A Study to Evaluate the Effects of Ocrelizumab on Immune Responses In Participants With Relapsing Forms of Multiple Sclerosis

A Phase IIIB, Multicenter, Randomized, Parallel-Group, Open-Label Study to Evaluate the Effects of Ocrelizumab on Immune Responses in Patients With Relapsing Forms of Multiple Sclerosis

This multicenter, randomized, open-label study will evaluate the immune response to vaccines (tetanus toxoid [TT]-containing adsorbed vaccine, 23-valent pneumococcal polysaccharide vaccine [23-PPV] either unboosted or boosted with 13-valent pneumococcal conjugate vaccine [13-PCV], influenza vaccine, keyhole limpet hemocyanin [KLH]) after administration of a dose of ocrelizumab (OCR) in participants with relapsing multiple sclerosis (RMS).

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis, Relapsing-Remitting
• Intervention / Treatment: Biological: 23-PPV; Biological: 13-PCV Booster; Biological: Influenza Vaccine; Biological: KLH; Drug: OCR; Biological: TT Vaccine

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • University of Calgary
  • British Columbia
    • Vancouver, British Columbia, Canada, V6T 2B5
      • University of British Columbia Hospital; Division of Neurology
• United States
  • Alabama
    • Cullman, Alabama, United States, 35058
      • North Central Neurology Associates
  • Arizona
    • Tucson, Arizona, United States, 85704
      • Territory Neurology and Research Institute
  • California
    • Fullerton, California, United States, 92835
      • Fullerton Neurology and Headache Center
    • La Jolla, California, United States, 92037
      • Scripps Clinic
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami School of Medicine; Dept. of Neurology Movement Disorder Center
    • Tampa, Florida, United States, 33612
      • University of South Florida
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Michigan Institute for Neurological Disorders
  • Minnesota
    • Golden Valley, Minnesota, United States, 55422
      • The Minneapolis Clinic of Neurology
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • Mercy Hospital St. Louis / Mercy Clinic Neurology
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Cleveland Clinic Lou Ruvo; Center for Brain Research
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • New York
    • Staten Island, New York, United States, 10306
      • Staten Island Univ Hospital
  • North Carolina
    • Hickory, North Carolina, United States, 28602
      • Neurology Associates PA
  • Ohio
    • Columbus, Ohio, United States, 43214
      • Ohio Health Research Institute Grant Medical Center
    • Westerville, Ohio, United States, 43082
      • MDH Research LLC
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Abington Neurological Associates
  • Tennessee
    • Cordova, Tennessee, United States, 38018
      • Neurology Clinic PC
  • Texas
    • Round Rock, Texas, United States, 78681
      • Central Texas Neurology Consultants
  • Utah
    • Salt Lake City, Utah, United States, 84103
      • Rocky Mountain MS Clinic
  • Washington
    • Seattle, Washington, United States, 98104-1360
      • Swedish Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of RMS in accordance with the revised McDonald criteria
• Received at least one previous immunization against TT or tetanus and diphtheria (DT/Td) or tetanus, diphtheria, and acellular pertussis (DTaP/Tdap)
• Expanded Disability Status Scale (EDSS) at Screening from 0 to 5.5 points, inclusive
• For sexually active female participants of reproductive potential, use of reliable means of contraception

Exclusion Criteria:

