Clinical trial NCT05758831: RItuximab Versus Ocrelizumab in Relapsing-remitting Multiple Sclerosis.
Official title: A Prospective Randomized Trial of Non-inferiority Comparing RItuximab Versus Ocrelizumab in Relapsing-remitting Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Multiple Sclerosis
Relapsing-remitting Multiple Sclerosis
Keywords: Multiple Sclerosis
Relapsing-remitting
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
First posted: 2023-03-07
Enrollment: 386
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: multicenter, prospective, comparative (non inferiority), randomized, double blinded phase III/IV study
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: at 2 years
Secondary outcomes:
measure: To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Annualized relapse rate
timeFrame: at 2 years
measure: To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Time of onset of the first relapse
timeFrame: at 2 years
measure: To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Percentage of patients without relapse
timeFrame: at 2 years
measure: To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Percentage of patients without disability progression
timeFrame: at 2 years
measure: MRI parameters : gadolinium (Gd) enhancing lesions
timeFrame: at 6 month
measure: MRI parameters : gadolinium (Gd) enhancing lesions
timeFrame: at 6 month
measure: MRI parameters : Mean Number of new T2 lesions
timeFrame: From Month 6 to Month 24
measure: MRI parameters : Percentage of patients with one or more new T2 lesions
timeFrame: From Month 6 to Month 24
measure: Patients quality of life : EQ-5D-5L
timeFrame: From baseline (Day 0) to every six month of follow up until Month 24
measure: Patients quality of life : MusiQOL (Multiple Sclerosis International Quality of Life questionnaire)
timeFrame: From baseline (Day 0) to Month 12
measure: Patients quality of life : MusiQOL
timeFrame: From baseline (Day 0) to Month 24
measure: Patients experience : Musicare
timeFrame: From baseline (Day 0) to Month 12
measure: Patients experience : Musicare
timeFrame: From baseline (Day 0) to Month 24
measure: Medico-economic impact: cost-utility ratio, QALY
timeFrame: At 2 years
measure: Safety: Number of each adverse event
timeFrame: At 2 years
measure: Safety: Number of each severe adverse events
timeFrame: At 2 years
Other outcomes:
Locations:
city: Lyon
country: France
facility: Hospices Civils de Lyon Hôpital Neurologique Pierre Wertheimer
state: Bron
city: Brest
country: France
facility: CHRU de Brest - Hôpital la Cavale Blanche
city: Caen
country: France
facility: Centre Hospitalier Universitaire de Caen
city: Cergy-Pontoise
country: France
facility: Centre Hospitalier de Pontoise - GHT NOVO
city: Clermont-Ferrand
country: France
facility: Hôpital Gabriel Montpieds
city: Gonesse
country: France
facility: Centre hospitalier de Gonnesse
city: Lille
country: France
facility: Groupe Hospitalier de l'Institut Catholique de Lille
city: Limoges
country: France
facility: Centre Hospitalier Universitaire de Limoges
city: Marseille
country: France
facility: AP-HM - Hôpital la Timone
city: Montpellier
country: France
facility: CHRU de Montpellier - Hôpital Gui de Chauliac
city: Nancy
country: France
facility: Centre Hospitalier Régional de Nancy
city: Nantes
country: France
facility: CHU de Nantes -Hôpital Nord Laennec
city: Nice
country: France
facility: CHU de Nice - Hôpital Pasteur 2
city: Nîmes
country: France
facility: CHU de Nîmes - Hôpital Caremeau
city: Paris
country: France
facility: AP-HP Höpital la Pitié-Salpétrière
city: Paris
country: France
facility: Groupe Hospitalier Universitaire Henri Mondor
city: Poissy
country: France
facility: Hôpital Saint-Germain
city: Quimper
country: France
facility: Centre Hospitalier de Cornouaille
city: Rennes
country: France
facility: Centre Hospitalier Universitaire de Rennes, Hôpital Pontchaillou
city: Rouen
country: France
facility: CHU de Rouen - Hôpital Charles Nicolle
city: Strasbourg
country: France
facility: CHRU de Strasbourg - Hôpital Hautpierre
city: Suresnes
country: France
facility: Hôpital Foch
city: Toulouse
country: France
facility: CHU de Toulouse - Bâtiment Pierre Paul Riquet
Study officials:
References: