Multiple Sclerosis, Relapsing-Remitting
Conditions
Brief summary
This is a phase II, multicenter, randomized, parallel-group, partially blinded, placebo and Avonex (interferon beta-1a) controlled dose finding study to evaluate the efficacy as measured by brain MRI lesions, and safety of 2 dose regimens of ocrelizumab in participants with Relapsing Remitting Multiple Sclerosis (RRMS).
Interventions
DRUGPlacebo
Placebo matching to ocrelizumab administered as IV infision in Cycle 1 Day 1.
DRUGOcrelizumab
Ocrelizumab 300 mg was administered in cycle 1 followed by an infusion of ocrelizumab 600 mg on Day 1. A single infusion of ocrelizumab 600 mg was administered on Day 1 of cycles 3 and 4.
DRUGAvonex
Avonex was administered weekly intramuscular injections of 30 mcg in cycle 1 Day 1.
Sponsors
Roche Pharma AG
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Ability to provide written informed consent and to be compliant with the schedule of protocol assessments * Relapsing-remitting multiple sclerosis (MS) * Ages 18-55 years inclusive * For sexually active female and male participants of reproductive potential, use of reliable means of contraception
Exclusion criteria
* Secondary or primary progressive multiple sclerosis at screening * Incompatibility with MRI * Contra-indications to or intolerance of oral or IV corticosteroids * Known presence of other neurologic disorders * Pregnancy or lactation * Lack of peripheral venous access * History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies * Significant, uncontrolled disease, such as cardiovascular, pulmonary, renal, hepatic, endocrine or gastrointestinal * Congestive heart failure * Known active bacterial, viral, fungal, mycobacterial infection or other infection or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks prior to screening or oral antibiotics within 2 weeks prior to screening * History or known presence of recurrent or chronic infection * History of cancer, including solid tumors and hematological malignancies (except basal cell, in situ squamous cell carcinomas of the skin, and in situ carcinoma of the cervix of the uterus that have been excised and resolved) * History of alcohol or drug abuse within 24 weeks prior to randomization * History of or currently active primary or secondary immunodeficiency * History of coagulation disorders * Treatment with any investigational agent within 4 weeks of screening * Receipt of a live vaccine within 6 weeks prior to randomization * Incompatibility with Avonex use * Previous treatment with rituximab * Previous treatment with lymphocyte-depleting therapies except mitoxantrone * Treatment with lymphocyte trafficking blockers within 24 weeks prior to randomization * Treatment with beta interferons, glatiramer acetate, IV immunoglobulin, plasmapheresis, or immunosuppressive therapies within 12 weeks prior to randomization * Systemic corticosteroid therapy within 4 weeks prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Gadolinium-Enhancing T1 Lesions Observed on Magnetic Resonance Imaging (MRI) Scans of the Brain | Week 12 to Week 24 | Mean of total number of gadolinium-enhancing T1 lesions observed on MRI scans of the brain at Weeks 12, 16, 20, 24 was determined using average imputation method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Protocol Defined Relapse Rate at Week 24 | Week 24 | Adjusted annualized relapse rate for geographical region is reported here. The relapse rate was calculated as the total number of relapses for each participant divided by the total number of patient-years. |
| Percentage of Participants Who Remained Relapse Free at Week 24 | Week 24 | Percentage of participants who remained relapse free at week 24 were reported. Percentages have been rounded off to the first decimal. |
| Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24 | Baseline, Week 24 | Change from baseline in total volume of T2 lesions on MRI scans of the brain at Week 24 was reported. |
| Total Number of New Gadolinium-Enhancing T1 Lesions Observed by MRI Scans of the Brain | Weeks 4 to Week 24 | Total number of new gadolinium-enhancing T1 lesions observed by MRI scans of the brain were reported. |
| Total Number of Gadolinium-Enhancing T1 Lesions | Weeks 4 to Week 24 | Total number of gadolinium-enhancing T1 lesions from Week 4 to Week 24 were reported. |
Countries
Belgium, Bulgaria, Canada, Czechia, Denmark, France, Germany, Italy, Mexico, Romania, Russia, Serbia, Slovakia, Spain, Switzerland, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 220 participants were randomized, of which 218 received study treatment. Participants took part in the study at 79 investigative sites across 18 countries from July 17, 2008, to November 08, 2023.