• Contraindications for or intolerance to oral or IV corticosteroids, including IV methylprednisolone, according to the country label
• Known presence of other neurologic disorders
• Treatment with any investigational agent within 24 weeks of screening or 5 half-lives of the investigational drug, whichever is longer, or treatment with any experimental procedure for multiple sclerosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: OCR + Vaccines; Participants will receive dual infusion of OCR 300 milligrams (mg) on Day 1 and then on Day 15, and then participants will further receive immunization course (TT-containing adsorbed vaccine, 23-PPV either unboosted or boosted with 13-PCV, influenza vaccine, and repeated administration with KLH) at 12 weeks post-OCR treatment until Week 24. Participants who complete the 24-week immunization study period will have the option for retreatment with a single infusion of 600 mg OCR on Day 169 and subsequent single infusions (600 mg OCR) at intervals of 24 weeks. Participants who have received one or more infusions of OCR will enter the 48-week safety follow-up period.	Biological: 23-PPV; The 23-PPV vaccine will be given as a 0.5-milliliter (mL) intramuscular (IM) injection in the deltoid muscle on Day 112 (Group A) or Day 28 (Group B).; Biological: 13-PCV Booster; The 13-PCV booster will be given as an IM injection in the deltoid muscle on Day 140 (select participants in Group A).; Biological: Influenza Vaccine; The influenza vaccine will be given as an IM injection in the deltoid muscle at any time between Day 85 and Day 144 (select participants in Group A) or any time between Day 1 and Day 85 (Group B).; Biological: KLH; KLH will be given as a 1-mg subcutaneous (SC) injection on Days 84, 112, and 140 (Group A) or Days 1, 28, and 56 (Group B).; Drug: OCR; OCR will be given as an intravenous (IV) infusion at a dose of 600 mg, with the first dose given as two infusions of 300mg 14 days apart, according to the specifications described in the corresponding Group A and Group B arms.; Other Names: RO4964913, PRO70769, rhuMAb 2H7; Biological: TT Vaccine; The TT-containing adsorbed vaccine will be given as a 0.5-mL IM injection in the deltoid muscle on Day 85 (Group A) or Day 1 (Group B).
Other: Group B: Vaccines (Optional OCR in Extension); Participants will receive immunizations (TT-containing adsorbed vaccine, 23-PPV, influenza vaccine, and repeated administration with KLH) on Day 1 until Week 12 of the immunization period.	Biological: 23-PPV; The 23-PPV vaccine will be given as a 0.5-milliliter (mL) intramuscular (IM) injection in the deltoid muscle on Day 112 (Group A) or Day 28 (Group B).; Biological: Influenza Vaccine; The influenza vaccine will be given as an IM injection in the deltoid muscle at any time between Day 85 and Day 144 (select participants in Group A) or any time between Day 1 and Day 85 (Group B).; Biological: KLH; KLH will be given as a 1-mg subcutaneous (SC) injection on Days 84, 112, and 140 (Group A) or Days 1, 28, and 56 (Group B).; Drug: OCR; OCR will be given as an intravenous (IV) infusion at a dose of 600 mg, with the first dose given as two infusions of 300mg 14 days apart, according to the specifications described in the corresponding Group A and Group B arms.; Other Names: RO4964913, PRO70769, rhuMAb 2H7; Biological: TT Vaccine; The TT-containing adsorbed vaccine will be given as a 0.5-mL IM injection in the deltoid muscle on Day 85 (Group A) or Day 1 (Group B).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Positive Response to TT Vaccine Measured 8 Weeks After TT Vaccine	For participants with pre-vaccination tetanus antibody titers < 0.1 IU/mL, a positive response was defined as an antibody titer >/= 0.2 IU/mL measured 8 weeks after vaccination. For participants with pre-vaccination tetanus antibody titers >/= 0.1 IU/mL, a positive response was defined as at least a 4-fold increase in antibody titers measured 8 weeks after vaccination compared with pre-vaccination levels.	8 weeks after TT vaccine

