Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication OCREVUS is indicated for the treatment of: Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults Primary progressive MS, in adults Relapsing-remitting MS, in pediatric patients 10 years of age and older who weigh 25 kg or more. FDA label
Also known as Ocrelizumab Test Formulation, Ocrelizumab Dose 1, Ocrelizumab IV, Ocrevus, RO4964913
Ocrelizumab · 24 trials · 11 indications
PROMISnq PFMS-15a includes 15 items that evaluate the impact of MS on a participant's physical functioning, including mobility, upper limb function and activities of daily living. Nine items assess the degree of difficulty in completing physical activities using a 5-point verbal rating scale ranging from 5="without any difficulty" to 1="unable to do". Four items assess physical function limitations, rated from 5="not at all" to 1="cannot do". Two items assess the amount of difficulty associated with selected physical activities, rated from 5="no difficulty" to 1="can't do". Scores are reported as a standardized T-score metric, with higher scores reflecting better physical functioning.
The population-level summary is rate ratio of ARR. The ARR is calculated as the total number of protocol-defined relapses divided by the total patient-years. Protocol-defined relapse is the occurrence of new/worsening neurological symptoms attributable to multiple sclerosis (MS) and immediately preceded by relatively stable or improving neurological state for ≥ 30 days. Symptoms must persist for \>24 hours \& should not be attributable to confounding clinical factors. The new/worsening neurological symptoms must be accompanied by objective neurological worsening consistent with an increase of at least half a step on the expanded disability status scale (EDSS) score, or 2 points on one of the appropriate functional system (FS) scores, or 1 point on two or more of the appropriate FS scores. The change must affect the selected FS (i.e., pyramidal, ambulation, cerebellar, brainstem, sensory, or visual). Adjusted values were reported. OM assessed non inferiority of ocrelizumab vs fingolimod.
Time to onset of 12-week cCDP=first occurrence of a 12-week cCDP according to at least 1 of the 3 criteria: 1) CDP=12-week confirmed increase (CI) from baseline (FB) in expanded disability status scale (EDSS) score of ≥1.0 point in participants with baseline EDSS score of ≤5.5 or 12-week CI≥0.5 point in participants with baseline EDSS score of \>5.5 OR 2) 12-week CI of ≥20% FB in Timed 25-foot Walk Test (T25FWT) score OR 3)12-week CI of ≥ 20% FB in 9-hole Peg Test (9-HPT) score. EDSS = disability scale that ranges in 0.5-point steps from 0 \[normal\]-10.0 \[death\]. In T25FWT test participants walked to a 25 foot course as quickly \& safely as possible. Score = average of 2 completed trials (in seconds). In 9-HPT, participants had to place \& remove pegs 1 by 1 into 9 holes arranged in a board \& complete 2 successful trials for each hand \& the amount of time (in seconds) required was recorded. In T25FWT \& 9-HPT the longer it took complete test= higher scores, indicating deterioration.
Time to onset of cCDP12=time from randomization to the first occurrence of at least one of the following progression events: 1) 20% worsening from baseline in 9-hole Peg Test (9-HPT) confirmed for at least 12 weeks; 2) increase of ≥ 1.0 point from baseline in Expanded Disability Status Scale (EDSS) score in participants with a baseline EDSS score ≤5.5 or an increase of ≥ 0.5 point in participants with a baseline EDSS score of \>5.5 that is confirmed for at least 12 weeks. EDSS disability scale is based on a standard neurological examination, incorporating functional systems \& ambulation, that ranges in 0.5-point steps from 0 \[normal\] to 10.0 \[death\]. 9-HPT is a quantitative measure of arm \& hand function, where participants placed \& removed pegs 1 by 1 into 9 holes arranged in a board \& complete 2 successful trials for each hand \& the total time (in seconds) required was recorded. The longer it took to complete the test, the higher the scores, indicating deterioration.
Time to onset of cCDP12 was defined as the time from randomization to the first occurrence of at least one of the following progression events: 1) 20% worsening from baseline in 9-HPT confirmed for at least 12 weeks; 2) increase of ≥ 1.0 point from baseline in EDSS score in participants with a baseline EDSS score ≤5.5 or an increase of ≥ 0.5 point in participants with a baseline EDSS score of \>5.5 that is confirmed for at least 12 weeks. EDSS disability scale is based on a standard neurological examination, incorporating functional systems \& ambulation, that ranges in 0.5-point steps from 0 \[normal\] to 10.0 \[death\]. 9-HPT is a quantitative measure of arm \& hand function, where participants placed \& removed pegs 1 by 1 into 9 holes arranged in a board \& complete 2 successful trials for each hand \& the total time (in seconds) required was recorded. The longer it took to complete the test, the higher the scores, indicating deterioration.
