Multiple Sclerosis
Conditions
Brief summary
This study will primarily compare the long-term effects of an early and continued treatment with Betaferon/Betaseron (patients who were treated with active medication during the double-blind BENEFIT study) to treatment initiated either after Clinically Definite Multiple Sclerosis (CDMS) has been diagnosed or after two years (those patients who were treated with placebo during the double-blind BENEFIT study). Analyses are based on the integrated data of the initial BENEFIT study and this follow-up study.
Detailed description
The study has previously been posted by Schering AG, Germany. Schering AG, Germany has been renamed to Bayer HealthCare Pharmaceuticals Inc.. Bayer HealthCare Pharmaceuticals Inc. is the sponsor of the trial.
Interventions
Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase
Sponsors
Bayer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 48 Years
Healthy volunteers
No
Inclusion criteria
* Patients who have reached scheduled end of study in BENEFIT, either by developing CDMS or by completing 24 months
Exclusion criteria
* No participation in the initial BENEFIT study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS at Selected Points in Time | up to 60 months after start of treatment | CDMS could be reached due to a qualifying relapse or sustained progression of 1.5 points on the expanded disability status scale (EDSS) as compared to the lowest EDSS obtained during screening or Day 1. The validity of CDMS diagnoses was confirmed by a central committee. The EDSS scale quantifies disability in MS in 8 functional systems, values vary between 0=normal neurological examination and 10=death due to MS measured in half-points on an ordinal scale. Time to CDMS = date of CDMS - date of Day 1 + 1 or time to CDMS = date of last clinical visit - date of Day 1 + 1 (right-censored) |
| Time to Confirmed Expanded Disability Status Scale (EDSS) Progression Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With Confirmed EDSS Progression at Selected Points in Time | up to 60 months after start of treatment | EDSS progression was defined as an increase in the expanded disability status scale (EDSS) of 1.0 point compared to the lowest EDSS score obtained during the screening or baseline visit, if this score was <= 5.5. A confirmed EDSS progression status was defined as an EDSS progression observed at two consecutive scheduled visits at least 140 days apart from each other. The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0=normal neurological examination and 10=death due to MS measured in half-points on a scale. |
| Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Month 60 | 60 months after start of treatment | As an index of health related quality of life in people diagnosed with MS, the FAMS Trial Outcome Index covers overall physical health (sum of sub-scale scores Mobility, Symptoms, Thinking/Fatigue, Additional Concerns) with a score range from 0 to 148. A higher score reflects a higher overall physical health as reported by patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disability-based Efficacy Domain: Multiple Sclerosis Functional Composite (MSFC) at Month 60 | 60 months after start of treatment | The MSFC score consists of three sub-tests (Timed-25-Foot-Walk, 9-Hole-Peg-Test, 3 Paced Auditory Serial Addition Test \[PASAT\]). Standardized results (Z-scores) of the sub-tests and the overall MSFC Z-score as an average of the three Z-scores were derived using baseline data pooled over both treatment arms as reference population. Higher Z-scores reflect a better neurological status. |
| MRI (Magnet-Resonance Imaging)-Based Efficacy Domain: Cumulative Number of Newly Active Lesions at Month 60 | up to 60 months after start of treatment | Newly active lesions are defined as displaying either new Gadolinium (Gd)-enhancement on T1-weighted scans or non-enhancement on T1-weighted scan but new on T2-weighted scan. The numbers of newly active lesions on yearly MRI scans were summed up to the cumulative number. |
| Relapse-based Efficacy Domain: Time to Multiple Sclerosis (MS) According to McDonald Criteria | up to 60 months after start of treatment | MS according to the criteria by McDonald was reached if, in addition to the single clinical demyelinating event, both dissemination in space and dissemination in time were established by MRI-criteria or a new relapse. Time to McDonald MS is the difference of date of McDonald MS to the date of Day 1 + 1. For subjects without McDonald MS, time to McDonald MS is the difference from the maximum (date of last magnetic resonance imaging scan, date of last clinical visit) to the date of Day 1 + 1 (right-censored observation). |
| MRI-based Efficacy Domain: Absolute Change of Volume of Black Holes From Screening MRI to Month 60 | 60 months after start of treatment | Absolute change of volume of black holes from screening MRI to month 60 was calculated as volume of black holes at month 60 minus volume of black holes at screening. |
| MRI-based Efficacy Domain: Percentage Change of Brain Volume From Screening MRI to Month 60 | 60 months after start of treatment | Two-timepoint percentage brain volume change was estimated with Structural Image Evaluation, using Normalisation, of Atrophy (SIENA) software. The measurements describe the percentage change from screening in brain volume at month 60. |
