A Study to Evaluate the Efficacy, Safety and Pharmacokinetics (PK) of a Higher Dose of Ocrelizumab in Adults With Relapsing Multiple Sclerosis (RMS)

Phase 3

Active, not recruiting

• Conditions: Multiple Sclerosis
• Interventions: Drug: Ocrelizumab; Drug: Antihistamine; Drug: Methylprednisolone

• Registration Number: NCT04544436
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

This is a randomized, double-blind, controlled, parallel group, multicenter study to evaluate efficacy, safety and PK of a higher dose of ocrelizumab per intravenous (IV) infusion every 24 weeks (Q24W) in participants with RMS, in comparison to the approved 600 milligrams (mg) dose of ocrelizumab.

Detailed Description

Participants will be treated for a minimum of 120 weeks in the double-blind treatment (DBT) phase. Upon positive primary results after the DBT phase, an optional higher dose extension treatment, open-label extension (OLE) phase is planned for eligible participants. The OLE will be carried out for approximately 96 weeks. Participants will be followed for safety for 48 weeks thereafter. Participants whose B-cell levels still did not replete to their baseline level or the low level of normal (LLN), whichever is lower, will move into the B-cell monitoring (BCM) phase following the safety follow-up phase. The study will end when all participants who were not treated with an alternative B-cell depleting therapy have repleted their B-cells to the baseline value or the LLN.

Study Timeline

• Study First Submitted: 2020-09-04
• Study First Submitted QC: 2020-09-04
• Study First Posted: 2020-09-10
• Study Start: 2020-11-26
• Primary Completion: 2024-12-19
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-23
• Last Update Posted: 2025-07-24
• Study Completion: 2028-08-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 864

Inclusion Criteria

• Diagnosis of RMS
• At least two documented clinical relapses within the last 2 years prior to screening, or one clinical relapse in the year prior to screening. No relapse 30 days prior to screening and at baseline
• Participants must be neurologically stable for at least 30 days prior to randomization and baseline
• EDSS score, at screening and baseline, from 0 to 5.5 inclusive
• Average T25FWT score over two trials at screening and over two trials at baseline respectively, up to 150 (inclusive) seconds
• Average 9HPT score over four trials at screening and over four trials at baseline respectively, up to 250 (inclusive) seconds
• Documented magnetic resonance imaging (MRI) of brain with abnormalities consistent with MS at screening
• Participants requiring symptomatic treatment for MS and/or physiotherapy must be treated at a stable dose. No initiation of symptomatic treatment for MS or physiotherapy within 4 weeks of randomization
• Females of childbearing potential, agreement to remain abstinent or use adequate contraceptive methods
• Female participants without reproductive potential may be enrolled e.g. if post-menopausal or if surgically sterile

Exclusion Criteria

• History of primary progressive MS at screening
• Any known or suspected active infection at screening or baseline (except nailbed infections), or any major episode of infection requiring hospitalization or treatment with IV antimicrobials within 8 weeks or treatment with oral antimicrobials within 2 weeks, prior to and during screening
• History of confirmed or suspected progressive multifocal leukoencephalopathy
• History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening
• Immunocompromised state
• Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization
• Inability to complete an MRI or contraindication to gadolinium administration
• Contraindications to mandatory pre-medications for infusion-related reaction (IRRs)
• Known presence of other neurologic disorders that could interfere with the diagnosis of MS or assessments of efficacy and/or safety during the study
• Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
• Significant, uncontrolled disease that may preclude participant from participating in the study
• History of or currently active primary or secondary, non-drug-related, immunodeficiency
• Pregnant or breastfeeding or intending to become pregnant
• Lack of peripheral venous access
• History of alcohol or other drug abuse within 12 months prior to screening
• Treatment with any investigational agent within 24 weeks prior to screening or treatment with any experimental procedure for MS
• Previous use of anti- cluster of differentiation 20 (CD20s) (including ocrelizumab), unless the last infusion was more than 2 years before screening, B-cell count is normal, and the stop of the treatment was not motivated by safety reasons or lack of efficacy
• Previous treatment with fingolimod, siponimod, or ozanimod within 6 weeks of baseline
• Previous treatment with natalizumab within 4.5 months of baseline
• Previous treatment with interferons beta (1a or 1b), or glatiramer acetate within 2 weeks of baseline
• Any previous treatment with mitoxantrone, cladribine, atacicept, alemtuzumab, and daclizumab - Previous treatment with any other immunomodulatory or immunosuppressive medication not already listed above without appropriate washout as described in the applicable local label. If the washout requirements are not described in the applicable local label, then the wash out period must be five times the half-life of the medication
• Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation
• Any previous history of transplantation or anti-rejection therapy
• Treatment with IV immunoglobulin (Ig) or plasmapheresis within 12 weeks prior to randomization
• Systemic corticosteroid therapy within 4 weeks prior to screening
• Positive screening tests for active, latent, or inadequately treated hepatitis B
• Sensitivity or intolerance to any ingredient (including excipients) of ocrelizumab
• Any additional exclusionary criterion as per ocrelizumab local label, if more stringent than the above

