BENEFIT Study (Betaferon® / Betaseron® in Newly Emerging Multiple Sclerosis for Initial Treatment) and BENEFIT Follow-up Study

This study has been completed.

Sponsor:

Information provided by:

Bayer

ClinicalTrials.gov Identifier:

NCT00185211

First received: September 9, 2005

Last updated: December 14, 2012

Last verified: December 2012

History of Changes

Results First Received: July 23, 2009

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Multiple Sclerosis
Intervention:	Drug: Interferon beta-1b (Betaseron, BAY86-5046)

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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

Reporting Groups

	Description
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
Initial Placebo	Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)

Participant Flow for 2 periods

Period 1: Placebo-controlled Study (92012)

	Initial IFNB-1b (Interferon Beta-1b)	Initial Placebo
STARTED	292	176
COMPLETED	271	166
NOT COMPLETED	21	10
Adverse Event	8	0
Lost to Follow-up	3	2
Withdrawal by Subject	9	7
fulfilled local def. and McDonald crit.	0	1
Adverse event, then subject's withdrawal	1	0

Period 2: Follow-up Study (91031 - This Study)

	Initial IFNB-1b (Interferon Beta-1b)	Initial Placebo
STARTED	261 ^[1]	157 ^[2]
COMPLETED	235	123
NOT COMPLETED	26	34
Adverse Event	5	6
Lack of Efficacy	1	0
Lost to Follow-up	6	4
Physician Decision	1	0
Pregnancy	0	1
Withdrawal by Subject	13	21
other disease modif. treatment	0	2

[1]	10 of the 271 subjects completing the placebo-controlled study did not consent to the Follow-up.
[2]	9 of the 166 subjects completing the placebo-controlled study did not consent to the Follow-up.

Baseline Characteristics

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Reporting Groups

	Description
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
Initial Placebo	Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)
Total	Total of all reporting groups

Baseline Measures

	Initial IFNB-1b (Interferon Beta-1b)	Initial Placebo	Total
Number of Participants [units: participants]	292	176	468
Age [units: years] Mean ± Standard Deviation	30.8 ± 7.6	30.7 ± 7.1	30.7 ± 7.4
Gender [units: participants]
Female	207	124	331
Male	85	52	137
Number of T2 lesions detected in screening MRI (Magnet-Resonance Imaging) ^[1] [units: participants]
2 to 4 T2 lesions	42	25	67
5 to 8 T2 lesions	43	28	71
at least 9 T2 lesions	207	123	330
Number of participants with steroid use during the first clinical demyelinating event ^[2] [units: participants]
Steroid Use	209	123	332
No Steroid Use	83	53	136
Type of onset of disease (classification of first demyelinating event) ^[3] [units: participants]
monofocal disease	153	93	246
multifocal disease	139	83	222

[1]	Only patients with at least two clinically silent lesions on the T2-weighted brain MRI scan with a size of at least 3 mm, at least one of which is ovoid or periventricular or infratentorial, were included. Number of T2 lesions with the three categories was used in the minimization procedure.
[2]	The allocation of participants to the treatment arms was according to a minimization procedure with an element of randomization to minimize imbalances of treatment groups with respect to e.g. steroid use during first clinical demyelinating event. Steroid treatment was at the discretion of the investigator.
[3]	On the basis of the central classification of the patient’s symptoms and signs, the first event was classified as either monofocal (a single central nervous system (CNS) lesion suffices to explain the patient’s symptoms and signs) or multifocal (the patient’s symptoms and signs can only be explained by multiple (i.e. more than one) CNS lesions.

Outcome Measures

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1. 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 [ Time Frame: up to 60 months after start of treatment ]

Measure Type	Primary
Measure Title	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
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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
Initial Placebo	Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)

Measured Values

	Initial IFNB-1b (Interferon Beta-1b)	Initial Placebo
Number of Participants Analyzed [units: participants]	292	176
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 [units: cum. percentage of particip. with CDMS]
Kaplan-Meier estimate at year 2	26.9	45.0
Kaplan-Meier estimate at year 3	36.7	51.2
Kaplan-Meier estimate at year 5	46.2	57.3

Statistical Analysis 1 for 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

Groups ^[1]	All groups
Method ^[2]	Log Rank
P Value ^[3]	0.0027

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	A 2-sided error level of 0.0253 was used for analyses at month 36 and 60 in order to keep the study-wise error level at 0.05. A conditional sequential testing approach was used for the family of null hypotheses of the primary efficacy variables.