| MRI-based Efficacy Domain: Absolute Change of T2 Lesion Volume From Screening MRI to Month 60 | 60 months after start of treatment | Absolute change of T2 lesion volume from screening MRI to month 60 was calculated as T2 lesion volume at month 60 minus T2 lesion volume at screening. |
| Relapse-based Efficacy Domain: Hazard Ratio for Recurrent Relapses | up to 60 months after start of treatment | A relapse was defined as the appearance of a new neurological abnormality or the reappearance of a neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The time to the onset of recurrent relapses was determined for each subject according to the counting process representation for recurrent events. Time to a relapse was right-censored if a relapse-risk period ended without relapse. Based on the Andersen-Gill model the hazard ratio for recurrent relapses was estimated. Annualized relapse rates are provided as another outcome measure. |
| Relapse-based Efficacy Domain (Supportive): Annualized Relapse Rate | up to 60 months after start of treatment | The annualized relapse rate is defined as total number of relapses up to month 60 divided by the total observation time (last clinical visit minus first day of study treatment administration plus 1 of all participants) in years. |
Countries
Austria, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Hungary, Israel, Italy, Netherlands, Norway, Poland, Portugal, Slovenia, Spain, Sweden, Switzerland, United Kingdom
Participant flow
Pre-assignment details
The full analysis set includes all 468 participants (particip.) with at least one administration of study drug in the placebo-controlled original study 92012, using treatment groups as randomized according to the minimization procedure regardless of the kind of study treatment (IFNB-1b/placebo) received. 19 subjects did not consent to the Follow-up
Participants by arm
| Arm | Count |
|---|---|
| Initial IFNB-1b (Interferon Beta-1b) Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase | 292 |
| Initial Placebo Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial) | 176 |
| Total | 468 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up Study (91031 - This Study) | Adverse Event | 5 | 6 |
| Follow-up Study (91031 - This Study) | Lack of Efficacy | 1 | 0 |
| Follow-up Study (91031 - This Study) | Lost to Follow-up | 6 | 4 |
| Follow-up Study (91031 - This Study) | other disease modif. treatment | 0 | 2 |
| Follow-up Study (91031 - This Study) | Physician Decision | 1 | 0 |
| Follow-up Study (91031 - This Study) | Pregnancy | 0 | 1 |
| Follow-up Study (91031 - This Study) | Withdrawal by Subject | 13 | 21 |
| Placebo-controlled Study (92012) | Adverse Event | 8 | 0 |
| Placebo-controlled Study (92012) | Adverse event, then subject's withdrawal | 1 | 0 |
| Placebo-controlled Study (92012) | fulfilled local def. and McDonald crit. | 0 | 1 |
| Placebo-controlled Study (92012) | Lost to Follow-up | 3 | 2 |
| Placebo-controlled Study (92012) | Withdrawal by Subject | 9 | 7 |
Baseline characteristics
| Characteristic | Initial IFNB-1b (Interferon Beta-1b) | Initial Placebo | Total |
|---|---|---|---|
| Age, Continuous | 30.8 years STANDARD_DEVIATION 7.6 | 30.7 years STANDARD_DEVIATION 7.1 | 30.7 years STANDARD_DEVIATION 7.4 |
| Number of participants with steroid use during the first clinical demyelinating event No Steroid Use | 83 participants | 53 participants | 136 participants |
| Number of participants with steroid use during the first clinical demyelinating event Steroid Use | 209 participants | 123 participants | 332 participants |
| Number of T2 lesions detected in screening MRI (Magnet-Resonance Imaging) 2 to 4 T2 lesions | 42 participants | 25 participants | 67 participants |
| Number of T2 lesions detected in screening MRI (Magnet-Resonance Imaging) 5 to 8 T2 lesions | 43 participants | 28 participants | 71 participants |
| Number of T2 lesions detected in screening MRI (Magnet-Resonance Imaging) at least 9 T2 lesions | 207 participants | 123 participants | 330 participants |
| Sex: Female, Male Female | 207 Participants | 124 Participants | 331 Participants |
| Sex: Female, Male Male | 85 Participants | 52 Participants | 137 Participants |
| Type of onset of disease (classification of first demyelinating event) monofocal disease | 153 participants | 93 participants | 246 participants |
| Type of onset of disease (classification of first demyelinating event) multifocal disease | 139 participants | 83 participants | 222 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 283 / 292 | 169 / 176 |
| serious Total, serious adverse events | 61 / 292 | 42 / 176 |
Outcome results
Primary
Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Month 60
As an index of health related quality of life in people diagnosed with MS, the FAMS Trial Outcome Index covers overall physical health (sum of sub-scale scores Mobility, Symptoms, Thinking/Fatigue, Additional Concerns) with a score range from 0 to 148. A higher score reflects a higher overall physical health as reported by patients.