Pre-assignment details
The study consisted of a 96-week Treatment Period (TP) followed by a Treatment-free period (TFP). Participants who completed both TP & TFP (at least Week 120) were invited to participate in the optional Open-label Extension (OLE) period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo / Ocrelizumab 600 mg In the Treatment Period, participants received placebo as IV infusion on Days 1 and 15 of Cycle 1 ( 1 Cycle = 168 days ), followed by ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600 mg, Q24W. | 54 |
| Ocrelizumab 600 mg / Ocrelizumab 600 mg In the Treatment Period, participants received ocrelizumab 300 mg as IV infusion on Days 1 and 15 of Cycle 1 ( 1 Cycle = 168 days ), followed by ocrelizumab, 600 mg, IV, on Day 1 and placebo IV on Day 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600 mg, Q24W. | 55 |
| Ocrelizumab 1000 mg/ Ocrelizumab 600 mg In the Treatment Period, participants received ocrelizumab 1000 mg as IV infusion on Days 1 and 15 of Cycle 1 ( 1 Cycle = 168 days ), followed by ocrelizumab, 1000 mg IV, on Day 1 and placebo IV on Day 15 of Cycle 2. Participants then received ocrelizumab, 1000 mg, IV, on Day 1 of Cycle 3 and ocrelizumab, 600 mg, IV, on Day 1 of Cycle 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600 mg, Q24W. | 55 |
| Avonex / Ocrelizumab 600 mg In the Treatment Period, participants received Avonex 30 mcg as IM injection once every week of Cycle 1 ( 1 Cycle = 168 days ), followed by ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600 mg, Q24W. | 54 |
| Total | 218 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Open Label Extension (OLE) | Adverse Event | 0 | 3 | 1 | 0 |
| Open Label Extension (OLE) | Death | 2 | 0 | 2 | 2 |
| Open Label Extension (OLE) | Lost to Follow-up | 0 | 0 | 1 | 1 |
| Open Label Extension (OLE) | Reason not provided | 3 | 4 | 1 | 4 |
| Open Label Extension (OLE) | Withdrawal by Subject | 2 | 4 | 3 | 3 |
| Treatment-free Period (TFP) | Adverse Event | 0 | 0 | 1 | 0 |
| Treatment-free Period (TFP) | Death | 1 | 1 | 1 | 0 |
| Treatment-free Period (TFP) | Lost to Follow-up | 2 | 2 | 6 | 2 |
| Treatment-free Period (TFP) | Reason not provided | 8 | 10 | 8 | 7 |
| Treatment-free Period (TFP) | Withdrawal by Subject | 3 | 3 | 4 | 5 |
| Treatment Period (TP) | Administrative | 0 | 0 | 0 | 1 |
| Treatment Period (TP) | Adverse Event | 0 | 3 | 2 | 2 |
| Treatment Period (TP) | Death | 0 | 0 | 1 | 0 |
| Treatment Period (TP) | Failure to return | 1 | 0 | 0 | 0 |
| Treatment Period (TP) | Insufficient therapeutic response | 1 | 1 | 2 | 1 |
| Treatment Period (TP) | Refused treatment/did not cooperate | 1 | 2 | 3 | 1 |
| Treatment Period (TP) | Violation of selection criteria at entry | 0 | 0 | 1 | 0 |
| Treatment Period (TP) | Withdrew consent | 3 | 3 | 3 | 3 |
Baseline characteristics
| Characteristic | Placebo / Ocrelizumab 600 mg | Ocrelizumab 600 mg / Ocrelizumab 600 mg | Ocrelizumab 1000 mg/ Ocrelizumab 600 mg | Avonex / Ocrelizumab 600 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 38.0 years STANDARD_DEVIATION 8.8 | 35.6 years STANDARD_DEVIATION 8.5 | 38.5 years STANDARD_DEVIATION 8.7 | 38.1 years STANDARD_DEVIATION 9.3 | 37.6 years STANDARD_DEVIATION 8.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 6 Participants | 7 Participants | 7 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants | 49 Participants | 48 Participants | 47 Participants | 192 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 2 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 52 Participants | 51 Participants | 53 Participants | 53 Participants | 209 Participants |
| Sex: Female, Male Female | 36 Participants | 35 Participants | 38 Participants | 32 Participants | 141 Participants |
| Sex: Female, Male Male | 18 Participants | 20 Participants | 17 Participants | 22 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 54 | 1 / 55 | 3 / 55 | 2 / 54 | 6 / 103 |
| other Total, other adverse events | 52 / 54 | 47 / 55 | 45 / 55 | 45 / 54 | 85 / 103 |
| serious Total, serious adverse events | 11 / 54 | 17 / 55 | 16 / 55 | 16 / 54 | 28 / 103 |
Outcome results
Primary
Total Number of Gadolinium-Enhancing T1 Lesions Observed on Magnetic Resonance Imaging (MRI) Scans of the Brain
Mean of total number of gadolinium-enhancing T1 lesions observed on MRI scans of the brain at Weeks 12, 16, 20, 24 was determined using average imputation method.
