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

Phase 3

Completed

• Conditions: Multiple Sclerosis, Relapsing-Remitting
• Interventions: Biological: 23-PPV; Biological: 13-PCV Booster; Biological: Influenza Vaccine; Biological: KLH; Drug: OCR; Biological: TT Vaccine

• Registration Number: NCT02545868
• Lead Sponsor: Hoffmann-La Roche

Brief 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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-09-08
• Study First Submitted QC: 2015-09-08
• Study First Posted: 2015-09-10
• Study Start: 2015-10-27
• Primary Completion: 2017-02-14
• Results First Submitted: 2018-02-13
• Results First Submitted QC: 2018-05-02
• Results First Posted: 2018-06-06
• Study Completion: 2021-09-21
• Status Verified: 2024-02
• Last Update Submitted: 2024-02-29
• Last Update Posted: 2024-03-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 102

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A: OCR + Vaccines	23-PPV	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.
Group A: OCR + Vaccines	13-PCV Booster	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.
Group A: OCR + Vaccines	Influenza Vaccine	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.
Group A: OCR + Vaccines	KLH	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.
Group A: OCR + Vaccines	OCR	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.
Group A: OCR + Vaccines	TT Vaccine	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.
Group B: Vaccines (Optional OCR in Extension)	23-PPV	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.
Group B: Vaccines (Optional OCR in Extension)	Influenza Vaccine	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.
Group B: Vaccines (Optional OCR in Extension)	KLH	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.
Group B: Vaccines (Optional OCR in Extension)	OCR	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.
Group B: Vaccines (Optional OCR in Extension)	TT Vaccine	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Positive Response to TT Vaccine Measured 8 Weeks After TT Vaccine	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Tetanus Antibody Titer >/=0.2 IU/mL or 2-Fold Increase in Tetanus Antibody Titers	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 2-fold increase in antibody titers measured 4 weeks after vaccination compared with pre-vaccination levels.
Mean Levels of Anti-Tetanus Antibody	Immediately prior to and at 4 and 8 weeks after TT vaccine	Anti-tetanus antibody levels were assessed by enzyme-linked immunosorbent assay (ELISA).
Mean Levels of Anti-Pneumococcal Antibody	Immediately prior to and 4 weeks after 23-PPV	Serotype-specific antibody levels (IgG) were assessed by bead-based multi-analyte immunodetection (MAID).
Percentage of Participants With Positive Response Against Individual Pneumococcal Serotypes in 13-PCV	8 weeks after 23-PPV, which was 4 weeks after Group A1 participants received 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.
Percentage of Participants With Positive Response to TT Vaccine Measured 4 Weeks After TT Vaccine	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.
Mean Levels of Anti-KLH Antibody: Ig M	Immediately prior to first KLH administration and 4, 8, and 12 weeks after first KLH administration	Anti-KLH antibody levels were assessed by ELISA.
Percentage of Participants With 2-Fold Increase in Strain-Specific HI Titers	4 weeks after seasonal influenza vaccine administration	2-fold increase from prevaccination HI titer.
Percentage of Participants With 4-Fold Increase in Strain-Specific HI Titers	4 weeks after seasonal influenza vaccine administration	4-fold increase from prevaccination HI titer.
Mean Levels of Anti-KLH Antibody: Immunoglobulin (Ig) G	Immediately prior to first KLH administration and 4, 8, and 12 weeks after first KLH administration	Anti-KLH antibody levels were assessed by ELISA.
Percentage of Participants With Positive Response Against Individual Pneumococcal Serotypes in 23-PPV	4 weeks after 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.
Mean Level of Anti-Pneumococcal Antibody	Immediately prior to 23-PPV and 4 and 8 weeks after 23-PPV	Serotype-specific antibody levels (IgG) were assessed by bead-based multi-analyte immunodetection (MAID).
Percentage of Participants With Seroprotection	4 weeks after seasonal influenza vaccine administration	Seroprotection was defined as specific hemagglutination inhibition (HI) titers \>40 at 4 weeks after vaccination.
Percentage of Participants With Positive Response Against >/=2 Pneumococcal Serotypes	4 weeks after 23-PPV	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.
Percentage of Participants With Positive Response Against >/=12 Pneumococcal Serotypes	4 weeks after 23-PPV	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.
Percentage of Participants With Seroconversion	4 weeks after influenza immunization	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.
Strain-Specific Geometric Mean Titer Levels	Baseline and Week 4	Geometric mean titers (GMTs) in participants in Groups A2 and B were measured 4 weeks after vaccination.
Ratio of Strain-Specific Geometric Mean Titer Levels Postvaccination to Prevaccination	Immediately prior to and 4 weeks after influenza vaccine	Strain-specific GMT ratios were calculated as post-vaccination : pre-vaccination.
Magnetic Resonance Imaging (MRI) Parameters: Volume of T2 Lesions	Baseline	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
MRI Parameters: Number of T2 Lesions	Baseline	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
MRI Parameters: Categorical Number of T2 Lesions	Baseline	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
MRI Parameters: Number of Gadolinium (Gd)-Enhancing T1 Lesions	Baseline	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
MRI Parameters: Categorical Number of Gd-enhancing T1 Lesions	Baseline	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
MRI Parameters: Cortical Grey Matter Volume	Baseline	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
MRI Parameters: Normalized Brain Volume	Baseline	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
MRI Parameters: Volume of T2 Lesions: White Matter Volume	Baseline	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
MRI Parameters: T1 Unenhancing Lesion Volume	Baseline	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
MRI Parameters: Total Number of Lesions	Baseline	MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
Cellular Immune Response Assessed by Flow Cytometry	Days 1, 15, 85, 112, 140 and 169	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.
Total Immunoglobulin	Days 1, 85, and 169
Percentage of Participants With Anti-Drug Antibody Formation	Up to 24 Weeks (ISP)	Anti-Drug Antibodies (ADA) may induce unwanted side effects, especially in biotechnology-derived pharmaceuticals, such as therapeutic antibodies and growth factors.
Percentage of Participants With Adverse Events (AEs), Serious AEs, or AEs Leading to Study Discontinuation	During ISP (24 weeks for Group A and 12 weeks for Group B)	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.