This outcome measure evaluates the occurrence of severe infusion-related reaction (IRR) with ocrelizumab 600 mg intravenously (IV) administered over the course of 2 hours. Rate and frequency of NCI CTCAE v4.0 Grade 3 and 4 IRRs
Disability progression was defined as an increase of ≥ 1.0 point from the baseline Expanded Disability Status Scale (EDSS) score that was not attributable to another etiology (e.g., fever, concurrent illness, or concomitant medication) when the baseline score was 5.5 or less, \& ≥ 0.5 when the baseline score was above 5.5. For participants with an EDSS of 0, progression is defined as a change ≥1.5 points. Disability progression was considered confirmed when increase in EDSS was confirmed at a regularly scheduled visit at least 24 weeks after initial documentation of neurological worsening. The EDSS is based on a standard neurological examination, incorporating 7 functional systems that were rated \& scored as Functional Systems Score (FSSs). Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death). Median was analysed using Kaplan-Meier(K-M) method.
Disability progression was defined as an increase of ≥ 1.0 point from the baseline EDSS score that was not attributable to another etiology (e.g., fever, concurrent illness, or concomitant medication) when the baseline score was 5.5 or less, \& ≥ 0.5 when the baseline score was above 5.5. For participants with an EDSS of 0, progression is defined as a change ≥1.5 points. Disability progression was considered confirmed when increase in EDSS was confirmed at a regularly scheduled visit at least 24 weeks after initial documentation of neurological worsening. The EDSS is based on a standard neurological examination, incorporating 7 functional systems that were rated \& scored as FSSs. Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death). Median was analysed using K-M method.
Disability progression was defined as an increase of ≥ 1.0 point from the baseline EDSS score that was not attributable to another etiology (e.g., fever, concurrent illness, or concomitant medication) when the baseline score was 5.5 or less, \& ≥ 0.5 when the baseline score was above 5.5. For participants with an EDSS of 0, progression is defined as a change ≥1.5 points. Disability progression was considered confirmed when increase in EDSS was confirmed at two scheduled visit at least 48 weeks after initial documentation of neurological worsening. The EDSS is based on a standard neurological examination, incorporating 7 functional systems that were rated \& scored as FSSs. Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death). Median was analysed using K-M method.
Disability progression was defined as an increase of ≥ 1.0 point from the baseline EDSS score that was not attributable to another etiology (e.g., fever, concurrent illness, or concomitant medication) when the baseline score was 5.5 or less, \& ≥ 0.5 when the baseline score was above 5.5. For participants with an EDSS of 0, progression is defined as a change ≥1.5 points. isability progression was considered confirmed when increase in EDSS was confirmed at two scheduled visit at least 48 weeks after initial documentation of neurological worsening. The EDSS is based on a standard neurological examination, incorporating 7 functional systems that were rated \& scored as FSSs. Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death). Median was analysed using K-M method.
Disability progression was defined as an increase of ≥ 1.0 point from the baseline EDSS score that was not attributable to another etiology (e.g., fever, concurrent illness, or concomitant medication) when the baseline score was 5.5 or less, \& ≥ 0.5 when the baseline score was above 5.5. For participants with an EDSS of 0, progression is defined as a change ≥1.5 points. Disability progression was considered confirmed when increase in EDSS was confirmed at a regularly scheduled visit at least 24 weeks after initial documentation of neurological worsening. The EDSS is based on a standard neurological examination, incorporating 7 functional systems that were rated \& scored as FSSs. Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death). Percentages are rounded off.
Disability progression was defined as an increase of ≥ 1.0 point from the baseline EDSS score that was not attributable to another etiology (e.g., fever, concurrent illness, or concomitant medication) when the baseline score was 5.5 or less, \& ≥ 0.5 when the baseline score was above 5.5. For participants with an EDSS of 0, progression is defined as a change ≥1.5 points. Disability progression was considered confirmed when increase in EDSS was confirmed at a regularly scheduled visit at least 24 weeks after initial documentation of neurological worsening. The EDSS is based on a standard neurological examination, incorporating 7 functional systems that were rated \& scored as FSSs. Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death). Percentages are rounded off.
Disability progression was defined as an increase of ≥ 1.0 point from the baseline EDSS score that was not attributable to another etiology (e.g., fever, concurrent illness, or concomitant medication) when the baseline score was 5.5 or less, \& ≥ 0.5 when the baseline score was above 5.5. For participants with an EDSS of 0, progression is defined as a change ≥1.5 points. isability progression was considered confirmed when increase in EDSS was confirmed at two scheduled visit at least 48 weeks after initial documentation of neurological worsening. The EDSS is based on a standard neurological examination, incorporating 7 functional systems that were rated \& scored as FSSs. Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death). Percentages are rounded off.