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ocrelizumab Approved Dose	Ocrelizumab	Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will be offered a higher dose of ocrelizumab (either 1200 or 1800 mg), based on their body weight at OLE baseline, for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion.
Ocrelizumab Higher Dose	Ocrelizumab	Participants will be randomized to receive a minimum of 5 higher treatment doses based on their body weight at baseline: 1200 mg (participant's body weight \<75 kilograms \[kg\]) or 1800 mg (participant's body weight ≥ 75 kg) of ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will continue with their assigned dose of ocrelizumab (either 1200 or 1800 mg) for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion.
Ocrelizumab Higher Dose	Antihistamine	Participants will be randomized to receive a minimum of 5 higher treatment doses based on their body weight at baseline: 1200 mg (participant's body weight \<75 kilograms \[kg\]) or 1800 mg (participant's body weight ≥ 75 kg) of ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will continue with their assigned dose of ocrelizumab (either 1200 or 1800 mg) for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion.
Ocrelizumab Approved Dose	Antihistamine	Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will be offered a higher dose of ocrelizumab (either 1200 or 1800 mg), based on their body weight at OLE baseline, for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion.
Ocrelizumab Higher Dose	Methylprednisolone	Participants will be randomized to receive a minimum of 5 higher treatment doses based on their body weight at baseline: 1200 mg (participant's body weight \<75 kilograms \[kg\]) or 1800 mg (participant's body weight ≥ 75 kg) of ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will continue with their assigned dose of ocrelizumab (either 1200 or 1800 mg) for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion.
Ocrelizumab Approved Dose	Methylprednisolone	Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will be offered a higher dose of ocrelizumab (either 1200 or 1800 mg), based on their body weight at OLE baseline, for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion.

Primary Outcome Measures

Name	Time	Method
Time to Onset of 12-week Composite Confirmed Disability Progression (cCDP12)	Baseline up to approximately 4.3 years	Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by Expanded Disability Status Scale (EDSS), Timed 25-foot Walk Test (T25FWT) or 9-hole Peg Test (9-HPT).

Secondary Outcome Measures

Name	Time	Method
Time to Onset of 24-week cCDP (cCDP24)	Baseline up to approximately 4.3 years	Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT.
Time to Onset of 48-week cCDP (cCDP48)	Baseline up to approximately 4.3 years	Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT.
Time to Onset of cCDP12 Independent of Protocol-defined Relapses (PDR)	Baseline up to approximately 4.3 years	Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT independent of PDR.
Time to Onset of 12-week Confirmed Disability Progression (CDP12)	Baseline up to approximately 4.3 years	CDP, defined as a sustained increase from baseline in EDSS score of ≥1.0 point in participants with a baseline EDSS score of ≤5.5 or a sustained increase of ≥0.5 points in participants with a baseline EDSS score of \>5.5.
Time to ≥ 20% Increase in 12-week Confirmed by T25FWT	Baseline up to approximately 4.3 years	The T25FWT is a performance measure used to assess walking speed based on a timed 25-foot walk. The participant is directed to start at one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly and safely as possible.
Annual Rate of Percent Change From Baseline in Total Brain Volume	Baseline up to approximately 4.3 years
Time to 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT)	Baseline up to approximately 4.3 years	The SDMT is a performance measure that has demonstrated sensitivity in detecting not only the presence of cognitive impairment but also changes in cognitive functioning over time and in response to treatment. Using a reference key, the examinee has 90 seconds to pair specific numbers with given geometric figures. Responses will be collected orally. A four-point change from baseline is typically considered clinically meaningful.
Time to 12-week Confirmed 8-point Increase in 12-item Multiple Sclerosis Walking Scale (MSWS-12)	Baseline up to approximately 4.3 years	Self-reported measure of the impact of multiple sclerosis (MS) on the individual's ability to walk
Change in Neurofilament Light (NfL) at Week 48 for Participants Assigned to the Higher Dose Ocrelizumab Group	Baseline (Week 0), Week 48	Biomarker for neurodegeneration NfL
Change in NfL at Week 48 for Participants Assigned to the Approved Dose Ocrelizumab Group	Baseline (Week 0), Week 48	Biomarker for neurodegeneration NfL
Percentage of Participants With Adverse Events (AEs)	Baseline up to approximately 7.5 years
Serum Concentration of Ocrelizumab at Specified Time Points	Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120
B-cell Levels in Blood	Baseline up to approximately 4.3 years	Levels of blood B-cells is based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood
Percentage of Participants Achieving 5 or Less B-cells per Microliter of Blood	Baseline up to approximately 4.3 years	Levels of blood B-cells is based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood
Change From Baseline in the Anti-drug Antibody (ADA) Levels	Week 0, 24, 48, 72, 96, 120

Trial Locations

Locations (121)

North Central Neurology Associates; 🇺🇸 Cullman, Alabama, United States

Alabama Neurology Associates; 🇺🇸 Homewood, Alabama, United States

21st Century Neurology; 🇺🇸 Phoenix, Arizona, United States

Profound Research, LLC; 🇺🇸 Carlsbad, California, United States

Stanford University Medical Center; 🇺🇸 Stanford, California, United States

Advanced Neurology of Colorado, LLC; 🇺🇸 Fort Collins, Colorado, United States

Neurology Associates, PA; 🇺🇸 Maitland, Florida, United States

University of South Florida; 🇺🇸 Tampa, Florida, United States

American Health Network Institute, LLC; 🇺🇸 Avon, Indiana, United States

University of Kansas Medical Center; 🇺🇸 Kansas City, Kansas, United States

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