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Clinical Trial Results:
BENEFIT 11 a long-term, follow-up study (16401) of the BENEFIT (304747), BENEFIT Follow-up (305207) Studies and BENEFIT Extension (311129) Study to further evaluate the progress of patients with first demyelinating event suggestive of multiple sclerosis

Summary
EudraCT number	2012-005262-35
Trial protocol	BE SE PT HU CZ NO AT FI DK GB ES IT SI PL
Global end of trial date	18 Jun 2014

Results information
Results version number	v2(current)
This version publication date	04 Sep 2016
First version publication date	26 Jul 2015
Other versions	v1
Version creation reason	New data added to full data set Correction of full data set Bayer sponsor contact information to be updated

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BAY86-5046/16401

ISRCTN number

US NCT number

NCT01795872

WHO universal trial number (UTN)

Sponsor organisation name

Bayer AG

Sponsor organisation address

Kaiser Wilhelm Allee, D-51368, Leverkusen, Germany,

Public contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Scientific contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

18 Jun 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 Jun 2014

Was the trial ended prematurely?

Main objective of the trial

The primary objectives were to describe the disease course (in particular conversion to clinically-definite multiple sclerosis [CDMS]), relapse activity, change in disability, cognitive function, resource use, and employment status, in relation to Interferon beta-1b treatment.

Protection of trial subjects

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Sep 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Norway: 3

Country: Number of subjects enrolled

Poland: 42

Country: Number of subjects enrolled

Portugal: 1

Country: Number of subjects enrolled

Slovenia: 4

Country: Number of subjects enrolled

Spain: 30

Country: Number of subjects enrolled

Sweden: 5

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

Austria: 6

Country: Number of subjects enrolled

Belgium: 16

Country: Number of subjects enrolled

Czech Republic: 36

Country: Number of subjects enrolled

Denmark: 2

Country: Number of subjects enrolled

Finland: 19

Country: Number of subjects enrolled

Germany: 44

Country: Number of subjects enrolled

Hungary: 23

Country: Number of subjects enrolled

Italy: 8

Country: Number of subjects enrolled

Switzerland: 6

Country: Number of subjects enrolled

Canada: 11

Country: Number of subjects enrolled

France: 15

Country: Number of subjects enrolled

Israel: 3

Worldwide total number of subjects

278

EEA total number of subjects

258

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

278

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study was conducted in 19 countries from 20 September 2013 (first subject first visit) to 11 April 2014 (last subject last visit). Subjects who did not participate in a physical/face-to-face visit, had the option of being assessed via telephone on selected key outcomes, in an attempt to keep the subject's ascertainment as high as possible.

Screening details

All subjects who were randomized and treated at least once in the BENEFIT Study NCT00185211 (inclusive of subjects, who prematurely discontinued study participation in that study) and enrolled into the BENEFIT 11 Study 2012-005262-35. Of 468 subjects from original BENEFIT study, a total of 278 subjects were enrolled into the BENEFIT 11 study.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)

Arm description

Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 microgram administered subcutaneously every other day in original BENEFIT (304747 / 92012 / NCT00185211) study; continued in BENEFIT Follow-up (305207 / 91031/ NCT00185211) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice.

Arm type

Experimental

Investigational medicinal product name

Interferon Beta-1b (IFNB-1b)

Investigational medicinal product code

BAY86-5046

Other name

Betaserons, Betaferon

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 microgram administered subcutaneously every other day in original BENEFIT (304747 / 92012 / NCT00185211) study; continued in BENEFIT Follow-up (305207 / 91031) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice.

Initial Placebo

Arm description

Initial placebo treatment administered in original BENEFIT (304747 / 92012 / NCT00185211) study; Betaferon/Betaseron, 250 microgram administered subcutaneous every other day offered in BENEFIT Follow-up (305207 / 91031) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Started	167	111
Completed	167	109
Not completed	0	2
Death	-	1
Unspecified reason	-	1

Baseline characteristics

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Reporting group title

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)

Reporting group description

Reporting group title

Initial Placebo

Reporting group description

Reporting group values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo	Total
Number of subjects	167	111	278
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	31.2 ± 7.5	30.8 ± 7.2	-
Gender categorical
Units: Subjects
Female	122	73	195
Male	45	38	83

End points

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Reporting group title

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)

Reporting group description

Reporting group title

Initial Placebo

Reporting group description

Subject analysis set title

BENEFIT 11 set

Subject analysis set type

Sub-group analysis

Subject analysis set description

BENEFIT 11 set is a subset of the FAS and included all subjects who were enrolled in the BENEFIT 11 study (16401) and treated with IFNB-1b (N=167) and Placebo (N=111).

Primary: Time to First Relapse by Kaplan-Meier Estimates

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End point title

Time to First Relapse by Kaplan-Meier Estimates

End point description

Relapses are key features of the clinical presentation of multiple sclerosis. Relapses were assessed retrospectively based on clinical records and subject history. Time to first relapse is the difference from date of first relapse to the date of the BENEFIT baseline visit +1 or time to first relapse is the difference from date of last clinical visit to the date of the BENEFIT baseline visit + 1 (right censored).

End point type

Primary

End point timeframe

Up to Year 11 (Day 3960)

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[1]	111 ^[2]
Units: cumulative probability of relapse
number (not applicable)	71.9	77.5

Notes
[1] - BENEFIT 11 set
[2] - BENEFIT 11 set

Statistical analysis 1

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1034

Method

Logrank

Confidence interval

Statistical analysis 2

Statistical analysis description

An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is IFNB-1b 250 microgram versus placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 - 4, 5 - 8, >=9).

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0991

Method

PH regression

Parameter type

Hazard ratio (HR)

Point estimate

0.792

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

1.045

Primary: Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates

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End point title

Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates

End point 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 and a total EDSS of >=2.5. The validity of CDMS diagnoses was confirmed by a central committee. The EDSS scale quantifies disability in multiple sclerosis (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 = the difference from date of CDMS to the date of Day 1 + 1 or time to CDMS = the difference from date of last clinical visit to the Day 1+1 (right censored).

End point type

Primary

End point timeframe

Up to Year 11 (Day 3960)

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[3]	111 ^[4]
Units: cumulative probability of CDMS
number (not applicable)	68.1	74.8

Notes
[3] - BENEFIT 11 set
[4] - BENEFIT 11 set

Statistical analysis 1

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1307

Method

Logrank

Confidence interval

Statistical analysis 2

Statistical analysis description

An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is, IFNB-1b 250 microgram versus placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 - 4, 5 - 8, >=9).

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1204

Method

PH regression

Parameter type

Hazard ratio (HR)

Point estimate

0.799

Confidence interval

level

95%

sides

2-sided

lower limit

0.601

upper limit

1.061

Primary: Number of Subjects With Diagnosis of Multiple Sclerosis Within Eleven years after Clinically-Isolated Syndrome (CIS) According to McDonald 2001 and 2010 Criteria

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End point title

Number of Subjects With Diagnosis of Multiple Sclerosis Within Eleven years after Clinically-Isolated Syndrome (CIS) According to McDonald 2001 and 2010 Criteria ^[5]

End point description

MS according to the criteria by McDonald was reached if, in addition to the single clinical demyelinating event, both dissemination in space (DIS) and dissemination in time (DIT) were established by magnetic resonance imaging (MRI) criteria or a new relapse. Number of subjects with diagnosis of MS within 11 years after CIS according to McDonald 2001 and 2010 criteria were reported. In the below table, "n" signifies subjects who were evaluable for the specified parameter for each arm, respectively.

End point type

Primary

End point timeframe

Year 11

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, no inferential statistical analyses were performed.

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	159 ^[6]	107 ^[7]
Units: Subjects
McDonald 2010: DIS (n=159,107)	154	105
McDonald 2010: DIT (n=159,107)	154	106
McDonald 2010: McDonald MS (n=159,107)	150	104
McDonald 2001: DIS (n=155,106)	152	104
McDonald 2001: DIT (n=155,106)	150	103
McDonald 2001: McDonald MS (n=155,106)	148	102

Notes
[6] - BENEFIT 11 set with evaluable subjects
[7] - BENEFIT 11 set with evaluable subjects

No statistical analyses for this end point

Primary: Disease Course as Assessed at the Time of BENEFIT 11

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End point title

Disease Course as Assessed at the Time of BENEFIT 11 ^[8]

End point description

Current diagnosis of MS type were categorized with regard to McDonald 2001 and McDonald 2010 criteria were recorded. CIS and silent disease (no relapse, no sustained EDSS progression and no new MRI lesion), McDonald MS not fulfilling the criteria for CDMS, RRMS (CDMS with relapses without evidence for a secondary disease course), SPMS (CDMS with relapses and evidence for a progressive disease course), Revised diagnosis (other reason than MS found for CIS) and Not assessable. Not assessable means McDonald 2001 and McDonald 2010 criteria could not be judged due to missing MRI scan at BENEFIT 11. Number of subjects with current diagnosis of MS at the time of BENEFIT 11 was assessed.

End point type

Primary

End point timeframe

Year 11

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, no inferential statistical analyses were performed.

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[9]	111 ^[10]
Units: subjects
McDonald2001: CIS and silent disease	19	15
McDonald2001: Not fulfilling the criteria for CDMS	10	3
McDonald2001: RRMS	127	87
McDonald2001: SPMS	7	5
McDonald2001: Revised diagnosis	1	0
McDonald2001: Not assessable	3	1
McDonald2010: CIS and silent disease	19	15
McDonald2010: Not fulfilling the criteria for CDMS	10	4
McDonald2010: RRMS	127	87
McDonald2010: SPMS	7	5
McDonald2010: Revised diagnosis	1	0
McDonald2010: Not assessable	2	0
McDonald2010: CIS not qualifying for McDonald MS	1	0

Notes
[9] - BENEFIT 11 set
[10] - BENEFIT 11 set

No statistical analyses for this end point

Primary: Percentage of Subjects Converting to Secondary Progressive Multiple Sclerosis (SPMS)

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End point title

Percentage of Subjects Converting to Secondary Progressive Multiple Sclerosis (SPMS) ^[11]

End point description

SPMS was defined for this study as progressive deterioration observed and sustained for at least 6 months with or without superimposed attacks. Percentage of subjects converting to SPMS were stratified by actual treatment group and baseline EDSS. Baseline EDSS defined as lowest of the EDSS scores obtained during BENEFIT screening or baseline (less than or equal to [<=] median or greater than [>] median). In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.

End point type

Primary

End point timeframe

Year 11

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, no inferential statistical analyses were performed.

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[12]	111 ^[13]
Units: percentage of subjects
number (not applicable)
Baseline EDSS <= median (N=100,64)	9	7.8
Baseline EDSS > median (N=67,47)	4.5	10.6

Notes
[12] - BENEFIT 11 set
[13] - BENEFIT 11 set

No statistical analyses for this end point

Primary: Time to Secondary Progressive Multiple Sclerosis (SPMS) Represented by Kaplan-Meier Estimates

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End point title

Time to Secondary Progressive Multiple Sclerosis (SPMS) Represented by Kaplan-Meier Estimates

End point description

SPMS was defined for this study as progressive deterioration observed and sustained for at least 6 months with or without superimposed attacks. Time to SPMS was represented by Kaplan-Meier estimates.

End point type

Primary

End point timeframe

Up to Year 11 (Day 3960)

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[14]	111 ^[15]
Units: cumulative probability of SPMS
number (not applicable)	4.8	9

Notes
[14] - BENEFIT 11 set
[15] - BENEFIT 11 set

Statistical analysis 1

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.525

Method

Logrank

Confidence interval

Statistical analysis 2

Statistical analysis description

An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is, IFNB-1b 250 microgram vs. placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 - 4, 5 - 8, >=9).

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.504

Method

PH regression

Parameter type

Hazard ratio (HR)

Point estimate

0.751

Confidence interval

level

95%

sides

2-sided

lower limit

0.324

upper limit

1.741

Primary: Expanded Disability Status Scale (EDSS) at Year 11

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End point title

Expanded Disability Status Scale (EDSS) at Year 11 ^[16]

End point description

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. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS.

End point type

Primary

End point timeframe

Year 11

Notes
[16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, no inferential statistical analyses were performed.

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[17]	111 ^[18]
Units: subjects
EDSS score: 0	31	11
EDSS score: 1	20	18
EDSS score: 1.5	25	18
EDSS score: 2	23	20
EDSS score: 2.5	19	9
EDSS score: 3	18	11
EDSS score: 3.5	13	8
EDSS score: 4	6	8
EDSS score: 4.5	3	2
EDSS score: 5	4	0
EDSS score: 5.5	0	0
EDSS score: 6	2	5
EDSS score: 6.5	1	1
EDSS score: 7	1	0
EDSS score: 7.5	0	0
EDSS score: 8	1	0

Notes
[17] - BENEFIT 11 set
[18] - BENEFIT 11 set

No statistical analyses for this end point

Primary: Number of Subjects With Confirmed and Sustained 1-point Expanded Disability Status Scale (EDSS) Progression at Year 11

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End point title

Number of Subjects With Confirmed and Sustained 1-point Expanded Disability Status Scale (EDSS) Progression at Year 11 ^[19]

End point description

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. EDSS progression was defined as an increase in the EDSS of at least 1.0 point compared to initial EDSS score or an increase in the EDSS of at least 1.5 points compared to initial EDSS score, if this score was = 0 points. Confirmed EDSS progression status in any of the previous BENEFIT studies (304747, 305207, 311129) was defined as an EDSS progression observed at two consecutive scheduled visits at least 140 days apart from each other. A confirmed EDSS progression is defined as a confirmed EDSS progression in any of the previous BENEFIT studies or EDSS progression in BENEFIT 11. A sustained EDSS progression is defined as a confirmed EDSS progression in any of the previous BENEFIT studies sustained up to and including the BENEFIT 11 visit.

End point type

Primary

End point timeframe

Year 11

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, no inferential statistical analyses were performed.

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[20]	111 ^[21]
Units: subjects
Confirmed 1-point EDSS progression	75	52
Sustained 1-point EDSS progression	31	27

Notes
[20] - BENEFIT 11 set
[21] - BENEFIT 11 set

No statistical analyses for this end point

Primary: Number of Subjects With Confirmed 2.5-point Expanded Disability Status Scale (EDSS) Progression at Year 11

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End point title

Number of Subjects With Confirmed 2.5-point Expanded Disability Status Scale (EDSS) Progression at Year 11 ^[22]

End point description

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. EDSS progression was defined as an increase in the EDSS of at least 2.5 points compared to initial EDSS score, if this score was <= 3.5 points, or an increase in the EDSS of at least 2.0 points compared to initial EDSS score, if this score was > 3.5 points. Confirmed EDSS increase status in any of the previous BENEFIT studies (304747, 305207, 311129) was defined as an EDSS increase confirmed at scheduled visits after at least 140 days. A confirmed EDSS increase is defined as a confirmed EDSS increase in any of the previous BENEFIT studies or EDSS increase in BENEFIT 11.

End point type

Primary

End point timeframe

Year 11

Notes
[22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, no inferential statistical analyses were performed.

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[23]	111 ^[24]
Units: subjects	19	14

Notes
[23] - BENEFIT 11 set
[24] - BENEFIT 11 set

No statistical analyses for this end point

Primary: Percentage of Subjects who Ever Reached a Disability Status Scale (DSS) 3 and 6

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End point title

Percentage of Subjects who Ever Reached a Disability Status Scale (DSS) 3 and 6 ^[25]

End point description

The DSS 3, and DSS 6 are important milestones in the course of disability progression and were documented if reached by the subject.

End point type

Primary

End point timeframe

Year 11

Notes
[25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, no inferential statistical analyses were performed.

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[26]	111 ^[27]
Units: percentage of subjects
number (not applicable)
DSS 3 reached	27.5	28.8
DSS 6 reached	3	4.5

Notes
[26] - BENEFIT 11 set
[27] - BENEFIT 11 set

No statistical analyses for this end point

Primary: Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 3 by Kaplan-Meier Estimates

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End point title

Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 3 by Kaplan-Meier Estimates

End point description

The DSS 3 is an important milestones in the course of disability progression and were documented if reached by the subject. The time point of reaching DSS 3 was obtained retrospectively in the BENEFIT 11 study. Time to respective DSS is the difference between the date of respective DSS and the date of the BENEFIT baseline visit +1. Subjects without event at BENEFIT 11 were censored at the BENEFIT 11 visit. This constituted a right-censored observation. Cumulative probability of reaching DSS 3 at Year 11 were estimated by Kaplan-Meier.

End point type

Primary

End point timeframe

Up to Year 11 (Day 3960)

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[28]	111 ^[29]
Units: cumulative probability of DSS 3
number (not applicable)	19.1	27.6

Notes
[28] - BENEFIT 11 set
[29] - BENEFIT 11 set

Statistical analysis 1

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5609

Method

Logrank

Confidence interval

Statistical analysis 2

Statistical analysis description

An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is IFNB1b 250 microgram versus placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 4, 5 8, >=9).