Disability progression was defined as an increase of ≥ 1.0 point from the baseline EDSS score that was not attributable to another etiology (e.g., fever, concurrent illness, or concomitant medication) when the baseline score was 5.5 or less, \& ≥ 0.5 when the baseline score was above 5.5. For participants with an EDSS of 0, progression is defined as a change ≥1.5 points. isability progression was considered confirmed when increase in EDSS was confirmed at two scheduled visit at least 48 weeks after initial documentation of neurological worsening. The EDSS is based on a standard neurological examination, incorporating 7 functional systems that were rated \& scored as FSSs. Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death). Percentages are rounded off.
CDI was defined as an improvement of ≥1 point on the EDSS score confirmed at a regular scheduled visit at least 24 weeks after the initial documentation of neurological status when the baseline score is 5.5 or less, and ≥ 0.5 when the baseline score is above 5.5. The CDI was measured only participants with a baseline EDSS of ≥2.0. The EDSS is based on a standard neurological examination, incorporating 7 functional systems that were rated \&scored as FSS. Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death). Percentages are rounded off.
CDI was defined as an improvement of ≥1 point on the EDSS score confirmed at a regular scheduled visit at least 24 weeks after the initial documentation of neurological status when the baseline score is 5.5 or less, and ≥ 0.5 when the baseline score is above 5.5. The CDI was measured only participants with a baseline EDSS of ≥2.0. The EDSS is based on a standard neurological examination, incorporating 7 functional systems that were rated \&scored as FSS. Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death). Percentages are rounded off.
CDI was defined as an improvement of ≥1 point on the EDSS score confirmed at two scheduled visits at least 48 weeks after the initial documentation of neurological status when the baseline score is 5.5 or less, and ≥ 0.5 when the baseline score is above 5.5. The CDI was measured only participants with a baseline EDSS of ≥2.0. The EDSS is based on a standard neurological examination, incorporating 7 functional systems that were rated \& scored as FSS. Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death). Percentages are rounded off.
CDI was defined as an improvement of ≥1 point on the EDSS score confirmed at two scheduled visits at least 48 weeks after the initial documentation of neurological status when the baseline score is 5.5 or less, and ≥ 0.5 when the baseline score is above 5.5. The CDI was measured only participants with a baseline EDSS of ≥2.0. The EDSS is based on a standard neurological examination, incorporating 7 functional systems that were rated \& scored as FSS. Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death). Percentages are rounded off.
The EDSS is based on a standard neurological examination, incorporating 7 functional systems (pyramidal, cerebellar, brainstem, sensory, bowel \& bladder, visual, \& cerebral) rated \&scored as FSSs. Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. These ratings were then used in conjunction with observations \& information concerning ambulation \& use of assistive devices to determine the EDSS score. The EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). Participants were considered stable when the change from baseline in score was between -0.5 and +0.5, worsened when the change was \> 0.5, and improved when the change in score was \< -0.5. Percentages are rounded off.
The EDSS is based on a standard neurological examination, incorporating 7 functional systems (pyramidal, cerebellar, brainstem, sensory, bowel \& bladder, visual, \& cerebral) rated \&scored as FSSs. Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. These ratings were then used in conjunction with observations \& information concerning ambulation \& use of assistive devices to determine the EDSS score. The EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). Participants were considered stable when the change from baseline in score was between -0.5 and +0.5 and worsened when the change was \> 0.5. Percentages are rounded off.
The EDSS is based on a standard neurological examination, incorporating 7 functional systems (pyramidal, cerebellar, brainstem, sensory, bowel \& bladder, visual, \& cerebral) rated \&scored as Functional Systems Score (FSSs). Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. These ratings were then used in conjunction with observations \& information concerning ambulation \& use of assistive devices to determine the EDSS score. The EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). Estimates are from analysis based on mixed-effect model of repeated measures (MMRM).
The EDSS is based on a standard neurological examination, incorporating 7 functional systems (pyramidal, cerebellar, brainstem, sensory, bowel \& bladder, visual, \& cerebral) rated \&scored as FSSs. Each FSS was ordinal clinical rating scale ranging from 0 to 5 or 6. These ratings were then used in conjunction with observations \& information concerning ambulation \& use of assistive devices to determine the EDSS score. The EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). Estimates are from analysis based on MMRM.
Sustained T25FWT was defined as a 24-week T25FWT still has a confirmed 20% increase until the last available visit. T25FWT test is a performance measure used to assess walking speed based on a timed 25-foot walk. The participant was directed to start at one end of a clearly marked 25-foot course and was instructed to walk 25 feet as quickly and safely as possible. The Examining Investigator timed the participants from the start of the walk to the end of the 25 feet. The task was immediately administered again by having the participant walk back the same distance. Participants could use assistive devices (e.g., cane, crutch, or rollator) when performing the task. Score was the average of the two completed trials, measured in seconds. The longer it takes to walk, higher the score, indicating deterioration. Median was analysed using K-M method.
