, rituximab is prescribed for 40% of RRMS patients treated in Sweden. Roche has then developed a humanized anti-CD20 monoclonal antibody (Ocrelizumab). Two phase III clinical trials (OPERA I and II) have demonstrated its efficacy in active RRMS. Ocrelizumab has just been authorized in France in this indication: RRMS patients with active disease (clinical or radiological). So, it can be prescribed as a first line or second line therapy in active RRMS patients.

According to literature, there are no biological arguments to think that ocrelizumab could be more effective in active RRMS compared to rituximab. Moreover, regarding safety, rituximab has been used for other indications for almost two decades and no serious concern has arisen.

The high cost of this new antibody (x6 to 10) compared to rituximab) makes it wonder about its place inside the anti-CD20 therapeutic strategy compared to rituximab for treating relapsing MS patients.

Hypothesis: Researchers hypothesize that rituximab and ocrelizumab have the same efficacy in active RRMS patients. Indeed, if the non-inferiority of rituximab on the % of patients without disease activity is confirmed by the trial, the potential medico-economic benefit from a societal perspective will be a strong argument to ask for authorization of rituximab in active RRMS.

Study Type

Interventional

Enrollment (Estimated)

386

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • France
      • Brest, France, 29609
      • Caen, France, 14033
        • Recruiting
        • Centre Hospitalier Universitaire de Caen
        • Contact:
      • Cergy-Pontoise, France, 95300
      • Clermont-Ferrand, France, 63003
      • Gonesse, France, 95503
      • Lille, France, 59160
        • Not yet recruiting
        • Groupe Hospitalier de l'Institut Catholique de Lille
        • Contact:
      • Limoges, France, 87042
      • Marseille, France, 13385
      • Montpellier, France, 34295
        • Recruiting
        • CHRU de Montpellier - Hôpital Gui de Chauliac
        • Contact:
      • Nancy, France, 54035
      • Nantes, France, 44800
      • Nice, France, 06002
      • Nîmes, France, 30029
      • Paris, France, 75010
        • Not yet recruiting
        • AP-HP Höpital la Pitié-Salpétrière
        • Contact:
      • Paris, France, 94000
        • Not yet recruiting
        • Groupe Hospitalier Universitaire Henri Mondor
        • Contact:
      • Poissy, France, 78303
      • Quimper, France, 29107
      • Rennes, France, 35000
        • Recruiting
        • Centre Hospitalier Universitaire de Rennes, Hôpital Pontchaillou
        • Contact:
          • Laure MICHEL, MD
        • Principal Investigator:
          • Laure MICHEL, PH-PD
      • Rouen, France, 76038
      • Strasbourg, France, 67200
      • Suresnes, France, 92150
      • Toulouse, France, 31059
        • Not yet recruiting
        • CHU de Toulouse - Bâtiment Pierre Paul Riquet
        • Contact:
    • Bron
      • Lyon, Bron, France, 69677
        • Not yet recruiting
        • Hospices Civils de Lyon Hôpital Neurologique Pierre Wertheimer
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 55 years (Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients presenting a relapsing remitting MS according to Mac Donald 2017 criteria, with clinical or radiological criteria of activity (ie at least one relapse AND/OR one new T2 lesion in the last 12 months before inclusion);
  • Age between 18 and 55 years
  • EDSS ≤ 5
  • Brain MRI within 6 months before inclusion
  • For women of childbearing potential*: effective contraception (effective contraception include oral contraception, intrauterine devices and other forms of contraception with failure rate <1%, for the duration of the study and until 12 months after last dose administered) * A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.