Time frame: Week 12 to Week 24
Population: The intent-to-treat population includes all randomized participants who had received any study drug. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo / Ocrelizumab 600 mg | Total Number of Gadolinium-Enhancing T1 Lesions Observed on Magnetic Resonance Imaging (MRI) Scans of the Brain | 5.6 lesions | Standard Deviation 12.53 |
| Ocrelizumab 600 mg / Ocrelizumab 600 mg | Total Number of Gadolinium-Enhancing T1 Lesions Observed on Magnetic Resonance Imaging (MRI) Scans of the Brain | 0.6 lesions | Standard Deviation 1.52 |
| Ocrelizumab 1000 mg/ Ocrelizumab 600 mg | Total Number of Gadolinium-Enhancing T1 Lesions Observed on Magnetic Resonance Imaging (MRI) Scans of the Brain | 0.2 lesions | Standard Deviation 0.65 |
| Avonex / Ocrelizumab 600 mg | Total Number of Gadolinium-Enhancing T1 Lesions Observed on Magnetic Resonance Imaging (MRI) Scans of the Brain | 6.9 lesions | Standard Deviation 16.01 |
Comparison: Van Elteren test is stratified by region and presence of baseline gadolinium-enhancing lesions (absent or present).p-value: <0.0001Van Elteren Test (stratified)
Comparison: Van Elteren test is stratified by region and presence of baseline gadolinium-enhancing lesions (absent or present).p-value: <0.0001Van Elteren Test (stratified)
Comparison: Van Elteren test is stratified by region and presence of baseline gadolinium-enhancing lesions (absent or present).p-value: 0.7496Van Elteren Test (stratified)
Secondary
Annualized Protocol Defined Relapse Rate at Week 24
Adjusted annualized relapse rate for geographical region is reported here. The relapse rate was calculated as the total number of relapses for each participant divided by the total number of patient-years.
Time frame: Week 24
Population: The intent-to-treat population includes all randomized participants who had received any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo / Ocrelizumab 600 mg | Annualized Protocol Defined Relapse Rate at Week 24 | 0.557 relapses per year |
| Ocrelizumab 600 mg / Ocrelizumab 600 mg | Annualized Protocol Defined Relapse Rate at Week 24 | 0.127 relapses per year |
| Ocrelizumab 1000 mg/ Ocrelizumab 600 mg | Annualized Protocol Defined Relapse Rate at Week 24 | 0.213 relapses per year |
| Avonex / Ocrelizumab 600 mg | Annualized Protocol Defined Relapse Rate at Week 24 | 0.364 relapses per year |
Comparison: Poisson model was fitted for adjusting for geographic region only.p-value: 0.0019Poisson model
Comparison: Poisson model was fitted for adjusting for geographic region only.p-value: 0.0136Poisson model
Comparison: Poisson model was fitted for adjusting for geographic region only.p-value: 0.1814Poisson model
Secondary
Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24
Change from baseline in total volume of T2 lesions on MRI scans of the brain at Week 24 was reported.
Time frame: Baseline, Week 24
Population: The intent-to-treat population includes all randomized participants who had received any study drug. Overall number of participants analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analyses at the specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Ocrelizumab 600 mg | Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24 | Baseline | 8950.84 cubic millimeter (mm^3) | Standard Deviation 9776.261 |
| Placebo / Ocrelizumab 600 mg | Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24 | Change at Week 24 | -112.31 cubic millimeter (mm^3) | Standard Deviation 1464.206 |
| Ocrelizumab 600 mg / Ocrelizumab 600 mg | Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24 | Change at Week 24 | -878.84 cubic millimeter (mm^3) | Standard Deviation 2756.839 |
| Ocrelizumab 600 mg / Ocrelizumab 600 mg | Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24 | Baseline | 13972.61 cubic millimeter (mm^3) | Standard Deviation 19930.158 |
| Ocrelizumab 1000 mg/ Ocrelizumab 600 mg | Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24 | Baseline | 13178.30 cubic millimeter (mm^3) | Standard Deviation 14271.383 |
| Ocrelizumab 1000 mg/ Ocrelizumab 600 mg | Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24 | Change at Week 24 | -600.89 cubic millimeter (mm^3) | Standard Deviation 2105.964 |
| Avonex / Ocrelizumab 600 mg | Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24 | Baseline | 13209.11 cubic millimeter (mm^3) | Standard Deviation 17206.511 |
| Avonex / Ocrelizumab 600 mg | Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24 | Change at Week 24 | 1040.06 cubic millimeter (mm^3) | Standard Deviation 4510.14 |
p-value: 0.1391Van Elteren Test (stratified)
p-value: 0.1596Van Elteren Test (stratified)
p-value: 0.474Van Elteren Test (stratified)
Secondary
Percentage of Participants Who Remained Relapse Free at Week 24
Percentage of participants who remained relapse free at week 24 were reported. Percentages have been rounded off to the first decimal.
