Relapsing-Remitting Multiple Sclerosis
Conditions
Keywords
relapsing, multiple sclerosis, oral, remitting
Brief summary
To determine if treatment with BG00012 can decrease the number of MS relapses during a certain time period. Other goals of the study are to determine if, over time, BG00012 treatment can decrease the number of certain types of brain lesions commonly seen in MS patients and slow down the time it takes for MS to get worse. Other objectives of the study are to determine the safety and tolerability of BG00012, as well as the effect it may have on tests and evaluations used to assess MS. Additionally, glatiramer acetate is being used to compare its benefits and risks with placebo and BG00012.
Detailed description
Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects approximately 400,000 persons in North America and 365,000 persons in Europe. It is predominantly a disease of young adults, primarily women, with disease onset typically occurring between the ages of 20 and 40.
Interventions
Sponsors
Biogen
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
Unless otherwise specified, to be eligible to participate in this study, candidates must meet the following eligibility criteria at the time of the randomization: Key Inclusion Criteria: * Must have confirmed diagnosis of RRMS according to McDonald criteria #1-4 * Must have a baseline EDSS between 0.0 and 5.0, inclusive. * Must have relapsing-remitting disease course. Key
Exclusion criteria
* Other chronic disease of immune system, malignancies, urologic, pulmonary, gastrointestinal disease * Pregnant or nursing women Note: Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Relapse Rate | 2 years | A protocol-defined relapse was defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted at least 24 hours, and were separated by at least 30 days from onset of a preceding relapse. All protocol-defined relapses were evaluated by an independent neurologic evaluation committee. The adjusted annualized relapse rate was calculated from a negative binomial regression model , adjusted for baseline Expanded Disability Status Scale (EDSS ) score(≤2.0 versus\>2.0), age (\<40 versus ≥40 years), region, and the number of relapses in the 1 year prior to enrollment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of New or Newly Enlarging T2 Hyperintense Lesions | 2 years | The number of new or newly enlarging T2 hyperintense lesions at 2 years that developed in each subject compared to baseline assessed on brain magnetic resonance imaging (MRI) scans. The estimates of mean T2 hyperintense lesion count were calculated from a negative binomial regression model adjusted for region and baseline T2 hyperintense lesion volume. |
| Number of New T1 Hypointense Lesions | 2 years | The number of new T1 hypointense lesions at 2 years that developed in each subject compared to baseline assessed on brain magnetic resonance imaging (MRI) scans. The estimates of mean T1 hypointense lesion count were calculated from a negative binomial regression model adjusted for region and baseline T1 hypointense lesion volume. |
| Proportion of Subjects Relapsed | 2 years | A protocol-defined relapse was defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted at least 24 hours, and were separated by at least 30 days from onset of a preceding relapse. All protocol-defined relapses were evaluated by an independent neurologic evaluation committee. The proportion of subjects with a relapse was estimated using the Kaplan-Meier method, which was based on the time-to-first-relapse survival distribution. |
| Proportion of Subjects Experiencing Progression of Disability Assessed Using the Expanded Disability Status Scale (EDSS) | 2 years | EDSS is based on a standardized neurological exam and focuses on symptoms that commonly occur in MS. Scores range from 0.0 (normal) to 10.0 (death due to MS). Disability progression was defined as ≥ 1.0 point increase in subjects with a baseline EDSS of ≥1.0, or ≥1.5 point increase in subjects with a baseline EDSS=0, and required that the increase from baseline was confirmed ≥ 12weeks later. The proportion of subjects with confirmed (12-week) disability progression was estimated using the Kaplan-Meier method, which was based on the time-to-first-progression survival distribution |
Countries
Belarus, Belgium, Bosnia and Herzegovina, Bulgaria, Canada, Costa Rica, Croatia, Czechia, Estonia, France, Germany, Greece, India, Ireland, Israel, Latvia, Mexico, Moldova, New Zealand, North Macedonia, Poland, Puerto Rico, Romania, Serbia, Slovakia, Spain, Ukraine, United States
Participant flow
Recruitment details
Subjects were randomized at 205 investigational sites in 28 countries.