Trial Locations

Locations (22)

The Minneapolis Clinic of Neurology; 🇺🇸 Golden Valley, Minnesota, United States

Territory Neurology and Research Institute; 🇺🇸 Tucson, Arizona, United States

North Central Neurology Associates; 🇺🇸 Cullman, Alabama, United States

Scripps Clinic; 🇺🇸 La Jolla, California, United States

Neurology Associates PA; 🇺🇸 Hickory, North Carolina, United States

MDH Research LLC; 🇺🇸 Westerville, Ohio, United States

Abington Neurological Associates; 🇺🇸 Abington, Pennsylvania, United States

University of British Columbia Hospital; Division of Neurology; 🇨🇦 Vancouver, British Columbia, Canada

Fullerton Neurology and Headache Center; 🇺🇸 Fullerton, California, United States

University of Miami School of Medicine; Dept. of Neurology Movement Disorder Center; 🇺🇸 Miami, Florida, United States

Michigan Institute for Neurological Disorders; 🇺🇸 Farmington Hills, Michigan, United States

Mercy Hospital St. Louis / Mercy Clinic Neurology; 🇺🇸 Chesterfield, Missouri, United States

Staten Island Univ Hospital; 🇺🇸 Staten Island, New York, United States

Ohio Health Research Institute Grant Medical Center; 🇺🇸 Columbus, Ohio, United States

Central Texas Neurology Consultants; 🇺🇸 Round Rock, Texas, United States

Swedish Medical Center; 🇺🇸 Seattle, Washington, United States

Cleveland Clinic Lou Ruvo; Center for Brain Research; 🇺🇸 Las Vegas, Nevada, United States

Rocky Mountain MS Clinic; 🇺🇸 Salt Lake City, Utah, United States

University of South Florida; 🇺🇸 Tampa, Florida, United States

University of New Mexico; 🇺🇸 Albuquerque, New Mexico, United States

Neurology Clinic PC; 🇺🇸 Cordova, Tennessee, United States

University of Calgary; 🇨🇦 Calgary, Alberta, Canada