Multiple Sclerosis, Primary Progressive
Conditions
Brief summary
This randomized, parallel group, double-blind, placebo controlled study will evaluate the efficacy and safety of ocrelizumab in participants with primary progressive multiple sclerosis. Eligible participants will be randomized 2 : 1 to receive either ocrelizumab or placebo.
Interventions
DRUGOcrelizumab
Two IV infusions of 300 mg in each treatment cycle of double blind treatment period; two IV infusions of ocrelizumab 300 mg for Cycle 1 and single IV infusion of ocrelizumab 600 mg for subsequent cycles in OLE phase.
OTHERPlacebo
Two IV infusions of placebo matched to ocrelizumab in each treatment cycle of double blind treatment period.
Sponsors
Hoffmann-La Roche
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
* Diagnosis of primary progressive multiple sclerosis (according to revised McDonald criteria) * EDSS at screening from 3 to 6.5 points * Disease duration from onset of MS symptoms less than (\<) 15 years if EDSS greater than (\>) 5.0; \<10 years if EDSS greater than or equal to (\>/=) 5.0 * Sexually active male and female participants of reproductive potential must use two methods of contraception throughout the study treatment phase and for 48 weeks after the last dose
Exclusion criteria
* History of relapsing remitting MS, secondary progressive, or progressive relapsing MS at screening * Inability to complete an MRI (contraindications for MRI) * Known presence of other neurologic disorders * Known active infection or history of or presence of recurrent or chronic infection * History of cancer, including solid tumors and hematological malignancies (except for basal cell, in situ squamous cell carcinomas of the skin and in situ carcinoma of the cervix that have been excised and resolved) * Previous treatment with B-cell targeted therapies (e.g. rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab) * Any previous treatment with lymphocyte trafficking blockers, with alemtuzumab, anti-cluster of differentiation 4 (CD4), cladribine, cyclophosphamide, mitoxantrone, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, total body irradiation, or bone marrow transplantation * Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 12 Weeks During the Double-Blind Treatment Period | Maximal follow up: 216 weeks for Placebo arm and 217 weeks for Ocrelizumab arm | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Timed 25-Foot Walk (T25-FW) at Week 120 | Baseline, Week 120 | — |
| Percent Change From Baseline in Total Volume of T2 Lesions at Week 120 | From Baseline to Week 120 | — |
| Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 24 Weeks During the Double-Blind Treatment Period | Maximal follow up: 216 weeks for Placebo arm and 217 weeks for Ocrelizumab arm | 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. |
| Change in From Baseline Physical Component Summary Score (PCS) SF- 36 Health Survey (SF-36) at Week 120 | From Baseline to Week 120 | The SF-36v2 is a 36-item, self- reported, generic measure of quality of life that has been widely used in multiple disease areas. It is composed of 8 health domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. The PCS score was derived based on the SF-36 V2 User's Manual. Scoring for PCS involves (a) recoding item response values, (b) summing recoded response values for all items in a given scale to obtain the scale raw score, (c) transforming scale raw score to a 0-100 score. The PCS score was computed by (a) multiplying each health domain z score by a scale-specific physical factor score coefficient, (b) summing the resulting products, (c) converting the product total to T score. The total score ranges from 0-100, higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. |
| Number of Participants With at Least One Adverse Event (AE) | From baseline to 9 years | AEs included infusion related reactions (IRRs) and serious multiple sclerosis (MS) relapses, but excluded non-serious MS relapses. |
| Percent Change in Total Brain Volume From Week 24 to Week 120 | From Week 24 to Week 120 | — |
Countries
Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Czechia, Finland, France, Germany, Greece, Hungary, Israel, Italy, Lithuania, Mexico, Netherlands, New Zealand, Norway, Peru, Poland, Portugal, Romania, Russia, Spain, Switzerland, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 943 participants were screened and 732 were randomized into the study, of which 725 received at least one dose of placebo or ocrelizumab.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks. | 244 |
| Ocrelizumab 600 mg 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. | 488 |
| Total | 732 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 22 | 40 |
| Overall Study | Death | 6 | 20 |
| Overall Study | Lack of Efficacy | 32 | 33 |
| Overall Study | Lost to Follow-up | 4 | 15 |
| Overall Study | Non-Compliance | 2 | 2 |
| Overall Study | Non-Compliance With Study Drug | 2 | 2 |
| Overall Study | Other | 18 | 47 |
| Overall Study | Physician Decision | 10 | 25 |
| Overall Study | Pregnancy | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Study Terminated By Sponsor | 0 | 1 |
| Overall Study | Withdrawal by Subject | 57 | 82 |
Baseline characteristics
| Characteristic | Placebo | Ocrelizumab 600 mg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 244 Participants | 488 Participants | 732 Participants |
| Age, Continuous | 44.4 years STANDARD_DEVIATION 8.3 | 44.7 years STANDARD_DEVIATION 7.9 | 44.6 years STANDARD_DEVIATION 8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 32 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 206 Participants | 385 Participants | 591 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 24 Participants | 71 Participants | 95 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 9 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 20 Participants | 24 Participants |
| Race (NIH/OMB) White | 235 Participants | 454 Participants | 689 Participants |
| Sex: Female, Male Female | 124 Participants | 237 Participants | 361 Participants |
| Sex: Female, Male Male | 120 Participants | 251 Participants | 371 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 239 | 3 / 486 | 4 / 158 | 19 / 369 |
| other Total, other adverse events | 175 / 239 | 400 / 486 | 134 / 158 | 318 / 369 |
| serious Total, serious adverse events | 58 / 239 | 104 / 486 | 59 / 158 | 167 / 369 |
Outcome results
Primary
Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 12 Weeks During the Double-Blind Treatment Period
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.
Time frame: Maximal follow up: 216 weeks for Placebo arm and 217 weeks for Ocrelizumab arm
Population: ITT population included all randomized participants in the study. Number of participants analyzed is the total participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 12 Weeks During the Double-Blind Treatment Period | NA weeks |
| Ocrelizumab 600 mg | Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 12 Weeks During the Double-Blind Treatment Period | NA weeks |
Secondary
Change in From Baseline Physical Component Summary Score (PCS) SF- 36 Health Survey (SF-36) at Week 120
The SF-36v2 is a 36-item, self- reported, generic measure of quality of life that has been widely used in multiple disease areas. It is composed of 8 health domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. The PCS score was derived based on the SF-36 V2 User's Manual. Scoring for PCS involves (a) recoding item response values, (b) summing recoded response values for all items in a given scale to obtain the scale raw score, (c) transforming scale raw score to a 0-100 score. The PCS score was computed by (a) multiplying each health domain z score by a scale-specific physical factor score coefficient, (b) summing the resulting products, (c) converting the product total to T score. The total score ranges from 0-100, higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.
Time frame: From Baseline to Week 120
Population: ITT population included all randomized participants in the study. Here, Number of participants analyzed is the total participants who were evaluated for this endpoint. Here, least square mean is indicating adjusted geometric mean.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change in From Baseline Physical Component Summary Score (PCS) SF- 36 Health Survey (SF-36) at Week 120 | -1.108 units on a scale |
| Ocrelizumab 600 mg | Change in From Baseline Physical Component Summary Score (PCS) SF- 36 Health Survey (SF-36) at Week 120 | -0.731 units on a scale |
Comparison: Estimates are from analysis based on MMRM using unstructured covariance matrix: Change = Baseline PCS Score + Geographical Region (US vs. ROW) + Age (\<=45, \> 45 years) + Week + Treatment + Treatment\*Week (repeated values over Week) + Baseline PCS Score\*Week.p-value: 0.603495% CI: [-1.048, 1.802]MMRM
Secondary
Number of Participants With at Least One Adverse Event (AE)
AEs included infusion related reactions (IRRs) and serious multiple sclerosis (MS) relapses, but excluded non-serious MS relapses.