Sustained T25FWT was defined as a 48-week T25FWT still has a confirmed 20% increase until the last available visit. T25FWT test is a performance measure used to assess walking speed based on a timed 25-foot walk. The participant was directed to start at one end of a clearly marked 25-foot course and was instructed to walk 25 feet as quickly and safely as possible. The Examining Investigator timed the participants from the start of the walk to the end of the 25 feet. The task was immediately administered again by having the participant walk back the same distance. Participants could use assistive devices (e.g., cane, crutch, or rollator) when performing the task. Score was the average of the two completed trials, measured in seconds. The longer it takes to walk, higher the score, indicating deterioration. Median was analysed using K-M method.
Sustained 9HPT was defined as a 24-week 9HPT still has a confirmed 20% increase until the last available visit. In 9-HPT, participants had to place \& remove pegs 1 by 1 into 9 holes arranged in a board \& complete 2 successful trials for each hand \& the amount of time (in seconds) required was recorded. The longer it took complete test, higher the scores, indicating deterioration. Median was analysed using K-M method.
Sustained 9HPT was defined as a 48-week 9HPT still has a confirmed 20% increase until the last available visit. In 9-HPT, participants had to place \& remove pegs 1 by 1 into 9 holes arranged in a board \& complete 2 successful trials for each hand \& the amount of time (in seconds) required was recorded. The longer it took complete test, higher the scores, indicating deterioration. Median was analysed using K-M method.
Sustained T25FWT was defined as a 24-week T25FWT still has a confirmed 20% increase until the last available visit. T25FWT test is a performance measure used to assess walking speed based on a timed 25-foot walk. The participant was directed to start at one end of a clearly marked 25-foot course and was instructed to walk 25 feet as quickly and safely as possible. The Examining Investigator timed the participants from the start of the walk to the end of the 25 feet. The task was immediately administered again by having the participant walk back the same distance. Participants could use assistive devices (e.g., cane, crutch, or rollator) when performing the task. Score was the average of the two completed trials, measured in seconds. The longer it takes to walk, higher the score, indicating deterioration. Percentage is rounded off.
Sustained T25FWT was defined as a 48-week T25FWT still has a confirmed 20% increase until the last available visit. T25FWT test is a performance measure used to assess walking speed based on a timed 25-foot walk. The participant was directed to start at one end of a clearly marked 25-foot course and was instructed to walk 25 feet as quickly and safely as possible. The Examining Investigator timed the participants from the start of the walk to the end of the 25 feet. The task was immediately administered again by having the participant walk back the same distance. Participants could use assistive devices (e.g., cane, crutch, or rollator) when performing the task. Score was the average of the two completed trials, measured in seconds. The longer it takes to walk, higher the score, indicating deterioration. Percentage is rounded off.
Sustained 9HPT was defined as a 24-week 9HPT still has a confirmed 20% increase until the last available visit. In 9-HPT, participants had to place \& remove pegs 1 by 1 into 9 holes arranged in a board \& complete 2 successful trials for each hand \& the amount of time (in seconds) required was recorded. The longer it took complete test, higher the scores, indicating deterioration. Percentage is rounded off.
Sustained 9HPT was defined as a 48-week 9HPT still has a confirmed 20% increase until the last available visit. In 9-HPT, participants had to place \& remove pegs 1 by 1 into 9 holes arranged in a board \& complete 2 successful trials for each hand \& the amount of time (in seconds) required was recorded. The longer it took complete test, higher the scores, indicating deterioration. Percentage is rounded off.
