Study to Evaluate the Effectiveness and Safety of Ocrelizumab in Participants With Early Stage Relapsing Remitting Multiple Sclerosis (RRMS)

Phase 3TerminatedNCT03085810

Hoffmann-La Roche1,225 enrolled

Overview

This is a prospective, multicenter, open-label, single-arm, phase 3b study which evaluates effectiveness and safety of ocrelizumab in participants with early stage RRMS. The study will consist of an open-label treatment period of 192 weeks and follow-up period of at least 48 weeks. The optional shorter infusion substudy will evaluate the safety of a shorter infusion of ocrelizumab in a subgroup of participants with early stage RRMS enrolled in the main MA30143 study. Approximately 700 patients will be enrolled in the substudy, and will receive additional 600 mg ocrelizumab administered in a shorter time frame.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

1,225

Conditions

Multiple Sclerosis, Relapsing-Remitting

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Have a definite diagnosis of RRMS, as per the revised McDonald 2010 criteria * Have a length of disease duration, from first documented clinical attack consistent with MS disease of less than or equal to (\</=) 3 years * Within the last 12 months one or more clinically reported relapse(s) or one or more signs of MRI activity * EDSS of 0.0 to 3.5 inclusive, at screening * An agreement to use an acceptable birth control method for women of childbearing potential, during the treatment period and for at least 6 months or longer after the last dose of study drug Exclusion Criteria: * Secondary progressive multiple sclerosis or history of primary progressive or progressive relapsing MS * Inability to complete an MRI * Known presence of other neurological disorders Exclusions Related to General Health: * Pregnancy or lactation * Participants intending to become pregnant during the study or within 6 months after the last dose of the study drug * Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study * History or currently active primary or secondary immunodeficiency * Lack of peripheral venous access * History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies * Significant or uncontrolled somatic disease or any other significant disease that may preclude participant from participating in the study * Congestive heart failure (New York Heart Association III or IV functional severity) * Known active bacterial, viral, fungal, mycobacterial infection or other infection, (excluding fungal infection of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks prior to screening or oral antibiotics 2 weeks prior to screening * History of malignancy, major opportunistic infections, alcohol or drug abuse, recurrent or chronic infection, and/or coagulation disorders Exclusions Related to Medications: * Received any prior approved disease modifying treatment (DMT) with a label for MS, for example, interferons, glatiramer acetate, natalizumab, alemtuzumab, daclizumab, fingolimod, teiflunomide and dimethylfumarate * Receipt of a live vaccine or attenuated live vaccine within 6 weeks prior to the baseline visit * Previous treatment with B-cell targeted therapies (i.e., rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab) * Any previous treatment with immunosuppressants/ immunomodulators/ antineoplastic therapies (cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, cladribine, mitoxantrone, laquinimod, total body irradiation, or bone marrow transplantation) * Treatment with investigational DMT * Treatment with fampridine/dalfamipridine unless on stable dose for \>/=30 days prior to screening Exclusion related to Shorter Infusion Substudy: \- Any previous serious IRRs experienced with ocrelizumab treatment

Locations (193)

University of California Irvine

Irvine, California, United States

Palo Alto Medical Foundation Research Center

Sunnyvale, California, United States

University of Colorado Denver

Aurora, Colorado, United States

Advanced Neurology of Colorado, LLC

Fort Collins, Colorado, United States

KI Health Partners, LLC; New England Institute for Clinical Research

Stamford, Connecticut, United States

Outcomes

Primary Outcomes

Time to Onset of Confirmed Disability Progression (CDP) Sustained for at Least 24 Weeks and 48 Weeks as Measured Using Expanded Disability Status Scale (EDSS)

The EDSS-Expanded Disability Status Scale is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). Disability progression as measured by EDSS is defined as ≥1 point increase in EDSS score from a baseline EDSS score of 1-5 inclusive, a 0.5-increase from a baseline EDSS score higher than 5 and a 1.5-increase from a baseline EDSS score from 0 to 1 exclusive. Disability progression was considered confirmed if a sustained change in EDSS for a minimum of 24 weeks (-2 weeks) from the initial progression event was seen i.e. the change in EDSS must have been sustained at all available visits for a minimum of 24 weeks/48 weeks.

Time frame: Baseline up to 4 years

Percentage of Participants With 24-Week and 48-Week Confirmed Disability Improvement (CDI) During the Year 1 Treatment Period, as Measured Using EDSS

CDI is defined as an improvement of ≥1 point on the EDSS score confirmed at a regular scheduled visit at least 24/48 weeks after the initial documentation of neurological worsening (measured only participants with a baseline EDSS of ≥2.0). EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death).

Time frame: At Weeks 24 and 48 during Year 1

Percentage of Participants Event-Free for CDP Sustained for at Least 24 and 48 Weeks at Year 1, as Measured Using EDSS

Time frame: Year 1 (Weeks 24 and 48)

Percentage of Participants With 24-Week and 48-Week CDI During the Year 2 Treatment Period, as Measured Using EDSS

CDI is defined as an improvement of 1 point on the EDSS score confirmed at a regular scheduled visit at least 24/48 weeks after the initial documentation of neurological worsening (measured only participants with a baseline EDSS of ≥2.0). EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death).

Time frame: At Weeks 48, 72 and 96 during Year 2

Percentage of Participants Event-free for CDP Sustained for at Least 24 and 48 Weeks at Year 2, as Measured Using EDSS

Time frame: Year 2 (Weeks 72 and 96)

Percentage of Participants With 24-Week and 48-Week CDI at Year 4, as Measured Using EDSS

CDI is 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 worsening (measured only participants with a baseline EDSS of ≥2.0). EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death).

Time frame: At Weeks 144, 168 and 192 during Year 4

Percentage of Participants Event-free for CDP Sustained for at Least 24 and 48 Weeks at Year 4, as Measured Using EDSS

Time frame: Year 4 (Weeks 168 and 192)

Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 1, As Measured Using EDSS

Time frame: Year 1 (Week 48)

Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 2, As Measured Using EDSS

Time frame: Year 2 (Week 96)

Percentage of Participants Who Have Improved, Stable, or Worsened Disability at Year 3, As Measured Using EDSS

Time frame: Year 3

Percentage of Participants Who Have Improved, Stable, or Worsened Disability at Year 4, As Measured Using EDSS

Time frame: Year 4

Mean Change From Baseline in EDSS Score at Week 24

Time frame: From Baseline to Week 24

Mean Change From Baseline in EDSS Score at Week 48

Time frame: From Baseline to Week 48

Mean Change From Baseline in EDSS Score at Week 72

Time frame: From Baseline to Week 72

Mean Change From Baseline in EDSS Score at Week 96

Time frame: Baseline, Week 96

Mean Change From Baseline in EDSS Score at Week 120

Time frame: Baseline, Week 120

Mean Change From Baseline in EDSS Score at Week 144

Time frame: Baseline, Week 144

Mean Change From Baseline in EDSS Score at Week 168

Time frame: Baseline, Week 168

Mean Change From Baseline in EDSS Score at Week 192

Time frame: Baseline, Week 192

Percentage of Participants Without Protocol-Defined Event of Disease Activity

Protocol-defined event of disease activity is defined as having at least one of the following: (1). protocol defined relapse (occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis \[MS\], as determined using EDSS/Functional Systems Score \[FSS\] assessment). (2). CDP, as determined using EDSS. (3). a T1 Gd-enhanced lesion after Week 8 (4). a new and/or enlarging T2 hyperintense lesion on magnetic resonance imaging (MRI) after Week 8 compared to the Week 8 MRI scan.

Time frame: Baseline up to 4 years

Percentage of Participants Without Relapse

Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment.

Time frame: Baseline up to 4 years

Annualized Relapse Rate

Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment. The adjusted annualized relapse rate is reported which is: Adjusted by age at disease diagnosis, Baseline EDSS, Presence of T1 Gd-enhanced lesion at screening and Presence of relapses in the last year prior to enrollment. Log-transformed exposure time is included as an offset variable. The report contains data up to week 192 of the treatment period of each individual participant.

Time frame: Baseline up to 4 years

Sub Study: Number of Participants With IRRs Occurring During or Within 24 Hours Following the First Infusion After Randomization to the Shorter Infusion Substudy

Time frame: Week 24 through Week 144

Secondary Outcomes

Percentage of Participants Who Are Relapse Free

Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment.

Time frame: Week 192

Percentage of Participants With No Evidence of Protocol Defined Disease Activity

Protocol-defined disease activity is defined as having at least one of the following: (1). protocol defined relapse (occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis \[MS\], as determined using EDSS/Functional Systems Score \[FSS\] assessment). (2). CDP, as determined using EDSS. (3). a T1 Gd-enhanced lesion after Week 8. (4). a new and/or enlarging T2 hyperintense lesion on magnetic resonance imaging (MRI) after Week 8 compared to the Week 8 MRI scan. Event-free rate

Time frame: Weeks 96, 144, 192

Percentage of Participants Without Protocol-defined Event of Evidence of Progression (NEP)

NEP is defined as no progression sustained for at least 24 weeks on all of the following three components (CDP; 20 percent \[%\] increase from baseline in timed 25 Foot Walk Test \[T25FWT\]; 20% increase from baseline in timed 9 hole peg test \[9HPT\]). CDP will be assessed using EDSS.

Time frame: Weeks 96, 192

Percentage of Participants With no Evidence of Progression Sustained for At Least 24 Weeks and no Active Disease (NEPAD)

NEPAD is defined as no progression on all of the three components of NEP (CDP, T25FWT, 9HPT), no new relapse and no enlarging or new T2 or T1 Gd-enhancing lesion. CDP will be assessed using EDSS. Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment.

Time frame: Weeks 96, 192

Secondary: Change From Baseline in Multiple Sclerosis Functional Composite Score (MSFC) Total

MSFC combines the following: Timed 25 Foot Walk Test \[T25FWT\] for leg function \&ambulation measured in seconds (sec). The longer it takes to walk, higher the score indicating deterioration; 9 Hole Peg Test \[9HPT\] for arm \& handf unction measured in sec. Higher score=more time taken to complete test indicating deterioration. Paced Auditory Serial Addition Test \[PASAT\] for cognitive function (score range: 0-60, higher score=better cognitive processing speed). MSFC composite={\[Average(1/9-HPT)-Baseline Mean(1/9-HPT)/Baseline Std Dev(1/9-HPT)\]+\[-(Average T25FWT-Baseline Mean T25FWT)/Baseline Std-Dev T25FWT\]+\[(PASAT-3-BaselineMean PASAT-3)/Baseline Std Dev PASAT-3\]}/ 3.0. MSFC is based on the concept that scores for these 3 dimensions are combined to create a single score to detect change over time in a group of MS patients. Higher composite score=better overall function. Lower score=worse overall function. Higher mean change in total MSFC score=functional improvement at cohort level.

Change From Baseline in MSFC Composite Timed 25 Foot Walk Test (T25FW) Score.

The change in the mean score of T25FW is reported below. The time taken to walk 25 feet, typically measured in seconds. The longer it takes to walk, the higher score, which indicates deterioration. Lower times indicate better performance and greater mobility. Higher times indicate worse performance and greater impairment. Subsequently, the lower the mean change in the score over time, the better performance.

Time frame: Baseline, Weeks 24, 48, 72, 96, 120, 144, 168, 192

Change From Baseline in MSFC Composite 9 Hole Peg Test (9HPT) Score

The mean change in 9 Hole Peg Test (9HPT)-score is reported. Participants are instructed to place pegs one by one into each of nine holes arranged in a board stabilized with a plastic nonslip sheet on a solid table, and then to remove these pegs from the holes. Both the dominant and non-dominant hands are tested twice (two consecutive trials for each hand). The participants are required to complete two successful trials for each hand. The amount of time (in seconds) required to place and remove all nine pegs is recorded for each trial. The number of seconds it takes to complete the test, the higher raw scores, which indicates deterioration. The lower mean change in the score over time, the better the performance.

Time frame: Weeks 24, 48, 72, 96, 120, 144, 168, 192

Change From Baseline in MSFC Composite (Paced Auditory Serial Addition Test [PASAT]) Score

Mean change in the Paced Auditory Serial Addition Test \[PASAT\] score is reported. PASAT measures cognitive function. A total of 60 single digit numbers are presented by an audiotape/CD-rom at a constant rate in every 3 seconds (PASAT-3). Participants are required to add each new number to the one immediately before it. Due to the relative complexity of this test, a practice trial with a set of 10 numbers should be performed before the original test. Participants are allowed up to 3 practice trials. Two sets of numbers (forms A \& B) are developed to be used alternatively in every visit to minimize memorizing. The number of correct answers is recorded. The PASAT score ranges from 0 to 60, with higher values representing a better outcome in cognitive processing speed. Subsequently, higher values in mean changes from baseline over the study time indicate improvement in cognitive function.

Time frame: Weeks 24, 48, 72, 96, 120, 144, 168, 192

Change From Baseline in Cognitive Performance as Measured by Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) - Symbol Digits Modalities Test (SDMT)

BICAMS is assessing cognitive processing speed and verbal and visual memory. SDMT assesses processing speed/working memory. 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 are asked to voice the digit associated with each symbol as rapidly as possible for 90 sec. There is a single outcome measure - the number correct over the 90 second time span. The higher the results, the better processing speed/working memory.

