Multiple Sclerosis
Conditions
Keywords
Relapsing Remitting Multiple Sclerosis; Higher Dose of CD20 Antibody Ocrelizumab; Efficacy, Safety and Pharmacokinetics
Brief summary
This is a randomized, double-blind, controlled, parallel group, multicenter study to evaluate efficacy, safety and PK of a higher dose of ocrelizumab per intravenous (IV) infusion every 24 weeks (Q24W) in participants with RMS, in comparison to the approved 600 milligrams (mg) dose of ocrelizumab.
Detailed description
Participants will be treated for a minimum of 120 weeks in the double-blind treatment (DBT) phase. Upon positive primary results after the DBT phase, an optional higher dose extension treatment, open-label extension (OLE) phase is planned for eligible participants. The OLE will be carried out for approximately 96 weeks. Participants will be followed for safety for 48 weeks thereafter. Participants whose B-cell levels still did not replete to their baseline level or the low level of normal (LLN), whichever is lower, will move into the B-cell monitoring (BCM) phase following the safety follow-up phase. The study will end when all participants who were not treated with an alternative B-cell depleting therapy have repleted their B-cells to the baseline value or the LLN.
Interventions
DRUGOcrelizumab
The actual higher dose of ocrelizumab will be assigned to participants based on their body weight at baseline: 1200 mg (body weight \<75 kg) or 1800 mg (body weight ≥ 75 kg). The first dose of ocrelizumab will be administered as two 600 mg or 900 mg IV infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 1200 mg or 1800 mg IV infusion Q24W. 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).
DRUGAntihistamine
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.
DRUGMethylprednisolone
Premedication with 100 mg of methylprednisolone (or equivalent) will be administered by IV infusion prior to each ocrelizumab infusion.
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 RMS * At least two documented clinical relapses within the last 2 years prior to screening, or one clinical relapse in the year prior to screening. No relapse 30 days prior to screening and at baseline * Participants must be neurologically stable for at least 30 days prior to randomization and baseline * EDSS score, at screening and baseline, from 0 to 5.5 inclusive * Average T25FWT score over two trials at screening and over two trials at baseline respectively, up to 150 (inclusive) seconds * Average 9HPT score over four trials at screening and over four trials at baseline respectively, up to 250 (inclusive) seconds * Documented magnetic resonance imaging (MRI) of brain with abnormalities consistent with MS at screening * Participants requiring symptomatic treatment for MS and/or physiotherapy must be treated at a stable dose. No initiation of symptomatic treatment for MS or physiotherapy within 4 weeks of randomization * Females of childbearing potential, agreement to remain abstinent or use adequate contraceptive methods * Female participants without reproductive potential may be enrolled e.g. if post-menopausal or if surgically sterile
Exclusion criteria
* History of primary progressive MS at screening * Any known or suspected active infection at screening or baseline (except nailbed infections), or any major episode of infection requiring hospitalization or treatment with IV antimicrobials within 8 weeks or treatment with oral antimicrobials within 2 weeks, prior to and during screening * History of confirmed or suspected progressive multifocal leukoencephalopathy * History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening * Immunocompromised state * Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization * Inability to complete an MRI or contraindication to gadolinium administration * Contraindications to mandatory pre-medications for infusion-related reaction (IRRs) * Known presence of other neurologic disorders that could interfere with the diagnosis of MS or assessments of efficacy and/or safety during the study * Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study * Significant, uncontrolled disease that may preclude participant from participating in the study * History of or currently active primary or secondary, non-drug-related, immunodeficiency * Pregnant or breastfeeding or intending to become pregnant * Lack of peripheral venous access * History of alcohol or other drug abuse within 12 months prior to screening * Treatment with any investigational agent within 24 weeks prior to screening or treatment with any experimental procedure for MS * Previous use of anti- cluster of differentiation 20 (CD20s) (including ocrelizumab), unless the last infusion was more than 2 years before screening, B-cell count is normal, and the stop of the treatment was not motivated by safety reasons or lack of efficacy * Previous treatment with fingolimod, siponimod, or ozanimod within 6 weeks of baseline * Previous treatment with natalizumab within 