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Positive Response to TT Vaccine Measured 4 Weeks After TT Vaccine	For participants with pre-vaccination tetanus antibody titers < 0.1 IU/mL, a positive response was defined as an antibody titer >/= 0.2 IU/mL measured 4 weeks after vaccination. For participants with pre-vaccination tetanus antibody titers >/= 0.1 IU/mL, a positive response was defined as at least a 4-fold increase in antibody titers measured 4 weeks after vaccination compared with pre-vaccination levels.	4 weeks after TT vaccine
Percentage of Participants With Tetanus Antibody Titer >/=0.2 IU/mL or 2-Fold Increase in Tetanus Antibody Titers	For participants with pre-vaccination tetanus antibody titers < 0.1 IU/mL, a positive response was defined as an antibody titer >/= 0.2 IU/mL measured 4 weeks after vaccination. For participants with pre-vaccination tetanus antibody titers >/= 0.1 IU/mL, a positive response was defined as at least a 2-fold increase in antibody titers measured 4 weeks after vaccination compared with pre-vaccination levels.	4 weeks after TT vaccine
Mean Levels of Anti-Tetanus Antibody	Anti-tetanus antibody levels were assessed by enzyme-linked immunosorbent assay (ELISA).	Immediately prior to and at 4 and 8 weeks after TT vaccine
Mean Levels of Anti-KLH Antibody: Immunoglobulin (Ig) G	Anti-KLH antibody levels were assessed by ELISA.	Immediately prior to first KLH administration and 4, 8, and 12 weeks after first KLH administration
Mean Levels of Anti-KLH Antibody: Ig M	Anti-KLH antibody levels were assessed by ELISA.	Immediately prior to first KLH administration and 4, 8, and 12 weeks after first KLH administration
Percentage of Participants With Positive Response Against Individual Pneumococcal Serotypes in 23-PPV	Positive response against a serotype was defined as a 2-fold increase in anti-pneumococcal antibody level or greater than (>) 1 microgram per milliliter (mcg/mL) rise compared with pre-vaccination levels.	4 weeks after 23-PPV
Percentage of Participants With Positive Response Against >/=2 Pneumococcal Serotypes	Positive response against a serotype was defined as a 2-fold increase in anti-pneumococcal antibody level or > 1 mcg/mL rise compared with pre-vaccination levels.	4 weeks after 23-PPV
Percentage of Participants With Positive Response Against >/=12 Pneumococcal Serotypes	Positive response against a serotype was defined as a 2-fold increase in anti-pneumococcal antibody level or > 1 mcg/mL rise compared with pre-vaccination levels.	4 weeks after 23-PPV
Mean Levels of Anti-Pneumococcal Antibody	Serotype-specific antibody levels (IgG) were assessed by bead-based multi-analyte immunodetection (MAID).	Immediately prior to and 4 weeks after 23-PPV
Percentage of Participants With Positive Response Against Individual Pneumococcal Serotypes in 13-PCV	Positive response against a serotype was defined as a 2-fold increase in anti-pneumococcal antibody level or > 1 mcg/mL rise compared with pre-vaccination levels.	8 weeks after 23-PPV, which was 4 weeks after Group A1 participants received 13-PCV
Mean Level of Anti-Pneumococcal Antibody	Serotype-specific antibody levels (IgG) were assessed by bead-based multi-analyte immunodetection (MAID).	Immediately prior to 23-PPV and 4 and 8 weeks after 23-PPV
Percentage of Participants With Seroprotection	Seroprotection was defined as specific hemagglutination inhibition (HI) titers >40 at 4 weeks after vaccination.	4 weeks after seasonal influenza vaccine administration
Percentage of Participants With 2-Fold Increase in Strain-Specific HI Titers	2-fold increase from prevaccination HI titer.	4 weeks after seasonal influenza vaccine administration
Percentage of Participants With 4-Fold Increase in Strain-Specific HI Titers	4-fold increase from prevaccination HI titer.	4 weeks after seasonal influenza vaccine administration
Percentage of Participants With Seroconversion	Seroconversion at 4 weeks after vaccination defined, as per protocol, as a prevaccination HI titer <10 and an HI titer >40 at 4 weeks after vaccination. Seroconversion at 4 weeks after vaccination, defined per FDA guidance, as either a) a pre-vaccination HI titer <10 and HI titer >/= 40 at 4 weeks after vaccination, or b) a pre-vaccination HI titer >/= 10 and at least 4-fold increase in HI antibody titer at 4 weeks after vaccination.	4 weeks after influenza immunization
Strain-Specific Geometric Mean Titer Levels	Geometric mean titers (GMTs) in participants in Groups A2 and B were measured 4 weeks after vaccination.	Baseline and Week 4
Ratio of Strain-Specific Geometric Mean Titer Levels Postvaccination to Prevaccination	Strain-specific GMT ratios were calculated as post-vaccination : pre-vaccination.	Immediately prior to and 4 weeks after influenza vaccine
Magnetic Resonance Imaging (MRI) Parameters: Volume of T2 Lesions	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
MRI Parameters: Number of T2 Lesions	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
MRI Parameters: Categorical Number of T2 Lesions	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
MRI Parameters: Number of Gadolinium (Gd)-Enhancing T1 Lesions	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
MRI Parameters: Categorical Number of Gd-enhancing T1 Lesions	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
MRI Parameters: Normalized Brain Volume	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
MRI Parameters: Volume of T2 Lesions: White Matter Volume	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
MRI Parameters: Cortical Grey Matter Volume	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
MRI Parameters: T1 Unenhancing Lesion Volume	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
MRI Parameters: Total Number of Lesions	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
Cellular Immune Response Assessed by Flow Cytometry	Flow cytometry is a laser-based technology commonly used for cell counting and sorting. In this study, this outcome measure is focusing on a single variable, CD19 count (total B cells). LLN = 80 cells/ul. Repleted is defined as CD19 >= LLN or baseline, whichever is lower.	Days 1, 15, 85, 112, 140 and 169
Total Immunoglobulin		Days 1, 85, and 169
Percentage of Participants With Anti-Drug Antibody Formation	Anti-Drug Antibodies (ADA) may induce unwanted side effects, especially in biotechnology-derived pharmaceuticals, such as therapeutic antibodies and growth factors.	Up to 24 Weeks (ISP)
Percentage of Participants With Adverse Events (AEs), Serious AEs, or AEs Leading to Study Discontinuation	An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious AE is any AE that is fatal, life-threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug, or is a significant medical event in the investigator's judgment.	During ISP (24 weeks for Group A and 12 weeks for Group B)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Publications and helpful links

General Publications

• Bar-Or A, Calkwood JC, Chognot C, Evershed J, Fox EJ, Herman A, Manfrini M, McNamara J, Robertson DS, Stokmaier D, Wendt JK, Winthrop KL, Traboulsee A. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: The VELOCE study. Neurology. 2020 Oct 6;95(14):e1999-e2008. doi: 10.1212/WNL.0000000000010380. Epub 2020 Jul 29.

Study record dates

Study Major Dates

• Study Start (Actual): October 27, 2015
• Primary Completion (Actual): February 14, 2017
• Study Completion (Actual): September 21, 2021

Study Registration Dates

• First Submitted: September 8, 2015
• First Submitted That Met QC Criteria: September 8, 2015
• First Posted (Estimated): September 10, 2015

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: February 29, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: BN29739; 2015-001357-32 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No