Study to Explore the Mechanism of Action of Ocrelizumab and B-Cell Biology in Participants With Relapsing Multiple Sclerosis (RMS) or Primary Progressive Multiple Sclerosis (PPMS)
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| ClinicalTrials.gov Identifier: NCT02688985 |
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Recruitment Status :
Active, not recruiting
First Posted : February 23, 2016
Last Update Posted : June 2, 2023
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Sponsor:
Genentech, Inc.
Information provided by (Responsible Party):
Genentech, Inc.
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Brief Summary:
This is an open-label, multicenter, biomarker study designed to be hypothesis-generating in order to better understand the mechanism of action of ocrelizumab and B-cell biology in RMS or PPMS. The study will be conducted in two cohorts i.e. RMS cohort (4 arm group) and PPMS cohort (one arm group). RMS cohort: Ocrelizumab will be administered as two intravenous (IV) infusions of 300 milligrams (mg) on Days 1 and 15. Subsequent doses will be given as single 600-mg infusions at Weeks 24 and 48. Participants will be randomized in 1:1:1 ratio to receive lumbar puncture (LP) post-treatment at Week 12, 24, or 52 following the first dose of ocrelizumab in three arm groups. A fourth RMS arm with delayed treatment start (Arm 4 [control group]) will not be a part of the randomization and will be recruited separately, wherein treatment with ocrelizumab will be delayed for 12 weeks from pre-treatment baseline. PPMS cohort: Ocrelizumab 600 mg will be administered as two 300-mg IV infusions separated by 14 days at a scheduled interval of every 24 weeks. Participants will receive a LP at the start of the study before dosing with ocrelizumab and second LP at Week 52 following the first dose of ocrelizumab. A long-term extension will be conducted for participants that complete the study and continue to receive ocrelizumab. Treatment with ocrelizumab in the entire study will continue for approximately 4.5 years after the first infusion.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Relapsing Multiple Sclerorsis Multiple Sclerosis, Primary Progressive | Drug: Ocrelizumab Procedure: Lumbar Puncture Drug: Methyloprednisolone Drug: Antihistamine | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 132 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | An Open-Label, Multicenter, Biomarker Study to Explore the Mechanism of Action of Ocrelizumab and B-Cell Biology in Patients With Relapsing Multiple Sclerosis or Primary Progressive Multiple Sclerosis |
| Actual Study Start Date : | April 29, 2016 |
| Estimated Primary Completion Date : | July 30, 2023 |
| Estimated Study Completion Date : | July 30, 2023 |
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: RMS Cohort Arm 1: Ocrelizumab + LP
Participants with RMS will receive ocrelizumab as two 300-mg IV infusion on Days 1 and 15 then as single infusion of 600 mg on Weeks 24 and 48. Participants will receive a LP before the start of dosing (Week 1, treatment baseline) with ocrelizumab and a second LP at Week 12. Participants will be asked to have an additional optional LP at Week 52. Participants that complete the study and continue to receive ocrelizumab will receive single infusions every 24 weeks starting from Week 72.
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Drug: Ocrelizumab
Ocrelizumab will be administered as IV infusion.
Other Name: RO4964913 Procedure: Lumbar Puncture Participants will receive LP as specified in individual arms. Lumbar puncture is optional at week 52, except for RMS Cohort Arm 3 and PPMS Cohort. In addition, the lumbar punctures in the Long Term Extension phase is every other year. Drug: Methyloprednisolone Participants will receive 100 mg of IV methylprenisolone (or an equivalent) prior to ocrelizumab infusion. Drug: Antihistamine Participants will receive an antihistamine, such as diphenhydramine, prior to ocrelizumab infusion. |
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Experimental: RMS Cohort Arm 2: Ocrelizumab + LP
Participants with RMS will receive ocrelizumab as two 300-mg IV infusion on Days 1 and 15 then as single infusion of 600 mg on Weeks 24 and 48. Participants will receive a LP before the start of dosing (Week 1, treatment baseline) with ocrelizumab and a second LP at Week 24. Participants will be asked to have an additional optional LP at Week 52. Participants that complete the study and continue to receive ocrelizumab will receive single infusions every 24 weeks starting from Week 72.
|
Drug: Ocrelizumab
Ocrelizumab will be administered as IV infusion.