A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

  • Having signed an informed consent form
  • Patients covered with social insurance

Non-Inclusion Criteria:

  • Secondary or primary progressive MS;
  • Previous treatment by mitoxantrone, cladribine, alemtuzumab and anti CD20 therapies in the last two years;
  • Previous treatment by fingolimod or natalizumab in the last 4 weeks;
  • Treatment with high dose corticosteroids during the 30 days preceding the inclusion;
  • Occurrence of a relapse less than 30 days before inclusion;
  • Pregnancy or breastfeeding;
  • Other neurologic or systemic disease;
  • Concomitant participation or Participation in another therapeutic trial in the last 6 months;
  • Incapacity to understand or sign the consent form;
  • Contraindication to MRI;

  • Contraindication to anti-CD20 therapies:

    • Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization
    • Active malignancy.
    • Any ongoing infection
    • Severe heart failure (New York Heart Association Class IV) or severe uncontrolled cardiac disease
    • Positive test for HIV, hepatitis B or C, or tuberculosis
    • Severe immune deficiency:
  • Lymphopenia grade 3 (0.2 to 0.5 × 10^9/L) or higher grades

  • Neutropenia grade 3 (0.5 to 1.0 × 10^9/L) or higher grades

    • Known hypersensitivity or other known side effects for any of the study medications, including co-medications such as high glucocorticosteroids
    • AST or ALT >=3ULN
    • Platelet (thrombocyte) count < 100 x 10^9/L
  • Adults legally protected (under judicial protection, guardianship, or supervision), persons deprived of their liberty.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Ocrelizumab
Day 0 (300mg), Day 15(300mg), and then 300 mg every 6 months (M6, M12, M18 and M24)
Drug: Perfusion of treatment Ocrelizumab
Perfusion of treatment (Ocrevus®)
Experimental: Rituximab
Day 0 (1000mg), Day 15 (1000 mg), and then 500 mg every 6 months (M6, M12, M18 and M24)
Drug: Perfusion of treatment Rituximab
Perfusion of treatment (Mabthera®, Truxima®, Rixathon®, Ruxience®)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To demonstrate the non-inferiority of rituximab versus ocrelizumab in active relapsing MS patients on the percentage of patients without disease activity at 2 years.
Time Frame: at 2 years

Percentage of patients without disease activity at 2 years (Disease activity is defined as:

  • At least one relapse between baseline and M24
  • OR MRI activity defined as Gd enhancing lesions at M6 or as the appearance of at least one new T2 lesion between M6 and M24)
at 2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Annualized relapse rate
Time Frame: at 2 years
Relapses: annualized relapse rate
at 2 years
To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Time of onset of the first relapse
Time Frame: at 2 years
mean time of onset of the first relapse
at 2 years
To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Percentage of patients without relapse
Time Frame: at 2 years
Percentage of patients without relapse
at 2 years
To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Percentage of patients without disability progression
Time Frame: at 2 years
Percentage of patients without disability progression (Expanded Disability Status Scale-EDSS) (Disability progression will be defined as an increase of 1.5 pt if baseline EDSS=0, 1pt EDSS (if baseline 1 ≤ EDSS<6), or an increase of 0.5pt if baseline EDSS is ≥ 6; confirmed at 6 months.) EDSS : Minimum Score 1, Maximum score 10, higher scores mean a worse outcome.
at 2 years
MRI parameters : gadolinium (Gd) enhancing lesions
Time Frame: at 6 month
- Mean number of Gd enhancing lesions at M6
at 6 month
MRI parameters : gadolinium (Gd) enhancing lesions
Time Frame: at 6 month
- Percentage of patients with at least one Gd enhancing lesion(s)
at 6 month
MRI parameters : Mean Number of new T2 lesions
Time Frame: From Month 6 to Month 24
- Mean number of new brain T2 lesions
From Month 6 to Month 24
MRI parameters : Percentage of patients with one or more new T2 lesions
Time Frame: From Month 6 to Month 24
- Percentage of patients with one or more new brain T2 lesions
From Month 6 to Month 24
Patients quality of life : EQ-5D-5L
Time Frame: From baseline (Day 0) to every six month of follow up until Month 24

Change in the EQ-5D-5L score

The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS).

The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.