Time frame: 60 months after start of treatment
Population: The analysis followed the ITT principle. Not all patients who completed the follow-up study could be included at month 60 as subject to copyright constraints and to the availability of validated language versions, FAMS assessments could not be conducted in all patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Initial IFNB-1b (Interferon Beta-1b) | Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Month 60 | 125 units on a scale |
| Initial Placebo | Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Month 60 | 125 units on a scale |
Comparison: The null hypothesis H0: The mean FAMS TOI at month 60, adjusted for baseline FAMS TOI, is identical for both treatment arms was tested against the alternative hypothesis HA: The mean FAMS TOI at month 60, adjusted for baseline FAMS TOI, is not the same in the two treatment arms using a parametric analysis of covariance (ANCOVA).p-value: 0.3832ANCOVA
Comparison: The null hypothesis H0: The distribution of FAMS TOI at month 60, adjusted for baseline FAMS TOI, is identical for both treatment arms was tested against the alternative hypothesis HA: The distribution of FAMS TOI at month 60, adjusted for baseline FAMS TOI, is not the same in the two treatment arms using a non-parametric analysis of covariance (ANCOVA).p-value: 0.888non-parametric ANCOVA
Primary
Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS at Selected Points in Time
CDMS could be reached due to a qualifying relapse or sustained progression of 1.5 points on the expanded disability status scale (EDSS) as compared to the lowest EDSS obtained during screening or Day 1. The validity of CDMS diagnoses was confirmed by a central committee. The EDSS scale quantifies disability in MS in 8 functional systems, values vary between 0=normal neurological examination and 10=death due to MS measured in half-points on an ordinal scale. Time to CDMS = date of CDMS - date of Day 1 + 1 or time to CDMS = date of last clinical visit - date of Day 1 + 1 (right-censored)
Time frame: up to 60 months after start of treatment
Population: The analysis followed the intention to treat (ITT) principle. After five years, in the initial placebo arm 94 participants and in the initial IFNB-1b arm 124 participants had reached CDMS diagnosis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Initial IFNB-1b (Interferon Beta-1b) | Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS at Selected Points in Time | Kaplan-Meier estimate at year 2 | 26.9 cum. percentage of particip. with CDMS |
| Initial IFNB-1b (Interferon Beta-1b) | Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS at Selected Points in Time | Kaplan-Meier estimate at year 3 | 36.7 cum. percentage of particip. with CDMS |
| Initial IFNB-1b (Interferon Beta-1b) | Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS at Selected Points in Time | Kaplan-Meier estimate at year 5 | 46.2 cum. percentage of particip. with CDMS |
| Initial Placebo | Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS at Selected Points in Time | Kaplan-Meier estimate at year 2 | 45.0 cum. percentage of particip. with CDMS |
| Initial Placebo | Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS at Selected Points in Time | Kaplan-Meier estimate at year 3 | 51.2 cum. percentage of particip. with CDMS |
| Initial Placebo | Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS at Selected Points in Time | Kaplan-Meier estimate at year 5 | 57.3 cum. percentage of particip. with CDMS |
Comparison: The null hypothesis for comparison of initial IFNB-1b versus initial placebo treatment was:~H0: The survival functions (i.e., the probability that time to CDMS is ≥ t) are identical for both treatment arms for all points in time t\>0.~The two-sided alternative hypothesis was:~H1: The survival functions (i.e., the probability that time to CDMS is ≥ t) are not identical for both treatment arms for some points in time t\>0.p-value: 0.0027Log Rank
Comparison: Time to CDMS was modelled by a Cox proportional hazards regression model with the following covariates: treatment group, steroid use during first event (yes vs. no), onset of disease (monofocal vs. multifocal) and number of T2 lesions at screening (categories: 2-4, 5-8 and at least 9 T2 lesions). The null hypothesis was: Initial IFNB-1b and initial placebo do not differ with regard to the hazard for CDMS, i.e. hazard ratio = 1.p-value: 0.002897.47% CI: [0.488, 0.902]Regression, Cox
Primary
Time to Confirmed Expanded Disability Status Scale (EDSS) Progression Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With Confirmed EDSS Progression at Selected Points in Time
EDSS progression was defined as an increase in the expanded disability status scale (EDSS) of 1.0 point compared to the lowest EDSS score obtained during the screening or baseline visit, if this score was <= 5.5. A confirmed EDSS progression status was defined as an EDSS progression observed at two consecutive scheduled visits at least 140 days apart from each other. The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0=normal neurological examination and 10=death due to MS measured in half-points on a scale.
Time frame: up to 60 months after start of treatment
Population: The analysis followed the ITT principle. The 25%-percentile for time to confirmed EDSS progression was 908 days in the initial placebo arm but was not estimable in the initial IFNB-1b arm. After five years, in the initial placebo arm 47 participants and in the initial IFNB-1b arm 65 participants had reached confirmed EDSS progression.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Initial IFNB-1b (Interferon Beta-1b) | Time to Confirmed Expanded Disability Status Scale (EDSS) Progression Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With Confirmed EDSS Progression at Selected Points in Time | Kaplan-Meier estimate at year 2 | 12.8 percentage of particip. with EDSS progr. |
| Initial IFNB-1b (Interferon Beta-1b) | Time to Confirmed Expanded Disability Status Scale (EDSS) Progression Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With Confirmed EDSS Progression at Selected Points in Time | Kaplan-Meier estimate at year 3 | 16.8 percentage of particip. with EDSS progr. |
| Initial IFNB-1b (Interferon Beta-1b) | Time to Confirmed Expanded Disability Status Scale (EDSS) Progression Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With Confirmed EDSS Progression at Selected Points in Time | Kaplan-Meier estimate at year 5 | 24.9 percentage of particip. with EDSS progr. |
| Initial Placebo | Time to Confirmed Expanded Disability Status Scale (EDSS) Progression Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With Confirmed EDSS Progression at Selected Points in Time | Kaplan-Meier estimate at year 2 | 19.9 percentage of particip. with EDSS progr. |
| Initial Placebo | Time to Confirmed Expanded Disability Status Scale (EDSS) Progression Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With Confirmed EDSS Progression at Selected Points in Time | Kaplan-Meier estimate at year 3 | 25.3 percentage of particip. with EDSS progr. |
| Initial Placebo | Time to Confirmed Expanded Disability Status Scale (EDSS) Progression Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With Confirmed EDSS Progression at Selected Points in Time | Kaplan-Meier estimate at year 5 | 28.9 percentage of particip. with EDSS progr. |
Comparison: The null hypothesis for comparison of initial IFNB-1b versus initial placebo treatment was: H0: The survival functions (i.e., the probability that time to confirmed EDSS progression is ≥ t) are not identical for both treatment arms for some points in time t\>0. The two-sided alternative hypothesis was: H1: The survival functions (i.e., the probability that time to confirmed EDSS progression is ≥ t) are identical for both treatment arms for some points in time t\>0.p-value: 0.1768Log Rank
Comparison: Time to confirmed EDSS progression was modelled by a Cox proportional hazards regression model with the following covariates: treatment group and volume of T2 lesions on screening MRI. The null hypothesis was: Initial IFNB-1b and initial placebo do not differ with regard to the hazard for confirmed EDSS progression, i.e. hazard ratio = 1.p-value: 0.160497.47% CI: [0.497, 1.174]Regression, Cox
Secondary
Disability-based Efficacy Domain: Multiple Sclerosis Functional Composite (MSFC) at Month 60
The MSFC score consists of three sub-tests (Timed-25-Foot-Walk, 9-Hole-Peg-Test, 3 Paced Auditory Serial Addition Test \[PASAT\]). Standardized results (Z-scores) of the sub-tests and the overall MSFC Z-score as an average of the three Z-scores were derived using baseline data pooled over both treatment arms as reference population. Higher Z-scores reflect a better neurological status.