Other Name: RO4964913 Procedure: Lumbar Puncture Participants will receive LP as specified in individual arms. Lumbar puncture is optional at week 52, except for RMS Cohort Arm 3 and PPMS Cohort. In addition, the lumbar punctures in the Long Term Extension phase is every other year. Drug: Methyloprednisolone Participants will receive 100 mg of IV methylprenisolone (or an equivalent) prior to ocrelizumab infusion. Drug: Antihistamine Participants will receive an antihistamine, such as diphenhydramine, prior to ocrelizumab infusion. |
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Experimental: RMS Cohort Arm 3: Ocrelizumab + LP
Participants with RMS will receive ocrelizumab as two 300-mg IV infusion on Days 1 and 15 then as single infusion of 600 mg on Weeks 24 and 48. Participants will receive a LP before the start of dosing (Week 1, treatment baseline) with ocrelizumab and a second LP at Week 52. Participants that complete the study and continue to receive ocrelizumab will receive single infusions every 24 weeks starting from Week 72.
|
Drug: Ocrelizumab
Ocrelizumab will be administered as IV infusion.
Other Name: RO4964913 Procedure: Lumbar Puncture Participants will receive LP as specified in individual arms. Lumbar puncture is optional at week 52, except for RMS Cohort Arm 3 and PPMS Cohort. In addition, the lumbar punctures in the Long Term Extension phase is every other year. Drug: Methyloprednisolone Participants will receive 100 mg of IV methylprenisolone (or an equivalent) prior to ocrelizumab infusion. Drug: Antihistamine Participants will receive an antihistamine, such as diphenhydramine, prior to ocrelizumab infusion. |
|
Experimental: RMS Cohort Arm 4: Ocrelizumab + LP
Ocrelizumab treatment will be delayed for 12 weeks from pre-treatment baseline. Participants with RMS will receive ocrelizumab as two 300-mg IV infusion on Days 1 and 15 then as single infusion of 600 mg on Weeks 24 and 48. Participants will receive a LP at Week -12 (pre-treatment baseline) and a second LP before the start of dosing (Week 1, treatment baseline). Participants will be asked to have an additional optional LP at Week 52. Participants that complete the study and continue to receive ocrelizumab will receive single infusions every 24 weeks starting from Week 72.
|
Drug: Ocrelizumab
Ocrelizumab will be administered as IV infusion.
Other Name: RO4964913 Procedure: Lumbar Puncture Participants will receive LP as specified in individual arms. Lumbar puncture is optional at week 52, except for RMS Cohort Arm 3 and PPMS Cohort. In addition, the lumbar punctures in the Long Term Extension phase is every other year. Drug: Methyloprednisolone Participants will receive 100 mg of IV methylprenisolone (or an equivalent) prior to ocrelizumab infusion. Drug: Antihistamine Participants will receive an antihistamine, such as diphenhydramine, prior to ocrelizumab infusion. |
|
Experimental: PPMS Cohort: Ocrelizumab + LP
For the PPMS cohort, ocrelizumab will be administered as two 300-mg IV infusions separated by 14 days at a scheduled interval of every 24 weeks during the treatment period and then as a single 600-mg dose every 24 weeks starting week 72 during the Long-Term Extension period.
|
Drug: Ocrelizumab
Ocrelizumab will be administered as IV infusion.
Other Name: RO4964913 Procedure: Lumbar Puncture Participants will receive LP as specified in individual arms. Lumbar puncture is optional at week 52, except for RMS Cohort Arm 3 and PPMS Cohort. In addition, the lumbar punctures in the Long Term Extension phase is every other year. Drug: Methyloprednisolone Participants will receive 100 mg of IV methylprenisolone (or an equivalent) prior to ocrelizumab infusion. Drug: Antihistamine Participants will receive an antihistamine, such as diphenhydramine, prior to ocrelizumab infusion. |
Primary Outcome Measures :
- Change in Levels of NfL in CSF from Treatment Baseline to Post-Treatment with Ocrelizumab [ Time Frame: From Baseline to post-treatment (Week 12, 24, 52, 144, or 240 according to randomization) ]RMS Cohort (Arms 1, 2, 3)
- Change in Number of CD19+ B cells in CSF from Treatment Baseline to Post-Treatment with Ocrelizumab [ Time Frame: From Baseline to post-treatment (Week 12, 24, 52, 144, or 240 according to randomization) ]RMS Cohort (Arms 1, 2, 3)
- Change From Baseline in Number of CD3+ T-Cells in CSF Post-Treatment With Ocrelizumab [ Time Frame: From Baseline to post-treatment (Week 12, 24, 52, 144, or 240 according to randomization) ]RMS Cohort (Arms 1, 2, 3)
Other Outcome Measures:
- Change in Levels of NfL in CSF from Treatment Baseline to Post-Treatment with Ocrelizumab [ Time Frame: From Baseline to post-treatment (Week 12, 24, 52, 144, or 240 according to randomization) ]PPMS Cohort
- Change in Number of CD19+ B cells in CSF from Treatment Baseline to Post-Treatment with Ocrelizumab [ Time Frame: From Baseline to post-treatment (Week 12, 24, 52, 144, or 240 according to randomization) ]PPMS Cohort
- Change From Baseline in Number of CD3+ T-Cells in CSF Post-Treatment With Ocrelizumab [ Time Frame: From Baseline to post-treatment (Week 12, 24, 52, 144, or 240 according to randomization) ]PPMS Cohort
- Percentage of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab [ Time Frame: Predose (Hour 0) on Day 1 of Weeks 1, 24, 48; early termination (up to Week 52); every 24 weeks after Week 48 dose for 48 weeks or until B-cell count returns to baseline value or to lower limit of normal range (up to 6.5 years overall) ]
- Percentage of Participants With Adverse Events [ Time Frame: From baseline up to approximately 6.5 years ]
- Serum Concentration of Ocrelizumab [ Time Frame: Predose (Hour 0) on Day 1 of Weeks 1,24,48; at Weeks 12, 52; at early termination (up to Week 52); every 24 weeks after Week 48 dose for 48 weeks or until B-cell count returns to baseline value or to lower limit of normal range (up to 6.5 years overall) ]
- Ocrelizumab Levels in CSF [ Time Frame: Baseline up to Week 52 (detailed timeframe is provided in outcome description) ]RMS Cohort (Arms 1, 2, 3): predose (Hour 0) on Week 1 (baseline), at Weeks 12, 24, or 52 (according to randomization); RMS Cohort (Arm 4): Week -12 (pre-treatment baseline), predose (Hour 0) on Week 1 (treatment baseline), Week 12 (optional); PPMS Cohort: predose (Hour 0) on Week 1 (baseline) and Week 52.
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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:
General Inclusion Criteria:
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1 percent (%) per year during the treatment period and for at least 24 weeks after the last dose of study treatment or until their B-cells have repleted, whichever is longer
Inclusion Criteria Specific to RMS Participants:
- Diagnosis of RMS in accordance with the 2010 revised McDonald criteria
- Expanded Disability Status Scale (EDSS) score of 0 to 5.5 points, inclusive, at Screening
- Disease duration from the onset of multiple sclerosis symptoms less than (<) 15 years in participants with an EDSS score greater than (>) 5.0 at Screening
- Either treatment-naive or receiving treatment with disease-modifying therapies, including prior use of interferon (IFN)-beta-1a (Avonex®, Rebif®), IFN-beta-1b (Betaseron®/Betaferon), or glatiramer acetate (Copaxone®).
