Clinical trial NCT02746744: RItuximab Versus FUmarate in Newly Diagnosed Multiple Sclerosis.
Official title: RItuximab Versus FUmarate in Newly Diagnosed Multiple Sclerosis. A Randomized Phase 3 Study Comparing Rituximab With Dimethyl Fumarate in Early Relapsing-Remitting Multiple Sclerosis and Clinically Isolated Syndrome.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Sclerosis, Relapsing-Remitting
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
First posted: 2016-04-21
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A randomized phase 3 study comparing Rituximab with Dimethyl Fumarate in early Relapsing-Remitting Multiple Sclerosis and Clinically Isolated Syndrome.

Detailed description: This is a prospective randomised phase 3 study comparing a novel treatment protocol of Rituximab with a present first line disease modifying drug regarding both clinical, radiological and biochemical parameters. This will be measured via clinical investigations, MRI and Cerebrospinal fluid analyses. Each patient will have one treating physician responsible for all ongoing medical questions and decisions regarding continuation in the study and one examining physician performing the blinded Expanded Disability Status Scale examination and assessments of exacerbations. The coordinating nurse will administer the study-related tests and administer the rituximab infusions. In order to keep the examining physician blinded the patients receiving disease modifying drug will receive infusions with sodium chloride solution at the same interval as the rituximab arm is receiving. In both instances an opaque cover bag will shield the content of the infusion solution. In this case the examining physician will not be able to identify rituximab patients in case of accidental meetings on the neurology unit.

Randomisation will be performed via a randomisation module in the national Swedish MS registry. The patients will be randomised in a 1:1 ratio and receive their treatments in accordance with clinical practice. Thus, the study will mimic the real-life situation in which the treatments will be administered which involves both positive and negative consequences. As positive consequence the result of the study will have a high degree of validity in relation to expected outcome in clinical practice. As negative consequence there may be psychological effects of knowing which medication one is receiving. Since both drugs probably are perceived as positive treatment options in MS today it is unlikely that there will be a predominant placebo effect of either of the treatment options.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of Relapsing Remitting MS according to the 2017 revised McDonald cri-teria 27 OR one demyelinating episode in conjunction with at least one asympto-matic high intensity T2 lesion with size and location compatible with MS.
* Untreated OR treated with first-line injectables (interferon or glatiramer acetate)
* Between the age of 18 and 50 years (inclusive) of age
* No more than ten years of disease duration
* During the previous year, clinical or radiological disease activity defined as at least one of the following:

  * ≥ 1 relapse
  * ≥ 2 T2 lesions
  * ≥ 1 Gd+ lesions
* Expanded Disability Status Scale: 0 - 5,5 (inclusive)
* In fertile females, willing to comply with effective contraceptive methods. These include birth control pills, surgical sterilization of patient or partner or intrauterine device. Non-fertile women is defined as more than 12 months of amenorrhea without an alternative medical cause or, in case of ambiguities, an follicle stimulation hormone level in the postmenopausal range.

Exclusion Criteria:

* Diagnosis of Progressive MS
* Pregnant or lactating women: human chorionic gonadotropin (s-HCG) will be tested on all women at screening, before each study-related infusion and in any situation where there is a reason to suspect pregnancy during the trial, eg delayed menstrual period more than five days above expected time.
* Patients having contraindication for or otherwise not compliant with MRI investigations
* Simultaneous treatment with other immunosuppressive drugs
* Active, severe infections Signs of infections are assessed before inclusion and each study-related infusion through clinical examination and further evaluated by laboratory and other relevant investigations in case of suspected ongoing infection. Hepatitis serology (HBsAg and anti-HBc) will be evaluated before treatment onset.
* Severe cardiac disorder, eg signs of congestive heart failure or coronary artery disease. This will be evaluated through clinical assessment before inclusion.
* Vaccination within 4 weeks of first dose of study medication.
* Documented allergy or intolerance to any of the investigational products.
* Severe psychiatric condition

Primary outcomes:
measure: Freedom of relapse
timeFrame: Within 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: Borås
country: Sweden
facility: South Älvsborg Hospital
city: Falun
country: Sweden
facility: Falun Hospital
city: Gävle
country: Sweden
facility: Gävle Hospital
city: Göteborg
country: Sweden
facility: Saghlgrenska Hospital
city: Helsingborg
country: Sweden
facility: Helsingborg Hospital
city: Karlstad
country: Sweden
facility: Karlstad Hospital
city: Kungsbacka
country: Sweden
facility: Halland Hospital Kungsbacka
city: Linköping
country: Sweden
facility: Linköping University Hospital
city: Nyköping
country: Sweden
facility: Nyköping Hospital
city: Stockholm
country: Sweden
facility: Capio StGöran Hospital
city: Stockholm
country: Sweden
facility: Danderyd hospital
city: Stockholm
country: Sweden
facility: Fredrik Piehl
city: Stockholm
country: Sweden
facility: Karolinska Hospital Huddinge
city: Umeå
country: Sweden
facility: Umeå University
city: Uppsala
country: Sweden
facility: Uppsala Academiska Hospital
city: Örebro
country: Sweden
facility: Örebro University Hospital
city: Östersund
country: Sweden
facility: Östersund Hospital
Study officials:
affiliation: Dept.of Medicine, Sect.of Neurology, Danderyd Hospital
name: Anders Svenningsson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Svenningsson A, Frisell T, Burman J, Salzer J, Fink K, Hallberg S, Hambraeus J, Axelsson M, Nimer FA, Sundstrom P, Gunnarsson M, Johansson R, Mellergard J, Rosenstein I, Ayad A, Sjoblom I, Risedal A, de Flon P, Gilland E, Lindeberg J, Shawket F, Piehl F, Lycke J. Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial. Lancet Neurol. 2022 Aug;21(8):693-703. doi: 10.1016/S1474-4422(22)00209-5.