4.5 months of baseline * Previous treatment with interferons beta (1a or 1b), or glatiramer acetate within 2 weeks of baseline * Any previous treatment with mitoxantrone, cladribine, atacicept, alemtuzumab, and daclizumab - Previous treatment with any other immunomodulatory or immunosuppressive medication not already listed above without appropriate washout as described in the applicable local label. If the washout requirements are not described in the applicable local label, then the wash out period must be five times the half-life of the medication * Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation * Any previous history of transplantation or anti-rejection therapy * Treatment with IV immunoglobulin (Ig) or plasmapheresis within 12 weeks prior to randomization * Systemic corticosteroid therapy within 4 weeks prior to screening * Positive screening tests for active, latent, or inadequately treated hepatitis B * Sensitivity or intolerance to any ingredient (including excipients) of ocrelizumab * Any additional exclusionary criterion as per ocrelizumab local label, if more stringent than the above
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of 12-week Composite Confirmed Disability Progression (cCDP12) | Up to approximately 4 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of 24-week cCDP (cCDP24) | Up to approximately 4 years | Time to onset of a 24 week cCDP=first occurrence of a 24-week cCDP according to at least 1 of 3 criteria: 1) CDP=24-week CI from baseline in EDSS score of ≥1.0 point in participants with baseline EDSS score of ≤5.5 or 24-week CI≥0.5 point in participants with baseline EDSS score of \>5.5 OR 2) 24-week CI of ≥20% FB in T25FWT score OR 3) 24-week CI of ≥ 20% FB in 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 48-week cCDP (cCDP48) | Up to approximately 4 years | Time to onset of a 48-week cCDP=first occurrence of a 48-week cCDP according to at least 1 of 3 criteria: 1) CDP=48-week CI from baseline in EDSS score of ≥1.0 point in participants with baseline EDSS score of ≤5.5 or 48-week CI≥0.5 point in participants with baseline EDSS score of \>5.5 OR 2) 48-week CI of ≥20% FB in T25FWT score OR 3) 48-week CI of ≥ 20% FB in 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 Independent of Protocol-defined Relapses (PDR) or Progression Independent of Relapse Activity (PIRA) | Up to approximately 4 years | Time to onset of 12-week cCDP=first occurrence of a 12-week cCDP according to at least 1 of 3 criteria: 1) CDP=12-week CI from baseline in 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 T25FWT score OR 3) 12-week CI of ≥ 20% FB in 9-HPT score. EDSS score, T25FWT \& 9-HPT are the same as defined in primary outcome measure. Protocol-defined relapse=occurrence of new or worsening neurological symptoms attributable to MS and immediately preceded by a relatively stable or improving neurological state of at least 30 days. Symptoms persist for at least 24 hours \& accompanied by objective neurological worsening consistent with an increase of one of the following: Half a step (0.5 point) on the EDSS; Two points on one of the functional system scores (FSS) (pyramidal, ambulation, cerebellar, brainstem, sensory, or visual); One point on ≥2 more of the FSS. |
| Time to Onset of 12-week Confirmed Disability Progression (CDP12) | Up to approximately 4 years | CDP was defined as a 12-week confirmed increase from baseline in EDSS score of ≥1.0 point in participants with a baseline EDSS score of ≤5.5 or a 12-week CI ≥0.5 points in participants with a baseline EDSS score of \>5.5. The EDSS was used to measure changes in the disability level of participants with MS over time. EDSS is based on a standard neurological examination, incorporating functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel and bladder, and cerebral \[or mental\]) that are rated and then scored as a FSS, and ambulation, which is scored as ambulation score. Each FSS is an ordinal clinical rating scale where score range from 0 to 5 or 6, and ambulation score that is rated from 0 to 16. These ratings along with observations and assistive devices were then used to determine the total EDSS score. The total EDSS score ranges from 0 (normal) to 10.0 (death) in 0.5-point steps. |
| Time to ≥ 20% Increase in 12-week Confirmed T25FWT | Up to approximately 4 years | 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. A 20% change from baseline of the averaged T25FWT was considered clinically meaningful. |
| Annual Rate of Percent Change From Baseline in Total Brain Volume | Up to approximately 4 years | Brain volume was measured using magnetic resonance imaging (MRI) scans. Mean difference in annual rate of percent change from baseline in total brain volume between the higher and approved dose of ocrelizumab arms in participants with RMS where no treatment discontinuation nor initiation of alternative MS treatment occurred, are reported. |