- At least one clinically documented relapse in the past year and/or at least one T1-weighted Gadolinium (Gd)-enhancing lesion in the past year and/or at least one new T2 lesion in the past year at the time of enrollment
Inclusion Criteria Specific to RMS Cohort Arm 4 Participants:
- Must meet inclusion criteria for the RMS cohort
- Separate signed Informed Consent Form for the RMS Delayed Time to Start Control Arm (Arm 4)
- Must be willing to remain on the same dose and regimen of current standard of care, or no treatment if treatment-naïve, for 12 weeks after study enrollment The treating and/or study physician must agree that the participant is eligible to remain on the same dose and regimen of their current standard of care at Screening, or to receive no treatment if the participant is treatment-naïve, for 12 weeks after study enrollment
Inclusion Criteria Specific to PPMS Participants:
- Diagnosis of PPMS in accordance with the 2010 revised McDonald criteria
- EDSS score of 3.0 - 6.5 points, inclusive, at Screening
- Disease duration from the onset of multiple sclerosis symptoms <10 years in participants with an EDSS at Screening less than or equal to (</=) 5.0
- Documented history of either elevated immunoglobulin G (IgG) Index or one or more IgG oligoclonal bands (OCBs) detected by isoelectric focusing
Exclusion Criteria:
- Diagnosis of secondary progressive multiple sclerosis without relapses for at least 1 year
- History or known presence of recurrent or chronic infection (e.g., human immunodeficiency virus [HIV], syphilis, tuberculosis)
- History of recurrent aspiration pneumonia requiring antibiotic therapy
- History of cancer, including solid tumors and hematological malignancies (except basal cell, in situ squamous cell carcinomas of the skin, and in situ carcinoma of the cervix of the uterus that have been excised and resolved with documented clean margins on pathology)
- History of or currently active primary or secondary immunodeficiency
- History of coagulation disorders
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
- History of alcohol or other drug abuse within 24 weeks prior to enrollment
- Known presence or history of other neurologic disorders Significant, uncontrolled disease, such as cardiovascular (including cardiac arrhythmia), pulmonary (including chronic obstructive pulmonary disease), renal, hepatic, endocrine, gastrointestinal, or any other significant disease
- Congestive heart failure (according to New York Heart Association III or IV functional severity)
- Known active bacterial, viral, fungal, mycobacterial infection, or any major episode of infection requiring hospitalization or treatment with IV antibiotics
- Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
- Contraindications or intolerance to oral or IV corticosteroids, including IV methylprednisolone, according to the country label
- Contraindication for LP
- Previous treatment with B cell-targeted therapies (such as rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab)
- Previous treatment with natalizumab/Tysabri®, alemtuzumab, anti-CD4 agents, cladribine, teriflunomide, cyclophosphamide, mitoxantrone, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, total body irradiation, or bone marrow transplantation
- Treatment with fingolimod/Gilenya®, dimethyl fumarate/Tecfidera®, or similar treatment within 6 months prior to enrollment
- Receipt of a live vaccine within 6 weeks prior to enrollment
- Systemic corticosteroid therapy within 4 weeks prior to Baseline
- Previous or concurrent treatment with any investigational agent or treatment with any experimental procedure for multiple sclerosis (such as treatment for chronic cerebrospinal venous insufficiency)
- Certain laboratory abnormalities or findings at Screening
- Inability to complete an MRI
- Lack of peripheral venous access
- Pregnant or lactating, or intending to become pregnant during the study
Exclusion Criteria Specific to RMS Participants:
- Diagnosis of PPMS or secondary progressive multiple sclerosis without relapses
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): NCT02688985
Locations
Show 17 study locations
Sponsors and Collaborators
Genentech, Inc.
Investigators
| Study Director: | Clinical Trials | Hoffmann-La Roche |
| Responsible Party: | Genentech, Inc. |
| ClinicalTrials.gov Identifier: | NCT02688985 |
| Other Study ID Numbers: |
ML29966 2015-004616-37 ( EudraCT Number ) |
| First Posted: | February 23, 2016 Key Record Dates |
| Last Update Posted: | June 2, 2023 |
| Last Verified: | June 2023 |
Additional relevant MeSH terms:
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Multiple Sclerosis Multiple Sclerosis, Chronic Progressive Sclerosis Pathologic Processes Demyelinating Autoimmune Diseases, CNS Autoimmune Diseases of the Nervous System Nervous System Diseases Demyelinating Diseases Autoimmune Diseases Immune System Diseases |
Chronic Disease Disease Attributes Ocrelizumab Histamine Antagonists Histamine H1 Antagonists Immunologic Factors Physiological Effects of Drugs Histamine Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action |