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)

NCT02688985 | Completed Phase 3 Results

• 2 other identifiers: ML299662015-004616-37
• Study Type: interventional
• Target: 131
• Locations: 4 countries
• Sites: 17

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.

Conditions

Relapsing Multiple Sclerorsis; Multiple Sclerosis, Primary Progressive

Outcome Measures

Primary Outcomes (3)

• Change in Levels of NfL (Neurofilament Light) in CSF From Treatment Baseline to Post-Treatment With Ocrelizumab

  Primary Analysis was based on following data-cut off: Arm 1: Baseline to post-treatment at 12 weeks Arm 2: Baseline to post-treatment at 24 weeks Arm 3: Baseline to post-treatment at 52 weeks Arm 4: Baseline to post-treatment at 12 weeks PPMS Cohort: Baseline to post-treatment at 52 weeks

  From Baseline to post-treatment (Week 12, 24, 52 according to randomization and Weeks 144 and 240)

• Change in Number of CD19+ B Cells in CSF From Treatment Baseline to Post-Treatment With Ocrelizumab

  Arm 1: Baseline to post-treatment at 12 weeks Arm 2: Baseline to post-treatment at 24 weeks Arm 3: Baseline to post-treatment at 52 weeks Arm 4: Baseline to post-treatment at 12 weeks PPMS Cohort: Baseline to post-treatment at 52 weeks

  From Baseline to post-treatment (Week 12, 24, 52 according to randomization and Weeks 144 and 240)

• Change From Baseline in Number of CD3+ T-Cells in CSF Post-Treatment With Ocrelizumab

  Arm 1: Baseline to post-treatment at 12 weeks Arm 2: Baseline to post-treatment at 24 weeks Arm 3: Baseline to post-treatment at 52 weeks Arm 4: Baseline to post-treatment at 12 weeks PPMS Cohort: Baseline to post-treatment at 52 weeks

  From Baseline to post-treatment (Week 12, 24, 52 according to randomization and Weeks 144 and 240)

Study Arms (5)

RMS Cohort Arm 1: Ocrelizumab + LP

EXPERIMENTAL

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; Procedure: Lumbar Puncture; Drug: Methyloprednisolone; Drug: Antihistamine

RMS Cohort Arm 2: Ocrelizumab + LP

EXPERIMENTAL

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; Procedure: Lumbar Puncture; Drug: Methyloprednisolone; Drug: Antihistamine

RMS Cohort Arm 3: Ocrelizumab + LP

EXPERIMENTAL

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; Procedure: Lumbar Puncture; Drug: Methyloprednisolone; Drug: Antihistamine

RMS Cohort Arm 4: Ocrelizumab + LP

EXPERIMENTAL

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; Procedure: Lumbar Puncture; Drug: Methyloprednisolone; Drug: Antihistamine

PPMS Cohort: Ocrelizumab + LP

EXPERIMENTAL

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; Procedure: Lumbar Puncture; Drug: Methyloprednisolone; Drug: Antihistamine

Interventions

Ocrelizumab DRUG

Ocrelizumab will be administered as IV infusion.

Also known as: RO4964913

PPMS Cohort: Ocrelizumab + LP; RMS Cohort Arm 1: Ocrelizumab + LP; RMS Cohort Arm 2: Ocrelizumab + LP; RMS Cohort Arm 3: Ocrelizumab + LP; RMS Cohort Arm 4: Ocrelizumab + LP

Lumbar Puncture PROCEDURE

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.

PPMS Cohort: Ocrelizumab + LP; RMS Cohort Arm 1: Ocrelizumab + LP; RMS Cohort Arm 2: Ocrelizumab + LP; RMS Cohort Arm 3: Ocrelizumab + LP; RMS Cohort Arm 4: Ocrelizumab + LP

Methyloprednisolone DRUG

Participants will receive 100 mg of IV methylprenisolone (or an equivalent) prior to ocrelizumab infusion.

PPMS Cohort: Ocrelizumab + LP; RMS Cohort Arm 1: Ocrelizumab + LP; RMS Cohort Arm 2: Ocrelizumab + LP; RMS Cohort Arm 3: Ocrelizumab + LP; RMS Cohort Arm 4: Ocrelizumab + LP

Antihistamine DRUG

Participants will receive an antihistamine, such as diphenhydramine, prior to ocrelizumab infusion.

PPMS Cohort: Ocrelizumab + LP; RMS Cohort Arm 1: Ocrelizumab + LP; RMS Cohort Arm 2: Ocrelizumab + LP; RMS Cohort Arm 3: Ocrelizumab + LP; RMS Cohort Arm 4: Ocrelizumab + LP

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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
• 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
• 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
• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (17)

Stanford University

Palo Alto, California, 94303, United States

Location

University of California at San Francisco

San Francisco, California, 94115, United States

Location

University Of Colorado

Aurora, Colorado, 80045, United States

Location

Yale University School of Medicine ; Pulmonary & Critical Care

New Haven, Connecticut, 06510, United States

Location

University of Massachusetts Medical School

Worcester, Massachusetts, 01655, United States

Location

Washington University; Wash Uni. Sch. Of Med

St Louis, Missouri, 63110, United States

Location

Empire Neurology, PC

Latham, New York, 12210, United States

Location

Weill Cornell MC-NY Presbyter; Dept. of Neurology/Neuroscience, Judith Jaffe Multiple Sclerosis Ctr

New York, New York, 63110, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

Oklahoma Medical Research Foundation; MS Center of Excellence

Oklahoma City, Oklahoma, 73104, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390-0001, United States

Location

University of British Columbia Hospital Site; Djavad Mowafaghian Centre for Brain Health

Vancouver, British Columbia, V6T 1Z3, Canada

Location

McGill University; Montreal Neurological Institute; Neurological and Psychiatric

Montreal, Quebec, H3A 2B4, Canada

Location

Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden

Dresden, 01307, Germany

Location

Universitätsmedizin Göttingen Georg-August-Universität

Göttingen, 37075, Germany

Location

Karolinska Universitetssjukhuset, Solna

Stockholm, 113 41, Sweden

Location

MeSH Terms

Conditions

Multiple Sclerosis, Chronic Progressive

Interventions

ocrelizumab; Spinal Puncture; Histamine Antagonists

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biopsy; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Neurological; Punctures; Therapeutics; Surgical Procedures, Operative; Investigative Techniques; Histamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Physiological Effects of Drugs

Results Point of Contact

• Title: Medical Communications
• Organization: Genentech, Inc.

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 18, 2016
• First Posted: February 23, 2016
• Study Start: April 29, 2016
• Primary Completion: April 11, 2023
• Study Completion: April 11, 2023
• Last Updated: June 4, 2024
• Results First Posted: June 4, 2024

Record last verified: 2024-05

Locations

CA (2); DE (2); US (12); SE (1)