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

Study Overview
=================
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).

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

Conditions
-----------------
Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
-----------------
* Biological: 23-PPV
* Biological: 13-PCV Booster
* Biological: Influenza Vaccine
* Biological: KLH
* Drug: OCR
* Biological: TT Vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: OCR + Vaccines<br>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<br>* 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).<br>Biological: 13-PCV Booster<br>* The 13-PCV booster will be given as an IM injection in the deltoid muscle on Day 140 (select participants in Group A).<br>Biological: Influenza Vaccine<br>* 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).<br>Biological: KLH<br>* 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).<br>Drug: OCR<br>* 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.<br>* Other names: RO4964913, PRO70769, rhuMAb 2H7;Biological: TT Vaccine<br>* 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).<br>|
| Other: Group B: Vaccines (Optional OCR in Extension)<br>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. Participants who complete the 12-week immunization study period will have the option to receive two single infusions of OCR 300 mg, on Day 84 and Day 98, 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<br>* 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).<br>Biological: Influenza Vaccine<br>* 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).<br>Biological: KLH<br>* 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).<br>Drug: OCR<br>* 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.<br>* Other names: RO4964913, PRO70769, rhuMAb 2H7;Biological: TT Vaccine<br>* 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).<br>|

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) |