Time frame: Week 24
Population: The intent-to-treat population includes all randomized participants who had received any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo / Ocrelizumab 600 mg | Percentage of Participants Who Remained Relapse Free at Week 24 | 75.9 percentage of participants |
| Ocrelizumab 600 mg / Ocrelizumab 600 mg | Percentage of Participants Who Remained Relapse Free at Week 24 | 85.5 percentage of participants |
| Ocrelizumab 1000 mg/ Ocrelizumab 600 mg | Percentage of Participants Who Remained Relapse Free at Week 24 | 87.3 percentage of participants |
| Avonex / Ocrelizumab 600 mg | Percentage of Participants Who Remained Relapse Free at Week 24 | 77.8 percentage of participants |
p-value: 0.197895% CI: [0.27, 1.34]Cochran-Mantel-Haenszel chi-square test
p-value: 0.13195% CI: [0.23, 1.22]CMH chi-square test
p-value: 0.820695% CI: [0.46, 1.84]CMH chi-square tes
Secondary
Total Number of Gadolinium-Enhancing T1 Lesions
Total number of gadolinium-enhancing T1 lesions from Week 4 to Week 24 were reported.
Time frame: Weeks 4 to Week 24
Population: The intent-to-treat population includes all randomized participants who had received any study drug. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo / Ocrelizumab 600 mg | Total Number of Gadolinium-Enhancing T1 Lesions | 8.7 lesions | Standard Deviation 17.54 |
| Ocrelizumab 600 mg / Ocrelizumab 600 mg | Total Number of Gadolinium-Enhancing T1 Lesions | 2.5 lesions | Standard Deviation 5.1 |
| Ocrelizumab 1000 mg/ Ocrelizumab 600 mg | Total Number of Gadolinium-Enhancing T1 Lesions | 1.8 lesions | Standard Deviation 5.26 |
| Avonex / Ocrelizumab 600 mg | Total Number of Gadolinium-Enhancing T1 Lesions | 10.3 lesions | Standard Deviation 22.15 |
p-value: 0.0004Van Elteren Test (stratified)
p-value: <0.0001Van Elteren Test (stratified)
p-value: 0.2725Van Elteren Test (stratified)
Secondary
Total Number of New Gadolinium-Enhancing T1 Lesions Observed by MRI Scans of the Brain
Total number of new gadolinium-enhancing T1 lesions observed by MRI scans of the brain were reported.
Time frame: Weeks 4 to Week 24
Population: The intent-to-treat population includes all randomized participants who had received any study drug. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo / Ocrelizumab 600 mg | Total Number of New Gadolinium-Enhancing T1 Lesions Observed by MRI Scans of the Brain | 5.1 lesions | Standard Deviation 11.99 |
| Ocrelizumab 600 mg / Ocrelizumab 600 mg | Total Number of New Gadolinium-Enhancing T1 Lesions Observed by MRI Scans of the Brain | 0.8 lesions | Standard Deviation 1.95 |
| Ocrelizumab 1000 mg/ Ocrelizumab 600 mg | Total Number of New Gadolinium-Enhancing T1 Lesions Observed by MRI Scans of the Brain | 0.8 lesions | Standard Deviation 2.16 |
| Avonex / Ocrelizumab 600 mg | Total Number of New Gadolinium-Enhancing T1 Lesions Observed by MRI Scans of the Brain | 6.2 lesions | Standard Deviation 13.79 |
p-value: <0.0001Van Elteren Test (stratified)
p-value: <0.0001Van Elteren Test (stratified)
p-value: 0.4985Van Elteren Test (stratified)