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.4768

Method

PH regression

Parameter type

Hazard ratio (HR)

Point estimate

0.842

Confidence interval

level

95%

sides

2-sided

lower limit

0.525

upper limit

1.351

Primary: Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 6 by Kaplan-Meier Estimates

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End point title

Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 6 by Kaplan-Meier Estimates

End point description

The DSS 6 is an important milestones in the course of disability progression and were documented if reached by the subject. The time point of reaching DSS 6 was obtained retrospectively in the BENEFIT 11 study. Time to respective DSS is the difference between the date of respective DSS and the date of the BENEFIT baseline visit +1. Subjects without event at BENEFIT 11 were censored at the BENEFIT 11 visit. This constituted a right-censored observation. Cumulative probability of reaching DSS 6 at Year 11 were estimated by Kaplan-Meier.

End point type

Primary

End point timeframe

Up to Year 11 (Day 3960)

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[30]	111 ^[31]
Units: cumulative probability of DSS 6
number (not applicable)	3	3.7

Notes
[30] - BENEFIT 11 set
[31] - BENEFIT 11 set

Statistical analysis 1

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5011

Method

Logrank

Confidence interval

Primary: Multiple Sclerosis Functional Composite (MSFC) at Year 11

Top of page

End point title

Multiple Sclerosis Functional Composite (MSFC) at Year 11 ^[32]

End point description

The MSFC score consists of three subtests (Timed 25 Foot Walk, 9 Hole Peg Test, 3" Paced Auditory Serial Addition Test [PASAT]) whose Z-standardized results (based on baseline values on Day 1 in Study 304747) were combined into a composite score including upper and lower extremities function, and cognitive function. Standardized results (Z-scores) of the subtests 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.

End point type

Primary

End point timeframe

Year 11

Notes
[32] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, no inferential statistical analyses were performed.

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	127 ^[33]	87 ^[34]
Units: Z-scores
median (inter-quartile range (Q1-Q3))	-0.137 (-0.765 to 0.307)	0.014 (-0.548 to 0.269)

Notes
[33] - BENEFIT 11 set with evaluable subjects
[34] - BENEFIT 11 set with evaluable subjects

No statistical analyses for this end point

Primary: Multiple Sclerosis Severity Score (MSSS) at Year 11

Top of page

End point title

Multiple Sclerosis Severity Score (MSSS) at Year 11 ^[35]

End point description

The MSSS added the element of disease duration to the EDSS and was designed to provide a measure of disease severity. It was derived from the EDSS during the data evaluation. The MSSS corrects the EDSS for the duration of disease by using an arithmetical method to compare an individual’s disability with the distribution of scores in case of having equivalent disease duration.

End point type

Primary

End point timeframe

Year 11

Notes
[35] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, no inferential statistical analyses were performed.

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[36]	111 ^[37]
Units: scores on a scale
median (inter-quartile range (Q1-Q3))	1.978 (0.641 to 3.246)	1.978 (0.641 to 3.246)

Notes
[36] - BENEFIT 11 set
[37] - BENEFIT 11 set

No statistical analyses for this end point

Primary: Cognitive Function: Paced Auditory Serial Addition Test-3 (PASAT-3) at Year 11

Top of page

End point title

Cognitive Function: Paced Auditory Serial Addition Test-3 (PASAT-3) at Year 11

End point description

The Paced Auditory Serial Addition Test (PASAT) is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability.

End point type

Primary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	133 ^[38]	90 ^[39]
Units: PASAT-3 total scores
median (inter-quartile range (Q1-Q3))	56 (50 to 59)	56 (49 to 59)

Notes
[38] - BENEFIT 11 set with evaluable subjects
[39] - BENEFIT 11 set with evaluable subjects

Statistical analysis 1: PASAT-3 score at baseline

Statistical analysis description

Parametric longitudinal linear mixed model, including PASAT-3 score at baseline in addition to time and initial treatment. An inferential statistical analysis included subjects with baseline and post-baseline values, hence number of subjects analysed for this analysis were 222. EudraCT database does auto-addition of number of subjects while reporting an explorative analysis of two treatment groups. Due to this format constraint, below table represents number of subjects in this analysis as 223.

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

223

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Regression, Linear

Parameter type

longitudinal linear mixed model

Point estimate

0.7415

Confidence interval

level

95%

sides

2-sided

lower limit

0.6829

upper limit

0.8001

Statistical analysis 2: Treatment (IFNB-1b)

Statistical analysis description

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

223

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0083

Method

Regression, Linear

Parameter type

longitudinal linear mixed model

Point estimate

1.3346

Confidence interval

level

95%

sides

2-sided

lower limit

0.3461

upper limit

2.323

Statistical analysis 3: Time

Statistical analysis description

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

223

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.016

Method

Regression, Linear

Parameter type

longitudinal linear mixed model

Point estimate

-0.0138

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0251

upper limit

-0.0026

Statistical analysis 4: Time*Treatment (IFNB-1b)

Statistical analysis description

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

223

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.8947

Method

Regression, Linear

Parameter type

longitudinal linear mixed model

Point estimate

-0.001

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0155

upper limit

0.0136

Statistical analysis 5: PASAT-3 at baseline-ANCOVA

Statistical analysis description

Parametric analysis of covariance including PASAT-3 score at baseline in addition to initial treatment. An inferential statistical analysis included subjects with baseline and post-baseline values, hence number of subjects analysed for this analysis were 222. EudraCT database does auto-addition of number of subjects while reporting an explorative analysis of two treatment groups. Due to this format constraint, below table represents number of subjects in this analysis as 223.

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

223

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

ANCOVA

Confidence interval

Statistical analysis 6: Treatment - ANCOVA

Statistical analysis description

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

223

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.422

Method

ANCOVA

Confidence interval

Primary: Cognitive function: Symbol Digit Modalities Test (SDMT)

Top of page

End point title

Cognitive function: Symbol Digit Modalities Test (SDMT)

End point description

The Symbol Digit Modalities Test (SDMT) is a cognitive test for sustained attention, concentration, and information-processing speed, with a high sensitivity. Nine different geometrical symbols have one corresponding number each. One-hundred-ten symbols are presented without these numbers; the subject must find the matching number from the top line and verbalize the number to the examiner. The subject is allowed to proceed for 90 seconds, and the number of correct responses in 90 seconds is counted as the total correct score. Also, the numbers of correct responses at 30 and 60 seconds were recorded in this study. Total score ranged from 0 (worst outcome) to best (outcome). In the below table, "N" signifies number of subjects analysed who were evaluable for the specified parameter for each arm, respectively.

End point type

Primary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[40]	111 ^[41]
Units: correct response
median (inter-quartile range (Q1-Q3))
Number of correct responses in 30 sec (N=131,85)	19 (16 to 21)	19 (16 to 21)
Number of correct responses in 60 sec (N=131,85)	34 (28 to 40)	34 (28 to 40)
Number of correct responses in 90 sec (N=141,92)	53 (42 to 60)	52.5 (44.5 to 59)

Notes
[40] - BENEFIT 11 set
[41] - BENEFIT 11 set

Time*Treatment (2nd interval, IFNB-1b)

Statistical analysis description

Parametric linear mixed-effect model including age and education status (categorized as primary school, high school diploma, vocational school diploma, collegial studies, university diploma) at BENFIT 11 in addition to time interval and initial treatment group.

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.7396

Method

Parametric linear mixed-effect model

Parameter type

SDMT scores

Point estimate

0.228

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1195

upper limit

1.5754

Time*Treatment (3rd interval, IFNB-1b)

Statistical analysis description

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1352

Method

Parametric linear mixed-effect model

Parameter type

SDMT scores

Point estimate

-1.026

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3734

upper limit

0.3215

Primary: Relapse-Based Efficacy domain: Hazard Ratio for Recurrent Relapses

Top of page

End point title

Relapse-Based Efficacy domain: Hazard Ratio for Recurrent Relapses ^[42]

End point 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 with actual treatment in BENEFIT (304747; i.e. IFNB-1b 250 microgram vs. placebo), steroid use during first event (yes vs. no), onset of disease (multifocal vs. monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2-4, 5-8, >=9) included in the model.

End point type

Primary

End point timeframe

Year 11

Notes
[42] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: EudraCT database does not allow to report only one treatment group in statistical analyses section. Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.

End point values	BENEFIT 11 set
Number of subjects analysed	278 ^[43]
Units: ratio
number (not applicable)	0.821

Attachments

Statistical Analysis_HR for Recurrent Relapses

Notes
[43] - BENEFIT 11 set

No statistical analyses for this end point

Primary: Relapse Based Efficacy Domain: Annualized Relapse Rate

Top of page

End point title

Relapse Based Efficacy Domain: Annualized Relapse Rate

End point description

The annualized relapse rate is defined as total number of relapses up to Year 11 divided by the total observation time (last clinical visit minus first day of study treatment administration plus 1 of all subjects) in years.