NEP is defined as no progression sustained for at least 24 weeks on all of the following three components (confirmed disability progression \[CDP\]; ≥20% increase in timed 25-foot walk test \[T25FWT\]; ≥20% increase in nine-hole peg test \[9HPT\])
NEPAD is defined as no progression sustained for at least 24 weeks on all of the three components of NEP (CDP, T25FWT, 9HPT), no protocol-defined relapse, no enlarging or new T2 lesion, and no T1 gadolinium (Gd+)-enhancing lesion
A protocol-defined event of disease activity was defined by the occurrence of at least one of the following while on treatment with ocrelizumab: * A protocol-defined relapse (PDR) * 24-week CDP based on increase in EDSS while on treatment with ocrelizumab * A T1 Gd-enhanced lesion after Week 8 * A new and/or enlarging T2 hyperintense lesion on MRI after Week 8 compared to the Week 8 MRI scan
Primary Analysis was based on following data-cut off: Arm 1: Baseline to post-treatment at 12 weeks Arm 2: Baseline to post-treatment at 24 weeks Arm 3: Baseline to post-treatment at 52 weeks Arm 4: Baseline to post-treatment at 12 weeks PPMS Cohort: Baseline to post-treatment at 52 weeks
Arm 1: Baseline to post-treatment at 12 weeks Arm 2: Baseline to post-treatment at 24 weeks Arm 3: Baseline to post-treatment at 52 weeks Arm 4: Baseline to post-treatment at 12 weeks PPMS Cohort: Baseline to post-treatment at 52 weeks
Arm 1: Baseline to post-treatment at 12 weeks Arm 2: Baseline to post-treatment at 24 weeks Arm 3: Baseline to post-treatment at 52 weeks Arm 4: Baseline to post-treatment at 12 weeks PPMS Cohort: Baseline to post-treatment at 52 weeks
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.
Rate and frequency of Grade 3 or 4 IRRs with onset on or after the shorter ocrelizumab infusion
ARR was protocol-defined and calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of exposure to that treatment.
ARR was protocol-defined and calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of exposure to that treatment.
The time to onset of CDP was defined as time from baseline to first disability progression, which is confirmed at next regularly scheduled visit \>=12 weeks (\>=84 days) after initial disability progression. Baseline for time to onset of CDP is the date of randomization, independent of the first day of dosing. Disability progression is defined as an increase of \>= 1.0 point from baseline expanded disability status scale (EDSS) score, if baseline EDSS value is \<=5.5 points (inclusive), or an increase of \>=0.5 points, if baseline EDSS is \>5.5 points. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). The randomized participants who did not receive any treatment were censored at days 0 in each Arm.
The population PK model was used to simulate concentration-time course and predict individual area under the concentration versus time curve. The data for the PK parameter: area under the concentration versus time curve was collected and analyzed as per body weight range (\<40kg to ≥40 kg).
The population PK model was used to simulate concentration-time course and predict individual Cmax. The data for the PK parameter: Cmax was collected and analyzed as per body weight range (\<40kg to ≥40 kg).
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.
| Arm | Type | Description |
|---|---|---|
| Ocrelizumab | EXPERIMENTAL | Participants will receive ocrelizumab at the currently approved dose of 600 mg, IV infusion or 920 mg, SC injection as per the schedule in the parent study until access to the treatment becomes locally available, unacceptable safety concern, death or withdrawal of consent. |
| Fingolimod | ACTIVE_COMPARATOR | Participants will receive fingolimod PO, QD as per the prescribing information provided with fingolimod. Participants will also receive a placebo of ocrelizumab administered as IV infusion on Days 1 and 15, and Q24W thereafter. |
| Ocrelizumab: Intravenous (IV) formulation | ACTIVE_COMPARATOR | Participants will receive the first dose of ocrelizumab IV as two IV infusions given 14 days apart. The subsequent doses of study drug will be administered as SC injections. A minimum of 22 weeks should be kept between SC doses. Participants will undergo 96 weeks of study treatment. |
| Ocrelizumab: Subcutaneous (SC) formulation | EXPERIMENTAL | Participants will receive the first dose of ocrelizumab SC as one SC injection at a dose which is expected to result in non-inferior exposure to ocrelizumab IV. The subsequent doses of study drug will be administered as SC injections. A minimum of 22 weeks should be kept between the first and second SC doses, and between subsequent SC doses. Participants will undergo 96 weeks of study treatment. |