Statistical Analysis 2 for 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

Groups ^[1]	All groups
Method ^[2]	Regression, Cox
P Value ^[3]	0.0028
Hazard Ratio (HR) ^[4]	0.663
97.47% Confidence Interval	( 0.488 to 0.902 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	covariate adjustment: steroid use during first event, onset of disease, categorized number of T2 lesions at screening
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[4]	Other relevant estimation information:
	The direction of comparison is initial IFNB-1b (numerator) versus initial placebo (denominator), i.e. the Hazard Ratio represents the relative risk of initial IFNB-1b treatment compared to initial placebo treatment.

2. 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 [ Time Frame: up to 60 months after start of treatment ]

Measure Type	Primary
Measure Title	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
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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
Initial Placebo	Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)

Measured Values

	Initial IFNB-1b (Interferon Beta-1b)	Initial Placebo
Number of Participants Analyzed [units: participants]	292	176
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 [units: percentage of particip. with EDSS progr.]
Kaplan-Meier estimate at year 2	12.8	19.9
Kaplan-Meier estimate at year 3	16.8	25.3
Kaplan-Meier estimate at year 5	24.9	28.9

Statistical Analysis 1 for 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

Groups ^[1]	All groups
Method ^[2]	Log Rank
P Value ^[3]	0.1768

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	A 2-sided error level of 0.0253 was used for analyses at month 36 and 60 in order to keep the study-wise error level at 0.05. A conditional sequential testing approach was used for the family of null hypotheses of the primary efficacy variables.

Statistical Analysis 2 for 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

Groups ^[1]	All groups
Method ^[2]	Regression, Cox
P Value ^[3]	0.1604
Hazard Ratio (HR) ^[4]	0.764
97.47% Confidence Interval	( 0.497 to 1.174 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	The variable used as additional covariate adjustment was volume of T2 lesions on screening MRI.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[4]	Other relevant estimation information:
	The direction of comparison is initial IFNB-1b (numerator) versus initial placebo (denominator), i.e. the Hazard Ratio represents the relative risk of initial IFNB-1b treatment compared to initial placebo treatment.

3. Primary:

Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Month 60 [ Time Frame: 60 months after start of treatment ]

Measure Type	Primary
Measure Title	Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Month 60
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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
Initial Placebo	Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)

Measured Values

	Initial IFNB-1b (Interferon Beta-1b)	Initial Placebo
Number of Participants Analyzed [units: participants]	169	91
Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Month 60 [units: units on a scale] Median ( Inter-Quartile Range )	125 ( 107 to 139 )	125 ( 104.83 to 140 )

Statistical Analysis 1 for Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Month 60

Groups ^[1]	All groups
Method ^[2]	non-parametric ANCOVA
P Value ^[3]	0.8880

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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).
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Variable used as covariate: FAMS TOI measured at baseline
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	A 2-sided error level of 0.0253 was used for analyses at month 36 and 60 in order to keep the study-wise error level at 0.05. A conditional sequential testing approach was used for the family of null hypotheses of the primary efficacy variables.

Statistical Analysis 2 for Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Month 60

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.3832

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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).
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Variable used as covariate: FAMS TOI measured at baseline
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

4. Secondary:

Relapse-based Efficacy Domain: Time to Multiple Sclerosis (MS) According to McDonald Criteria [ Time Frame: up to 60 months after start of treatment ]

Measure Type	Secondary
Measure Title	Relapse-based Efficacy Domain: Time to Multiple Sclerosis (MS) According to McDonald Criteria
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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
Initial Placebo	Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)

Measured Values

	Initial IFNB-1b (Interferon Beta-1b)	Initial Placebo
Number of Participants Analyzed [units: participants]	292	176
Relapse-based Efficacy Domain: Time to Multiple Sclerosis (MS) According to McDonald Criteria [units: months] Median ( 95% Confidence Interval )	9.4 ( 8.8 to 12.1 )	6 ( 4.8 to 6.17 )

Statistical Analysis 1 for Relapse-based Efficacy Domain: Time to Multiple Sclerosis (MS) According to McDonald Criteria

Groups ^[1]	All groups
Method ^[2]	Log Rank
P Value ^[3]	0.000006

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.

Statistical Analysis 2 for Relapse-based Efficacy Domain: Time to Multiple Sclerosis (MS) According to McDonald Criteria

Groups ^[1]	All groups
Method ^[2]	Regression, Cox
P Value ^[3]	< 0.000001
Hazard Ratio (HR) ^[4]	0.583
95% Confidence Interval	( 0.474 to 0.718 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	covariate adjustment: steroid use during first event, onset of disease, categorized number of T2 lesions at screening
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[4]	Other relevant estimation information:
	The direction of comparison is initial IFNB-1b versus initial placebo, i.e. the Hazard Ratio represents the relative risk of initial IFNB-1b treatment compared to initial placebo treatment.

5. Secondary:

Relapse-based Efficacy Domain: Hazard Ratio for Recurrent Relapses [ Time Frame: up to 60 months after start of treatment ]

Measure Type	Secondary
Measure Title	Relapse-based Efficacy Domain: Hazard Ratio for Recurrent Relapses
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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).

Reporting Groups

	Description
All Subjects	All subjects part of Intention-To-Treat (ITT) Population

Measured Values

	All Subjects
Number of Participants Analyzed [units: participants]	468
Relapse-based Efficacy Domain: Hazard Ratio for Recurrent Relapses [units: Ratio]	0.797

Statistical Analysis 1 for Relapse-based Efficacy Domain: Hazard Ratio for Recurrent Relapses

Groups ^[1]	All Subjects
Method ^[2]	Andersen-Gill Model
P Value ^[3]	0.1265
Hazard Ratio (HR) ^[4]	0.797
95% Confidence Interval	( 0.595 to 1.066 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Covariate adjustment: steroid use during first event, onset of disease, categorized number of T2 lesions at screening
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
[4]	Other relevant estimation information:
	The direction of comparison is initial IFNB-1b (numerator) versus initial placebo (denominator), i.e. the Hazard Ratio represents the relative risk of initial IFNB-1b treatment compared to initial placebo treatment.

6. Secondary:

Relapse-based Efficacy Domain (Supportive): Annualized Relapse Rate [ Time Frame: up to 60 months after start of treatment ]

Measure Type	Secondary
Measure Title	Relapse-based Efficacy Domain (Supportive): Annualized Relapse Rate
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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
Initial Placebo	Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)

Measured Values

	Initial IFNB-1b (Interferon Beta-1b)	Initial Placebo
Number of Participants Analyzed [units: participants]	292	176
Relapse-based Efficacy Domain (Supportive): Annualized Relapse Rate [units: number of relapses per patient and year] Mean ( 95% Confidence Interval )	0.2139 ( 0.1895 to 0.2406 )	0.2695 ( 0.2337 to 0.3093 )

Statistical Analysis 1 for Relapse-based Efficacy Domain (Supportive): Annualized Relapse Rate

Groups ^[1]	All groups
Method ^[2]	generalized linear Poisson regression
P Value ^[3]	0.0141
Risk Ratio (RR) ^[4]	0.7971
95% Confidence Interval	( 0.6650 to 0.9554 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	covariate adjustment: steroid use during first event, onset of disease, categorized number of T2 lesions at screening
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
[4]	Other relevant estimation information:
	The direction of comparison is initial IFNB-1b (numerator) versus initial placebo (denominator), i.e. the Risk Ratio represents the relative risk of initial IFNB-1b treatment compared to initial placebo treatment.

7. Secondary:

Disability-based Efficacy Domain: Multiple Sclerosis Functional Composite (MSFC) at Month 60 [ Time Frame: 60 months after start of treatment ]

Measure Type	Secondary
Measure Title	Disability-based Efficacy Domain: Multiple Sclerosis Functional Composite (MSFC) at Month 60
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The analysis followed the ITT principle. Not all FAS patients completed the follow-up study or had MSFC results at month 60 available.

Reporting Groups

	Description
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
Initial Placebo	Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)

Measured Values

	Initial IFNB-1b (Interferon Beta-1b)	Initial Placebo
Number of Participants Analyzed [units: participants]	228	120
Disability-based Efficacy Domain: Multiple Sclerosis Functional Composite (MSFC) at Month 60 [units: Z-scores] Median ( Inter-Quartile Range )	0.226 ( -0.163 to 0.502 )	0.225 ( -0.207 to 0.619 )

Statistical Analysis 1 for Disability-based Efficacy Domain: Multiple Sclerosis Functional Composite (MSFC) at Month 60

Groups ^[1]	All groups
Method ^[2]	non-parametric ANCOVA
P Value ^[3]	0.6078

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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).
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Variable used as covariate: MSFC Z-scores measured at baseline
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.