End point type

Primary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[44]	111 ^[45]
Units: number of relapses per subject and year
arithmetic mean (confidence interval 95%)	0.2123 (0.192 to 0.2341)	0.2536 (0.2264 to 0.2831)

Notes
[44] - BENEFIT 11 set
[45] - BENEFIT 11 set

Statistical analysis 1

Statistical analysis description

Relapse rate was analyzed by a generalized linear Poisson regression model with individual relapse counts as dependent variable, covariates: actual treatment in BENEFIT (304747; i.e., IFNB-1b 250 microgram vs. placebo), steroid use during first event (yes vs. no), onset of disease (multifocal vs. monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2-4, 5-8, >=9) and offset variable natural log of time (in years) as difference between last clinical and baseline visits+1.

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0094

Method

generalized linear Poisson regression

Parameter type

Risk ratio (RR)

Point estimate

0.8224

Confidence interval

level

95%

sides

2-sided

lower limit

0.7096

upper limit

0.9531

Primary: Time to use of Ambulatory Device Represented by Kaplan-Meier Estimates

Top of page

End point title

Time to use of Ambulatory Device Represented by Kaplan-Meier Estimates

End point description

Date of use of ambulatory device is defined as the retrospectively obtained time point of first use/dependence. Time to use of ambulatory device is the difference between the date of first use/dependence and the date of the BENEFIT baseline visit +1.

End point type

Primary

End point timeframe

Up to Year 11 (Day 3960)

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[46]	111 ^[47]
Units: cumulative probability of device usage
number (not applicable)	4.2	7.3

Notes
[46] - BENEFIT 11 set
[47] - BENEFIT 11 set

Statistical analysis 1

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2895

Method

Logrank

Confidence interval

Statistical analysis 2

Statistical analysis description

An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is IFNB-1b 250 microgram versus placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 - 4, 5 - 8, >=9).

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2951

Method

PH regression

Parameter type

Hazard ratio (HR)

Point estimate

0.581

Confidence interval

level

95%

sides

2-sided

lower limit

0.211

upper limit

1.605

Primary: Time to Dependence of Ambulatory Device for Walking Represented by Kaplan-Meier Estimates

Top of page

End point title

Time to Dependence of Ambulatory Device for Walking Represented by Kaplan-Meier Estimates

End point description

Date of dependence from ambulatory device is defined as the retrospectively obtained time point of first use/dependence. Time to dependence from ambulatory device is the difference between the date of first use/dependence and the date of the BENEFIT baseline visit +1. Cumulative probability of dependence of ambulatory device for walking represented by Kaplan-Meier estimates at Year 11.

End point type

Primary

End point timeframe

Up to Year 11 (Day 3960)

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[48]	111 ^[49]
Units: probability of subjects
number (not applicable)	4.2	7.3

Notes
[48] - BENEFIT 11 set
[49] - BENEFIT 11 set

Statistical analysis 1

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2904

Method

Logrank

Confidence interval

Statistical analysis 2

Statistical analysis description

Comparison groups

Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2957

Method

PH regression

Parameter type

Hazard ratio (HR)

Point estimate

0.582

Confidence interval

level

95%

sides

2-sided

lower limit

0.211

upper limit

1.606

Primary: Number of Subjects With Wheelchair Use After 11 years

Top of page

End point title

Number of Subjects With Wheelchair Use After 11 years ^[50]

End point description

End point type

Primary

End point timeframe

Year 11

Notes
[50] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, no inferential statistical analyses were performed.

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[51]	111 ^[52]
Units: subjects	2	1

Notes
[51] - BENEFIT 11 set
[52] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Education Status at Year 11

Top of page

End point title

Education Status at Year 11

End point description

Subjects with educational status was categorized as primary school, high school diploma, vocational diploma, collegial studies, university diploma, and missing educational status.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[53]	111 ^[54]
Units: subjects
Missing	1	1
Primary school	17	11
High school diploma	41	34
Vocational diploma	28	18
Collegial studies	33	17
University diploma	47	30

Notes
[53] - BENEFIT 11 set
[54] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Living Conditions at Year 11

Top of page

End point title

Living Conditions at Year 11

End point description

Subjects living condition were categorized as 'living alone', 'long term care facility', living with spouse, partner, family', 'other' and 'missing'.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[55]	111 ^[56]
Units: subjects
Missing	1	0
Living alone	20	12
Long term care facility	3	0
Living with spouse, partner, family	141	98
Other	2	1

Notes
[55] - BENEFIT 11 set
[56] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Employment Status at Year 11

Top of page

End point title

Employment Status at Year 11

End point description

Subject's employment status was categorized as 'retired', 'homemaker', 'long term disability', 'employment less than 20 hours (hrs) per week (hrs/week)', employment more than 20 hours per week, 'early retired', 'other', and 'missing'.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[57]	111 ^[58]
Units: subjects
Missing	1	0
Retired	0	4
Homemaker	14	9
Long term disability	7	5
Employment, less than 20 hrs/week	14	11
Employment, more than 20 hrs/week	111	68
Early retired	13	9
Other	7	5

Notes
[57] - BENEFIT 11 set
[58] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Multiple Sclerosis Impact on Employment at Year 11

Top of page

End point title

Multiple Sclerosis Impact on Employment at Year 11

End point description

Subject's MS impact on employment was categorized as, 'unrelated to MS condition', 'ceased work due to MS', 'never worked', 'reduced working hours', or missing.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[59]	111 ^[60]
Units: subjects
Missing	1	1
Unrelated to MS condition	108	71
Ceased work due to MS	22	15
Never worked	5	1
Reduced working hours	31	23

Notes
[59] - BENEFIT 11 set
[60] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Resource Use: Hospitalization During Last 12 months

Top of page

End point title

Resource Use: Hospitalization During Last 12 months

End point description

Hospitalizations were assessed at year 11 only referring to past 12 months. Number of hospitalizations per subject were categorized as, 'none', '1', '2', '3', and '6'.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[61]	111 ^[62]
Units: subjects
Number of hospitalizations per subject: none	154	100
Number of hospitalizations per subject: 1	12	8
Number of hospitalizations per subject: 2	0	1
Number of hospitalizations per subject: 3	1	1
Number of hospitalizations per subject: 6	0	1

Notes
[61] - BENEFIT 11 set
[62] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Resource Use: Visits to Other Specialists During Last 12 months

Top of page

End point title

Resource Use: Visits to Other Specialists During Last 12 months

End point description

Visits to Other Specialists were assessed at year 11 only referring to past 12 months. The visits to other specialists were categorized as, 'missing', 'no', 'yes', 'never', and 'unsure'. The other specialists includes, neurologist, nurse clinician, home health aide, visiting nurse, physiotherapist, psychiatrist, psychologist, physician, urologist, social worker and gynecologist.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[63]	111 ^[64]
Units: subjects
Neurologist: missing	7	1
Neurologist: no	19	16
Neurologist: yes	134	86
Neurologist: never	5	6
Neurologist: unsure	2	2
Nurse clinician: missing	14	2
Nurse clinician: no	39	30
Nurse clinician: yes	58	34
Nurse clinician: never	55	45
Nurse clinician: unsure	1	0
Home health aide: missing	17	2
Home health aide: no	24	16
Home health aide: yes	4	2
Home health aide: never	120	89
Home health aide: unsure	2	2
Visiting nurse: missing	17	2
Visiting nurse: no	27	19
Visiting nurse: yes	4	6
Visiting nurse: never	119	83
Visiting nurse: unsure	0	1
Physiotherapist: missing	16	2
Physiotherapist: no	31	27
Physiotherapist: yes	37	27
Physiotherapist: never	80	52
Physiotherapist: unsure	3	3
Psychiatrist: missing	16	3
Psychiatrist: no	28	21
Psychiatrist: yes	16	13
Psychiatrist: never	106	73
Psychiatrist: unsure	1	1
Psychologist: missing	16	2
Psychologist: no	34	22
Psychologist: yes	12	15
Psychologist: never	103	71
Psychologist: unsure	2	1
Physician: missing	12	2
Physician: no	24	20
Physician: yes	88	60
Physician: never	32	25
Physician: unsure	11	4
Urologist: missing	16	2
Urologist: no	33	26
Urologist: yes	10	12
Urologist: never	107	70
Urologist: unsure	1	1
Social worker: missing	17	3
Social worker: no	25	21
Social worker: yes	3	9
Social worker: never	120	77
Social worker: unsure	2	1
Gynecologist: missing	15	4
Gynecologist: no	38	20
Gynecologist: yes	53	39
Gynecologist: never	53	42
Gynecologist: unsure	8	6