| Ocrelizumab Higher Dose | EXPERIMENTAL | Participants will be randomized to receive a minimum of 5 higher treatment doses based on their body weight at baseline: 1200 mg (participant's body weight \<75 kilograms \[kg\]) or 1800 mg (participant's body weight ≥ 75 kg) of ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will continue with their assigned dose of ocrelizumab (either 1200 or 1800 mg) for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion. |
| Ocrelizumab Approved Dose | ACTIVE_COMPARATOR | Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will be offered a higher dose of ocrelizumab (either 1200 or 1800 mg), based on their body weight at OLE baseline, for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion. |
| Placebo | PLACEBO_COMPARATOR | Participants will receive placebo matched to ocrelizumab by IV infusion every 24 weeks. |
| Cohort 1 | EXPERIMENTAL | This cohort will examine the effect of administering ocrelizumab per a shorter infusion protocol for Dose 2 or Dose 3. Participants who have already received one or two doses of ocrelizumab according to the approved infusion protocol and have reported no serious infusion-related reactions (IRRs) will be enrolled. They will then receive the next infusion of ocrelizumab (Dose 2 or Dose 3) at a dosage of 600 milligram (mg) over the course of approximately 2 hours. Dose 2 is administered at Week 24, Dose 3 is administered at Week 48 after initial infusion. |
| Cohort 2 | EXPERIMENTAL | This cohort will examine the effect of administering ocrelizumab per a shorter infusion protocol for the second infusion of Dose 1. Ocrelizumab-naïve participants will be enrolled who, after receiving Dose 1 of ocrelizumab at the approved rate have no reported serious IRRs, will then receive the second 300-mg shorter infusion over approximately 1.5 hours. |
| RMS Cohort Arm 1: Ocrelizumab + LP | EXPERIMENTAL | Participants with RMS will receive ocrelizumab as two 300-mg IV infusion on Days 1 and 15 then as single infusion of 600 mg on Weeks 24 and 48. Participants will receive a LP before the start of dosing (Week 1, treatment baseline) with ocrelizumab and a second LP at Week 12. Participants will be asked to have an additional optional LP at Week 52. Participants that complete the study and continue to receive ocrelizumab will receive single infusions every 24 weeks starting from Week 72. |
| RMS Cohort Arm 2: Ocrelizumab + LP | EXPERIMENTAL | Participants with RMS will receive ocrelizumab as two 300-mg IV infusion on Days 1 and 15 then as single infusion of 600 mg on Weeks 24 and 48. Participants will receive a LP before the start of dosing (Week 1, treatment baseline) with ocrelizumab and a second LP at Week 24. Participants will be asked to have an additional optional LP at Week 52. Participants that complete the study and continue to receive ocrelizumab will receive single infusions every 24 weeks starting from Week 72. |
| RMS Cohort Arm 3: Ocrelizumab + LP | EXPERIMENTAL | Participants with RMS will receive ocrelizumab as two 300-mg IV infusion on Days 1 and 15 then as single infusion of 600 mg on Weeks 24 and 48. Participants will receive a LP before the start of dosing (Week 1, treatment baseline) with ocrelizumab and a second LP at Week 52. Participants that complete the study and continue to receive ocrelizumab will receive single infusions every 24 weeks starting from Week 72. |
| RMS Cohort Arm 4: Ocrelizumab + LP | EXPERIMENTAL | Ocrelizumab treatment will be delayed for 12 weeks from pre-treatment baseline. Participants with RMS will receive ocrelizumab as two 300-mg IV infusion on Days 1 and 15 then as single infusion of 600 mg on Weeks 24 and 48. Participants will receive a LP at Week -12 (pre-treatment baseline) and a second LP before the start of dosing (Week 1, treatment baseline). Participants will be asked to have an additional optional LP at Week 52. Participants that complete the study and continue to receive ocrelizumab will receive single infusions every 24 weeks starting from Week 72. |
| PPMS Cohort: Ocrelizumab + LP | EXPERIMENTAL | For the PPMS cohort, ocrelizumab will be administered as two 300-mg IV infusions separated by 14 days at a scheduled interval of every 24 weeks during the treatment period and then as a single 600-mg dose every 24 weeks starting week 72 during the Long-Term Extension period. |
| Ocrelizumab (substudy) | EXPERIMENTAL | Participants with no serious IRR throughout the main study will be eligible to enroll in an optional substudy and receive one additional shorter infusion of ocrelizumab at the Week 96 visit. Ocrelizumab will be administered IV as a single 600-mg dose at a shorter infusion rate (approximately 2 hours instead of 3.5 hours) |
| Interferon beta-1a 44 mcg SC | ACTIVE_COMPARATOR | Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks). |
| Ocrelizumab 600 mg | PLACEBO_COMPARATOR | Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks. |
| Ocrelizumab Test Formulation | EXPERIMENTAL | Participants will receive ocrelizumab test formulation, as SC injection, as per a pre-defined dosing regimen during the controlled phase and continuation phase. |