Statistical Analysis 2 for Disability-based Efficacy Domain: Multiple Sclerosis Functional Composite (MSFC) at Month 60

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.8245

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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).
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Variable used as covariate: MSFC Z-scores measured at baseline
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.

8. Secondary:

MRI (Magnet-Resonance Imaging)-Based Efficacy Domain: Cumulative Number of Newly Active Lesions at Month 60 [ Time Frame: up to 60 months after start of treatment ]

Measure Type	Secondary
Measure Title	MRI (Magnet-Resonance Imaging)-Based Efficacy Domain: Cumulative Number of Newly Active Lesions at Month 60
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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
Initial Placebo	Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)

Measured Values

	Initial IFNB-1b (Interferon Beta-1b)	Initial Placebo
Number of Participants Analyzed [units: participants]	219	114
MRI (Magnet-Resonance Imaging)-Based Efficacy Domain: Cumulative Number of Newly Active Lesions at Month 60 [units: cumulative number of lesions] Median ( Inter-Quartile Range )	4 ( 1 to 12 )	7 ( 2 to 18 )

Statistical Analysis 1 for MRI (Magnet-Resonance Imaging)-Based Efficacy Domain: Cumulative Number of Newly Active Lesions at Month 60

Groups ^[1]	All groups
Method ^[2]	non-parametric ANCOVA
P Value ^[3]	0.0062

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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).
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Variable used as covariate: number of Gd-enhancing lesions on T1 at screening
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.

Statistical Analysis 2 for MRI (Magnet-Resonance Imaging)-Based Efficacy Domain: Cumulative Number of Newly Active Lesions at Month 60

Groups ^[1]	All groups
Method ^[2]	generalized linear model
P Value ^[3]	0.0435
Relative effect size ^[4]	0.7351
95% Confidence Interval	( 0.5436 to 0.9940 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Distribution: negative binomial distribution; covariate: number of Gd-enhancing lesions on T1 at screening
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
[4]	Other relevant estimation information:
	The direction of comparison is initial IFNB-1b versus initial placebo.

9. Secondary:

MRI-based Efficacy Domain: Absolute Change of T2 Lesion Volume From Screening MRI to Month 60 [ Time Frame: 60 months after start of treatment ]

Measure Type	Secondary
Measure Title	MRI-based Efficacy Domain: Absolute Change of T2 Lesion Volume From Screening MRI to Month 60
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The analysis followed the ITT principle. Not all FAS patients completed the follow-up study or had MRI scan readings at month 60 available.

Reporting Groups

	Description
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
Initial Placebo	Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)

Measured Values

	Initial IFNB-1b (Interferon Beta-1b)	Initial Placebo
Number of Participants Analyzed [units: participants]	215	112
MRI-based Efficacy Domain: Absolute Change of T2 Lesion Volume From Screening MRI to Month 60 [units: cubic millimeter] Median ( Inter-Quartile Range )	-123.0 ( -849.0 to 240.0 )	-194.5 ( -657.5 to 367.5 )

Statistical Analysis 1 for MRI-based Efficacy Domain: Absolute Change of T2 Lesion Volume From Screening MRI to Month 60

Groups ^[1]	All groups
Method ^[2]	non-parametric ANCOVA
P Value ^[3]	0.7801

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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).
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Variable used as covariate: T2 lesion volume at screening
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.

Statistical Analysis 2 for MRI-based Efficacy Domain: Absolute Change of T2 Lesion Volume From Screening MRI to Month 60

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.9408

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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).
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Variable used as covariate: T2 lesion volume at screening
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.

10. Secondary:

MRI-based Efficacy Domain: Absolute Change of Volume of Black Holes From Screening MRI to Month 60 [ Time Frame: 60 months after start of treatment ]

Measure Type	Secondary
Measure Title	MRI-based Efficacy Domain: Absolute Change of Volume of Black Holes From Screening MRI to Month 60
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The analysis followed the ITT principle. Not all FAS patients completed the follow-up study or had MRI scan readings at month 60 available.