Time frame: 60 months after start of treatment
Population: The analysis followed the ITT principle. Not all FAS patients completed the follow-up study or had MSFC results at month 60 available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Initial IFNB-1b (Interferon Beta-1b) | Disability-based Efficacy Domain: Multiple Sclerosis Functional Composite (MSFC) at Month 60 | 0.226 Z-scores |
| Initial Placebo | Disability-based Efficacy Domain: Multiple Sclerosis Functional Composite (MSFC) at Month 60 | 0.225 Z-scores |
Comparison: The null hypothesis H0: The distribution of MSFC Z-scores at month 60 adjusted for baseline MSFC Z-score is identical for both treatment arms was tested against the alternative hypothesis HA: The distribution of MSFC Z-scores at month 60 adjusted for baseline MSFC Z-score is not the same in the two treatment groups based on a non-parametric analysis of covariance (ANCOVA).p-value: 0.6078non-parametric ANCOVA
Comparison: The null hypothesis H0: The mean MSFC Z-scores at month 60 adjusted for baseline MSFC Z-score are identical for both treatment arms was tested against the alternative hypothesis HA: The mean MSFC Z-scores at month 60 adjusted for baseline MSFC Z-score are not the same in the two treatment groups based on a non-parametric analysis of covariance (ANCOVA).p-value: 0.8245ANCOVA
Secondary
MRI-based Efficacy Domain: Absolute Change of T2 Lesion Volume From Screening MRI to Month 60
Absolute change of T2 lesion volume from screening MRI to month 60 was calculated as T2 lesion volume at month 60 minus T2 lesion volume at screening.
Time frame: 60 months after start of treatment
Population: The analysis followed the ITT principle. Not all FAS patients completed the follow-up study or had MRI scan readings at month 60 available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Initial IFNB-1b (Interferon Beta-1b) | MRI-based Efficacy Domain: Absolute Change of T2 Lesion Volume From Screening MRI to Month 60 | -123.0 cubic millimeter |
| Initial Placebo | MRI-based Efficacy Domain: Absolute Change of T2 Lesion Volume From Screening MRI to Month 60 | -194.5 cubic millimeter |
Comparison: The null hypothesis H0: The distribution of the absolute change of T2 lesion volume at month 60 adjusted for the T2 lesion volume at screening is identical for both treatment arms. was tested against the corresponding two-sided alternative hypothesis based on a non-parametric analysis of covariance (ANCOVA).p-value: 0.7801non-parametric ANCOVA
Comparison: The null hypothesis H0: The mean absolute change of T2 lesion volume at month 60 adjusted for the T2 lesion volume at screening is identical for both treatment arms. was tested against the corresponding two-sided alternative hypothesis based on a parametric analysis of covariance (ANCOVA).p-value: 0.9408ANCOVA
Secondary
MRI-based Efficacy Domain: Absolute Change of Volume of Black Holes From Screening MRI to Month 60
Absolute change of volume of black holes from screening MRI to month 60 was calculated as volume of black holes at month 60 minus volume of black holes at screening.
