Safety of Switching From Rituximab to Ocrelizumab in MS Patients

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT02980042
• Collaborator: (none)
• Enrollment: 200
• Location: 1
• Arms: 2
• Actual Duration (Months): 26.1
• Patients Per Site Per Month: 7.7

Study Details

Study Description

Brief Summary

This is a prospective between and within group observational study to determine differences in tolerability, immunogenicity and safety related outcomes for 100 multiple sclerosis (MS) patients who have been administered at least two infusions of rituximab, six months apart and are willing to be switched to ocrelizumab compared to a 100 patients who are continuing on rituximab as a comparison cohort from the clinic population treated as part of clinical care.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: Ocrelizumab; Drug: Rituximab	Phase 3

Detailed Description

Studies of rituximab, a chimeric monoclonal antibody against CD20 have shown that B-cell depletion is of clinical benefit as a potential treatment in relapsing forms of multiple sclerosis (MS).1 Ocrelizumab is a humanized monoclonal antibody that targets CD20 and selectively depletes CD20 expressing cells, while preserving the capacity for B cell reconstitution. When compared with rituximab, ocrelizumab is associated with increased antibody-dependent cell-mediated cytotoxic effects, and reduced complement-dependent cytotoxic effects in vitro.2 By increasing antibody-dependent cell mediated cytotoxic effects, ocrelizumab might modulate tissue-dependent mechanisms of pathogenic response more effectively compared to rituximab. As a humanized molecule, ocrelizumab is expected to be less immunogenic with repeated infusions and might thus present a more favorable safety profile when compared to rituximab.2

Despite rituximab's current off label use in the treatment of MS, currently there is only data available from phase 2 trials. The HERMES group conducted a phase 2, double-blind, 48-week trial involving 104 patients with relapsing forms of MS; 69 patients received 1000 mg of intravenous rituximab and 35 patients received placebo on days 1 and 15.3 A significantly higher number of patients in the rituximab group (78.3%) versus the placebo group (40.0%) had an infusion related reaction (IRR) events within 24 hours after the first infusion. Within 24 hours after the second infusion, fewer patients in the rituximab group (20.3%) than in the placebo group (40%) had similar events. A majority of the rituximab group with IRR events (92.6%) were classified as mild to moderate (grade 1 or 2) in severity.

Safety data from the Investigators Brochure on the OPERA I and II phase 3 trials comparing ocrelizumab to interferon β-1a on relapsing MS patients showed that IRRs were the most common adverse events experienced by patients treated with 600 mg of ocrelizumab.4 The percentage of patients experiencing IRRs was higher in the ocrelizumab group (relapsing forms of MS: 34.3%; primary progressive forms of MS 39.9%) compared with the interferon β-1a (active control) group who received placebo infusions (relapsing forms of MS: 9.7%; primary progressive forms of MS: 25.5%). The rate of IRRs was highest during the first infusion or Dose 1 (27.5% on Day 1; 4.71% on Day 15 of Dose 1) and decreased over time (13.7%; 9.6% and 7.8% following Dose 2, 3, and 4 respectively) for the ocrelizumab treated group. Comparatively, interferon β-1a users experienced 6.5% of IRRs on Day 1, 2.58% on Day 15, < 2.00% after doses 2, 3 and 4 respectively. The reported IRRs were primarily mild-to-moderate in severity (Grades 1 and 2). Serious IRRs occurred in 0.1% and 1.0% respectively of relapsing and progressive patients and treated with ocrelizumab.

Clinical data describing the efficacy and tolerability profile of rituximab and ocrelizumab has utilized populations with different prior treatment characteristics. In the phase 2 HERMES trials, a majority (78.5%) of rituximab patients had been previously been treated with a disease modifying therapy in the last 2 years.3 In contrast, the OPERA I and II phase 3 clinical trials, a majority of ocrelizumab patients (72.9% in OPERA I and 73.8% in OPERA II) represented a treatment naïve population.4 Examining IRRs in patients who have switched from rituximab to ocrelizumab versus those continuing on rituximab will examine the magnitude of the IRRs and subsequent tolerability of ocrelizumab in a real world population.

Earlier concepts of MS disease pathology have suggested that pathogenic T cells are sufficient for the full expression of MS. However, it is now evident that full autoimmune B cells and humoral immune mechanisms also play key roles. 5 Ocrelizumab is a humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells. CD20 is a B cell surface molecule that is expressed on pre B cells and mature B cells, but not expressed earlier in the development of B cells or on mature plasma cells. In all three ocrelizumab studies (with relapsing and progressive populations), treatment with 600 mg of ocrelizumab led to rapid and complete depletion of circulating CD19+ B cells within 14 days post treatment. 4 B cell depletion was sustained throughout treatment period. The median time to repletion of B cells was 72 weeks (range 27-175 weeks). We hypothesize that in switching rituximab treated patients to ocrelizumab, the proportion of patients with B cell depletion (< 1%) 6 months after the first and third infusion of ocrelizumab will be the same as the baseline assessment which will be 6 months after the last dose of rituximab and similar to findings in OPERA I and II.

Immunogenicity results from the OPERA I and II trials examined the number of patients who had treatment induced anti-drug antibodies (ADA) to ocrelizumab. 4 Of the 807 patients who received ocrelizumab and had an ADA assay from a post baseline sample during the controlled treatment period, 3 patients (0.4%) showed treatment induced ADA to ocrelizumab. Of these, 1 patient tested positive for neutralizing antibodies (NAB) to ocrelizumab. During the open label extension phase, the prevalence of ADA continued to remain low with post baseline incidence of 1.9% (2/103 with treatment induced ADA). Currently there is little evidence examining the prevalence of treatment induced ADAs to both rituximab and ocrelizumab in patients that switch from the former to the latter in comparison to continuing rituximab patients. Therefore, we will perform assays to detect ADAs to both rituximab and ocrelizumab in all patients switching from rituximab to ocrelizumab at Day 1, 6 months and 12 months on ocrelizumab.