| Time to Onset of 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT) | Up to approximately 4 years | The SDMT is a performance measure that demonstrated sensitivity in detecting the presence of cognitive impairment and changes in cognitive functioning over time \& in response to treatment. The SDMT presents a series of nine symbols, each paired with a single digit in a key at the top of a standard sheet of paper. Participants were asked to pair specific numbers with given geometric figures within 90 seconds. Responses were collected orally. The score is the number of correctly paired items in 90 seconds with a maximum score of 110 and minimum of 0. Higher scores indicate improvement. A four-point change from baseline was considered clinically meaningful. |
| Time to Onset of 24-week Confirmed 8-point Increase in 12-item Multiple Sclerosis Walking Scale (MSWS-12) | Up to approximately 4 years | The MSWS-12 was a 12-item self-report measure of the impact of MS on the participant's ability to walk during the past 2 weeks. Each item was scored on a 5-point Likert scale ranging from 1 (not at all) to 5 (extremely likely). Scores were summed and linearly converted to a 0-100 scale with higher scores indicating greater impact of MS on walking ability. An 8-point change was considered clinically meaningful. |
| Fold Change From Baseline in Neurofilament Light (NfL) Chain at Week 48 for Participants Assigned to the Higher Dose Ocrelizumab Group | Week 48 | NfL is a biomarker of neuroinflammation in CSF. Ratio of change from baseline in NfL at Week 48 for RMS participants where no treatment discontinuation nor initiation of alternative MS treatment occurred within the ocrelizumab higher dose arm has been reported. The results correspond to fold change from baseline (ie ratio of adjusted geometric means at week 48 vs baseline). |
| Fold Change From Baseline in NfL Chain at Week 48 for Participants Assigned to the Approved Dose Ocrelizumab Group | Week 48 | NfL is a biomarker of neuroinflammation in CSF. Ratio of change from baseline in NfL at Week 48 for RMS participants where no treatment discontinuation nor initiation of alternative MS treatment occurred within the ocrelizumab approved dose arm has been reported. The results correspond to fold change from baseline (ie ratio of adjusted geometric means at week 48 vs baseline). |
| Number of Participants With Adverse Events (AEs) | From initiation of study drug up to approximately 4 years | AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| Area Under the Serum Concentration-Time Curve (AUC) of Ocrelizumab Over the First Dosing Interval | Day 1 to Week 24 | — |
| B-cell Levels in Blood | Baseline, Weeks 2, 24, 48, 72, 96, 120, 144, 168, and 192 | — |
| Percent Change From Baseline in B-cell Levels | Weeks 2, 24, 48, 72, 96, 120, 144, 168, and 192 | — |
| Percentage of Participants Who Achieved ≤ 5 B-cells/μL of Blood | Baseline, Weeks 2, 24, 48, 72, 96, 120, 144, 168, and 192 | — |
| Percentage of Participants With Anti-drug Antibodies (ADAs) to Ocrelizumab | Baseline up to approximately 4 years | Prevalence of ADAs at baseline was defined as the percentage of participants that is ADA positive at baseline. For determining post-baseline incidence, participants were considered to be ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure, or if they were ADA-positive at baseline and the titer of 1 or more post-baseline samples was at least 0.60 titer unit (t.u.) greater than the baseline titer result. Percentages have been rounded off. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Denmark, France, Germany, Greece, Hungary, Italy, Peru, Poland, Portugal, Russia, Spain, Switzerland, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 864 participants with relapsing multiple sclerosis (RMS) took part in the study at 122 investigative sites across 21 countries. The study is still ongoing.
Pre-assignment details
Participants received double-blinded treatment (DBT) with either ocrelizumab higher dose (1200 milligrams \[mg\] or 1800 mg) based on the participant's body weight (BW) or ocrelizumab 600 mg for a minimum of up to 120 weeks. 4 participants had a major good clinical practice (GCP) violation and were hence excluded from all analysis sets used in this study. Therefore, results are presented for 860 participants.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 36.0 years STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 101 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 466 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 55 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants |
| Race (NIH/OMB) More than one race | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 760 Participants |
| Sex: Female, Male Female | 540 Participants |
| Sex: Female, Male Male | 103 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 283 | 4 / 577 |
| other Total, other adverse events | 241 / 283 | 502 / 577 |
| serious Total, serious adverse events | 34 / 283 | 77 / 577 |
Outcome results
None listed