A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults With Relapsing Multiple Sclerosis (RMS)
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| ClinicalTrials.gov Identifier: NCT04544436 |
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Recruitment Status :
Active, not recruiting
First Posted : September 10, 2020
Last Update Posted : May 22, 2023
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Sponsor:
Hoffmann-La Roche
Information provided by (Responsible Party):
Hoffmann-La Roche
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Brief Summary:
This is a randomized, double blind, controlled, parallel group, multicenter study to evaluate efficacy, safety and pharmacokinetics of a higher dose of ocrelizumab per intravenous (IV) infusion every 24 weeks in participants with RMS, in comparison to the approved 600 mg dose of ocrelizumab.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Multiple Sclerosis | Drug: Ocrelizumab Drug: Antihistamine Drug: Methylprednisolone | Phase 3 |
Participants will be treated for a minimum of 120 weeks in the double-blind phase. Upon positive primary results after the double-blind phase, an optional higher dose extension treatment (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 lower limit of normal.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 865 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase IIIb Multicenter, Randomized, Double-Blind, Controlled Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults With Relapsing Multiple Sclerosis |
| Actual Study Start Date : | November 26, 2020 |
| Estimated Primary Completion Date : | March 3, 2025 |
| Estimated Study Completion Date : | August 31, 2028 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Multiple sclerosis
MedlinePlus related topics:
Multiple Sclerosis
Drug Information available for:
Ocrelizumab
| Arm | Intervention/treatment |
|---|---|
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Experimental: Ocrelizumab Higher Dose
Participants will be randomized to receive a minimum of 5 higher treatment doses (1200 mg or 1800 mg) of ocrelizumab administered by intravenous (IV) infusion every 24 weeks in the double blind treatment (DBT) phase. During the optional open-label extension (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.
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Drug: Ocrelizumab
The actual higher dose of ocrelizumab will be assigned to participants based on their body weight at baseline: 1200 mg (participants's body weight <75 kg) or 1800 mg (participant's body weight >/=75 kg). The first dose of ocrelizumab will be administered as two 600 mg or 900 mg intravenous (IV) infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 1200 mg or 1800 mg IV infusion every 24 weeks.
Other Name: Ocrevus Drug: Antihistamine Premedication with oral or IV antihistaminic drug (i.e., diphenhydramine 50 mg or an equivalent dose of an alternative) will be administered prior to each ocrelizumab infusion.
Other Name: Non-Investigational Medicinal Product Drug: Methylprednisolone Premedication with 100 mg of methylprednisolone (or equivalent) will be administered by IV infusion prior to each ocrelizumab infusion.
Other Name: Non-Investigation Medicinal Product |
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Active Comparator: Ocrelizumab Approved Dose
Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by intravenous (IV) infusion every 24 weeks 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.
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Drug: Ocrelizumab
Ocrelizumab will be administered at a dose of 600 milligram (mg) every 24 weeks. The first dose of ocrelizumab will be administered as two 300 mg intravenous (IV) infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 600 mg IV infusion every 24 weeks.
Other Name: Ocrevus Drug: Antihistamine Premedication with oral or IV antihistaminic drug (i.e., diphenhydramine 50 mg or an equivalent dose of an alternative) will be administered prior to each ocrelizumab infusion.
Other Name: Non-Investigational Medicinal Product Drug: Methylprednisolone Premedication with 100 mg of methylprednisolone (or equivalent) will be administered by IV infusion prior to each ocrelizumab infusion.
Other Name: Non-Investigation Medicinal Product |
Primary Outcome Measures :
- Reduction in cCDP sustained for at least 12 weeks, measured by time to onset of cCDP sustained for at least 12 weeks. [ Time Frame: 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.
Secondary Outcome Measures :
- Time to Onset of 24-week cCDP (cCDP24) [ Time Frame: 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 12-week CDP (CDP12) [ Time Frame: 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 Onset of 24-week CDP (CDP24) [ Time Frame: 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 Timed 25-Foot Walk Test (T25FWT) [ Time Frame: 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.
- Time to >/= 20% Increase in 24-week Confirmed T25FWT [ Time Frame: 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.
- Change from baseline in the Multiple Sclerosis Impact Scale-29 (MSIS-29) physical scale at Week 120 [ Time Frame: Baseline, Week 120 ]The MSIS-29 is a 29-item participant-reported measure of the physical and psychological impacts of MS. Participants are asked to rate how much their functioning and well-being has been impacted over the past 14 days on a 4-point scale, from "Not at all" (1) to "Extremely" (4).
- Annual rate of percent change from baseline in total brain volume [ Time Frame: Baseline up to approximately 4.3 years ]
- Time to 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT) [ Time Frame: 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.
- Serum Concentration of Ocrelizumab at Specified Time points [ Time Frame: Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120 ]
- Change in B-cell Levels in Blood [ Time Frame: Baseline up to approximately 4.3 years ]
- Proportion of Participants Achieving 5 or Less B-cells per Microliter of Blood [ Time Frame: Baseline up to approximately 4.3 years ]
- Proportion of Participants Achieving 5 or Less B-cells per Microliter of Blood in Participants with the High versus Low Affinity Fcgamma Receptor 3A (FcgR3A) Genotype per Arm [ Time Frame: Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120 ]
- Change from Baseline in the Anti-Drug Antibody (ADA) Levels [ Time Frame: Week 0, 24, 48, 72, 96, 120 ]
- Levels of Neurofilament Light Chain (NfL) in Blood [ Time Frame: Baseline up to approximately 4.3 years ]
- Levels of Interleukin-6 (IL-6) in Blood [ Time Frame: Baseline up to approximately 4.3 years ]
- Levels of Blood B-cells [ Time Frame: 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
- Levels of Lymphocytes in Blood [ Time Frame: Baseline up to approximately 4.3 years ]
- Proportion of Participants with Different DNA Genotypes [ Time Frame: Week 0, 2, 12, 24, 48, 72, 96, 120 ]
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| Ages Eligible for Study: | 18 Years to 55 Years (Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Diagnosis of relapsing multiple sclerosis (RMS) (i.e., RRMS or aSPMS where participants still experience relapses) in accordance with the revised McDonald Criteria 2017
- 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.
- Expanded disability status scale (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 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.
- For females of childbearing potential, agreement to remain abstinent or use adequate contraceptive methods.
- For female participants, without reproductive potential may be enrolled if post-menopausal, unless receiving a hormonal therapy for her menopause 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 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-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 intravenous (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.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04544436
Locations
Show 126 study locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
| Study Director: | Clinical Trials | Hoffmann-La Roche |
| Responsible Party: | Hoffmann-La Roche |
| ClinicalTrials.gov Identifier: | NCT04544436 |
| Other Study ID Numbers: |
BN42082 2020-000893-69 ( EudraCT Number ) |
| First Posted: | September 10, 2020 Key Record Dates |
| Last Update Posted: | May 22, 2023 |
| Last Verified: | May 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm). |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Multiple Sclerosis Sclerosis Pathologic Processes Demyelinating Autoimmune Diseases, CNS Autoimmune Diseases of the Nervous System Nervous System Diseases Demyelinating Diseases Autoimmune Diseases Immune System Diseases Methylprednisolone Ocrelizumab Histamine Antagonists Histamine H1 Antagonists Anti-Inflammatory Agents |
Antiemetics Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs Gastrointestinal Agents Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Neuroprotective Agents Protective Agents Immunologic Factors Histamine Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action |