Finally, IRRs have been hypothesized to be a reaction by autoantibodies to the treatment drug or possibly from the release of cytokines from CD20 expressing cells as they are destroyed by ocrelizumab causing a "cytokine storm". Understanding this process may lead to mechanisms that may aid in ameliorating these infusion reactions. If they are associated with ADA, then it might be possible to predictively premedicate these patients only. Alternatively, if they are associated with cytokine release, it may be possible to eliminate premedication in patients who are already CD20+cell depleted in subsequent infusions. Therefore, we will assay the profile of certain cytokines in the serum 4 hours after start of ocrelizumab infusion.

With ocrelizumab expected to enter the MS therapeutic market within the next year, we expect third party payers within and outside the US will require that the FDA or EMA approved versions of anti-CD20 monoclonal antibodies be used in the treatment of MS, namely ocrelizumab. Currently, we estimate several thousand MS patients in the US and Sweden are taking rituximab currently. Thus, it will be important to demonstrate that switching from a chimeric anti-CD20 to a fully humanized anti-CD20 does not lead to unexpected infusion reactions and does not increase the probability of development of anti-drug antibodies.

The Rocky Mountain MS Center (RMMSC) at the University of Colorado Anschutz Medical Campus prescribed rituximab infusions for 533 MS patients in the last 12 months, of which 323 patients received their infusion at the University of Colorado Hospital's Outpatient Infusion Center between September, 2015-March, 2016. The RMMSC is one of the few sites nationwide with large numbers of MS patients treated with rituximab. With the anticipated approval of ocrelizumab, current rituximab users are being counselled by their MS providers at RMMSC to consider switching to ocrelizumab post approval, particularly if US Payers adopt the FDA approved version as the preferred anti-CD20 agent for MS.

Study Design

• Study Type: Interventional
• Actual Enrollment: 200 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Evaluating the Tolerability and Safety Profile of Switching From Rituximab to Ocrelizumab: A Real World Evaluation of Patients With Relapsing Forms of Multiple Sclerosis
• Actual Study Start Date: Jan 1, 2017
• Actual Primary Completion Date: Mar 6, 2019
• Actual Study Completion Date: Mar 6, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Switching Group 600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line.	Drug: Ocrelizumab; A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells; Other Names: Ocrevus
Active Comparator: Comparator Group Standard of care rituximab doses are 1000 mg infusion given as first dose followed by 500mg (or 1000 mg if evidence of early B cell recovery) infusion every 6 months thereafter. Rituximab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and rituximab should be infused through a dedicated line	Drug: Rituximab; A chimeric monoclonal antibody against CD20.; Other Names: Rituxan

Outcome Measures

Primary Outcome Measures

1. Proportion of Infusions With >= 1 IRR Between the Switching and Comparator Groups [Day 1, Day 15, Week 24]

   The investigators will report the proportion of infusions with >= 1 IRR (infusion-related reaction) between the switching and comparator groups. Data was collected at Day 1, Day 15, and Week 24 and combined to determine the overall proportion of IRRs over the life of the study.

2. Difference in the Total Number of IRRs After Each Infusion of Ocrelizumab Compared to Rituximab Infusions in the Comparator Group. [Pre-study (Enrollment), Day 1, Day 15, Week 24]

   The investigators will report the difference in the total number of IRRs after each infusion of ocrelizumab compared to combined rituximab infusions in the comparator group.

3. Severity of IRRs Following the Day 1 Infusion of Ocrelizumab in the Switching and the Comparator Groups Infusions [Day 1, pre-study infusions]

   The severity of IRRs will be assessed following each infusion of ocrelizumab in the switching and comparator group using the National Cancer Institute's Common Terminology for Adverse Events Scale (Grades range from 1-5, with higher Grades indicating more severe reactions). The frequency of each severity grade of IRR will be compared in a similar fashion .

4. Severity of IRRs Following the Day 15 Infusion of Ocrelizumab in the Switching and the Comparator Groups Infusions [Day 15, pre-study infusions]

   The severity of IRRs will be assessed following each infusion of ocrelizumab in the switching and comparator group using the National Cancer Institute's Common Terminology for Adverse Events Scale (Grades range from 1-5, with higher Grades indicating more severe reactions). The frequency of each severity grade of IRR will be compared in a similar fashion.

5. Severity of IRRs Following the Week 24 Infusion of Ocrelizumab in the Switching and the Comparator Groups Infusions [Week 24, pre-study infusions]

   The severity of IRRs will be assessed following each infusion of ocrelizumab in the switching and comparator group using the National Cancer Institute's Common Terminology for Adverse Events Scale (Grades range from 1-5, with higher Grades indicating more severe reactions). The frequency of each severity grade of IRR will be compared in a similar fashion .

6. Proportion of Patients With an IRR at Day 1 Versus Day 15 and Week 24 Infusions [Day 1, Day 15, Week 24]

   We will also compare the proportion of patients with an IRR following day 1 infusion versus the proportion of patients with an IRR at day 15 and month 6 infusions of ocrelizumab in the switching group.

Secondary Outcome Measures

1. Presence of Ocrelizumab Anti-drug Anti-bodies [Day 1 and Week 24]

   Proportion of ocrelizumab patients who test positive for ocrelizumab anti-drug anti-bodies

2. Presence of Rituximab Anti-drug Anti-bodies [Day 1 and Week 24]

   Proportion of patients who test positive for rituximab anti-drug anti-bodies.

3. B Cell Depletion (CD19) [Day 1, Week 24, 1 Year]

   Proportion of patients with CD19% <= 1%.

4. B Cell Depletion (CD20) [Day 1, Week 24, 1 Year]

   Proportion of patients with CD20% <= 1%

5. Cytokine: Eotaxin - Pre-Post Infusion - Day 1 [Day 1]

   Comparing Eotaxin concentration between pre and post ocrelizumab infusion - Day 1

6. Cytokine: IFN-gamma - Pre-Post Infusion - Day 1 [Day 1]

   Comparing IFN-gamma concentration between pre and post ocrelizumab infusion - Day 1

7. Cytokine: IL-10 - Pre-Post Infusion - Day 1 [Day 1]

   Comparing IL-10 concentration between pre and post ocrelizumab infusion - Day 1

8. Cytokine: IL-12/IL-23p40 - Pre-Post Infusion - Day 1 [Day 1]

   Comparing IL-12/IL-23p40 concentration between pre and post ocrelizumab infusion - Day 1

9. Cytokine: IL-16 - Pre-Post Infusion - Day 1 [Day 1]

   Comparing IL-16 concentration between pre and post ocrelizumab infusion - Day 1

10. Cytokine: IL-1RA - Pre-Post Infusion - Day 1 [Day 1]

    Comparing IL-1RA concentration between pre and post ocrelizumab infusion - Day 1

11. Cytokine: IL-27 - Pre-Post Infusion - Day 1 [Day 1]

    Comparing IL-27 concentration between pre and post ocrelizumab infusion - Day 1

12. Cytokine: IL-6 - Pre-Post Infusion - Day 1 [Day 1]

    Comparing IL-6 concentration between pre and post ocrelizumab infusion - Day 1

13. Cytokine: IL-7 - Pre-Post Infusion - Day 1 [Day 1]

    Comparing IL-7 concentration between pre and post ocrelizumab infusion - Day 1

14. Cytokine: IL-8(HA) - Pre-Post Infusion - Day 1 [Day 1]

    Comparing IL-8(HA) concentration between pre and post ocrelizumab infusion - Day 1

15. Cytokine: MCP-1 - Pre-Post Infusion - Day 1 [Day 1]

    Comparing MCP-1 concentration between pre and post ocrelizumab infusion - Day 1

16. Cytokine: MDC - Pre-Post Infusion - Day 1 [Day 1]

    Comparing MDC concentration between pre and post ocrelizumab infusion - Day 1

17. Cytokine: MIP-1alpha - Pre-Post Infusion - Day 1 [Day 1]

    Comparing MIP-1alpha concentration between pre and post ocrelizumab infusion - Day 1

18. Cytokine: MIP-1beta - Pre-Post Infusion - Day 1 [Day 1]

    Comparing MIP-1beta concentration between pre and post ocrelizumab infusion - Day 1

19. Cytokine: MIP-3alpha - Pre-Post Infusion - Day 1 [Day 1]

    Comparing MIP-3alpha concentration between pre and post ocrelizumab infusion - Day 1

20. Cytokine: TARC - Pre-Post Infusion - Day 1 [Day 1]

    Comparing TARC concentration between pre and post ocrelizumab infusion - Day 1

21. Cytokine: TNF-alpha - Pre-Post Infusion - Day 1 [Day 1]

    Comparing TNF-alpha concentration between pre and post ocrelizumab infusion - Day 1

22. Cytokine: Exotaxin - Pre-Post Infusion - Day 15 [Day 15]

    Comparing Exotaxin concentration between pre and post ocrelizumab infusion - Day 15

23. Cytokine: IFN-gamma - Pre-Post Infusion - Day 15 [Day 15]

    Comparing IFN-gamma concentration between pre and post ocrelizumab infusion - Day 15

24. Cytokine: IL-10 - Pre-Post Infusion - Day 15 [Day 15]

    Comparing IL-10 concentration between pre and post ocrelizumab infusion - Day 15

25. Cytokine: IL-12/IL-23p40 - Pre-Post Infusion - Day 15 [Day 15]

    Comparing IL-12/IL-23p40 concentration between pre and post ocrelizumab infusion - Day 15

26. Cytokine: IL-16 - Pre-Post Infusion - Day 15 [Day 15]

    Comparing IL-16 concentration between pre and post ocrelizumab infusion - Day 15

27. Cytokine: IL-1beta - Pre-Post Infusion - Day 15 [Day 15]

    Comparing IL-1beta concentration between pre and post ocrelizumab infusion - Day 15

28. Cytokine: IL-7 - Pre-Post Infusion - Day 15 [Day 15]

    Comparing IL-7 concentration between pre and post ocrelizumab infusion - Day 15

29. Cytokine: IL-8 - Pre-Post Infusion - Day 15 [Day 15]

    Comparing IL-8 concentration between pre and post ocrelizumab infusion - Day 15

30. Cytokine: MCP-1 - Pre-Post Infusion - Day 15 [Day 15]

    Comparing MCP-1 concentration between pre and post ocrelizumab infusion - Day 15

31. Cytokine: MCP-4 - Pre-Post Infusion - Day 15 [Day 15]

    Comparing MCP-4 concentration between pre and post ocrelizumab infusion - Day 15

32. Cytokine: MDC - Pre-Post Infusion - Day 15 [Day 15]

    Comparing MDC concentration between pre and post ocrelizumab infusion - Day 15

33. Cytokine: MIP-1beta - Pre-Post Infusion - Day 15 [Day 15]

    Comparing MIP-1beta concentration between pre and post ocrelizumab infusion - Day 15

34. Cytokine: MIP-3alpha - Pre-Post Infusion - Day 15 [Day 15]

    Comparing MIP-3alpha concentration between pre and post ocrelizumab infusion - Day 15

35. Cytokine: TNF-alpha - Pre-Post Infusion - Day 15 [Day 15]

    Comparing TNF-alpha concentration between pre and post ocrelizumab infusion - Day 15

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

Switching group:

• Current active patient of RMMSC

• 18-65 years

• Diagnosis of relapsing forms of MS

• Completed ≥ two doses of rituximab with the last dose having been administered:

1. Within 12 months of screening and

2. At least 6 months prior to the first planned infusion of study drug

• Are receiving their current infusions of rituximab at the University of Colorado Outpatient Infusion Center

• Have discussed the possibility of switching to ocrelizumab with their MS provider

• Screened for Hepatitis B and C and TB within 2 years of first dose of ocrelizumab

• A negative serum pregnancy test must be available for premenopausal women and for women <12 months after the onset of menopause, unless they have undergone surgical sterilization.

• Women of childbearing potential must agree to use a "highly effective", hormonal form of contraception or two "effective" forms of non-hormonal contraception. Contraception must continue for the duration of study treatment and for at least three months after the last dose of study treatment

• Are able to complete patient reported outcomes developed as English written scales.

• Must be able and willing to give meaningful, written informed consent prior to participation in the trial, in accordance with local regulatory requirements

Comparator group:

• Current active patient of RMMSC

• 18-65 years

• Diagnosis of relapsing forms of MS

• Completed ≥ two doses of rituximab with the last dose having been administered within 12 months of screening as standard of care

• Are receiving their current infusions of rituximab as standard of care at the University of Colorado Outpatient Infusion Center and will continue to do so

• Are willing to be followed for up to two additional rituximab infusions during the study period as standard of care

• Must be able and willing to give meaningful, written informed consent prior to participation in the trial, in accordance with local regulatory requirements

Exclusion Criteria:

Both groups:

• Pregnant or lactating women

• Hypersensitivity to trial medications

• Hepatic Dysfunction (liver enzymes are 5 times greater than normal)

• History of Congestive Heart Failure

• Any history of a positive blood assay for Hepatitis B or C

• Any history of TB or a positive Quantiferon Gold Assay

• Concurrent use of immunosuppressant medications

• Any history of immunodeficiency or other medical condition increasing risk of anti-CD 20 therapy.

• No serious infection at the time of a scheduled study infusion.

• Any medical, psychiatric or other condition that could result in the patient not being able to give fully informed consent, or to comply with the protocol requirements as determined by the investigator

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Hospital	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver

Investigators

• Principal Investigator: Timothy Vollmer, MD, University of Colorado, Denver
• Principal Investigator: Kavita Nair, PhD, University of Colorado, Denver
• Principal Investigator: Enrique Alvarez, MD, PhD, University of Colorado, Denver

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 7, 2018

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT02980042
• Other Study ID Numbers: 16-1354
• First Posted: Dec 2, 2016
• Last Update Posted: Jul 21, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Rituximab; Ocrelizumab

Study Results

Participant Flow

Arm/Group Title	Switching Group	Comparator Group
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells	Standard of care rituximab doses are 1000 mg infusion given as first dose followed by 500mg (or 1000 mg if evidence of early B cell recovery) infusion every 6 months thereafter. Rituximab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and rituximab should be infused through a dedicated line Rituximab: A chimeric monoclonal antibody against CD20.
Period Title: Overall Study
STARTED	100	100
COMPLETED	93	100
NOT COMPLETED	7	0

Baseline Characteristics

Arm/Group Title	Switching Group	Comparator Group	Total
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells	Standard of care rituximab doses are 1000 mg infusion given as first dose followed by 500mg (or 1000 mg if evidence of early B cell recovery) infusion every 6 months thereafter. Rituximab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and rituximab should be infused through a dedicated line Rituximab: A chimeric monoclonal antibody against CD20.	Total of all reporting groups
Overall Participants	100	100	200
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.30 (11.01)	43.82 (9.97)	44.56 (10.50)
Sex: Female, Male (Count of Participants)
Female	68 68%	75 75%	143 71.5%
Male	32 32%	25 25%	57 28.5%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	8 8%	7 7%	15 7.5%
Not Hispanic or Latino	92 92%	89 89%	181 90.5%
Other	0 0%	4 4%	4 2%
Race/Ethnicity, Customized (Count of Participants)
Black/African American	5 5%	12 12%	17 8.5%
White	90 90%	82 82%	172 86%
Asian	1 1%	0 0%	1 0.5%
Native American	0 0%	1 1%	1 0.5%
Other	4 4%	5 5%	9 4.5%
Expanded Disability Status Scale (EDSS) (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	3.5	3.5
Patient Determined Disease Steps (PDDS) (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	3	3
Disease Duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	11.20 (7.91)	11.32 (7.97)	11.26 (7.92)
Number of Years on rituximab (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	2.38 (1.37)	2.44 (1.45)	2.41 (1.41)

Outcome Measures

1. Primary Outcome

Title	Proportion of Infusions With >= 1 IRR Between the Switching and Comparator Groups
Description	The investigators will report the proportion of infusions with >= 1 IRR (infusion-related reaction) between the switching and comparator groups. Data was collected at Day 1, Day 15, and Week 24 and combined to determine the overall proportion of IRRs over the life of the study.
Time Frame	Day 1, Day 15, Week 24

Outcome Measure Data

Analysis Population Description

The Switching group received 3 infusions (Day 1, Day 15 and week 24), and the Comparator group received 2 infusions. There were a total of 300 infusions in the Switching group and 200 in the Comparator group. Proportion of IRRs are taken out of total number of infusions.

Arm/Group Title	Switching Group	Comparator Group
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells	Standard of care rituximab doses are 1000 mg infusion given as first dose followed by 500mg (or 1000 mg if evidence of early B cell recovery) infusion every 6 months thereafter. Rituximab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and rituximab should be infused through a dedicated line Rituximab: A chimeric monoclonal antibody against CD20.
Measure Participants	100	100
Measure Infusions	300	200
Number [percentage of infusions with IRRs]	10	14

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1996
	Comments
	Method	Generalized estimating equations
	Comments	GEE was necessary because there are repeated measures on subjects.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	.6616
	Confidence Interval	(2-Sided) 95%; .3666 to 1.1942
	Parameter Dispersion	Type: Value:
	Estimation Comments	This is comparing the Switching group to the Comparator group

2. Primary Outcome

Title	Difference in the Total Number of IRRs After Each Infusion of Ocrelizumab Compared to Rituximab Infusions in the Comparator Group.
Description	The investigators will report the difference in the total number of IRRs after each infusion of ocrelizumab compared to combined rituximab infusions in the comparator group.
Time Frame	Pre-study (Enrollment), Day 1, Day 15, Week 24

Outcome Measure Data

Analysis Population Description

Participants in the comparator group were assessed to have had two pre-study infusions at time of enrollment. A retrospective chart review was conducted to determine the number of IRRs experienced during these previous infusions. The collected number of IRRs was used as a comparison measure against the switching group.

