A clincial study comparing the effectiveness of two doses of the drug Rituximab during long-term treatment of the neurological disease Multiple Sclerosis.

• Register: EUCTR
• Last refreshed on: 6 April 2020
• Main ID: EUCTR2018-000721-31-SE
• Date of registration: 24/04/2018
• Prospective Registration: Yes
• Primary sponsor: Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital
• Public title: A clincial study comparing the effectiveness of two doses of the drug Rituximab during long-term treatment of the neurological disease Multiple Sclerosis.
• Scientific title: RItuximab Long-Term DOSE Trial in Multiple Sclerosis – RIDOSE-MS A randomized trial of long-term dosage of rituximab in multiple sclerosis The RIDOSE-MS trial is a multi-centre trial of long-term treatment with rituximab in MS, randomised between two different dosing regimens. Population: Patients with RRMS that has completed the RIFUND-MS trial in either the rituximab or DMF arm. In addition, patients will be recruited that has not participated in the RIFUND trial but has been treated with rituximab with the same protocol as in the RIFUND trial as part of clinical practice. Intervention: Treatment with rituximab (Mabthera®) 500 mg every six months. Both the previous rituximab and DMF arms from the RIFUND trial will be treated with rituximab in the RIDOSE trial. Control: After one year of treatment in RIDOSE-MS, patients will be randomised 1:1 to either continue with 500 mg every 6 months or 500 mg every 12 months and continue on this treatment schedule for another 3 years. Outcome: Primary outcome will be the proportion of patients remaining with no evidence of disease activity (NEDA) -3 over the randomised period of 3 years. As secondary endpoints progression of disability, brain atrophy, cognitive function and level of serum Neurofilament-Light will be evaluated. In addition, Patient-related outcome scales measuring fatigue, work ability and treatment satisfaction will be analysed. - RIDOSE-MS
• Date of first enrolment: 04/07/2018
• Target sample size: 200
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-000721-31
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: yes; Double blind: no; Parallel group: yes; Cross over: no; Other: yes; Other trial design description: Dose comparison; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: yes; Other specify the comparator: Another dose of the same medicinal product; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Sweden

Contacts

• Name: Department of Clinical Sciences, KI
• Affiliation: Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital

• Name: Department of Clinical Sciences, KI
• Affiliation: Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital

Key inclusion & exclusion criteria

Inclusion criteria:
A subject will be eligible for inclusion in this study if all of the following criteria apply:

• Diagnosis of Relapsing Remitting MS according to the 2017 revised McDonald criteria OR one demyelinating episode in conjunction with at least one asymptomatic high intensity T2 lesion with size and location compatible with MS
• The patient has completed the RIFUND-MS trial and is treated with either of the study medications rituximab or DMF at the last visit of the RIFUND trial OR has been treated with rituximab with a dose regimen of 500 – 1000 mg followed by 500 mg every 6 months* for a total of up to two years as part of clinical practice
• Age 20 – 52 years (inclusive)
• EDSS 0 – 5,5 (inclusive)
• The patient is willing and able to give written informed consent, according to the judgement of the investigator.
• 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 FSH level in the postmenopausal range.
* Occasional extended dose interval for up to 12 months in conjunction with the COVID epidemic is allowed
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 200
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
A subject will not be eligible for inclusion in this study if any of the following criteria ap-plies:

• Diagnosis of Progressive MS
• Previous treatment with any “second-line” immunomodulatory drug, eg natalizumab, alemtuzumab**, fingolimod, or other long-acting immunosuppressive agents.
• Pregnant or lactating women
s-HCG will be tested on all women at screening, before each study-related infu-sion 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 investi-gations
• 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 rele-vant investigations in case of suspected ongoing infection. Hepatitis serology (HBsAg and anti-HBc) will be evaluated before treatment onset if not tested within the previous three years.
• 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 IP:s
• Severe psychiatric condition
** Up to 6 months initial treatment with natalizumab in conjunction with the COVID epidemic or for completing vaccination before inclusion in the trial is allowed.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Patients with multiple sclerosis (MS), 20 - 52 years of age, that have completed the RIFUND-MS trial (EudraCT 2015-004116-38) will be offered to continue in this extension trial, RODOSE-MS. In addition, patients will be recruited that has not participated in the RIFUND trial but has been treated with rituximab with the same protocol as in the RIFUND trial as part of clinical practice.

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Trade Name: Mabthera
Product Name: Mabthera
Pharmaceutical Form: Infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Trade Name: Mabthera
Product Name: Mabthera
Pharmaceutical Form: Infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 500-1000

Primary Outcome(s)

Primary end point(s): The primary endpoint of this study is
• The proportion of patients maintaining No Evidence of Disease Activity-3 (NEDA-3) during year 2 – 4 of the trial: No relapse, no new T2 lesions (> 3 mm), no EDSS progression in either dose arm.

Main Objective: The primary objective of this study is
• To assess long-term efficacy and safety of rituximab in RRMS while comparing two different dosing regimens.

Secondary Objective: The secondary objectives of the study are
• To compare effects on brain atrophy measures via magnetic resonance imaging between treatment with two long-term dosing regimens of Rituximab in MS.
• To compare effects on cerebrospinal fluid markers between axonal damage from treatment with two long-term dosing regimens of Rituximab in MS.
• To compare effects on serum markers for axonal damage between treatment with two long-term dosing regimens of Rituximab in MS.
• To compare the rate of disability progression between treatment with two long-term dosing regimens of Rituximab in MS.
• To compare the occurrence of immunological side-effects such as hypogammag-lobulinaemia and late onset neutropenia between treatment with two long-term dosing regimens of Rituximab in MS.
• To compare the occurrence of severe infections between treatment with two long-term dosing regimens of Rituximab in MS.

Timepoint(s) of evaluation of this end point: When all included subjects have been followed for the full duration of 4 years in the trial

Secondary Outcome(s)

Secondary end point(s): The secondary endpoints are
• The proportion of patients maintaining NEDA-3 comparing the previous rituximab arm with the previous DMF arm from the RIFUND trial
• Time to first relapse for the two dosing regimens
• Treatment effect evaluated by MRI
o Proportion without new/enlarging T2 lesions
o Evolution of brain atrophy measured as brain parenchymal fraction (BPF) and corpus callosum area or -volume
• Treatment effect as confirmed worsening evaluated via EDSS
o Proportion of patient with confirmed progression in EDSS according to pre-specified criteria
o The mean change in EDSS over the trial period
• Treatment effect evaluated via levels of Neurofilament-Light protein in serum
o Serum will be stored from blood samples each six month during the study, in total nine occasions
• Treatment effect evaluated via levels of Neurofilament-Light protein in the CSF
o The patients will be asked to participate in this part as an optional study involving LP at three occasions.
• Time to discontinuation of dosing regimen allocation, ie “dose survival” analysis.
• The occurrence of hypogammaglobulinaemia in the two dose arms
• The occurrence of neutropenia in the two dose arms
• The occurrence of infections in the two dose arms

Timepoint(s) of evaluation of this end point: When all included subjects have been followed for the full duration of 4 years in the trial

Secondary ID(s)

RIDOSE-MS

Source(s) of Monetary Support

Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital

Ethics review

Status: Approved
Approval date: 04/07/2018
Contact: