A study to find out the best length of time between ocrelizumab doses for patients with relapsing remitting multiple sclerosis using a trial design with multiple groups and multiple stages

ISRCTN	ISRCTN17105865
DOI	https://doi.org/10.1186/ISRCTN17105865
Integrated Research Application System (IRAS)	1013232
Sponsor's protocol code number	ND004
Sponsor	University College London
Funder	National Institute for Health and Care Research

Submission date: 25/02/2026
Registration date: 26/03/2026
Last edited: 27/05/2026

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Nervous System Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Not provided at time of registration.

Contact information

REFINE-MS Team
Public

MRC CTU at UCL, ICTM 2nd Floor, 90 High Holborn
London
WC1V 6LJ
United Kingdom

Email	mrcctu.refinems@ucl.ac.uk

Prof Olga Ciccarelli
Scientific, Principal investigator

10-12 Russell Square
London
WC1B 5EH
United Kingdom

Phone	+44 (0)7950949908
Email	o.ciccarelli@ucl.ac.uk

Study information

Primary study design	Interventional
Allocation	Randomized controlled trial
Masking	Blinded (masking used)
Control	Active
Assignment	Parallel
Purpose	Treatment, Safety
Scientific title	REFINE-MS: A randomised, rater-blind, phase 3 trial to determine the optimal dose frequency of ocrelizumab for patients with relapsing remitting multiple sclerosis using a novel multi-arm multi-stage frequency-optimisation design
Study acronym	REFINE-MS
Study objectives	To test whether people with relapsing-remitting MS who have been stable on ocrelizumab for a minimum of 2 years can take it less often and still keep their MS under similar control (measured by looking at whether or not there are any new signs of damage on a brain MRI scan) compared with the standard schedule of every 6 months. Secondary objectives of REFINE-MS are: to determine the effects of taking ocrelizumab less often on how well-controlled the participant’s condition is (including whether or not their disability progresses), participant quality of life, patient reported outcomes and cost-savings to the NHS.
Ethics approval(s)	Approved 07/04/2026, East Midlands - Leicester Central Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 0207 104 8118; leicestercentral.rec@hra.nhs.uk), ref: 26/EM/0057
Health condition(s) or problem(s) studied	Medical condition: Relapsing-remitting multiple sclerosis (RRMS) Medical condition in lay language: A long-term condition affecting the brain and spinal cord, where people experience episodes of new or worsening symptoms (relapses) followed by periods of recovery (remission). Therapeutic areas: Diseases [C] - Nervous System Diseases [C10]
Intervention	Participants will be randomised in the REFINE-MS electronic data capture (eDC) system to receive ocrelizumab (ocrelizumab 600mg intravenous or 920mg subcutaneous). The dose frequency depends on the arm to which the participant is randomised. This trial includes 2 Stages (Stage 1 (divided into 1a and 1b) and Stage 2. In Stage 1a, 6-monthly vs 12-monthly frequencies will be tested, with 100 patients randomised across these two arms. Following this, the study will proceed directly to Stage 1b, in which 3 additional arms will open (9-monthly, 15-monthly and 18-monthly), meaning that participants can be randomised to all five arms. An interim analysis of 12 months of data in 90 of the original 100 participants randomised to 6 vs 12 months will be carried out to determine the design of Stage 2 of the trial. If 12-monthly is not inferior to 6-monthly in terms of proportion of patients with new T2 lesions after one year, patients will continue to be recruited to all five arms; if it is inferior, the trial will convert into a 2-arm non-inferiority trial of 9-monthly vs. 6-monthly frequencies. All participants will be followed up with for at least 2 years.
Intervention type	Drug
Phase	Phase III
Drug / device / biological / vaccine name(s)	Ocrevus 300 mg concentrate for solution for infusion [Ocrelizumab] , Ocrevus 920 mg solution for injection [Ocrelizumab]
Primary outcome measure(s)	The proportion of participants without new T2 lesions measured using brain MRI scans at baseline, 1 year for the Stage 1 (interim) analysis and at 2 years for the Stage 2 (final) analysis
Key secondary outcome measure(s)	Number of new T2 lesions measured using brain MRI at 2 years Time-to-relapse measured using the MS relapse notable events reported by site clinician at 2 years Annualised relapse rate measured using the MS relapse notable events reported by site clinician at 2 years Proportion of participants without disability progression (defined by Expanded Disability Status Scale (EDSS) score increase of ≥1 point or ≥0.5 point if baseline EDSS >5.5) measured using data collected by a blinded rater at site at 2 years Rate of adverse events (graded by severity) and infections measured using data reported by site clinician at 2 years Rate of whole brain atrophy measured using brain MRI at 2 years Proportion of participants with hypogammaglobulinaemia measured using immunoglobulin laboratory test results at 2 years Changes in serum neurofilament light concentration measured using laboratory tests results at 2 years Changes in cognitive functions assessed by Symbol Digit Modalities Test (SDMT)) measured using data collected by a blinded rater at site at 2 years Changes in quality-of-life, patient-reported outcomes, and therapy administration satisfaction measured using EuroQol EQ5D-5L, Multiple Sclerosis Impact Scale (MSIS-29) and the Client Services Receipt Inventory and Work Productivity and Activity Impairment participant-reported outcome measures (PROMs) questionnaires at 2 years
Completion date	30/09/2030

Eligibility

Participant type(s)
Age group	Mixed
Lower age limit	18 Years
Upper age limit	110 Years
Sex	All
Target sample size at registration	540
Key inclusion criteria	1. Adult participants aged ≥18 yrs 2. Diagnosis of RRMS, according to the 2017 or 2024 revised McDonald criteria 3. Received 4 or more 6-monthly cycles of ocrelizumab (IV or SC) according to NICE TA533 guidelines and the ocrelizumab summary of product characteristics (SPC), prior to randomisation 4. Expanded Disability Status Scale (EDSS) score between 0 and ≤6.5 inclusive at baseline 5. Participants who wish to remain on ocrelizumab 6. Written informed consent provided 7. At randomisation, participants must have a QC-approved Baseline MRI scan (per the MRI Guide), performed up to 6 weeks after the Screening/Baseline/M0 visit
Key exclusion criteria	1. Clinical relapse(s) within 12 months prior to randomisation 2. New MRI lesions prior to randomisation, assessed by the treating site through comparison of the trial baseline scan with the most recent preceding MRI performed at least 3 months earlier while the participant was receiving ocrelizumab 3. Co-treatment with other immunosuppressive medications 4. Any condition or circumstance that prevents the participant from undergoing regular MRI scanning 5. Pregnancy or intention to become pregnant during the study period
Date of first enrolment	26/05/2026
Date of final enrolment	30/06/2028

Locations

Countries of recruitment

United Kingdom
England

Study participating centres

UCLH National Hospital for Neurology and Neurosurgery

Queen Square
London
WC1N 3BG
England

University Hospital Coventry and Warwickshire

Clifford Bridge Road
Coventry
CV2 2DX
England

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan	The datasets generated during and/or analysed during the current study will be available upon request (following the publication of the primary outcome) from the REFINE-MS Trial Management Group (contactable via the REFINE-MS trial mailbox mrcctu.refinems@ucl.ac.uk). Data will be shared according to the Clinical Trials Unit’s controlled access approach, based on the following principles: • No data should be released that would compromise an ongoing trial or study. • There must be a strong scientific or other legitimate rationale for the data to be used for the requested purpose. • Investigators who have invested time and effort into developing a trial or study should have a period of exclusivity in which to pursue their aims with the data, before key trial data are made available to other researchers. • The resources required to process requests should not be under-estimated, particularly successful requests which lead to preparing data for release. Therefore, adequate resources must be available in order to comply in a timely manner or at all, and the scientific aims of the study must justify the use of such resources. • Data exchange complies with Information Governance and Data Security Policies in all of the relevant countries. • Only tabulated, pseudonymised data will be shared. • Data Transfer Agreements and relevant approvals will be sought. • Participant consent will be sought for use of data for future research via the main trial consent form when participants join the study. Data will be available for sharing following publication of the primary outcome. Researchers wishing to access REFINE- MS data should contact the Trial Management Group in the first instance. Any remaining samples collected as part of the mechanistic immunology substudy will be destroyed at the end of the trial and therefore will not be available for future research.

Individual participant data (IPD) Intention to share

Yes

IPD sharing plan

The datasets generated during and/or analysed during the current study will be available upon request (following the publication of the primary outcome) from the REFINE-MS Trial Management Group (contactable via the REFINE-MS trial mailbox mrcctu.refinems@ucl.ac.uk).
Data will be shared according to the Clinical Trials Unit’s controlled access approach, based on the following principles:
• No data should be released that would compromise an ongoing trial or study.
• There must be a strong scientific or other legitimate rationale for the data to be used for the requested purpose.
• Investigators who have invested time and effort into developing a trial or study should have a period of exclusivity in which to pursue their aims with the data, before key trial data are made available to other researchers.
• The resources required to process requests should not be under-estimated, particularly successful requests which lead to preparing data for release. Therefore, adequate resources must be available in order to comply in a timely manner or at all, and the scientific aims of the study must justify the use of such resources.
• Data exchange complies with Information Governance and Data Security Policies in all of the relevant countries.
• Only tabulated, pseudonymised data will be shared.
• Data Transfer Agreements and relevant approvals will be sought.
• Participant consent will be sought for use of data for future research via the main trial consent form when participants join the study.

Data will be available for sharing following publication of the primary outcome. Researchers wishing to access REFINE- MS data should contact the Trial Management Group in the first instance.
Any remaining samples collected as part of the mechanistic immunology substudy will be destroyed at the end of the trial and therefore will not be available for future research.

Editorial Notes

27/05/2026: Date of first enrolment was changed from 21/05/2026 to 26/05/2026.
18/05/2026: Date of first enrolment was changed from 15/05/2026 to 21/05/2026.
06/05/2026: Ethics approval added, and the date of first enrolment was changed from 30/04/3036 to 15/05/2026.
18/04/2026: ISRCTN received notification of combined HRA/MHRA approval for this trial on 18/04/2026.
25/02/2026: Study's existence confirmed by Health Research Authority (HRA) (UK).