The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'.
From baseline (Day 0) to every six month of follow up until Month 24
Patients quality of life : MusiQOL (Multiple Sclerosis International Quality of Life questionnaire)
Time Frame: From baseline (Day 0) to Month 12

Change in the MusiQOL score

The MusiQoL is a specific questionnaire comprising 31 questions describing nine dimensions of quality of life (Appendix 1):

activities of daily living (eight items); psychological well-being (four); relationships with friends (four); symptoms (three); relationships with family (three); relationships with the health care system (three); emotional and sexual life (two); coping (two); rejection (two).

Each item is scored from 1 (never/not at all) to 5 (always/very much). Before calculating the score of the dimensions, the scores of negatively written items are reversed. The score of a dimension is obtained by averaging the scores of its constituent items. The dimension scores are then transformed linearly into scores ranging from 0 to 100 (100 being the maximum quality of life level). A global quality of life score is also available.
From baseline (Day 0) to Month 12
Patients quality of life : MusiQOL
Time Frame: From baseline (Day 0) to Month 24

Change in the MusiQOL score

The MusiQoL is a specific questionnaire comprising 31 questions describing nine dimensions of quality of life (Appendix 1):

activities of daily living (eight items); psychological well-being (four); relationships with friends (four); symptoms (three); relationships with family (three); relationships with the health care system (three); emotional and sexual life (two); coping (two); rejection (two).

Each item is scored from 1 (never/not at all) to 5 (always/very much). Before calculating the score of the dimensions, the scores of negatively written items are reversed. The score of a dimension is obtained by averaging the scores of its constituent items. The dimension scores are then transformed linearly into scores ranging from 0 to 100 (100 being the maximum quality of life level). A global quality of life score is also available.
From baseline (Day 0) to Month 24
Patients experience : Musicare
Time Frame: From baseline (Day 0) to Month 12

Change in the Musicare score

Musicare is a questionnaire to assess the experience of both patients and caregivers of quality of care in MS, in accordance with psychometric standards. It comprises 35 items encompassing 5 domains: Information about the disease (11), Information about the treatments/medical investigation (8), Relationships with health care teams (8) Health care access (5) Reception in care structures (3).

Each item is scored from 1 (Strongly agree) to 5 (Don't know).
From baseline (Day 0) to Month 12
Patients experience : Musicare
Time Frame: From baseline (Day 0) to Month 24

Change in the Musicare score

Musicare is a questionnaire to assess the experience of both patients and caregivers of quality of care in MS, in accordance with psychometric standards. It comprises 35 items encompassing 5 domains: Information about the disease (11), Information about the treatments/medical investigation (8), Relationships with health care teams (8) Health care access (5) Reception in care structures (3).

Each item is scored from 1 (Strongly agree) to 5 (Don't know).
From baseline (Day 0) to Month 24
Medico-economic impact: cost-utility ratio, QALY
Time Frame: At 2 years
Incremental Cost-Effectiveness Ratio (ICER) defined as the cost for QALY gained in "ocrelizumab group" versus "rituximab group" at 24 months.
At 2 years
Safety: Number of each adverse event
Time Frame: At 2 years
Number of each adverse event will be compared between the two groups
At 2 years
Safety: Number of each severe adverse events
Time Frame: At 2 years
Number of each severe adverse events will be compared between the two groups
At 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Rennes University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 1, 2023

Primary Completion (Estimated)

March 31, 2030

Study Completion (Estimated)

May 1, 2030

Study Registration Dates

First Submitted

February 17, 2023

First Submitted That Met QC Criteria

March 6, 2023

First Posted (Actual)

March 7, 2023

Study Record Updates

Last Update Posted (Actual)

April 16, 2024

Last Update Submitted That Met QC Criteria

April 15, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 35RC20_9812_TRIO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Multiple Sclerosis

Clinical Trials on Perfusion of treatment Ocrelizumab

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Poland

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe