Multiple Sclerosis, Relapsing-Remitting
Conditions
Brief summary
This study will evaluate the efficacy and safety of ocrelizumab in participants with RRMS who have had a suboptimal response to an adequate course of DMT. Participants will receive ocrelizumab as an initial dose of two 300-milligrams (mg) intravenous (IV) infusions (600 mg total) separated by 14 days followed by one 600-mg IV infusion for a maximum of 4 doses (up to 96 weeks). Anticipated time on study treatment is 96 weeks.
Detailed description
Participants who complete their Week 72 ocrelizumab infusion and do not experience any serious infusion related reaction (IRR) throughout the main study will be eligible to enroll in an optional, open-label, non-randomized substudy to MN30035 and receive one additional shorter infusion of ocrelizumab at the Week 96 visit. This substudy will enroll approximately 100 patients from MN30035 main study.
Interventions
DRUGOcrelizumab
Participants will receive ocrelizumab as an initial dose of two 300-mg IV infusions (600 mg total) separated by 14 days (on Days 1 and 15) followed by one 600-mg IV infusion every 24 weeks for a maximum of 4 doses (up to 96 weeks).
Sponsors
Genentech, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of multiple sclerosis (specifically RRMS), in accordance with the revised 2010 McDonald criteria * Disease duration from first symptom of less than or equal to (\</=) 12 years * Treated with an adequate course of treatment with no more than three prior DMT regimens of greater than or equal to (\>/=) 6 months, and the discontinuation of the most recent adequately used DMT was due to suboptimal response * Suboptimal response while the participant was on his/her last adequately used DMT for \>/=6 months (defined by having one of the following qualifying events despite being on a stable dose of the same DMT for at least 6 months: one or more clinically reported relapses, one or more T1 Gd-enhanced lesions, or two or more new or enlarging T2 lesions on MRI); these qualifying events must have occurred while on the last adequately used DMT. In participants receiving stable doses of the same approved DMT for more than a year, the event must have occurred within the last 12 months of treatment with this DMT from the date of screening
Exclusion criteria
* History of primary progressive multiple sclerosis (PPMS), progressive relapsing multiple sclerosis (PRMS), or secondary progressive multiple sclerosis (SPMS) * Contraindications for MRI * Known presence of other neurological disorders that may mimic multiple sclerosis * Pregnancy or lactation, or intention to become pregnant during the study * Requirement for chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study * History of or currently active primary or secondary immunodeficiency * Lack of peripheral venous access * History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies * Active infection, or history of or known presence of recurrent or chronic infection such as human immunodeficiency virus (HIV), syphilis, or tuberculosis * History of progressive multifocal leukoencephalopathy * Contraindications to or intolerance of oral or IV corticosteroids * Previous treatment with fingolimod (Gilenya®) or dimethyl fumarate (Tecfidera®) in participants whose lymphocyte count is below the lower limit of normal (LLN) * Treatment with alemtuzumab (Lemtrada®) * Previous treatment with systemic cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, or methotrexate * Previous treatment with natalizumab within 12 months prior to screening unless failure was due to confirmed, persistent anti-drug antibodies (ADAs). Participants previously treated with natalizumab will be eligible for this study only if duration of treatment with natalizumab was less than (\<) 1 year and natalizumab was not used in the 12 months prior to screening. Anti-John Cunningham virus (JCV) antibody status (positive or negative) and titer (both assessed within the year of screening) must be documented prior to enrollment * Treatment with dalfampridine (Ampyra®) unless on stable dose for \>/=30 days prior to screening * Treatment with a B-cell targeted therapies (e.g., rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab) * Treatment with a drug that is experimental (Exception: treatment with an experimental drug that was subsequently approved in the participant's country is allowed)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Without Any Protocol-Defined Events During 96-Week Period | Baseline up to Week 96 | Protocol-defined event is the occurrence of either protocol-defined relapse (occurrence of new or worsening neurological symptoms attributable to multiple sclerosis) or T1 gadolinium (Gd)-enhanced lesion on brain magnetic resonance imaging (MRI) or new and/or enlarging T2 lesion on brain MRI or confirmed disability progression at 24 weeks. |
| Percentage of Participants With Infusion Related Reactions (IRRs) in Optional Substudy | Week 96 to Week 100 | Rate and frequency of Grade 3 or 4 IRRs with onset on or after the shorter ocrelizumab infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Protocol-Defined Relapses Per Participant Year During 96-week Period | Baseline up to Week 96 | Protocol-defined relapse is an occurrence of new or worsening neurological symptoms attributable to multiple sclerosis which must persist for greater than (\>) 24 hours and should not be attributable to confounding clinical factors (e.g., fever, infection, injury, adverse reactions to medications) and immediately preceded by a stable or improving neurological state for least 30 days. The Adjusted Annualized Relapse Rate was adjusted by baseline Expanded Disability Status Scale (EDSS \<2.5 vs. \>=2.5) and number of previous disease-modifying treatments (DMTs =1 vs. \>1) |
| Time to Onset of First Protocol-Defined Relapse | Baseline up to Week 96 | Protocol-defined relapse is an occurrence of new or worsening neurological symptoms attributable to multiple sclerosis which must persist for \>24 hours and should not be attributable to confounding clinical factors (e.g., fever, infection, injury, adverse reactions to medications) and immediately preceded by a stable or improving neurological state for least 30 days. |
| Time to Onset of First T1 Gd-Enhanced Lesion as Detected by Brain MRI | Baseline up to Week 96 | — |
| Time to Onset of First New and/or Enlarging T2 Lesion as Detected by Brain MRI | Baseline up to Week 96 | — |
| Percentage of Participants Without Any Protocol-Defined Events During 24-Week and 48-Week Period | Baseline up to Weeks 24 and 48 | Protocol-defined event is the occurrence of either protocol-defined relapse (occurrence of new or worsening neurological symptoms attributable to multiple sclerosis) or T1 Gd-enhanced lesion on brain MRI or new and/or enlarging T2 lesion on brain MRI or confirmed disability progression at 24 weeks. |
| Total Number of T1 Gd-Enhancing Lesions as Detected by Brain MRI | Weeks 24, 48, and 96 | The analyses included participants who had an interpretable MRI at the time point of interest. Participants having 0, 1, 2, 3, and greater than 3 lesions at weeks 24, 48, and 96 were included in the analysis. |
| Change From Baseline in Total T2 Lesion Volume as Detected by Brain MRI | Baseline, Weeks 24, 48, and 96 | Baseline data is represented as mean; post-Baseline date are represented as mean changes. |
| Total Number of New and/or Enlarging T2 Lesions as Detected by Brain MRI | Weeks 24, 48, and 96 | — |
| Percentage of Participants With Adverse Events | Baseline up to 100 weeks | An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. |
| Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks According to Expanded Disability Status Scale (EDSS) Score | Baseline up to Week 96 | — |
| Time to Protocol-Defined Event | Baseline up to Week 96 | Protocol-defined event is the occurrence of either protocol-defined relapse (occurrence of new or worsening neurological symptoms attributable to multiple sclerosis) or T1 Gd-enhanced lesion on brain MRI or new and/or enlarging T2 lesion on brain MRI or confirmed disability progression at 24 weeks. |
Countries
Canada, United States
Participant flow
Recruitment details
The study was conducted in North America at 90 study sites in the U.S. and Canada.
Pre-assignment details
Participants with relapsing remitting multiple sclerosis (RRMS) were enrolled, who had had a suboptimal response to an adequate course of a disease-modifying treatment (DMT). An adequate course of prior DMT was defined as the same DMT administered for at least 6 months.
Participants by arm
| Arm | Count |
|---|---|
| Ocrelizumab Participants received ocrelizumab as an initial dose of two 300-mg IV infusions (600 mg total) separated by 14 days (on Days 1 and 15) followed by one 600-mg IV infusion every 24 weeks for a maximum of 4 doses (up to 96 weeks) | 608 |
| Total | 608 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Main Study (Baseline to Week 100) | Adverse Event | 9 | 0 |
| Main Study (Baseline to Week 100) | Continued on Commercial Ocrevus | 164 | 0 |
| Main Study (Baseline to Week 100) | Failed Drug Test | 1 | 0 |
| Main Study (Baseline to Week 100) | Incarceration | 1 | 0 |
| Main Study (Baseline to Week 100) | Lost to Follow-up | 5 | 0 |
| Main Study (Baseline to Week 100) | Physician Decision | 2 | 0 |
| Main Study (Baseline to Week 100) | Pregnancy | 7 | 0 |
| Main Study (Baseline to Week 100) | Pregnancy Attempts | 2 | 0 |
| Main Study (Baseline to Week 100) | Protocol Deviation | 2 | 0 |
| Main Study (Baseline to Week 100) | Site Closing | 6 | 0 |
| Main Study (Baseline to Week 100) | Withdrawal by Subject | 20 | 0 |
| Sub-Study (Week 72 to Week 100) | Lost to Follow-up | 0 | 3 |
| Sub-Study (Week 72 to Week 100) | Non-safety reason (moved out of state) | 0 | 1 |
Baseline characteristics
| Characteristic | Ocrelizumab |
|---|---|
| Age, Continuous | 37.2 Years STANDARD_DEVIATION 8.6 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants |
| Race/Ethnicity, Customized Asian | 13 Participants |
| Race/Ethnicity, Customized Black or African American | 72 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 68 Participants |
| Race/Ethnicity, Customized Multiple | 6 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islande | 3 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 526 Participants |
| Race/Ethnicity, Customized Not Stated | 7 Participants |
| Race/Ethnicity, Customized Unknown | 7 Participants |
| Race/Ethnicity, Customized White | 495 Participants |
| Sex: Female, Male Female | 438 Participants |
| Sex: Female, Male Male | 170 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 608 | 0 / 129 |
| other Total, other adverse events | 406 / 608 | 16 / 129 |
| serious Total, serious adverse events | 47 / 608 | 2 / 129 |
Outcome results
Primary
Percentage of Participants With Infusion Related Reactions (IRRs) in Optional Substudy
Rate and frequency of Grade 3 or 4 IRRs with onset on or after the shorter ocrelizumab infusion
Time frame: Week 96 to Week 100
Population: Participants who completed their Week 72 ocrelizumab infusion and did not experience any serious IRRs throughout the main study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ocrelizumab | Percentage of Participants With Infusion Related Reactions (IRRs) in Optional Substudy | 0 Percentage of Participants |
Primary
Percentage of Participants Without Any Protocol-Defined Events During 96-Week Period
Protocol-defined event is the occurrence of either protocol-defined relapse (occurrence of new or worsening neurological symptoms attributable to multiple sclerosis) or T1 gadolinium (Gd)-enhanced lesion on brain magnetic resonance imaging (MRI) or new and/or enlarging T2 lesion on brain MRI or confirmed disability progression at 24 weeks.
Time frame: Baseline up to Week 96
Population: The modified Intent-to-Treat (mITT) population was a subset of the ITT population which excluded participants who discontinued ocrelizumab treatment early without any protocol-defined events for reasons other than death and lack of efficacy. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ocrelizumab | Percentage of Participants Without Any Protocol-Defined Events During 96-Week Period | 48.1 Percentage of Participants |
Secondary
Change From Baseline in Total T2 Lesion Volume as Detected by Brain MRI
Baseline data is represented as mean; post-Baseline date are represented as mean changes.
Time frame: Baseline, Weeks 24, 48, and 96
Population: All enrolled participants who received any ocrelizumab. Participants who prematurely withdrew from the study for any reason and who did not have any assessments for any reason were still included in the ITT population as long as the participant received ocrelizumab. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ocrelizumab | Change From Baseline in Total T2 Lesion Volume as Detected by Brain MRI | Baseline | 11.551 cubic centimeter (cm3) | Standard Error 0.59 |
| Ocrelizumab | Change From Baseline in Total T2 Lesion Volume as Detected by Brain MRI | Week 24 | -0.484 cubic centimeter (cm3) | Standard Error 0.118 |
| Ocrelizumab | Change From Baseline in Total T2 Lesion Volume as Detected by Brain MRI | Week 48 | -0.549 cubic centimeter (cm3) | Standard Error 0.123 |
| Ocrelizumab | Change From Baseline in Total T2 Lesion Volume as Detected by Brain MRI | Week 96 | -0.560 cubic centimeter (cm3) | Standard Error 0.129 |
Secondary
Percentage of Participants With Adverse Events
An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: Baseline up to 100 weeks
Population: All enrolled participants who received any ocrelizumab. Participants who prematurely withdrew from the study for any reason and who did not have any assessments for any reason were still included in the ITT population as long as the participant received ocrelizumab
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ocrelizumab | Percentage of Participants With Adverse Events | 86.3 Percentage of Participants |
Secondary
Percentage of Participants Without Any Protocol-Defined Events During 24-Week and 48-Week Period
Protocol-defined event is the occurrence of either protocol-defined relapse (occurrence of new or worsening neurological symptoms attributable to multiple sclerosis) or T1 Gd-enhanced lesion on brain MRI or new and/or enlarging T2 lesion on brain MRI or confirmed disability progression at 24 weeks.
Time frame: Baseline up to Weeks 24 and 48
Population: The modified Intent-to-Treat (mITT) population was a subset of the ITT population which excluded participants who discontinued ocrelizumab treatment early without any protocol-defined events for reasons other than death and lack of efficacy. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ocrelizumab | Percentage of Participants Without Any Protocol-Defined Events During 24-Week and 48-Week Period | Week 24 | 59.0 Percentage of Participants |
| Ocrelizumab | Percentage of Participants Without Any Protocol-Defined Events During 24-Week and 48-Week Period | Week 48 | 51.2 Percentage of Participants |
Secondary
Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks According to Expanded Disability Status Scale (EDSS) Score
Time frame: Baseline up to Week 96
Population: All enrolled participants who received any ocrelizumab. Participants who prematurely withdrew from the study for any reason and who did not have any assessments for any reason were still included in the ITT population as long as the participant received ocrelizumab
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ocrelizumab | Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks According to Expanded Disability Status Scale (EDSS) Score | NA Weeks |
Secondary
Time to Onset of First New and/or Enlarging T2 Lesion as Detected by Brain MRI
Time frame: Baseline up to Week 96
Population: All enrolled participants who received any ocrelizumab. Participants who prematurely withdrew from the study for any reason and who did not have any assessments for any reason were still included in the ITT population as long as the participant received ocrelizumab
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ocrelizumab | Time to Onset of First New and/or Enlarging T2 Lesion as Detected by Brain MRI | NA Weeks |
Secondary
Time to Onset of First Protocol-Defined Relapse
Protocol-defined relapse is an occurrence of new or worsening neurological symptoms attributable to multiple sclerosis which must persist for \>24 hours and should not be attributable to confounding clinical factors (e.g., fever, infection, injury, adverse reactions to medications) and immediately preceded by a stable or improving neurological state for least 30 days.