| Ocrelizumab Reference Formulation | ACTIVE_COMPARATOR | Participants will receive ocrelizumab reference formulation, 920 mg, as SC injection, on Day 1 during the controlled phase. Thereafter, participants will receive ocrelizumab test formulation, as SC injection, as per a pre-defined dosing regimen during the continuation phase. |
| Cohort 3 (optional) | EXPERIMENTAL | Based on PK, PD, safety, and tolerability data analyses of Cohorts 1 and 2, additional participants with a body weight from \>/= 25 kg to \< 40 kg may be enrolled and receive another dose level of ocrelizumab |
| Cohort 4 (optional) | EXPERIMENTAL | Based on PK, PD, safety, and tolerability data analyses of Cohorts 1 and 2, additional participants with a body weight \>/= 40 kg may be enrolled and receive another dose level of ocrelizumab |
| Ocrelizumab 1000 mg | EXPERIMENTAL | Participants received two IV infusions of ocrelizumab 1000 mg separated by 14 days in Cycle 1, followed by an infusion of ocrelizumab 1000 mg on Day 1 and an infusion of placebo on Day 15 of Cycle 2. A single infusion of ocrelizumab 1000 mg was administered on Day 1 of Cycle 3 and a single infusion of ocrelizumab 600 mg was administered on Day 1 of Cycle 4. Each cycle was of 168 days. |
| Avonex | ACTIVE_COMPARATOR | Participants received weekly intramuscular injections of Avonex 30 microgram (mcg) in Cycle 1, followed by two infusions of OCR 300 mg separated by 14 days in Cycle 2. A single infusion of ocrelizumab 600 mg was administered on Day 1 of Cycles 3 and 4. Each cycle was of 168 days. |
| Ocrelizumab SC | EXPERIMENTAL | Participants will receive single ascending doses of ocrelizumab SC, co-formulated with recombinant human hyaluronidase (rHuPH20) on Day 1 of the 24 week dose-escalation phase. Participants who opt to continue treatment in the dose continuation phase will receive ocrelizumab SC at a dose determined in the dose escalation phase, every 24 weeks (Q24W) for 144 weeks. |
| Group A: Cohorts A1-A4 | EXPERIMENTAL | Participants (participants pretreated with ocrelizumab) will receive a single injection of subcutaneous (SC) ocrelizumab co-mixed with rHuPH20 in the abdomen. For every new dose level, recruitment will be staggered by enrolling 1 participant in each cohort followed by a 48-hour waiting period to review safety and tolerability data by the Safety Monitoring Committee (SMC) prior to enrolling subsequent participants in the same cohort. Currently, the planned dose escalation steps for patients who enroll in Group A are as follows: * Cohort A1: 40 mg of SC ocrelizumab * Cohort A2: 200 mg of SC ocrelizumab * Cohort A3: 600 mg of SC ocrelizumab * Cohort A4: 1200 mg of SC ocrelizumab |
| Group A: Cohort A5 | EXPERIMENTAL | In the non-randomized subphase, participants will receive a single SC injection of ocrelizumab co-mixed with rHuPH20 in the abdomen. |
| Group A: Cohort AA | EXPERIMENTAL | Participants will receive a single 600-mg dose ocrelizumab by intravenous (IV) infusion |
| Group B: Cohorts B1-B4 | EXPERIMENTAL | Ocrelizumab treatment- naive participants will receive a minimum of 3 patients in Cohort B will receive a single SC injection of ocrelizumab co-mixed with rHuPH20 in the abdomen. * Cohort B1: 40 mg of SC ocrelizumab * Cohort B2: 200 mg of SC ocrelizumab * Cohort B3: 600 mg of SC ocrelizumab * Cohort B4: 1200 mg of SC ocrelizumab |
| Cohort A: Ocrelizumab 200 mg/m^2 | EXPERIMENTAL | Participants will receive a total of 8 infusions of ocrelizumab 200 milligram per square meter (mg/m\^2) given at intervals of 3 weeks, until disease progression or unacceptable toxicity. |
| Cohort B: Ocrelizumab 375 mg/m^2 | EXPERIMENTAL | Participants will receive a total of 8 infusions of ocrelizumab 375 mg/m\^2 given at intervals of 3 weeks, until disease progression or unacceptable toxicity. |
| Cohort C: Ocrelizumab 375/750 mg/m^2 | EXPERIMENTAL | Participants will receive first infusion of ocrelizumab 375 mg/m\^2 followed by 7 infusions of 750 mg/m\^2 given at intervals of 3 weeks, until disease progression or unacceptable toxicity. |
| Name | Type | Description |
|---|---|---|
| Ocrelizumab | DRUG | Ocrelizumab will be administered at the approved dose of 600 mg, IV infusion or 920 mg, SC injection, according to the regimen in the parent study. |
| Ocrelizumab Placebo | OTHER | Ocrelizumab matching placebo will be administered as IV infusion on Day 1 and Day 15, and Q24W thereafter. |
| Fingolimod | DRUG | Fingolimod will be administered QD as a capsule per the prescribing information (0.25 mg to participants who weigh ≤ 40 kg and 0.5 mg to participants who weigh \> 40 kg). |
| Fingolimod Placebo | OTHER | Fingolimod matching placebo will be administered QD as a capsule. |
| Ocrelizumab IV | DRUG | IV Injection |
| Ocrelizumab SC | DRUG | SC Injection |