Notes
[63] - BENEFIT 11 set
[64] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Resource Use Assessment Questionnaire: Help from Family/Regular Ambulatory Services

Top of page

End point title

Resource Use Assessment Questionnaire: Help from Family/Regular Ambulatory Services

End point description

Resources use data was assessed cross-sectionally at 11 years. Supportive care was assessed as “assistance given” for the help from family members or friends with “care given” for the number f hors per week needed, as well as “ambulatory services-yes/no” with sub-categories home care, home help, day care center, meals on wheels and child care for the help from professional caregiver.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[65]	111 ^[66]
Units: subjects
Assistance given: missing	0	1
Assistance given: no	142	92
Assistance given: yes	25	18
Care given: missing	1	1
Care given: none	142	92
Care given: 1-8 hours/week	16	11
Care given: 9-16 hours/week	3	6
Care given: 17-24 hours/week	2	0
Care given: 32-40 hours/week	1	1
Care given: >40 hours/week	2	0
Ambulatory services: missing	0	1
Ambulatory services: no	162	107
Ambulatory services: yes	5	3
Home care: missing	0	1
Home care: no	167	109
Home care: yes	0	1
Home help: missing	0	1
Home help: no	162	108
Home help: yes	5	2
Day care center: missing	0	1
Day care center: no	167	110
Meals on wheels: missing	0	1
Meals on wheels: no	167	110
Child care: missing	0	1
Child care: no	167	110

Notes
[65] - BENEFIT 11 set
[66] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Resource Use Assessment Questionnaire: Additional Ambulatory Services During Relapse

Top of page

End point title

Resource Use Assessment Questionnaire: Additional Ambulatory Services During Relapse

End point description

Resources use data was assessed cross-sectionally at 11 years. Additional ambulatory services during relapse were categorized as, 'missing', 'no', and 'yes'. The additional ambulatory services during relapses were home care, home help, day care center, meals on wheels, and child care.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[67]	111 ^[68]
Units: subjects
Ambulatory services during relapse: missing	0	2
Ambulatory services during relapse: no	161	106
Ambulatory services during relapse: yes	6	3
Home care: missing	0	2
Home care: no	167	109
Home help: missing	0	2
Home help: no	164	107
Home help: yes	3	2
Day care center: missing	0	2
Day care center: no	166	108
Day care center: yes	1	1
Meals on wheels: missing	0	2
Meals on wheels: no	166	109
Meals on wheels: yes	1	0
Child care: missing	0	2
Child care: no	166	109
Child care: yes	1	0

Notes
[67] - BENEFIT 11 set
[68] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Resource Use Assessment Questionnaire: Adaptions past 6 months

Top of page

End point title

Resource Use Assessment Questionnaire: Adaptions past 6 months

End point description

Resources use data was assessed cross-sectionally at 11 years. The kind of adaptation was categorized as “other part of living”, “star lift”. “ramps”, “alarm”, “work”, “car”, “walking aids”, “wheel chair”, “spectacles”, “special kitchen utensils”, “special hygiene utensils”, “special writing devices” and “ other” with sub-categories as 'missing', 'no', and 'yes'.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[69]	111 ^[70]
Units: subjects
Adaptions: missing	0	1
Adaptions: no	156	100
Adaptions: yes	11	10
Other part of living: missing	0	1
Other part of living: no	165	106
Other part of living: yes	2	4
Stair lift: missing	0	1
Stair lift: no	167	110
Stair lift: yes	0	0
Ramps: missing	0	1
Ramps: no	166	110
Ramps: yes	1	0
Alarm: missing	0	1
Alarm: no	167	110
Work: missing	0	1
Work: no	166	109
Work: yes	1	1
Car: missing	0	1
Car: no	162	107
Car: yes	5	3
Walking aids: missing	0	1
Walking aids: no	163	105
Walking aids: yes	4	5
Wheel chair: missing	0	1
Wheel chair: no	165	109
Wheel chair: yes	2	1
Spectacles: missing	0	1
Spectacles: no	167	110
Special kitchen utensils: missing	0	1
Special kitchen utensils: no	165	109
Special kitchen utensils: yes	2	1
Special hygiene utensils: missing	0	1
Special hygiene utensils: no	163	110
Special hygiene utensils: yes	4	0
Special writing devices: missing	0	1
Special writing devices: no	167	110
Other: missing	0	1
Other: no	165	109
Other: yes	2	1

Notes
[69] - BENEFIT 11 set
[70] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Patient-Reported Outcomes (PRO)-based Efficacy Domain: Center of Epidemiological Studies Depression Scale (CES-D) Total Score at Year 11

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End point title

Patient-Reported Outcomes (PRO)-based Efficacy Domain: Center of Epidemiological Studies Depression Scale (CES-D) Total Score at Year 11

End point description

The CES-D is a measure of depressive symptomatology. The CES-D was a self-administered questionnaire for adults comprising 20 items which evaluated the frequency and severity of depressive symptoms. Subjects were asked to recall the previous 7 days. The total score (0-60) was the sum of the scores of the 20 items. A score of >= 16 suggested a mild to moderate level of depressive symptoms; a score >21 suggested major depressive symptoms.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	165 ^[71]	110 ^[72]
Units: scores on a scale
arithmetic mean (standard deviation)	12.44 ± 11.91	12.12 ± 11.15

Notes
[71] - BENEFIT 11 set with evaluable subjects
[72] - BENEFIT 11 set with evaluable subjects

No statistical analyses for this end point

Secondary: PRO-based Efficacy Domain: Fatigue Scale for Sensory and Motor Functions (FSMC)

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End point title

PRO-based Efficacy Domain: Fatigue Scale for Sensory and Motor Functions (FSMC)

End point description

The cognitive and physical fatigue was assessed by the FSMC. The scale comprised of 20 questions (10 items for physical and 10 items for cognitive fatigue) and could be completed within 5 minutes. The items are rated on a 5-point Likert scale (1=does not apply at all to 5=applies completely). The FSMC total score ranges from 20 to 100 where a higher score is associated with a higher severity of fatigue.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	161 ^[73]	110 ^[74]
Units: scores on a scale
arithmetic mean (standard deviation)	49.08 ± 22.68	47.23 ± 23.11

Notes
[73] - BENEFIT 11 set with evaluable subjects
[74] - BENEFIT 11 set with evaluable subjects

No statistical analyses for this end point

Secondary: Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Year 11

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End point title

Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Year 11

End point description

The Functional Assessment of Multiple Sclerosis (FAMS) instrument is a self-reporting, multi-dimensional, health-related QoL index for use in subjects diagnosed with MS. It comprised 58 items on 7 subscales (mobility, symptoms, emotional well-being, general contentment, thinking and fatigue, family/social well-being, and additional concerns). FAMS-TOI is the sum of the subscale scores mobility, symptoms, thinking/fatigue, and additional concerns. The items were rated on a 5-point scale (0 to 4). Score range of FAM-TOI is 0 to 148; the higher the score, the higher the quality of life. The evaluation period was the previous 7 days.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	162 ^[75]	108 ^[76]
Units: scores on a scale
arithmetic mean (standard deviation)	110.82 ± 28.09	111.91 ± 26.08

Notes
[75] - BENEFIT 11 set with evaluable subjects
[76] - BENEFIT 11 set with evaluable subjects

No statistical analyses for this end point

Secondary: Functional Assessment of Multiple Sclerosis (FAMS) Total Score at Year 11

Top of page

End point title

Functional Assessment of Multiple Sclerosis (FAMS) Total Score at Year 11

End point description

The Functional Assessment of Multiple Sclerosis (FAMS) instrument is a self-reporting, multi-dimensional, health-related QoL index for use in subjects diagnosed with MS. It comprised 58 items on 7 subscales: mobility, symptoms, emotional well-being, general contentment, thinking and fatigue, family/social well-being, and additional concerns. The items were rated on a 5-point scale (0 to 4). Total score is sum of all sub-scale scores except 14 items for "Additional concerns", ranging 0 to 176; the higher the score, the higher the quality of life. The evaluation period was the previous 7 days.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	162 ^[77]	108 ^[78]
Units: scores on a scale
arithmetic mean (standard deviation)	133.99 ± 33.03	134.93 ± 30.67

Notes
[77] - BENEFIT 11 set with evaluable subjects
[78] - BENEFIT 11 set with evaluable subjects

No statistical analyses for this end point

Secondary: PRO-based Efficacy Domain: European Quality of Life – 5 Dimensions (EQ-5D) Score at Year 11

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End point title

PRO-based Efficacy Domain: European Quality of Life – 5 Dimensions (EQ-5D) Score at Year 11