Time frame: 60 months after start of treatment
Population: The analysis followed the ITT principle. Not all FAS patients completed the follow-up study or had MRI scan readings at month 60 available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Initial IFNB-1b (Interferon Beta-1b) | MRI-based Efficacy Domain: Absolute Change of Volume of Black Holes From Screening MRI to Month 60 | 0 cubic millimeter |
| Initial Placebo | MRI-based Efficacy Domain: Absolute Change of Volume of Black Holes From Screening MRI to Month 60 | 0 cubic millimeter |
Comparison: The null hypothesis H0: The distribution of the absolute change of volume of black holes at month 60 adjusted for the volume of black holes at screening is identical for both treatment arms. was tested against the corresponding two-sided alternative hypothesis based on a non-parametric analysis of covariance (ANCOVA).p-value: 0.6619non-parametric ANCOVA
Comparison: The null hypothesis H0: The mean absolute change of volume of black holes at month 60 adjusted for the volume of black holes at screening is identical for both treatment arms. was tested against the corresponding two-sided alternative hypothesis based on a parametric analysis of covariance (ANCOVA).p-value: 0.8558ANCOVA
Secondary
MRI-based Efficacy Domain: Percentage Change of Brain Volume From Screening MRI to Month 60
Two-timepoint percentage brain volume change was estimated with Structural Image Evaluation, using Normalisation, of Atrophy (SIENA) software. The measurements describe the percentage change from screening in brain volume at month 60.
Time frame: 60 months after start of treatment
Population: The analysis followed the ITT principle. Not all patients in the full analysis set completed the follow-up study or had MRI scan readings at month 60 available. There were several missing values in both treatment arms regarding the percentage brain volume change.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Initial IFNB-1b (Interferon Beta-1b) | MRI-based Efficacy Domain: Percentage Change of Brain Volume From Screening MRI to Month 60 | -2.281 Percentage of brain volume |
| Initial Placebo | MRI-based Efficacy Domain: Percentage Change of Brain Volume From Screening MRI to Month 60 | -1.771 Percentage of brain volume |
Comparison: The null hypothesis H0: The distribution of the percentage change of brain volume at month 60 adjusted for the brain volume at screening is identical for both treatment arms. was tested against the corresponding two-sided alternative hypothesis based on a non-parametric analysis of covariance (ANCOVA).p-value: 0.1208non-parametric ANCOVA
Comparison: The null hypothesis H0: The mean percentage change of brain volume at month 60 adjusted for the brain volume at screening is identical for both treatment arms. was tested against the corresponding two-sided alternative hypothesis based on a parametric analysis of covariance (ANCOVA).p-value: 0.0719ANCOVA
Secondary
MRI (Magnet-Resonance Imaging)-Based Efficacy Domain: Cumulative Number of Newly Active Lesions at Month 60
Newly active lesions are defined as displaying either new Gadolinium (Gd)-enhancement on T1-weighted scans or non-enhancement on T1-weighted scan but new on T2-weighted scan. The numbers of newly active lesions on yearly MRI scans were summed up to the cumulative number.
Time frame: up to 60 months after start of treatment
Population: The analysis followed the ITT principle. Not all patients in the full analysis set completed the follow-up study or had MRI scan readings at month 60 available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Initial IFNB-1b (Interferon Beta-1b) | MRI (Magnet-Resonance Imaging)-Based Efficacy Domain: Cumulative Number of Newly Active Lesions at Month 60 | 4 cumulative number of lesions |
| Initial Placebo | MRI (Magnet-Resonance Imaging)-Based Efficacy Domain: Cumulative Number of Newly Active Lesions at Month 60 | 7 cumulative number of lesions |
Comparison: The null hypothesis H0: The distribution of the cumulative number of newly active lesions at month 60 adjusted for the number of Gadolinium (Gd)-enhancing lesions on T1 at screening is identical for both treatment arms. was tested against the corresponding two-sided alternative hypothesis based on a non-parametric analysis of covariance (ANCOVA).p-value: 0.0062non-parametric ANCOVA
Comparison: Assuming that the cumulative number of newly active lesions at month 60 follows a negative binomial distribution, a generalized linear model (logarithmic link function, covariate: number of Gd-enhancing lesions on T1 at BENEFIT screening) was set up in order to analyze the treatment effect on that MRI outcome.p-value: 0.043595% CI: [0.5436, 0.994]generalized linear model
Secondary
Relapse-based Efficacy Domain: Hazard Ratio for Recurrent Relapses
A relapse was defined as the appearance of a new neurological abnormality or the reappearance of a neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The time to the onset of recurrent relapses was determined for each subject according to the counting process representation for recurrent events. Time to a relapse was right-censored if a relapse-risk period ended without relapse. Based on the Andersen-Gill model the hazard ratio for recurrent relapses was estimated. Annualized relapse rates are provided as another outcome measure.
