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)

Sponsor

Genentech, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02688985

Collaborator

(none)

132

Enrollment

Locations

Arms

Anticipated Duration (Months)

7.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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 Design

Study Type:

Interventional

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 :

Apr 29, 2016

Anticipated Primary Completion Date :

Jul 30, 2023

Anticipated Study Completion Date :

Jul 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: Ocrelizumab Ocrelizumab will be administered as IV infusion. Other Names: 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 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 Names: 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 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 Names: 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 Names: 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 Names: 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.

Outcome Measures

Primary Outcome Measures

Change in Levels of NfL in CSF from Treatment Baseline to Post-Treatment with Ocrelizumab [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 [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 [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 [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 [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 [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 [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 [From baseline up to approximately 6.5 years]
Serum Concentration of Ocrelizumab [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 [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University	Palo Alto	California	United States	94303
2	University of California at San Francisco	San Francisco	California	United States	94115
3	University Of Colorado	Aurora	Colorado	United States	80045
4	Yale University School of Medicine ; Pulmonary & Critical Care	New Haven	Connecticut	United States	06510
5	University of Massachusetts Medical School	Worcester	Massachusetts	United States	01655
6	Washington University; Wash Uni. Sch. Of Med	Saint Louis	Missouri	United States	63110
7	Empire Neurology, PC	Latham	New York	United States	12210
8	Weill Cornell MC-NY Presbyter; Dept. of Neurology/Neuroscience, Judith Jaffe Multiple Sclerosis Ctr	New York	New York	United States	63110
9	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
10	Ohio State University	Columbus	Ohio	United States	43210
11	Oklahoma Medical Research Foundation; MS Center of Excellence	Oklahoma City	Oklahoma	United States	73104
12	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
13	University of British Columbia Hospital Site; Djavad Mowafaghian Centre for Brain Health	Vancouver	British Columbia	Canada	V6T 1Z3
14	McGill University; Montreal Neurological Institute; Neurological and Psychiatric	Montreal	Quebec	Canada	H3A 2B4
15	Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden	Dresden		Germany	01307
16	Universitätsmedizin Göttingen Georg-August-Universität	Göttingen		Germany	37075
17	Karolinska Universitetssjukhuset, Solna	Stockholm		Sweden	113 41