Arm/Group Title	Switching Group	Comparator Group
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line.	Standard of care rituximab doses are 1000 mg infusion given as first dose followed by 500mg (or 1000 mg if evidence of early B cell recovery) infusion every 6 months thereafter. Rituximab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and rituximab should be infused through a dedicated line Rituximab: A chimeric monoclonal antibody against CD20.
Measure Participants	100	100
Measure Infusions	100	200
Pre-study infusions	28
Day 1	14
Day 15	4
Week 24	12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0000
	Comments
	Method	Generalized estimating equations
	Comments	GEE was used because there are repeated measures on subjects
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.0000
	Confidence Interval	(2-Sided) 95%; .5299 to 1.8872
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparing Switching group Day 1 to combined Comparator group

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0053
	Comments
	Method	Generalized estimating equations
	Comments	GEE was used because there are repeated measures on subjects.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	.2857
	Confidence Interval	(2-Sided) 95%; .1006 to .8114
	Parameter Dispersion	Type: Value:
	Estimation Comments	Switching group Day 15 was compared to combined Comparator group.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6474
	Comments
	Method	Generalized estimating equations
	Comments	GEE was used because there are repeated measures on subjects.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	.8571
	Confidence Interval	(2-Sided) 95%; .4385 to 1.6753
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Severity of IRRs Following the Day 1 Infusion of Ocrelizumab in the Switching and the Comparator Groups Infusions
Description	The severity of IRRs will be assessed following each infusion of ocrelizumab in the switching and comparator group using the National Cancer Institute's Common Terminology for Adverse Events Scale (Grades range from 1-5, with higher Grades indicating more severe reactions). The frequency of each severity grade of IRR will be compared in a similar fashion .
Time Frame	Day 1, pre-study infusions

Outcome Measure Data

Analysis Population Description

The Switching group received 3 infusions (Day 1, Day 15 and week 24), and the Comparator group received 2 infusions prior to enrollment (as assessed via retrospective chart review). This analysis is comparing IRRs of the Switching group's Day 1 infusion, with the comparator group's pre-study infusion 1 and 2.

Arm/Group Title	Switching Group	Comparator Group
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells	Standard of care rituximab doses are 1000 mg infusion given as first dose followed by 500mg (or 1000 mg if evidence of early B cell recovery) infusion every 6 months thereafter. Rituximab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and rituximab should be infused through a dedicated line Rituximab: A chimeric monoclonal antibody against CD20.
Measure Participants	100	200
Measure Infusions	100	200
No Infusion Reaction	86	172
Grade 1 Infusion Reaction	8	3
Grade 2 Infusion Reaction	6	25
Grade 3, 4, or 5 Infusion Reaction	0	0

4. Primary Outcome

Title	Severity of IRRs Following the Day 15 Infusion of Ocrelizumab in the Switching and the Comparator Groups Infusions
Description	The severity of IRRs will be assessed following each infusion of ocrelizumab in the switching and comparator group using the National Cancer Institute's Common Terminology for Adverse Events Scale (Grades range from 1-5, with higher Grades indicating more severe reactions). The frequency of each severity grade of IRR will be compared in a similar fashion.
Time Frame	Day 15, pre-study infusions

Outcome Measure Data

Analysis Population Description

The Switching group received 3 infusions (Day 1, Day 15 and week 24), and the Comparator group received 2 infusions. Proportion of IRRs are taken out of total number of infusions. This analysis is comparing IRRs of the Switching group's Day 15 infusion, with the comparator group's pre-study infusion 1 and 2.

Arm/Group Title	Switching Group	Comparator Group
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells	Standard of care rituximab doses are 1000 mg infusion given as first dose followed by 500mg (or 1000 mg if evidence of early B cell recovery) infusion every 6 months thereafter. Rituximab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and rituximab should be infused through a dedicated line Rituximab: A chimeric monoclonal antibody against CD20.
Measure Participants	100	100
Measure Infusions	100	200
No Infusion Reaction	96	172
Grade 1 Infusion Reaction	0	3
Grade 2 Infusion Reaction	4	25
Grade 3, 4, and 5 Infusion Reaction	0	0

5. Primary Outcome

Title	Severity of IRRs Following the Week 24 Infusion of Ocrelizumab in the Switching and the Comparator Groups Infusions
Description	The severity of IRRs will be assessed following each infusion of ocrelizumab in the switching and comparator group using the National Cancer Institute's Common Terminology for Adverse Events Scale (Grades range from 1-5, with higher Grades indicating more severe reactions). The frequency of each severity grade of IRR will be compared in a similar fashion .
Time Frame	Week 24, pre-study infusions

Outcome Measure Data

Analysis Population Description

The Switching group received 3 infusions (Day 1, Day 15 and week 24), and the Comparator group received 2 infusions. Proportion of IRRs are taken out of total number of infusions. This analysis is comparing IRRs of the Switching group's Week 24 infusion, with the comparator group's pre-study infusion 1 and 2.

Arm/Group Title	Switching Group	Comparator Group
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells	Standard of care rituximab doses are 1000 mg infusion given as first dose followed by 500mg (or 1000 mg if evidence of early B cell recovery) infusion every 6 months thereafter. Rituximab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and rituximab should be infused through a dedicated line Rituximab: A chimeric monoclonal antibody against CD20.
Measure Participants	100	100
Measure Infusions	100	200
No Infusion Reaction	88	172
Grade 1 Infusion Reaction	9	3
Grade 2 Infusion Reaction	3	25
Grade 3, 4, and 5 Infusion Reaction	0	0

6. Primary Outcome

Title	Proportion of Patients With an IRR at Day 1 Versus Day 15 and Week 24 Infusions
Description	We will also compare the proportion of patients with an IRR following day 1 infusion versus the proportion of patients with an IRR at day 15 and month 6 infusions of ocrelizumab in the switching group.
Time Frame	Day 1, Day 15, Week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Switching Group - Day 1 Infusion	Switching Group - Day 15 Infusion	Switching Group - Week 24 Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells
Measure Participants	100	100	100
Count of Participants [Participants]	14 14%	4 4%	12 6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0075
	Comments
	Method	Generalized estimating equations
	Comments	GEE was used because there are repeated measures on subjects.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	.2857
	Confidence Interval	(2-Sided) 95%; .1072 to .7613
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Switching Group - Week 24 Infusion
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5930
	Comments
	Method	Generalized estimating equations
	Comments	GEE was used because there are repeated measures on subjects.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	.8571
	Confidence Interval	(2-Sided) 95%; .4868 to 1.5093
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Comparator Group, Switching Group - Week 24 Infusion
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0209
	Comments
	Method	Generalized estimating equations
	Comments	GEE was used because there are repeated measures on subjects.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	3.0000
	Confidence Interval	(2-Sided) 95%; 1.1260 to 7.9932
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Presence of Ocrelizumab Anti-drug Anti-bodies
Description	Proportion of ocrelizumab patients who test positive for ocrelizumab anti-drug anti-bodies
Time Frame	Day 1 and Week 24

Outcome Measure Data

Analysis Population Description

Reporting proportions of patients. 95% confidence intervals calculating using either the standard Z score method or the exact Clopper-Pearson method as necessary.

Arm/Group Title	Switching Group - Day 1 Infusion	Switching Group - Week 24 Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells
Measure Participants	100	100
Number (95% Confidence Interval) [percentage of patients]	1.00	1.00

8. Secondary Outcome

Title	Presence of Rituximab Anti-drug Anti-bodies
Description	Proportion of patients who test positive for rituximab anti-drug anti-bodies.
Time Frame	Day 1 and Week 24

Outcome Measure Data

Analysis Population Description

Reporting proportions of patients. 95% confidence intervals calculating using either the standard Z score method or the exact Clopper-Pearson method as necessary.

Arm/Group Title	Switching Group - Day 1	Switching Group - Week 24
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells
Measure Participants	100	100
Number (95% Confidence Interval) [percentage of patients]	16.00	7.00

9. Secondary Outcome

Title	B Cell Depletion (CD19)
Description	Proportion of patients with CD19% <= 1%.
Time Frame	Day 1, Week 24, 1 Year

Outcome Measure Data

Analysis Population Description

Reporting proportions of patients. 95% confidence intervals calculating using either the standard Z score method or the exact Clopper-Pearson method as necessary.

Arm/Group Title	Switching Group - Day 1	Switching Group - Week 24	Switching Group - 1 Year
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells
Measure Participants	98	100	93
Number (95% Confidence Interval) [percentage of patients]	57.14	92.00	90.32

10. Secondary Outcome

Title	B Cell Depletion (CD20)
Description	Proportion of patients with CD20% <= 1%
Time Frame	Day 1, Week 24, 1 Year

Outcome Measure Data

Analysis Population Description

Reporting proportions of patients. 95% confidence intervals calculating using either the standard Z score method or the exact Clopper-Pearson method as necessary.

Arm/Group Title	Switching Group - Day 1	Switching Group - Week 24	Switching Group - 1 Year
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells
Measure Participants	97	100	88
Number (95% Confidence Interval) [percentage of patients]	56.70	92.00	88.64

11. Secondary Outcome

Title	Cytokine: Eotaxin - Pre-Post Infusion - Day 1
Description	Comparing Eotaxin concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	117.44 (50.19)	101.41 (55.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	--16.03
	Confidence Interval	(2-Sided) 95%; -27.05 to -5.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

12. Secondary Outcome

Title	Cytokine: IFN-gamma - Pre-Post Infusion - Day 1
Description	Comparing IFN-gamma concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	2.03 (1.42)	4.58 (5.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.55
	Confidence Interval	(2-Sided) 95%; 1.54 to 3.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

13. Secondary Outcome

Title	Cytokine: IL-10 - Pre-Post Infusion - Day 1
Description	Comparing IL-10 concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	0.18 (0.27)	8.75 (11.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	8.58
	Confidence Interval	(2-Sided) 95%; 6.33 to 10.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

14. Secondary Outcome

Title	Cytokine: IL-12/IL-23p40 - Pre-Post Infusion - Day 1
Description	Comparing IL-12/IL-23p40 concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	59.79 (38.79)	52.42 (35.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.37
	Confidence Interval	(2-Sided) 95%; -10.19 to -4.55
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

15. Secondary Outcome

Title	Cytokine: IL-16 - Pre-Post Infusion - Day 1
Description	Comparing IL-16 concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	85.48 (40.77)	129.80 (80.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	44.32
	Confidence Interval	(2-Sided) 95%; 29.59 to 59.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

16. Secondary Outcome

Title	Cytokine: IL-1RA - Pre-Post Infusion - Day 1
Description	Comparing IL-1RA concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	196.71 (202.10)	550.06 (920.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	353.35
	Confidence Interval	(2-Sided) 95%; 175.23 to 531.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

17. Secondary Outcome

Title	Cytokine: IL-27 - Pre-Post Infusion - Day 1
Description	Comparing IL-27 concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	643.32 (269.50)	820.23 (340.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	176.90
	Confidence Interval	(2-Sided) 95%; 124.50 to 229.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

18. Secondary Outcome

Title	Cytokine: IL-6 - Pre-Post Infusion - Day 1
Description	Comparing IL-6 concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	0.29 (0.29)	0.49 (0.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0020
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; 0.07 to 0.32
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

19. Secondary Outcome

Title	Cytokine: IL-7 - Pre-Post Infusion - Day 1
Description	Comparing IL-7 concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	0.84 (0.36)	1.38 (2.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; 0.32 to 0.77
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

20. Secondary Outcome

Title	Cytokine: IL-8(HA) - Pre-Post Infusion - Day 1
Description	Comparing IL-8(HA) concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	306.89 (186.64)	260.73 (147.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0091
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-46.16
	Confidence Interval	(2-Sided) 95%; -80.61 to -11.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

21. Secondary Outcome

Title	Cytokine: MCP-1 - Pre-Post Infusion - Day 1
Description	Comparing MCP-1 concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	34.83 (14.37)	90.09 (146.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	55.26
	Confidence Interval	(2-Sided) 95%; 27.00 to 83.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

22. Secondary Outcome

Title	Cytokine: MDC - Pre-Post Infusion - Day 1
Description	Comparing MDC concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	468.96 (138.66)	451.72 (139.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0044
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-17.24
	Confidence Interval	(2-Sided) 95%; -28.96 to -5.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