Time frame: Baseline up to Week 96
Population: All enrolled participants who received any ocrelizumab. Participants who prematurely withdrew from the study for any reason and who did not have any assessments for any reason were still included in the ITT population as long as the participant received ocrelizumab
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ocrelizumab | Time to Onset of First Protocol-Defined Relapse | NA Weeks |
Secondary
Time to Onset of First T1 Gd-Enhanced Lesion as Detected by Brain MRI
Time frame: Baseline up to Week 96
Population: All enrolled participants who received any ocrelizumab. Participants who prematurely withdrew from the study for any reason and who did not have any assessments for any reason were still included in the ITT population as long as the participant received ocrelizumab
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ocrelizumab | Time to Onset of First T1 Gd-Enhanced Lesion as Detected by Brain MRI | NA Weeks |
Secondary
Time to Protocol-Defined Event
Protocol-defined event is the occurrence of either protocol-defined relapse (occurrence of new or worsening neurological symptoms attributable to multiple sclerosis) or T1 Gd-enhanced lesion on brain MRI or new and/or enlarging T2 lesion on brain MRI or confirmed disability progression at 24 weeks.
Time frame: Baseline up to Week 96
Population: All enrolled participants who received any ocrelizumab. Participants who prematurely withdrew from the study for any reason and who did not have any assessments for any reason were still included in the ITT population as long as the participant received ocrelizumab
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ocrelizumab | Time to Protocol-Defined Event | NA Weeks |
Secondary
Total Number of New and/or Enlarging T2 Lesions as Detected by Brain MRI
Time frame: Weeks 24, 48, and 96
Population: All enrolled participants who received any ocrelizumab. Participants who prematurely withdrew from the study for any reason and who did not have any assessments for any reason were still included in the ITT population as long as the participant received ocrelizumab. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ocrelizumab | Total Number of New and/or Enlarging T2 Lesions as Detected by Brain MRI | Week 24 | 640 Number of Lesions |
| Ocrelizumab | Total Number of New and/or Enlarging T2 Lesions as Detected by Brain MRI | Week 48 | 39 Number of Lesions |
| Ocrelizumab | Total Number of New and/or Enlarging T2 Lesions as Detected by Brain MRI | Week 96 | 38 Number of Lesions |
Secondary
Total Number of Protocol-Defined Relapses Per Participant Year During 96-week Period
Protocol-defined relapse is an occurrence of new or worsening neurological symptoms attributable to multiple sclerosis which must persist for greater than (\>) 24 hours and should not be attributable to confounding clinical factors (e.g., fever, infection, injury, adverse reactions to medications) and immediately preceded by a stable or improving neurological state for least 30 days. The Adjusted Annualized Relapse Rate was adjusted by baseline Expanded Disability Status Scale (EDSS \<2.5 vs. \>=2.5) and number of previous disease-modifying treatments (DMTs =1 vs. \>1)
Time frame: Baseline up to Week 96
Population: All enrolled participants who received any ocrelizumab. Participants who prematurely withdrew from the study for any reason and who did not have any assessments for any reason were still included in the ITT population as long as the participant received ocrelizumab
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ocrelizumab | Total Number of Protocol-Defined Relapses Per Participant Year During 96-week Period | 0.046 Number of Relapses/Participant Year |
Secondary
Total Number of T1 Gd-Enhancing Lesions as Detected by Brain MRI
The analyses included participants who had an interpretable MRI at the time point of interest. Participants having 0, 1, 2, 3, and greater than 3 lesions at weeks 24, 48, and 96 were included in the analysis.
Time frame: Weeks 24, 48, and 96
Population: All enrolled participants who received any ocrelizumab. Participants who prematurely withdrew from the study for any reason and who did not have any assessments for any reason were still included in the ITT population as long as the participant received ocrelizumab. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ocrelizumab | Total Number of T1 Gd-Enhancing Lesions as Detected by Brain MRI | Week 24 | 33 Number of Lesions |
| Ocrelizumab | Total Number of T1 Gd-Enhancing Lesions as Detected by Brain MRI | Week 48 | 16 Number of Lesions |
| Ocrelizumab | Total Number of T1 Gd-Enhancing Lesions as Detected by Brain MRI | Week 96 | 7 Number of Lesions |