Pre-assignment details
From screening, 1430 eligible subjects were equally randomized. Of these, 1417 subjects received at least one dose of study treatment and comprised the intent-to-treat (ITT) and safety populations.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received two placebo capsules orally three times daily (TID) | 363 |
| BG00012 240 mg Twice Daily (BID) Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD) | 359 |
| BG00012 240 mg 3 Times Daily (TID) Participants received two 120 mg BG00012 capsules orally three times daily (TID) | 345 |
| Glatiramer Acetate (GA) 20 mg Injection Once Daily (QD) Participants received glatiramer acetate (GA) 20 mg subcutaneous injection once daily (QD) | 350 |
| Total | 1,417 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 21 | 26 | 10 |
| Overall Study | Consent Withdrawn | 14 | 9 | 17 | 17 |
| Overall Study | Death | 1 | 0 | 0 | 1 |
| Overall Study | Investigator Decision | 6 | 2 | 1 | 2 |
| Overall Study | Lost to Follow-up | 11 | 9 | 8 | 11 |
| Overall Study | Other Reasons for Not Completing Study | 34 | 30 | 17 | 14 |
| Overall Study | Subject Non-Compliance | 8 | 4 | 3 | 3 |
Baseline characteristics
| Characteristic | Placebo | BG00012 240 mg Twice Daily (BID) | BG00012 240 mg 3 Times Daily (TID) | Glatiramer Acetate (GA) 20 mg Injection Once Daily (QD) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 36.9 Years STANDARD_DEVIATION 9.24 | 37.8 Years STANDARD_DEVIATION 9.35 | 37.8 Years STANDARD_DEVIATION 9.39 | 36.7 Years STANDARD_DEVIATION 9.06 | 37.3 Years STANDARD_DEVIATION 9.26 |
| Mean Expanded Disability Status Scale (EDSS) score | 2.59 units on a scale STANDARD_DEVIATION 1.17 | 2.56 units on a scale STANDARD_DEVIATION 1.202 | 2.52 units on a scale STANDARD_DEVIATION 1.185 | 2.57 units on a scale STANDARD_DEVIATION 1.223 | 2.56 units on a scale STANDARD_DEVIATION 1.194 |
| Mean number of Gadolinium(Gd)-enhancing T1-weighted lesions | 2.7 Number of Gd enhancing lesions STANDARD_DEVIATION 7.71 | 2.7 Number of Gd enhancing lesions STANDARD_DEVIATION 6.22 | 1.9 Number of Gd enhancing lesions STANDARD_DEVIATION 5.02 | 2.4 Number of Gd enhancing lesions STANDARD_DEVIATION 6.81 | 2.4 Number of Gd enhancing lesions STANDARD_DEVIATION 6.51 |
| Mean number of relapses within the past 12 months | 1.4 Number of relapses STANDARD_DEVIATION 0.8 | 1.3 Number of relapses STANDARD_DEVIATION 0.63 | 1.4 Number of relapses STANDARD_DEVIATION 0.72 | 1.4 Number of relapses STANDARD_DEVIATION 0.64 | 1.4 Number of relapses STANDARD_DEVIATION 0.7 |
| Mean number of relapses within the previous 3 years | 2.5 Number of relapses STANDARD_DEVIATION 1.46 | 2.4 Number of relapses STANDARD_DEVIATION 1.27 | 2.6 Number of relapses STANDARD_DEVIATION 1.5 | 2.4 Number of relapses STANDARD_DEVIATION 1.32 | 2.5 Number of relapses STANDARD_DEVIATION 1.39 |
| Sex: Female, Male Female | 251 Participants | 245 Participants | 250 Participants | 247 Participants | 993 Participants |
| Sex: Female, Male Male | 112 Participants | 114 Participants | 95 Participants | 103 Participants | 424 Participants |
| Time since first multiple sclerosis (MS) diagnosis | 4.8 years STANDARD_DEVIATION 5.01 | 4.9 years STANDARD_DEVIATION 5.11 | 4.6 years STANDARD_DEVIATION 5.23 | 4.4 years STANDARD_DEVIATION 4.7 | 4.7 years STANDARD_DEVIATION 5.01 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 332 / 363 | 336 / 359 | 316 / 344 | 652 / 703 | 303 / 351 |
| serious Total, serious adverse events | 79 / 363 | 61 / 359 | 54 / 344 | 115 / 703 | 60 / 351 |
Outcome results
Primary
Annualized Relapse Rate
A protocol-defined relapse was defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted at least 24 hours, and were separated by at least 30 days from onset of a preceding relapse. All protocol-defined relapses were evaluated by an independent neurologic evaluation committee. The adjusted annualized relapse rate was calculated from a negative binomial regression model , adjusted for baseline Expanded Disability Status Scale (EDSS ) score(≤2.0 versus\>2.0), age (\<40 versus ≥40 years), region, and the number of relapses in the 1 year prior to enrollment.
Time frame: 2 years
Population: The intent-to-treat (ITT) population was defined as all subjects who were randomized and received at least 1 dose of study treatment. Among subjects who switched to an alternative therapy for multiple sclerosis, all the data before the switch were used for the analysis. In all other subjects, all relapses were included in the analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Annualized Relapse Rate | 0.401 Relapses Per Year |
| BG00012 240 mg Twice Daily (BID) | Annualized Relapse Rate | 0.224 Relapses Per Year |
| BG00012 240 mg 3 Times Daily (TID) | Annualized Relapse Rate | 0.198 Relapses Per Year |
| Glatiramer Acetate (GA) 20 mg Injection Once Daily (QD) | Annualized Relapse Rate | 0.286 Relapses Per Year |
Secondary
Number of New or Newly Enlarging T2 Hyperintense Lesions
The number of new or newly enlarging T2 hyperintense lesions at 2 years that developed in each subject compared to baseline assessed on brain magnetic resonance imaging (MRI) scans. The estimates of mean T2 hyperintense lesion count were calculated from a negative binomial regression model adjusted for region and baseline T2 hyperintense lesion volume.
Time frame: 2 years
Population: Of the 681 subjects in the MRI cohort, 572 (139 placebo, 140 BG00012 BID, 140 BG00012 TID, 153 GA) had post-baseline T2 hyperintense data \& were included in the analysis. Missing data before the use of alternative MS medications \& visits after subjects switched to alternative MS medications were imputed with the use of a constant rate assumption.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Number of New or Newly Enlarging T2 Hyperintense Lesions | 17.4 Number of lesions |
| BG00012 240 mg Twice Daily (BID) | Number of New or Newly Enlarging T2 Hyperintense Lesions | 5.1 Number of lesions |
| BG00012 240 mg 3 Times Daily (TID) | Number of New or Newly Enlarging T2 Hyperintense Lesions | 4.7 Number of lesions |
| Glatiramer Acetate (GA) 20 mg Injection Once Daily (QD) | Number of New or Newly Enlarging T2 Hyperintense Lesions | 8.0 Number of lesions |
Secondary
Number of New T1 Hypointense Lesions
The number of new T1 hypointense lesions at 2 years that developed in each subject compared to baseline assessed on brain magnetic resonance imaging (MRI) scans. The estimates of mean T1 hypointense lesion count were calculated from a negative binomial regression model adjusted for region and baseline T1 hypointense lesion volume.
Time frame: 2 years
Population: Of the 681 subjects in the MRI cohort, 573 (139 placebo,140 BG00012 BID,140 BG00012 TID,154 GA) had post-baseline new T1 hypointense data \& were included in the analysis. Missing data before the use of alternative MS medications \& visits after subjects switched to alternative MS medications were imputed with the use of a constant rate assumption
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Number of New T1 Hypointense Lesions | 7.0 Number of lesions |
| BG00012 240 mg Twice Daily (BID) | Number of New T1 Hypointense Lesions | 3.0 Number of lesions |
| BG00012 240 mg 3 Times Daily (TID) | Number of New T1 Hypointense Lesions | 2.4 Number of lesions |
| Glatiramer Acetate (GA) 20 mg Injection Once Daily (QD) | Number of New T1 Hypointense Lesions | 4.1 Number of lesions |
Secondary
Proportion of Subjects Experiencing Progression of Disability Assessed Using the Expanded Disability Status Scale (EDSS)
EDSS is based on a standardized neurological exam and focuses on symptoms that commonly occur in MS. Scores range from 0.0 (normal) to 10.0 (death due to MS). Disability progression was defined as ≥ 1.0 point increase in subjects with a baseline EDSS of ≥1.0, or ≥1.5 point increase in subjects with a baseline EDSS=0, and required that the increase from baseline was confirmed ≥ 12weeks later. The proportion of subjects with confirmed (12-week) disability progression was estimated using the Kaplan-Meier method, which was based on the time-to-first-progression survival distribution
Time frame: 2 years
Population: The analysis population consisted of the intent-to-treat (ITT) population (all subjects who were randomized and received at least 1 dose of study treatment) who had a baseline EDSS assessment. Analyses were based on all observed data. Onset of disability progression must begin before a subject switched to alternative MS medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Subjects Experiencing Progression of Disability Assessed Using the Expanded Disability Status Scale (EDSS) | 0.169 Proportion of Participants |
| BG00012 240 mg Twice Daily (BID) | Proportion of Subjects Experiencing Progression of Disability Assessed Using the Expanded Disability Status Scale (EDSS) | 0.128 Proportion of Participants |
| BG00012 240 mg 3 Times Daily (TID) | Proportion of Subjects Experiencing Progression of Disability Assessed Using the Expanded Disability Status Scale (EDSS) | 0.130 Proportion of Participants |
| Glatiramer Acetate (GA) 20 mg Injection Once Daily (QD) | Proportion of Subjects Experiencing Progression of Disability Assessed Using the Expanded Disability Status Scale (EDSS) | 0.156 Proportion of Participants |
Secondary
Proportion of Subjects Relapsed
A protocol-defined relapse was defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted at least 24 hours, and were separated by at least 30 days from onset of a preceding relapse. All protocol-defined relapses were evaluated by an independent neurologic evaluation committee. The proportion of subjects with a relapse was estimated using the Kaplan-Meier method, which was based on the time-to-first-relapse survival distribution.
Time frame: 2 years
Population: The analysis was based on the ITT population, defined as all subjects who were randomized and received at least 1 dose of study treatment. Among subjects who switched to an alternative therapy for MS, all the data before the switch were used for the analysis. In all other subjects, all relapses were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Subjects Relapsed | 0.410 Proportion of subjects,confirmed relapse |
| BG00012 240 mg Twice Daily (BID) | Proportion of Subjects Relapsed | 0.291 Proportion of subjects,confirmed relapse |
| BG00012 240 mg 3 Times Daily (TID) | Proportion of Subjects Relapsed | 0.241 Proportion of subjects,confirmed relapse |
| Glatiramer Acetate (GA) 20 mg Injection Once Daily (QD) | Proportion of Subjects Relapsed | 0.321 Proportion of subjects,confirmed relapse |