23. Secondary Outcome

Title	Cytokine: MIP-1alpha - Pre-Post Infusion - Day 1
Description	Comparing MIP-1alpha concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	29.50 (26.72)	45.52 (34.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	16.01
	Confidence Interval	(2-Sided) 95%; 9.75 to 22.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

24. Secondary Outcome

Title	Cytokine: MIP-1beta - Pre-Post Infusion - Day 1
Description	Comparing MIP-1beta concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	24.27 (9.63)	453.35 (671.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	429.08
	Confidence Interval	(2-Sided) 95%; 296.07 to 562.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

25. Secondary Outcome

Title	Cytokine: MIP-3alpha - Pre-Post Infusion - Day 1
Description	Comparing MIP-3alpha concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	3.90 (2.64)	5.13 (5.70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0101
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95%; 0.30 to 2.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

26. Secondary Outcome

Title	Cytokine: TARC - Pre-Post Infusion - Day 1
Description	Comparing TARC concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	24.02 (13.54)	32.72 (21.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	8.69
	Confidence Interval	(2-Sided) 95%; 4.87 to 12.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

27. Secondary Outcome

Title	Cytokine: TNF-alpha - Pre-Post Infusion - Day 1
Description	Comparing TNF-alpha concentration between pre and post ocrelizumab infusion - Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 1 - Pre Infusion	Switching Group - Day 1 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	100
Mean (Standard Deviation) [pg/ml]	0.99 (0.39)	2.53 (2.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 1 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 99.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.53
	Confidence Interval	(2-Sided) 95%; 1.04 to 2.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre.

28. Secondary Outcome

Title	Cytokine: Exotaxin - Pre-Post Infusion - Day 15
Description	Comparing Exotaxin concentration between pre and post ocrelizumab infusion - Day 15
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 15 - Pre Infusion	Switching Group - Day 15 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	99
Mean (Standard Deviation) [pg/ml]	128.38 (54.32)	95.79 (60.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	99 patients with non-missing change scores used. Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 15 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 98.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-33.17
	Confidence Interval	(2-Sided) 95%; -38.91 to -27.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre. 99 usable change scores.

29. Secondary Outcome

Title	Cytokine: IFN-gamma - Pre-Post Infusion - Day 15
Description	Comparing IFN-gamma concentration between pre and post ocrelizumab infusion - Day 15
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 15 - Pre Infusion	Switching Group - Day 15 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	99
Mean (Standard Deviation) [pg/ml]	2.02 (1.37)	1.40 (1.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments	99 patients with non-missing change scores used. Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 15 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 98.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) 95%; -0.98 to -0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre. 99 usable change scores.

30. Secondary Outcome

Title	Cytokine: IL-10 - Pre-Post Infusion - Day 15
Description	Comparing IL-10 concentration between pre and post ocrelizumab infusion - Day 15
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 15 - Pre Infusion	Switching Group - Day 15 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	99
Mean (Standard Deviation) [pg/ml]	0.12 (0.12)	2.12 (3.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	99 patients with non-missing change scores used. Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 15 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 98.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.01
	Confidence Interval	(2-Sided) 95%; 1.23 to 2.79
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre. 99 usable change scores.

31. Secondary Outcome

Title	Cytokine: IL-12/IL-23p40 - Pre-Post Infusion - Day 15
Description	Comparing IL-12/IL-23p40 concentration between pre and post ocrelizumab infusion - Day 15
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 15 - Pre Infusion	Switching Group - Day 15 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	99
Mean (Standard Deviation) [pg/ml]	49.36 (31.75)	41.31 (29.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	99 patients with non-missing change scores used. Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 15 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 98.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.84
	Confidence Interval	(2-Sided) 95%; -9.87 to -5.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre. 99 usable change scores.

32. Secondary Outcome

Title	Cytokine: IL-16 - Pre-Post Infusion - Day 15
Description	Comparing IL-16 concentration between pre and post ocrelizumab infusion - Day 15
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 15 - Pre Infusion	Switching Group - Day 15 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	99
Mean (Standard Deviation) [pg/ml]	90.35 (54.78)	76.62 (29.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0022
	Comments	99 patients with non-missing change scores used. Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 15 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 98.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-14.20
	Confidence Interval	(2-Sided) 95%; -23.15 to -5.25
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre. 99 usable change scores.

33. Secondary Outcome

Title	Cytokine: IL-1beta - Pre-Post Infusion - Day 15
Description	Comparing IL-1beta concentration between pre and post ocrelizumab infusion - Day 15
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 15 - Pre Infusion	Switching Group - Day 15 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	99
Mean (Standard Deviation) [pg/ml]	0.65 (0.73)	0.95 (0.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	99 patients with non-missing change scores used. Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 15 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 98.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 95%; 0.17 to 0.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre. 99 usable change scores.

34. Secondary Outcome

Title	Cytokine: IL-7 - Pre-Post Infusion - Day 15
Description	Comparing IL-7 concentration between pre and post ocrelizumab infusion - Day 15
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 15 - Pre Infusion	Switching Group - Day 15 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	99
Mean (Standard Deviation) [pg/ml]	0.88 (0.64)	1.29 (0.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	99 patients with non-missing change scores used. Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 15 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 98.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.41
	Confidence Interval	(2-Sided) 95%; 0.22 to 0.61
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre. 99 usable change scores.

35. Secondary Outcome

Title	Cytokine: IL-8 - Pre-Post Infusion - Day 15
Description	Comparing IL-8 concentration between pre and post ocrelizumab infusion - Day 15
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 15 - Pre Infusion	Switching Group - Day 15 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	99
Mean (Standard Deviation) [pg/ml]	1.82 (1.48)	1.09 (0.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	99 patients with non-missing change scores used. Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 15 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 98.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.72
	Confidence Interval	(2-Sided) 95%; -0.95 to -0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre. 99 usable change scores.

36. Secondary Outcome

Title	Cytokine: MCP-1 - Pre-Post Infusion - Day 15
Description	Comparing MCP-1 concentration between pre and post ocrelizumab infusion - Day 15
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 15 - Pre Infusion	Switching Group - Day 15 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	99
Mean (Standard Deviation) [pg/ml]	35.57 (18.08)	16.33 (9.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	99 patients with non-missing change scores used. Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 15 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 98.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-19.31
	Confidence Interval	(2-Sided) 95%; -22.64 to -15.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre. 99 usable change scores.

37. Secondary Outcome

Title	Cytokine: MCP-4 - Pre-Post Infusion - Day 15
Description	Comparing MCP-4 concentration between pre and post ocrelizumab infusion - Day 15
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 15 - Pre Infusion	Switching Group - Day 15 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	99
Mean (Standard Deviation) [pg/ml]	37.38 (23.70)	30.38 (15.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	99 patients with non-missing change scores used. Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 15 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 98.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-6.96
	Confidence Interval	(2-Sided) 95%; -9.85 to -4.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre. 99 usable change scores.

38. Secondary Outcome

Title	Cytokine: MDC - Pre-Post Infusion - Day 15
Description	Comparing MDC concentration between pre and post ocrelizumab infusion - Day 15
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 15 - Pre Infusion	Switching Group - Day 15 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	99
Mean (Standard Deviation) [pg/ml]	458.13 (154.72)	435.00 (165.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0061
	Comments	99 patients with non-missing change scores used. Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 15 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 98.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-23.22
	Confidence Interval	(2-Sided) 95%; -39.66 to -6.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre. 99 usable change scores.

39. Secondary Outcome

Title	Cytokine: MIP-1beta - Pre-Post Infusion - Day 15
Description	Comparing MIP-1beta concentration between pre and post ocrelizumab infusion - Day 15
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 15 - Pre Infusion	Switching Group - Day 15 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	99
Mean (Standard Deviation) [pg/ml]	23.09 (9.46)	17.23 (7.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	99 patients with non-missing change scores used. Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 15 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 98.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.69
	Confidence Interval	(2-Sided) 95%; -7.24 to -4.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre. 99 usable change scores.

40. Secondary Outcome

Title	Cytokine: MIP-3alpha - Pre-Post Infusion - Day 15
Description	Comparing MIP-3alpha concentration between pre and post ocrelizumab infusion - Day 15
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 15 - Pre Infusion	Switching Group - Day 15 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	99
Mean (Standard Deviation) [pg/ml]	4.15 (4.32)	3.31 (2.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0077
	Comments	99 patients with non-missing change scores used. Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 15 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 98.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.84
	Confidence Interval	(2-Sided) 95%; -1.45 to -0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre. 99 usable change scores.

41. Secondary Outcome

Title	Cytokine: TNF-alpha - Pre-Post Infusion - Day 15
Description	Comparing TNF-alpha concentration between pre and post ocrelizumab infusion - Day 15
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

Change in mean concentration between pre and post infusion. Only cytokines with statistically significant pre-post changes reported.

Arm/Group Title	Switching Group - Day 15 - Pre Infusion	Switching Group - Day 15 - Post Infusion
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Pre-Infusion	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells Post-Infusion
Measure Participants	100	99
Mean (Standard Deviation) [pg/ml]	1.14 (0.45)	0.81 (0.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching Group, Comparator Group
	Comments	Paired T-test for change in means. Null hypothesis: no pre-post difference.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	99 patients with non-missing change scores used. Controlled for the false discovery rate (alpha = 0.05) for all cytokines on day 15 using the Benjamini-Hochberg procedure.
	Method	t-test, 2 sided
	Comments	Paired T-test. Degrees of freedom = 98.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -0.37 to -0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean of post minus pre. 99 usable change scores.

Adverse Events

Time Frame	1 year - enrollment to month 12 infusion.
Adverse Event Reporting Description	Because data for the comparator group was collected retrospectively using chart review, 0 participants in that group were at risk for All-Cause Mortality, and All-Cause Mortality was not monitored for that group.
Arm/Group Title	Switching Group		Comparator Group
Arm/Group Description	600 mg of ocrelizumab will be administered as one 600-mg IV infusions at a scheduled interval of every 24 weeks. The first dose of ocrelizumab will be a split dose of 300 mg on day 1 and day 15 followed by 600 mg, six months later. Each ocrelizumab infusion should be given as a slow IV infusion over approximately 150 minutes (2.5 hours) for the 300-mg dose. Ocrelizumab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and ocrelizumab should be infused through a dedicated line. Ocrelizumab: A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells		Standard of care rituximab doses are 1000 mg infusion given as first dose followed by 500mg (or 1000 mg if evidence of early B cell recovery) infusion every 6 months thereafter. Rituximab must not be administered as an IV push or bolus. Well-adjusted infusion pumps should be used to control the infusion rate, and rituximab should be infused through a dedicated line Rituximab: A chimeric monoclonal antibody against CD20.
All Cause Mortality
	Switching Group		Comparator Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/100 (0%)		0/0 (NaN)
Serious Adverse Events
	Switching Group		Comparator Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/100 (8%)		0/100 (0%)
Gastrointestinal disorders
clostridium difficile colitis	1/100 (1%)	1	0/100 (0%)	0
General disorders
Acute Encephalopathy	1/100 (1%)	1	0/100 (0%)	0
Immune system disorders
Sepsis	1/100 (1%)	1	0/100 (0%)	0
Metabolism and nutrition disorders
Hyperammonemia	1/100 (1%)	1	0/100 (0%)	0
Musculoskeletal and connective tissue disorders
Hip Dislocation	1/100 (1%)	1	0/100 (0%)	0
Renal and urinary disorders
Liver and renal failure	1/100 (1%)	1	0/100 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia	1/100 (1%)	1	0/100 (0%)	0
Unknown pulmonary complications	1/100 (1%)	1	0/100 (0%)	0
Other (Not Including Serious) Adverse Events
	Switching Group		Comparator Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/100 (52%)		0/100 (0%)
General disorders
Headache	14/100 (14%)	17	0/100 (0%)	0
Nausea	14/100 (14%)	14	0/100 (0%)	0
Numbness	11/100 (11%)	11	0/100 (0%)	0
Respiratory, thoracic and mediastinal disorders
Upper Respiratory Infection	36/100 (36%)	47	0/100 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.