End point description

The EQ-5D measured five state-of-health dimensions: mobility, self-care, usual activities (work, leisure, etc.), pain/discomfort, and anxiety/depression. Every item had a score of 1 (no problems), 2 (some/moderate problems), or 3 (extreme problems). An individual’s health status was defined in a combination of 5 digits. Subjects with missing answers to all questions were not considered for the respective visit.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	166 ^[79]	110 ^[80]
Units: subjects
EQ-5D, question 1, mobility: missing	1	0
EQ-5D, question 1, mobility: 1	119	79
EQ-5D, question 1, mobility: 2	46	31
EQ-5D, question 2, self care: missing	0	0
EQ-5D, question 2, self care: 1	150	99
EQ-5D, question 2, self care: 2	15	11
EQ-5D, question 2, self care: 3	1	0
EQ-5D, question 3, usual activities: missing	0	0
EQ-5D, question 3, usual activities: 1	120	77
EQ-5D, question 3, usual activities: 2	44	31
EQ-5D, question 3, usual activities: 3	2	2
EQ-5D, question 4, pain/ discomfort: missing	0	0
EQ-5D, question 4, pain/ discomfort: 1	88	62
EQ-5D, question 4, pain/ discomfort: 2	71	48
EQ-5D, question 4, pain/ discomfort: 3	7	0
EQ-5D, question 5, anxiety/ depression: missing	0	0
EQ-5D, question 5, anxiety/ depression: 1	107	60
EQ-5D, question 5, anxiety/ depression: 2	52	46
EQ-5D, question 5, anxiety/ depression	7	4

Notes
[79] - BENEFIT 11 set with evaluable subjects
[80] - BENEFIT 11 set with evaluable subjects

No statistical analyses for this end point

Secondary: European Quality of Life – 5 Dimensions (EQ-5D) Health-related quality of life (HRQoL) Score at Year 11

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End point title

European Quality of Life – 5 Dimensions (EQ-5D) Health-related quality of life (HRQoL) Score at Year 11

End point description

Based on large population surveys, an algorithm was developed to combine the recordings of each of these five EQ-5D dimensions in 1 single HRQoL score, ranging from +1 (best imaginable HRQoL score) to -0.59 (worst imaginable HRQoL score). A relatively higher score represents better quality of life.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	165 ^[81]	110 ^[82]
Units: scores on a scale
arithmetic mean (standard deviation)	0.7842 ± 0.2487	0.7965 ± 0.2

Notes
[81] - BENEFIT 11 set with evaluable subjects
[82] - BENEFIT 11 set with evaluable subjects

No statistical analyses for this end point

Secondary: Number of Subjects who Started Second Line Therapy at Year 11

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End point title

Number of Subjects who Started Second Line Therapy at Year 11

End point description

Subjects were treated exclusively at the discretion of their treating physician and according to locally applicable standards and treatment guidelines. Subjects received second line therapy as a MS treatment such as alemtuzumab, cyclophosphamide, ciclosporin, fingolimod, methotrexate, mycophenolate mitoxantrone, natalizumab, etc.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[83]	111 ^[84]
Units: subjects	31	24

Notes
[83] - BENEFIT 11 set
[84] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Number of Subjects who Started First Disease-Modifying Treatment (DMT) other than IFNB at Year 11

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End point title

Number of Subjects who Started First Disease-Modifying Treatment (DMT) other than IFNB at Year 11

End point description

Subjects were treated exclusively at the discretion of their treating physician and according to locally applicable standards and treatment guidelines. All DMTs other than interferon beta, interferon beta-1a und interferon beta-1b were recorded as DMT other than IFNB.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[85]	111 ^[86]
Units: subjects	54	39

Notes
[85] - BENEFIT 11 set
[86] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Magnet-Resonance Imaging (MRI): Number of Newly Active Lesions

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End point title

Magnet-Resonance Imaging (MRI): Number of Newly Active Lesions

End point description

Contrast-enhanced MRI (with an extracellular gadolinium-based contrast agent) technique was used for the evaluation of brain lesions in MS. Newly active lesions defined as displaying either new enhancement on T1-weighted scans, or non-enhancing on T1-weighted scan but new on T2-weighted scans.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	114 ^[87]	77 ^[88]
Units: subjects
Gd-enhancing lesions on T1: missing	6	4
Gd-enhancing lesions on T1: 0	96	69
Gd-enhancing lesions on T1: 1	7	3
Gd-enhancing lesions on T1: 2-5	5	1
New lesions in T2: missing	1	1
New lesions in T2: 0	37	26
New lesions in T2: 1	13	9
New lesions in T2: 2-5	34	19
New lesions in T2: 6-9	10	10
New lesions in T2: >=10	19	12
Hypointense lesions on T1: missing	2	2
Hypointense lesions on T1: 0	17	16
Hypointense lesions on T1: 1	16	11
Hypointense lesions on T1: 2-5	33	29
Hypointense lesions on T1: 6-9	13	10
Hypointense lesions on T1: >=10	33	9
Count of cortical lesions: missing	8	3
Count of cortical lesions: 0	27	21
Count of cortical lesions: 1	15	16
Count of cortical lesions: 2-5	39	23
Count of cortical lesions: 6-9	14	5
Count of cortical lesions: >=10	11	9

Notes
[87] - BENEFIT 11 set with evaluable subjects
[88] - BENEFIT 11 set with evaluable subjects

No statistical analyses for this end point

Secondary: Magnet-Resonance Imaging (MRI): Number of Lesions on T1- and T2-Weighted Scans

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End point title

Magnet-Resonance Imaging (MRI): Number of Lesions on T1- and T2-Weighted Scans

End point description

Contrast-enhanced MRI (with an extracellular gadolinium-based contrast agent) technique was used for the evaluation of brain lesions in MS. Number of lesions on T1- and T2-Weighted scans were recorded. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[89]	111 ^[90]
Units: lesions
arithmetic mean (standard deviation)
Hypointense lesions on T1 (N=112,75)	7.1 ± 8.9	4.7 ± 6.6
New lesions in T2 (N=113,76)	6 ± 11.4	4.9 ± 8

Notes
[89] - BENEFIT 11 set
[90] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Magnet-Resonance Imaging (MRI): Volume of Lesions on T1- and T2-Weighted Scans

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End point title

Magnet-Resonance Imaging (MRI): Volume of Lesions on T1- and T2-Weighted Scans

End point description

Contrast-enhanced MRI (with an extracellular gadolinium-based contrast agent) technique was used for the evaluation of brain lesions in MS. Volume of lesions on T1- and T2-Weighted scans were recorded. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[91]	111 ^[92]
Units: cubic millimeter
arithmetic mean (standard deviation)
Gd-enhancing lesion on T1 (N=108,73)	16.6 ± 78.7	4.1 ± 25.5
Hypointense lesion on T1 (N=112,75)	1044.8 ± 2294.8	470.9 ± 742.5
Hyperintense lesion on T2 (N=113,76)	4232.9 ± 5920.4	3139.9 ± 4447.5

Notes
[91] - BENEFIT 11 set
[92] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Magnet-Resonance Imaging (MRI): Normalized Brain Volume

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End point title

Magnet-Resonance Imaging (MRI): Normalized Brain Volume

End point description

Contrast-enhanced MRI (with an extracellular gadolinium-based contrast agent) technique was used for the evaluation of brain lesions in MS. Brain volume was analysed and reported.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	111 ^[93]	72 ^[94]
Units: cubic centimeter
arithmetic mean (standard deviation)	1496.6 ± 135.4	1502.1 ± 114.2

Notes
[93] - BENEFIT 11 set with evaluable subjects
[94] - BENEFIT 11 set with evaluable subjects

No statistical analyses for this end point

Secondary: Optical Coherence Tomography (OCT) Parameter - Retinal Nerve Fiber Layer (RNFL)

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End point title

Optical Coherence Tomography (OCT) Parameter - Retinal Nerve Fiber Layer (RNFL)

