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

Multiple Sclerosis, Relapsing-Remitting Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02545868
• Other study ID #: BN29739
• Secondary ID: 2015-001357-32
• Status: Completed
• Phase: Phase 3
• Start date: October 27, 2015
• Est. completion date: September 21, 2021

Study information

• Verified date: February 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 102
• Est. completion date: September 21, 2021
• Est. primary completion date: February 14, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

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).
• 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).
• 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).
• 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.

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).

Locations

Country	Name	City	State
Canada	University of Calgary	Calgary	Alberta
Canada	University of British Columbia Hospital; Division of Neurology	Vancouver	British Columbia
United States	Abington Neurological Associates	Abington	Pennsylvania
United States	University of New Mexico	Albuquerque	New Mexico
United States	Mercy Hospital St. Louis / Mercy Clinic Neurology	Chesterfield	Missouri
United States	Ohio Health Research Institute Grant Medical Center	Columbus	Ohio
United States	Neurology Clinic PC	Cordova	Tennessee
United States	North Central Neurology Associates	Cullman	Alabama
United States	Michigan Institute for Neurological Disorders	Farmington Hills	Michigan
United States	Fullerton Neurology and Headache Center	Fullerton	California
United States	The Minneapolis Clinic of Neurology	Golden Valley	Minnesota
United States	Neurology Associates PA	Hickory	North Carolina
United States	Scripps Clinic	La Jolla	California
United States	Cleveland Clinic Lou Ruvo; Center for Brain Research	Las Vegas	Nevada
United States	University of Miami School of Medicine; Dept. of Neurology Movement Disorder Center	Miami	Florida
United States	Central Texas Neurology Consultants	Round Rock	Texas
United States	Rocky Mountain MS Clinic	Salt Lake City	Utah
United States	Swedish Medical Center	Seattle	Washington
United States	Staten Island Univ Hospital	Staten Island	New York
United States	University of South Florida	Tampa	Florida
United States	Territory Neurology and Research Institute	Tucson	Arizona
United States	MDH Research LLC	Westerville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Magnetic Resonance Imaging (MRI) Parameters: Volume of T2 Lesions	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
Secondary	MRI Parameters: Number of T2 Lesions	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
Secondary	MRI Parameters: Categorical Number of T2 Lesions	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
Secondary	MRI Parameters: Number of Gadolinium (Gd)-Enhancing T1 Lesions	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
Secondary	MRI Parameters: Categorical Number of Gd-enhancing T1 Lesions	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
Secondary	MRI Parameters: Normalized Brain Volume	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
Secondary	MRI Parameters: Volume of T2 Lesions: White Matter Volume	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
Secondary	MRI Parameters: Cortical Grey Matter Volume	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
Secondary	MRI Parameters: T1 Unenhancing Lesion Volume	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
Secondary	MRI Parameters: Total Number of Lesions	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.	Baseline
Secondary	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
Secondary	Total Immunoglobulin		Days 1, 85, and 169
Secondary	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)
Secondary	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)