RItuximab Long-Term DOSE Trial in Multiple Sclerosis - RIDOSE-MS (RIDOSE-MS)

RItuximab Long-Term DOSE Trial in Multiple Sclerosis - RIDOSE-MS. A Randomized Trial of Long-term Dosage of Rituximab in Multiple Sclerosis

A randomized trial of long-term dosage of rituximab in multiple sclerosis

Study Overview

• Status: Active, not recruiting
• Conditions: Multiple Sclerosis, Relapsing-Remitting
• Intervention / Treatment: Drug: Rituximab

Detailed Description

This is a prospective randomized phase 3 study comparing two dosing regimens of Rituximab in long-term treatment of MS. Primary endpoint is no evidence of disease activity (NEDA) in a non-inferiority analysis between 12-months dosing interval of 500 mg rituximab with 6-months dosing interval. The endpoint is a compound of being free from release, new or enlarging MRI lesions and sustained progression of disability measured by EDSS.

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. MRI investigations will be performed blinded for the dosing arm allocation.

Randomization will be performed via a randomization module in the national Swedish MS registry. The patients will be randomized 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. This will lead to a high degree of validity in relation to expected outcome in clinical practice.

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 3

Contacts and Locations

Study Locations

• Sweden
  • Borås, Sweden
    • South Älvsborg Hospital
  • Falun, Sweden
    • Falun hospital
  • Gävle, Sweden
    • Gävle Hospital
  • Göteborg, Sweden
    • Saghlgrenska Hospital
  • Helsingborg, Sweden
    • Helsingborg Hospital
  • Karlstad, Sweden
    • Karlstad Hospital
  • Kungsbacka, Sweden
    • Halland Hospital Kungsbacka
  • Linköping, Sweden
    • Linkoping University Hospital
  • Nyköping, Sweden
    • Nyköping Hospital
  • Stockholm, Sweden
    • Fredrik Piehl
  • Stockholm, Sweden
    • Capio StGöran Hospital
  • Stockholm, Sweden
    • Karolinska Hospital Huddinge
  • Umeå, Sweden
    • Umea University
  • Uppsala, Sweden
    • Uppsala Academiska Hospital
  • Örebro, Sweden
    • Orebro University Hospital
  • Östersund, Sweden
    • Östersund hospital
  • Stockholm
    • Danderyd, Stockholm, Sweden, 18288
      • Anders Svenningsson

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 52 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• 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 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.

Exclusion criteria:

• 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, e.g 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 if not tested within the previous three years.
• Severe cardiac disorder, e.g 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 the IP
• Severe psychiatric condition

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 6-month dosing interval; This arm is receiving standard dose rituximab 500 mg every 6 months	Drug: Rituximab; After one year in the trial, the patients are split in the two dosing-arms described above. The dose-comparison phase continues four years.; Other Names: Mabthera
EXPERIMENTAL: 12-month dosing interval; This arm is receiving the comparator dose rituximab 500 mg every 12 months	Drug: Rituximab; After one year in the trial, the patients are split in the two dosing-arms described above. The dose-comparison phase continues four years.; Other Names: Mabthera

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
No evidence of disease activity (NEDA)	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	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
No evidence of disease activity (NEDA) in subgroups	The proportion of patients maintaining NEDA-3 comparing the previous rituximab arm with the previous DMF arm from the RIFUND trial	4 years
Time to first relapse	Time to first relapse for the two dose arms	3 yeas
Freedom of new or enlarged lesions on MRI	Proportion of patients in each dosing arm without new/enlarging T2 lesions	3 years
Development of brain atrophy	Evolution of brain atrophy measured as brain parenchymal fraction (BPF) and corpus callosum area or -volume	3 years
Development of confirmed sustained disability	Proportion of patient with confirmed progression in EDSS according to pre-specified criteria	3 years
Mean progression of disability	The mean change in EDSS over the trial period in the two dosing arms	3 years
Neurodegeneration	The mean change of s-NFL concentration between the two dosing arms	3 years
Dose persistence	Time to discontinuation of dosing regimen allocation	3 years
Development of hypogammaglobulinaemia	The occurrence of hypogammaglobulinaemia in the two dosing arms	3 years
Development of neutropenia	The occurrence of neutropenia in the two dosing arms	3 years
Development of infections	The occurrence of infections in the two dosing arms	3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Health economy	Estimation of societal costs per year to supply the two dosing arms	3 years
Treatment Satisfaction Questionnaire	Validated scale that evaluate the degree of treatment satisfaction through 10 5- or 7 grade likert-scale questions	3 years

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Investigators: Principal Investigator: Anders Svenningsson, Professor, Dept of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 4, 2018
• Primary Completion (ANTICIPATED): December 20, 2024
• Study Completion (ANTICIPATED): June 1, 2025

Study Registration Dates

• First Submitted: June 3, 2019
• First Submitted That Met QC Criteria: June 6, 2019
• First Posted (ACTUAL): June 7, 2019

Study Record Updates

• Last Update Posted (ACTUAL): April 19, 2021
• Last Update Submitted That Met QC Criteria: April 15, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Multiple sclerosis; Randomized trial; Relapsing-Remitting; Dosing protocols
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: EudraCT 2018-000721-31

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No