End point description

OCT is a noninvasive ocular imaging recognized in MS as a marker of axonal loss. Retinal nerve fiber layer (RNFL) thinning measured by OCT in subjects with MS occurs even in the absence of acute optic neuritis and is associated with worse scores for low-contrast letter acuity and other visual acuity tests. OCT measures peripapillary RNFL. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[95]	111 ^[96]
Units: micrometer
arithmetic mean (standard deviation)
Right eye: Global RNFL at 12 degree (N=41,27)	93.8 ± 11	89.6 ± 14.3
Right eye: Global RNFL at 14 degree (N=42,27)	81.3 ± 8.7	77 ± 11.5
Right eye: Global RNFL at 16 degree (N=43,27)	71.3 ± 8	67.8 ± 9.9
Right eye: PMB RNFL at 12 degree (N=41,27)	48.3 ± 9.6	47.4 ± 11.1
Right eye: PMB RNFL at 14 degree (N=42,27)	42.5 ± 7.5	41.9 ± 9
Right eye: PMB RNFL at 16 degree (N=43,27)	37.7 ± 7.2	36.2 ± 6.9
Right eye: Temp. RNFL at 12 degree (N=41,27)	64.2 ± 12.4	64 ± 14.7
Right eye: Temp. RNFL at 14 degree (N=42,27)	57.9 ± 10.5	57.4 ± 12.6
Right eye: Temp. RNFL at 16 degree (N=43,27)	53.2 ± 9.7	52.5 ± 10.6
Left eye: Global RNFL at 12 degree (N=42,26)	92 ± 11.2	90.7 ± 15.9
Left eye: Global RNFL at 14 degree (N=40,25)	80 ± 9.6	77.7 ± 14.3
Left eye: Global RNFL at 16 degree (N=42,26)	70.6 ± 8.2	68.4 ± 11.8
Left eye: PMB RNFL at 12 degree (N=42,26)	45.3 ± 9.3	45.2 ± 10.7
Left eye: PMB RNFL at 14 degree (N=41,25)	39.6 ± 7.8	37.7 ± 8.6
Left eye: PMB RNFL at 16 degree (N=42,26)	35.6 ± 6.2	34 ± 6.5
Left eye: Temp. RNFL at 12 degree (N=42,26)	58.9 ± 11.3	58.9 ± 13.7
Left eye: Temp. RNFL at 14 degree (N=41,25)	53.2 ± 9.9	52.1 ± 11.8
Left eye: Temp. RNFL at 16 degree (N=42,26)	48.8 ± 8.6	48.6 ± 9.8

Notes
[95] - BENEFIT 11 set
[96] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Optical Coherence Tomography (OCT) Parameter - Total Macular Volume (TMV)

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End point title

Optical Coherence Tomography (OCT) Parameter - Total Macular Volume (TMV)

End point description

OCT is a noninvasive ocular imaging recognized in MS as a marker of axonal loss. OCT is a potential method for capturing neuronal in addition to axonal degeneration in MS. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[97]	111 ^[98]
Units: cubic millimeter
arithmetic mean (standard deviation)
Right eye: TMV (N=48,28)	7.798 ± 1.836	8.044 ± 1.538
Left eye: TMV (N=45,28)	7.775 ± 1.929	8.002 ± 1.536

Notes
[97] - BENEFIT 11 set
[98] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Optical Coherence Tomography (OCT) Parameter - Pupillo Macular Bundle (PMB)

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End point title

Optical Coherence Tomography (OCT) Parameter - Pupillo Macular Bundle (PMB)

End point description

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[99]	111 ^[100]
Units: micrometer
arithmetic mean (standard deviation)
Right eye: PMB (N=47,26)	309.4 ± 19	306.7 ± 15
Left eye: PMB (N=45,28)	307.4 ± 17.3	303.8 ± 18.9

Notes
[99] - BENEFIT 11 set
[100] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Optical Coherence Tomography (OCT) Parameter – Ganglion Cell Inner Plexiform Layer

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End point title

Optical Coherence Tomography (OCT) Parameter – Ganglion Cell Inner Plexiform Layer

End point description

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[101]	111 ^[102]
Units: micrometer
arithmetic mean (standard deviation)
Right eye (N=47,31)	78.9 ± 10.1	77.6 ± 10.5
Left eye (N=44,29)	78.6 ± 9.7	76.8 ± 13.2

Notes
[101] - BENEFIT 11 set
[102] - BENEFIT 11 set

No statistical analyses for this end point

Secondary: Ophthalmological examination – Optic Nerve Head

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End point title

Ophthalmological examination – Optic Nerve Head

End point description

Standard clinical ophthalmic examination and test were applied for visual assessment and the differential diagnosis of OCT-related findings.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	51 ^[103]	32 ^[104]
Units: subjects
Right eye: Optic nerve head-normal	48	27
Right eye: Optic nerve head-abnormal	3	5
Left eye: Optic nerve head-normal	46	27
Left eye: Optic nerve head-abnormal	5	5

Notes
[103] - BENEFIT 11 set with evaluable subjects
[104] - BENEFIT 11 set with evaluable subjects

No statistical analyses for this end point

Secondary: Ophthalmological examination - Slit lamp Biomicroscopy

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End point title

Ophthalmological examination - Slit lamp Biomicroscopy

End point description

Standard clinical ophthalmic examination and test were applied for visual assessment and the differential diagnosis of OCT-related findings. Ocular medical and surgical history, visual acuity (Early Treatment Diabetic Retinopathy Study Chart), low-contrast letter acuity (Sloan charts), and eye examination through slit-lamp biomicroscopy were assessed.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	50 ^[105]	34 ^[106]
Units: subjects
Right: Anterior segment and vitreous body-missing	1	1
Right: Anterior segment and vitreous body-normal	48	31
Right: Anterior segment and vitreous body-abnormal	1	2
Right: Pupil-missing	0	0
Right: Pupil-normal	46	33
Right: Pupil-abnormal	4	1
Left: Anterior segment and vitreous body-missing	1	1
Left: Anterior segment and vitreous body-normal	47	31
Left: Anterior segment and vitreous body-abnormal	2	2
Left: Pupil-missing	1	0
Left: Pupil-normal	49	33
Left: Pupil-abnormal	0	1

Notes
[105] - Subjects with ophthalmological examination from BENEFIT 11 set.
[106] - Subjects with ophthalmological examination from BENEFIT 11 set.

No statistical analyses for this end point

Secondary: Ophthalmological examination - Visual Acuity

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End point title

Ophthalmological examination - Visual Acuity

End point description

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	49 ^[107]	30 ^[108]
Units: scores on a scale
arithmetic mean (standard deviation)
Right eye	86.5 ± 6.9	87.3 ± 7.1
Left eye	86.3 ± 5.7	83.9 ± 8.7

Notes
[107] - Subjects with ophthalmological examination from BENEFIT 11 set.
[108] - Subjects with ophthalmological examination from BENEFIT 11 set.

No statistical analyses for this end point

Secondary: Number of Subjects with Vitamin D Intake

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End point title

Number of Subjects with Vitamin D Intake

End point description

Number of subjects with intake of Vitamin D were categorized as, 'since beginning of the BENEFIT study', and 'within the past 12 months'.

End point type

Secondary

End point timeframe

Year 11

End point values	Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)	Initial Placebo
Number of subjects analysed	167 ^[109]	111 ^[110]
Units: subjects
Since beginning of the BENEFIT study: missing	2	0
Since beginning of the BENEFIT study: no	136	102
Since beginning of the BENEFIT study: yes	29	9
Within the past 12 months: missing	21	11
Within the past 12 months: no	100	68
Within the past 12 months: yes	46	32

Notes
[109] - BENEFIT 11 set
[110] - BENEFIT 11 set

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

After signing the informed consent form up to the end of study (approximately 1 year)

Adverse event reporting additional description

The death reported in this study was not considered an AE or an SAE as per the definitions provided in the protocol, but rather was categorized under “Medical history.”

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Overall

Reporting group description

This overall reporting group includes both of the reporting groups below: Initial Interferon Beta-1b: Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 microgram administered subcutaneously every other day in original BENEFIT (304747 / 92012 / NCT00185211) study. Initial Placebo: Initial placebo treatment administered in original BENEFIT study; Betaferon/Betaseron, 250 microgram administered subcutaneous every other day offered in BENEFIT Follow-up (305207 / 91031) phase. At the time of study 16401 subjects were on any MS disease modifying or on no therapy.