Reporting Groups

	Description
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
Initial Placebo	Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)

Measured Values

	Initial IFNB-1b (Interferon Beta-1b)	Initial Placebo
Number of Participants Analyzed [units: participants]	217	114
MRI-based Efficacy Domain: Absolute Change of Volume of Black Holes From Screening MRI to Month 60 [units: cubic millimeter] Median ( Inter-Quartile Range )	0 ( -169 to 40 )	0 ( -94 to 54 )

Statistical Analysis 1 for MRI-based Efficacy Domain: Absolute Change of Volume of Black Holes From Screening MRI to Month 60

Groups ^[1]	All groups
Method ^[2]	non-parametric ANCOVA
P Value ^[3]	0.6619

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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).
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Variable used as covariate: Volume of black holes at screening
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.

Statistical Analysis 2 for MRI-based Efficacy Domain: Absolute Change of Volume of Black Holes From Screening MRI to Month 60

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.8558

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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).
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Variable used as covariate: Volume of black holes at screening
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.

11. Secondary:

MRI-based Efficacy Domain: Percentage Change of Brain Volume From Screening MRI to Month 60 [ Time Frame: 60 months after start of treatment ]

Measure Type	Secondary
Measure Title	MRI-based Efficacy Domain: Percentage Change of Brain Volume From Screening MRI to Month 60
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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
Initial Placebo	Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)

Measured Values

	Initial IFNB-1b (Interferon Beta-1b)	Initial Placebo
Number of Participants Analyzed [units: participants]	141	80
MRI-based Efficacy Domain: Percentage Change of Brain Volume From Screening MRI to Month 60 [units: Percentage of brain volume] Median ( Inter-Quartile Range )	-2.281 ( -3.672 to -1.062 )	-1.771 ( -3.294 to -0.667 )

Statistical Analysis 1 for MRI-based Efficacy Domain: Percentage Change of Brain Volume From Screening MRI to Month 60

Groups ^[1]	All groups
Method ^[2]	non-parametric ANCOVA
P Value ^[3]	0.1208

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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).
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Variable used as covariate: Brain volume at screening
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.

Statistical Analysis 2 for MRI-based Efficacy Domain: Percentage Change of Brain Volume From Screening MRI to Month 60

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.0719

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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).
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Variable used as covariate: Brain volume at screening
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Submit for review any manuscript / abstract related to the Study at least 90 days prior to publication.The proposed publication / presentation shall only be made after BSP has obtained adequate patent protection for the Results, or after the patentable information has been taken out of the publication/presentation.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Participant Flow: Subject with "Other" as reason for not completing a study period are presented according to the NIH pre-specified categories as far as possible.

Results Point of Contact:

Name/Title: Therapeutic Area Head
Organization: BAYER
e-mail: clinical-trials-contact@bayerhealthcare.com

Publications of Results:

Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalbán X, Barkhof F, Radü EW, Metzig C, Bauer L, Lanius V, Sandbrink R, Pohl C; BENEFIT Study Group. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009 Nov;8(11):987-97. Epub 2009 Sep 10.

Hartung HP, Freedman MS, Polman CH, Edan G, Kappos L, Miller DH, Montalbán X, Barkhof F, Petkau J, White R, Sahajpal V, Knappertz V, Beckmann K, Lanius V, Sandbrink R, Pohl C; BENEFIT Study Group. Interferon β-1b-neutralizing antibodies 5 years after clinically isolated syndrome. Neurology. 2011 Aug 30;77(9):835-43. doi: 10.1212/WNL.0b013e31822c90d7. Epub 2011 Aug 17. Erratum in: Neurology. 2011 Sep 27;77(13):1317.

Penner IK, Stemper B, Calabrese P, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalbán X, Barkhof F, Pleimes D, Lanius V, Pohl C, Kappos L, Sandbrink R. Effects of interferon beta-1b on cognitive performance in patients with a first event suggestive of multiple sclerosis. Mult Scler. 2012 Oct;18(10):1466-71. Epub 2012 Apr 4.

Freedman MS, Metzig C, Kappos L, Polman CH, Edan G, Hartung HP, Miller DH, Montalban X, Yarden J, Spector L, Fire E, Dotan N, Schwenke S, Lanius V, Sandbrink R, Pohl C. Predictive nature of IgM anti-α-glucose serum biomarker for relapse activity and EDSS progression in CIS patients: a BENEFIT study analysis. Mult Scler. 2012 Jul;18(7):966-73. doi: 10.1177/1352458511432327. Epub 2011 Dec 19.

