RItuximab Versus Ocrelizumab in Relapsing-remitting Multiple Sclerosis.

Multiple Sclerosis Clinical Trial

— TRIO  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05758831
• Other study ID #: 35RC20_9812_TRIO
• Status: Recruiting
• Phase: Phase 3
• Start date: June 1, 2023
• Est. completion date: May 1, 2030

Study information

• Verified date: April 2024
• Source: Rennes University Hospital
• Contact: Laure MICHEL, MD
• Phone: 0299286774
• Email: laure.michel[@]chu-rennes.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 386
• Est. completion date: May 1, 2030
• Est. primary completion date: March 31, 2030
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Relapsing-remitting Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Perfusion of treatment Rituximab
Perfusion of treatment (Mabthera®, Truxima®, Rixathon®, Ruxience®)
• Perfusion of treatment Ocrelizumab
Perfusion of treatment (Ocrevus®)

Locations

Country	Name	City	State
France	CHRU de Brest - Hôpital la Cavale Blanche	Brest
France	Centre Hospitalier Universitaire de Caen	Caen
France	Centre Hospitalier de Pontoise - GHT NOVO	Cergy-Pontoise
France	Hôpital Gabriel Montpieds	Clermont-Ferrand
France	Centre hospitalier de Gonnesse	Gonesse
France	Groupe Hospitalier de l'Institut Catholique de Lille	Lille
France	Centre Hospitalier Universitaire de Limoges	Limoges
France	Hospices Civils de Lyon Hôpital Neurologique Pierre Wertheimer	Lyon	Bron
France	AP-HM - Hôpital la Timone	Marseille
France	CHRU de Montpellier - Hôpital Gui de Chauliac	Montpellier
France	Centre Hospitalier Régional de Nancy	Nancy
France	CHU de Nantes -Hôpital Nord Laennec	Nantes
France	CHU de Nice - Hôpital Pasteur 2	Nice
France	CHU de Nîmes - Hôpital Caremeau	Nîmes
France	AP-HP Höpital la Pitié-Salpétrière	Paris
France	Groupe Hospitalier Universitaire Henri Mondor	Paris
France	Hôpital Saint-Germain	Poissy
France	Centre Hospitalier de Cornouaille	Quimper
France	Centre Hospitalier Universitaire de Rennes, Hôpital Pontchaillou	Rennes
France	CHU de Rouen - Hôpital Charles Nicolle	Rouen
France	CHRU de Strasbourg - Hôpital Hautpierre	Strasbourg
France	Hôpital Foch	Suresnes
France	CHU de Toulouse - Bâtiment Pierre Paul Riquet	Toulouse

Sponsors (1)

Lead Sponsor	Collaborator
Rennes University Hospital

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	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	To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Annualized relapse rate	Relapses: annualized relapse rate	at 2 years
Secondary	To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Time of onset of the first relapse	mean time of onset of the first relapse	at 2 years
Secondary	To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Percentage of patients without relapse	Percentage of patients without relapse	at 2 years
Secondary	To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Percentage of patients without disability progression	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
Secondary	MRI parameters : gadolinium (Gd) enhancing lesions	- Mean number of Gd enhancing lesions at M6	at 6 month
Secondary	MRI parameters : gadolinium (Gd) enhancing lesions	- Percentage of patients with at least one Gd enhancing lesion(s)	at 6 month
Secondary	MRI parameters : Mean Number of new T2 lesions	- Mean number of new brain T2 lesions	From Month 6 to Month 24
Secondary	MRI parameters : Percentage of patients with one or more new T2 lesions	- Percentage of patients with one or more new brain T2 lesions	From Month 6 to Month 24
Secondary	Patients quality of life : EQ-5D-5L	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
Secondary	Patients quality of life : MusiQOL (Multiple Sclerosis International Quality of Life questionnaire)	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
Secondary	Patients quality of life : MusiQOL	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
Secondary	Patients experience : Musicare	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
Secondary	Patients experience : Musicare	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
Secondary	Medico-economic impact: cost-utility ratio, QALY	Incremental Cost-Effectiveness Ratio (ICER) defined as the cost for QALY gained in "ocrelizumab group" versus "rituximab group" at 24 months.	At 2 years
Secondary	Safety: Number of each adverse event	Number of each adverse event will be compared between the two groups	At 2 years
Secondary	Safety: Number of each severe adverse events	Number of each severe adverse events will be compared between the two groups	At 2 years