| Methylprednisolone IV | DRUG | Participants will receive mandatory (corticosteroids and antihistamine) and optional (analgesic) prophylactic treatment before the start of each ocrelizumab infusion |
| Diphenhydramine IV | DRUG | Participants will receive mandatory (corticosteroids and antihistamine) and optional (analgesic) prophylactic treatment before the start of each ocrelizumab infusion |
| Dexamethasone given orally | DRUG | Participants will receive mandatory (corticosteroids and antihistamine) and optional (analgesic) prophylactic treatment before the start of each ocrelizumab injection |
| Desloratadine given orally | DRUG | Participants will receive mandatory (corticosteroids and antihistamine) and optional (analgesic) prophylactic treatment before the start of each ocrelizumab injection |
| Antihistamine | DRUG | Premedication with oral or IV antihistaminic drug (i.e., diphenhydramine 50 mg or an equivalent dose of an alternative) will be administered prior to each ocrelizumab infusion. |
| Methylprednisolone | DRUG | Premedication with 100 mg of methylprednisolone (or equivalent) will be administered by IV infusion prior to each ocrelizumab infusion. |
| Placebo | DRUG | The first dose of placebo will be administered as two IV infusions given 14 days apart. For the subsequent doses, placebo will be administered as a single infusion every 24 weeks, with a minimum interval of 20 or 22 weeks, depending on if the previous dose was administered in one or two infusions, maintained between each infusion. |
| Ocrelizumab Dose 1 | DRUG | 300 mg infusion administered to ocrelizumab-naive participants per approved protocol (over approximately 2.5 hours or longer) as per standard of care followed by a second 300 mg shorter infusion over approximately 1.5 hours. |
| Ocrelizumab Dose 2 and Dose 3 | DRUG | 600 mg infusion of ocrelizumab administered at a shorter rate (i.e. over the course of approximately 2 hours) at Week 24 and at Week 48 |
| Lumbar Puncture | PROCEDURE | Participants will receive LP as specified in individual arms. Lumbar puncture is optional at week 52, except for RMS Cohort Arm 3 and PPMS Cohort. In addition, the lumbar punctures in the Long Term Extension phase is every other year. |
| Methyloprednisolone | DRUG | Participants will receive 100 mg of IV methylprenisolone (or an equivalent) prior to ocrelizumab infusion. |
| Interferon beta-1a | DRUG | - |
| Ocrelizumab-matching placebo | DRUG | - |
| Interferon beta-1a-matching placebo | DRUG | - |
| Ocrelizumab co-formulated with rHuPH20 | DRUG | Ocrelizumab co-formulated with rHuPH20 will be administered as per the schedule specified in the arm. |
| Ocrelizumab Test Formulation | DRUG | Ocrelizumab test formulation will be administered as per the schedule specified in the respective arm. |
| Ocrelizumab Reference Formulation | DRUG | Ocrelizumab reference formulation will be administered as per the schedule specified in the respective arm. |
| Avonex | DRUG | Avonex was administered weekly intramuscular injections of 30 mcg in cycle 1 Day 1. |
| rHuPH20 | DRUG | Administered in a 2-mL glass vial as a sterile, single-use, injectable liquid to be manually mixed with SC ocrelizumab |
Inclusion Criteria: * Participants who were on ongoing ocrelizumab treatment on one of the following parent-studies \[Studies MN39159/CONSONANCE (NCT03523858), BN42082/MUSETTE (NCT04544436), BN42083/GAVOTTE (NCT04548999), BN44083/GLOBEAM, MN43978/CONSONANCE Ext., WA40404/O'HAND (NCT04035005), MN439...
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Ocrelizumab is an investigational monoclonal antibody developed by Roche Holding AG for multiple sclerosis and non-Hodgkin's lymphoma. It is being studied across relapsing and progressive forms of multiple sclerosis, including primary progressive and relapsing multiple sclerosis, and is currently in Phase 3 clinical development.
Ocrelizumab targets MS4A1, also known as CD20, a protein found on the surface of B cells. By binding this target, the monoclonal antibody is designed to deplete B cells, which are thought to contribute to the inflammatory process in multiple sclerosis. It is classified as a binding agent.
Ocrelizumab is developed by Roche Holding AG, which trades under the ticker RHHBY. Roche is running the clinical development program, which includes studies of both intravenous and subcutaneous formulations across multiple sclerosis indications and non-Hodgkin's lymphoma.
Ocrelizumab is in Phase 3 clinical development. It is an investigational agent and is not described as approved. Its trial program includes Phase 1, Phase 2, and Phase 3 studies, with 10 trials in total, of which 7 are active and 3 are completed.
Ocrelizumab trials include NCT06675955, a Phase 3 extension study providing continued treatment and assessing the impact of multiple sclerosis on physical function, and NCT07074886, a Phase 2 bioequivalence study of two subcutaneous formulations. Earlier-stage studies include NCT07667322 and NCT07503340.