Serious adverse events	Overall
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 278 (0.00%)
number of deaths (all causes)	1
number of deaths resulting from adverse events	0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Overall
Total subjects affected by non serious adverse events
subjects affected / exposed	24 / 278 (8.63%)
Vascular disorders
HYPERTENSION
subjects affected / exposed	3 / 278 (1.08%)
occurrences all number	3
MICROANGIOPATHY
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
Pregnancy, puerperium and perinatal conditions
PREGNANCY
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
General disorders and administration site conditions
INJECTION SITE INFLAMMATION
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	2
INFLUENZA LIKE ILLNESS
subjects affected / exposed	3 / 278 (1.08%)
occurrences all number	3
FATIGUE
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
PYREXIA
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
Respiratory, thoracic and mediastinal disorders
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
RHINITIS ALLERGIC
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
ASTHMA
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
PULMONARY EMBOLISM
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
Psychiatric disorders
DYSTHYMIC DISORDER
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
ANXIETY
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
DEPRESSION
subjects affected / exposed	4 / 278 (1.44%)
occurrences all number	4
Investigations
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
GAMMA-GLUTAMYLTRANSFERASE INCREASED
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
Injury, poisoning and procedural complications
RIB FRACTURE
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
LIGAMENT SPRAIN
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
FALL
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
Cardiac disorders
TACHYCARDIA
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
Nervous system disorders
EPILEPSY
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
DIABETIC NEUROPATHY
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
MULTIPLE SCLEROSIS RELAPSE
subjects affected / exposed	6 / 278 (2.16%)
occurrences all number	11
PRESYNCOPE
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
Blood and lymphatic system disorders
LEUKOPENIA
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
Eye disorders
VISION BLURRED
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
GLAUCOMA
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
Gastrointestinal disorders
HYPERCHLORHYDRIA
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
Skin and subcutaneous tissue disorders
ECZEMA
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
PSORIASIS
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
LIPOATROPHY
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
SKIN REACTION
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
Endocrine disorders
HYPOTHYROIDISM
subjects affected / exposed	2 / 278 (0.72%)
occurrences all number	2
HYPERTHYROIDISM
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
MENISCAL DEGENERATION
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
Infections and infestations
FUNGAL SKIN INFECTION
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
PYELONEPHRITIS
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
SINUSITIS
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
PERIODONTITIS
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
SUBCUTANEOUS ABSCESS
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
Metabolism and nutrition disorders
ABNORMAL LOSS OF WEIGHT
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
DIABETES MELLITUS
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
VITAMIN B12 DEFICIENCY
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1
HYPERLIPIDAEMIA
subjects affected / exposed	2 / 278 (0.72%)
occurrences all number	2
HYPERCHOLESTEROLAEMIA
subjects affected / exposed	1 / 278 (0.36%)
occurrences all number	1

More information

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Were there any global substantial amendments to the protocol? Yes

22 Jan 2013

This amendment was included following change: - modifications were made to provide clearer study procedures and provide greater consistency; generalized contrast agent procedure guidance instead of confining to Gadobutrol administration; removed references to magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) imaging procedures; clarification of Adverse events reporting details

05 Dec 2013

The enrollment date as extended to increase the number of subjects.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Results of the DNA, RNA and Biomarkers were not reported as they would be reported in a separate report, as planned.

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Clinical trials

Clinical Trial Results: BENEFIT 11 a long-term, follow-up study (16401) of the BENEFIT (304747), BENEFIT Follow-up (305207) Studies and BENEFIT Extension (311129) Study to further evaluate the progress of patients with first demyelinating event suggestive of multiple sclerosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time to First Relapse by Kaplan-Meier Estimates

Primary: Time to First Relapse by Kaplan-Meier Estimates

Primary: Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates

Primary: Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates

Primary: Number of Subjects With Diagnosis of Multiple Sclerosis Within Eleven years after Clinically-Isolated Syndrome (CIS) According to McDonald 2001 and 2010 Criteria

Primary: Number of Subjects With Diagnosis of Multiple Sclerosis Within Eleven years after Clinically-Isolated Syndrome (CIS) According to McDonald 2001 and 2010 Criteria

Primary: Disease Course as Assessed at the Time of BENEFIT 11

Primary: Disease Course as Assessed at the Time of BENEFIT 11

Primary: Percentage of Subjects Converting to Secondary Progressive Multiple Sclerosis (SPMS)

Primary: Percentage of Subjects Converting to Secondary Progressive Multiple Sclerosis (SPMS)

Primary: Time to Secondary Progressive Multiple Sclerosis (SPMS) Represented by Kaplan-Meier Estimates

Primary: Time to Secondary Progressive Multiple Sclerosis (SPMS) Represented by Kaplan-Meier Estimates

Primary: Expanded Disability Status Scale (EDSS) at Year 11

Primary: Expanded Disability Status Scale (EDSS) at Year 11

Primary: Number of Subjects With Confirmed and Sustained 1-point Expanded Disability Status Scale (EDSS) Progression at Year 11

Primary: Number of Subjects With Confirmed and Sustained 1-point Expanded Disability Status Scale (EDSS) Progression at Year 11

Primary: Number of Subjects With Confirmed 2.5-point Expanded Disability Status Scale (EDSS) Progression at Year 11

Primary: Number of Subjects With Confirmed 2.5-point Expanded Disability Status Scale (EDSS) Progression at Year 11

Primary: Percentage of Subjects who Ever Reached a Disability Status Scale (DSS) 3 and 6

Primary: Percentage of Subjects who Ever Reached a Disability Status Scale (DSS) 3 and 6

Primary: Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 3 by Kaplan-Meier Estimates

Primary: Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 3 by Kaplan-Meier Estimates

Primary: Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 6 by Kaplan-Meier Estimates

Primary: Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 6 by Kaplan-Meier Estimates

Primary: Multiple Sclerosis Functional Composite (MSFC) at Year 11

Primary: Multiple Sclerosis Functional Composite (MSFC) at Year 11

Primary: Multiple Sclerosis Severity Score (MSSS) at Year 11

Primary: Multiple Sclerosis Severity Score (MSSS) at Year 11

Primary: Cognitive Function: Paced Auditory Serial Addition Test-3 (PASAT-3) at Year 11

Primary: Cognitive Function: Paced Auditory Serial Addition Test-3 (PASAT-3) at Year 11

Primary: Cognitive function: Symbol Digit Modalities Test (SDMT)

Primary: Cognitive function: Symbol Digit Modalities Test (SDMT)

Primary: Relapse-Based Efficacy domain: Hazard Ratio for Recurrent Relapses

Primary: Relapse-Based Efficacy domain: Hazard Ratio for Recurrent Relapses

Primary: Relapse Based Efficacy Domain: Annualized Relapse Rate

Primary: Relapse Based Efficacy Domain: Annualized Relapse Rate

Primary: Time to use of Ambulatory Device Represented by Kaplan-Meier Estimates

Primary: Time to use of Ambulatory Device Represented by Kaplan-Meier Estimates

Primary: Time to Dependence of Ambulatory Device for Walking Represented by Kaplan-Meier Estimates

Primary: Time to Dependence of Ambulatory Device for Walking Represented by Kaplan-Meier Estimates

Primary: Number of Subjects With Wheelchair Use After 11 years

Primary: Number of Subjects With Wheelchair Use After 11 years

Secondary: Education Status at Year 11

Secondary: Education Status at Year 11

Secondary: Living Conditions at Year 11

Secondary: Living Conditions at Year 11

Secondary: Employment Status at Year 11

Secondary: Employment Status at Year 11

Secondary: Multiple Sclerosis Impact on Employment at Year 11

Secondary: Multiple Sclerosis Impact on Employment at Year 11

Secondary: Resource Use: Hospitalization During Last 12 months

Secondary: Resource Use: Hospitalization During Last 12 months

Secondary: Resource Use: Visits to Other Specialists During Last 12 months

Secondary: Resource Use: Visits to Other Specialists During Last 12 months

Secondary: Resource Use Assessment Questionnaire: Help from Family/Regular Ambulatory Services

Secondary: Resource Use Assessment Questionnaire: Help from Family/Regular Ambulatory Services

Secondary: Resource Use Assessment Questionnaire: Additional Ambulatory Services During Relapse

Secondary: Resource Use Assessment Questionnaire: Additional Ambulatory Services During Relapse

Secondary: Resource Use Assessment Questionnaire: Adaptions past 6 months

Secondary: Resource Use Assessment Questionnaire: Adaptions past 6 months

Secondary: Patient-Reported Outcomes (PRO)-based Efficacy Domain: Center of Epidemiological Studies Depression Scale (CES-D) Total Score at Year 11

Secondary: Patient-Reported Outcomes (PRO)-based Efficacy Domain: Center of Epidemiological Studies Depression Scale (CES-D) Total Score at Year 11

Secondary: PRO-based Efficacy Domain: Fatigue Scale for Sensory and Motor Functions (FSMC)

Secondary: PRO-based Efficacy Domain: Fatigue Scale for Sensory and Motor Functions (FSMC)

Secondary: Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Year 11

Secondary: Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Year 11

Secondary: Functional Assessment of Multiple Sclerosis (FAMS) Total Score at Year 11

Secondary: Functional Assessment of Multiple Sclerosis (FAMS) Total Score at Year 11

Secondary: PRO-based Efficacy Domain: European Quality of Life – 5 Dimensions (EQ-5D) Score at Year 11

Secondary: PRO-based Efficacy Domain: European Quality of Life – 5 Dimensions (EQ-5D) Score at Year 11

Clinical Trial Results:
BENEFIT 11 a long-term, follow-up study (16401) of the BENEFIT (304747), BENEFIT Follow-up (305207) Studies and BENEFIT Extension (311129) Study to further evaluate the progress of patients with first demyelinating event suggestive of multiple sclerosis