Time frame: up to 60 months after start of treatment
Population: The analysis followed the Intention-To-Treat (ITT) principle. The hazard for recurrent relapses was modelled by an extension of the Cox Proportional Hazards (PH) regression model (Andersen-Gill Model).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Initial IFNB-1b (Interferon Beta-1b) | Relapse-based Efficacy Domain: Hazard Ratio for Recurrent Relapses | 0.797 Ratio |
Comparison: The time to recurrent relapses was modelled by an extension of Cox's PH regression model (Andersen-Gill Model) for recurrent events with the following covariates: treatment group, steroid use during first event (yes vs. no), onset of disease (monofocal vs. multifocal) and number of T2 lesions at screening (2-4, 5-8 and at least 9 T2 lesions). The null hypothesis was: Initial IFNB-1b and initial placebo do not differ with regard to the hazard for recurrent relapses, i.e. hazard ratio = 1.p-value: 0.126595% CI: [0.595, 1.066]Andersen-Gill Model
Secondary
Relapse-based Efficacy Domain (Supportive): Annualized Relapse Rate
The annualized relapse rate is defined as total number of relapses up to month 60 divided by the total observation time (last clinical visit minus first day of study treatment administration plus 1 of all participants) in years.
Time frame: up to 60 months after start of treatment
Population: The analysis followed the ITT principle. For each treatment arm, the relapse rate is defined as total number of relapses up to month 60 divided by the total observation time in years.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Initial IFNB-1b (Interferon Beta-1b) | Relapse-based Efficacy Domain (Supportive): Annualized Relapse Rate | 0.2139 number of relapses per patient and year |
| Initial Placebo | Relapse-based Efficacy Domain (Supportive): Annualized Relapse Rate | 0.2695 number of relapses per patient and year |
Comparison: Relapse rate was analyzed by a generalized linear Poisson regression model with individual relapse counts as dependent variable, covariates: treatment arm, steroid use during first event, onset of disease and categorized number of T2 lesions at screening and offset variable natural log of time (in years) as difference between last clinical visit and baseline visit. The treatment effect on the relapse rate was of primary interest.p-value: 0.014195% CI: [0.665, 0.9554]generalized linear Poisson regression
Secondary
Relapse-based Efficacy Domain: Time to Multiple Sclerosis (MS) According to McDonald Criteria
MS according to the criteria by McDonald was reached if, in addition to the single clinical demyelinating event, both dissemination in space and dissemination in time were established by MRI-criteria or a new relapse. Time to McDonald MS is the difference of date of McDonald MS to the date of Day 1 + 1. For subjects without McDonald MS, time to McDonald MS is the difference from the maximum (date of last magnetic resonance imaging scan, date of last clinical visit) to the date of Day 1 + 1 (right-censored observation).
Time frame: up to 60 months after start of treatment
Population: The analysis followed the ITT principle. After five years, in the initial placebo arm 151 participants and in the initial IFNB-1b arm 224 participants had reached McDonald MS diagnosis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Initial IFNB-1b (Interferon Beta-1b) | Relapse-based Efficacy Domain: Time to Multiple Sclerosis (MS) According to McDonald Criteria | 9.4 months |
| Initial Placebo | Relapse-based Efficacy Domain: Time to Multiple Sclerosis (MS) According to McDonald Criteria | 6 months |
Comparison: The null hypothesis for comparison of initial IFNB-1b versus initial placebo treatment was:~H0: The survival functions (i.e., the probability that time to McDonald MS is ≥ t) are identical for both treatment arms for all points in time t\>0.~The two-sided alternative hypothesis was:~H1: The survival functions (i.e., the probability that time to McDonald MS is ≥ t) are not identical for both treatment arms for some points in time t\>0.p-value: 0.000006Log Rank
Comparison: Time to McDonald MS was modelled by a Cox proportional hazards regression model with the following covariates: treatment group, steroid use during first event (yes vs. no), onset of disease (monofocal vs. multifocal) and number of T2 lesions at screening (categories: 2-4, 5-8 and at least 9 T2 lesions). The null hypothesis was: Initial IFNB-1b and initial placebo do not differ with regard to the hazard for McDonald MS, i.e. hazard ratio = 1.p-value: <0.00000195% CI: [0.474, 0.718]Regression, Cox