Waschbisch A, Sandbrink R, Hartung HP, Kappos L, Schwab S, Pohl C, Wiendl H. Evaluation of soluble HLA-G as a biomarker for multiple sclerosis. Neurology. 2011 Aug 9;77(6):596-8. doi: 10.1212/WNL.0b013e318228c14d. Epub 2011 Jul 27.

Moraal B, Pohl C, Uitdehaag BM, Polman CH, Edan G, Freedman MS, Hartung HP, Kappos L, Miller DH, Montalban X, Lanius V, Sandbrink R, Barkhof F. Magnetic resonance imaging predictors of conversion to multiple sclerosis in the BENEFIT study. Arch Neurol. 2009 Nov;66(11):1345-52. doi: 10.1001/archneurol.2009.243.

Polman C, Kappos L, Freedman MS, Edan G, Hartung HP, Miller DH, Montalbán X, Barkhof F, Selmaj K, Uitdehaag BM, Dahms S, Bauer L, Pohl C, Sandbrink R; BENEFIT investigators. Subgroups of the BENEFIT study: risk of developing MS and treatment effect of interferon beta-1b. J Neurol. 2008 Apr;255(4):480-7. Epub 2007 Nov 15.

Caloyeras JP, Zhang B, Wang C, Eriksson M, Fredrikson S, Beckmann K, Knappertz V, Pohl C, Hartung HP, Shah D, Miller JD, Sandbrink R, Lanius V, Gondek K, Russell MW. Cost-effectiveness analysis of interferon beta-1b for the treatment of patients with a first clinical event suggestive of multiple sclerosis. Clin Ther. 2012 May;34(5):1132-44. doi: 10.1016/j.clinthera.2012.03.004. Epub 2012 Apr 27.

Nielsen JM, Pohl C, Polman CH, Barkhof F, Freedman MS, Edan G, Miller DH, Bauer L, Sandbrink R, Kappos L, Uitdehaag BM. MRI characteristics are predictive for CDMS in monofocal, but not in multifocal patients with a clinically isolated syndrome. BMC Neurol. 2009 May 20;9:19.

Barkhof F, Polman CH, Radue EW, Kappos L, Freedman MS, Edan G, Hartung HP, Miller DH, Montalban X, Poppe P, de Vos M, Lasri F, Bauer L, Dahms S, Wagner K, Pohl C, Sandbrink R. Magnetic resonance imaging effects of interferon beta-1b in the BENEFIT study: integrated 2-year results. Arch Neurol. 2007 Sep;64(9):1292-8.

Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Radu EW, Bauer L, Dahms S, Lanius V, Pohl C, Sandbrink R; BENEFIT Study Group. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet. 2007 Aug 4;370(9585):389-97.

De Jager PL, Chibnik LB, Cui J, Reischl J, Lehr S, Simon KC, Aubin C, Bauer D, Heubach JF, Sandbrink R, Tyblova M, Lelkova P; Steering committee of the BENEFIT study; Steering committee of the BEYOND study; Steering committee of the LTF study; Steering committee of the CCR1 study, Havrdova E, Pohl C, Horakova D, Ascherio A, Hafler DA, Karlson EW. Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score. Lancet Neurol. 2009 Dec;8(12):1111-9. doi: 10.1016/S1474-4422(09)70275-3. Epub 2009 Oct 29.

Responsible Party:	Therapeutic Area Head, Bayer HealthCare Pharmaceuticals Inc.
ClinicalTrials.gov Identifier:	NCT00185211 History of Changes
Other Study ID Numbers:	91031, 305207
Study First Received:	September 9, 2005
Results First Received:	July 23, 2009
Last Updated:	December 14, 2012
Health Authority:	United States: Food and Drug Administration Austria: Federal Ministry for Health and Women Canada: Health Canada Netherlands: Dutch Health Care Inspectorate Switzerland: Swissmedic Czech Republic: State Institute for Drug Control Germany: Federal Institute for Drugs and Medical Devices Denmark: Danish Medicines Agency Spain: Ministry of Health and Consumption France: French Data Protection Authority France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis) Finland: Finnish Medicines Agency Hungary: National Institute of Pharmacy Italy: Ministry of Health Norway: Norwegian Medicines Agency Portugal: National Pharmacy and Medicines Institute Poland: Ministry of Health Sweden: Medical Products Agency Slovenia: Ministry of Health United Kingdom: Medicines and Healthcare Products Regulatory Agency

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