Time frame: Baseline, Weeks 48, 96, 144, 192

Change From Baseline in Cognitive Performance as Measured by BICAMS -California Verbal Learning Test-II (CVLT-II)

BICAMS assesses cognitive processing speed and verbal and visual memory. The CLVT-II is an assessment of verbal learning and memory which measures recall and recognition scores, encoding strategies, learning rates and error types. A list learning task with 16 words from 4 semantic categories are read over a series of 5 list presentations. Recall is assessed after learning and at a 20-minute delay. The maximum possible score is 80 and a minimum is 0. A higher score indicated better recall.

Time frame: Baseline, Weeks 48, 96, 144, 192

Change From Baseline in Cognitive Performance as Measured by BICAMS - Brief Visuospatial Memory Test-Revised (BVMT-R)

BICAMS assesses cognitive processing speed and verbal and visual memory. BVMT-R assesses visuospatial memory. In this test, six abstract designs are presented for 10 sec. The display is removed from view and patients render the stimuli via pencil on paper manual responses. Each design receives from 0 to 2 points representing accuracy and location. There are three learning trials, and the outcome measure is the total number of points earned over the three learning trials, thus the scale range is 0-36. The higher the result, the better visual/spatial memory.

Time frame: Baseline, Weeks 48, 96, 144, 192

Total Number of T1 Gd-Enhancing Lesions as Detected by Brain MRI

Number of Lesions are categorized as followed: 1, 2, 3, \>1, \>3

Time frame: Weeks 24, 48, 96, 144, 192

Total Number of New and/or Enlarging T2 Lesion as Detected by Brain MRI

Number of Lesions are categorized as followed: 1, 2, 3, \>1

Time frame: Baseline, Weeks 24, 48, 96, 144, 192

Total Number of Fluid-Attenuated Inversion-Recovery (FLAIR) Lesion as Detected by Brain MRI

Fluid-Attenuated Inversion-Recovery (FLAIR) Lesion as Detected by Brain MRI was measured for its volumes.

Time frame: Baseline, Weeks 8, 24, 48, 96, 144, 192

Change From Baseline in Brain Volume as Detected by Brain MRI

Percentage change from Normalized brain volume in cm3 (cubic centimeter)values are reported

Time frame: From Baseline to Weeks 24, 48, 96, 144, 192

Employment Status: Work Productivity and Activity Impairment Questionnaire (WAPI) Score

WPAI scale measures impact of health problems on work productivity and regular activities: Absenteeism (Work Time Missed) measuring % of work time missed due to health issues; Presenteeism:Calculated as the percentage of impairment while working due to health problems. Overall Work Impairment:Calculated by combining absenteeism and presenteeism using the formula:Overall Work Impairment=Absenteeism+(1-Absenteeism)×Presenteeism Overall Work Impairment=Absenteeism+(1-Absenteeism)×Presenteeism This formula accounts for both the time missed and the reduced productivity while at work. Activity Impairment: Calculated as the percentage of impairment in regular activities outside of work. Range: Each component is scored as 0%-100%). Higher % indicate greater impairment and worse outcomes.

Time frame: Baseline, Weeks 24, 48, 96, 120, 144, 192

SymptoMScreen Composite Score

The SMSS consists of 12 items which are assessed on a seven-point Likert scale that ranges from 0 (not at all affected) to 6 (total limitation) \[7\]. The total score ranges from 0 to 72, with higher scores indicating more severe symptom endorsement.

Time frame: Baseline, Weeks 24, 48, 96, 144, 192

Quality of Life: Multiple Sclerosis Impact Scale (MSIS)-29 Questionnaire Score

The 29-item Multiple Sclerosis Impact Scale (MSIS-29) is a questionnaire to examine the impact of multiple sclerosis (MS) on physical and psychological functioning from a patient's perspective, which includes 29 items self-reported measures associated with a physical scale and 9 items with a psychological scale. MSIS-29 scales are generated by summing items and it's ranging from 29-145'. The higher total MSIS-29 scores indicate a greater degree of disability. The mean change in MSIS-29 scores from baseline is reported. The decreasing values in the mean change from baseline indicate functional improvement from patients' perspective

Time frame: Baseline, Weeks 24, 48, 96, 144, 192

Substudy: Severity of IRRs

The number of participants with IRRs by most extreme intensity were reported (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 =life-threatening, grade 5 = fatal). Multiple IRRs in one participant are counted only once at the most extreme (highest) intensity observed.

Time frame: From Week 24 to Week 144