Time frame: From baseline to 9 years
Population: The safety population includes all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With at Least One Adverse Event (AE) | Serious Adverse Events | 53 Participants |
| Placebo | Number of Participants With at Least One Adverse Event (AE) | Adverse Events | 215 Participants |
| Ocrelizumab 600 mg | Number of Participants With at Least One Adverse Event (AE) | Adverse Events | 462 Participants |
| Ocrelizumab 600 mg | Number of Participants With at Least One Adverse Event (AE) | Serious Adverse Events | 99 Participants |
| Placebo (Open Label Extension) | Number of Participants With at Least One Adverse Event (AE) | Serious Adverse Events | 59 Participants |
| Placebo (Open Label Extension) | Number of Participants With at Least One Adverse Event (AE) | Adverse Events | 148 Participants |
| Ocrelizumab (Open Label Extension) | Number of Participants With at Least One Adverse Event (AE) | Serious Adverse Events | 167 Participants |
| Ocrelizumab (Open Label Extension) | Number of Participants With at Least One Adverse Event (AE) | Adverse Events | 354 Participants |
Secondary
Percent Change From Baseline in Timed 25-Foot Walk (T25-FW) at Week 120
Time frame: Baseline, Week 120
Population: ITT population included all randomized participants in the study. Here, number of participants analyzed is the total participants who were evaluated for this endpoint. Here, least square mean is indicating adjusted geometric mean.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline in Timed 25-Foot Walk (T25-FW) at Week 120 | 55.097 percent change |
| Ocrelizumab 600 mg | Percent Change From Baseline in Timed 25-Foot Walk (T25-FW) at Week 120 | 38.933 percent change |
Comparison: Estimates (back-transformed) based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix: log(Post-baseline(BL)/BL) = log(BL 25-FTW) + Geographical Region (US vs. ROW) + Age (\<=45, \> 45 years) + Week + Treatment + Treatment\*Week (repeated values over Week) + log (BL 25-FTW)\*Week. Relative reduction was calculated as -Relative change = -(OCR response-Placebo response)/Placebo response\*100%. The 95% CI for relative reduction was obtained using the Bootstrap method.p-value: 0.040495% CI: [-1.618, 51.456]Ranked ANCOVA
Secondary
Percent Change From Baseline in Total Volume of T2 Lesions at Week 120
Time frame: From Baseline to Week 120
Population: ITT population included all randomized participants in the study. Here, Number of participants analyzed is the total participants who were evaluated for this endpoint. Here, least square mean is indicating adjusted geometric mean.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline in Total Volume of T2 Lesions at Week 120 | 7.426 percent change |
| Ocrelizumab 600 mg | Percent Change From Baseline in Total Volume of T2 Lesions at Week 120 | -3.366 percent change |
Comparison: Estimates (back-transformed) are based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix: log(Post-BL/BL) = log(BL T2 lesion volume) + Geographical Region (US vs. ROW) + Age (\<=45, \> 45 years) + Week + Treatment + Treatment\*Week (repeated values over Week) + log (BL T2 lesion volume)\*Week.p-value: <0.000195% CI: [0.876, 0.924]Ranked ANCOVA
Secondary
Percent Change in Total Brain Volume From Week 24 to Week 120
Time frame: From Week 24 to Week 120
Population: ITT population included all randomized participants in the study. Number of participants analyzed is the total participants who were evaluable for this endpoint. Here, least square mean is indicating adjusted mean.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change in Total Brain Volume From Week 24 to Week 120 | -1.093 percent change |
| Ocrelizumab 600 mg | Percent Change in Total Brain Volume From Week 24 to Week 120 | -0.902 percent change |
Comparison: Estimates are from analysis based on MMRM using unstructured covariance matrix: Percentage Change = Brain Volume at Week 24 + Geographical Region (US vs. ROW) + Age (\<=45, \> 45 years) + Week + Treatment + Treatment\*Week (repeated values over Week) + Brain Volume at Week 24\*Week. Relative reduction was calculated as - Relative change = - (OCR response-Placebo response)/Placebo response\*100%. The 95% CI for relative reduction was obtained using Bootstrap method.p-value: 0.020695% CI: [3.206, 29.251]MMRM
Secondary
Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 24 Weeks During the Double-Blind Treatment Period
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.
Time frame: Maximal follow up: 216 weeks for Placebo arm and 217 weeks for Ocrelizumab arm
Population: ITT population included all randomized participants in the study. Number of participants analyzed is the total participants who were evaluable for this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 24 Weeks During the Double-Blind Treatment Period | NA weeks |
| Ocrelizumab 600 mg | Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 24 Weeks During the Double-Blind Treatment Period | NA weeks |