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

Sponsor
Bayer (Industry)
Overall Status
Completed
CT.gov ID
NCT00185211
Collaborator
(none)
468
94
2
69
5
0.1

Study Details

Study Description

Brief Summary

This study will primarily compare the long-term effects of an early and continued treatment with Betaferon/Betaseron (patients who were treated with active medication during the double-blind BENEFIT study) to treatment initiated either after Clinically Definite Multiple Sclerosis (CDMS) has been diagnosed or after two years (those patients who were treated with placebo during the double-blind BENEFIT study).

Analyses are based on the integrated data of the initial BENEFIT study and this follow-up study.

Condition or Disease Intervention/Treatment Phase
  • Drug: Interferon beta-1b (Betaseron, BAY86-5046)
  • Drug: Interferon beta-1b (Betaseron, BAY86-5046)
Phase 3

Detailed Description

The study has previously been posted by Schering AG, Germany. Schering AG, Germany has been renamed to Bayer HealthCare Pharmaceuticals Inc..

Bayer HealthCare Pharmaceuticals Inc. is the sponsor of the trial.

Study Design

Study Type:
Interventional
Actual Enrollment :
468 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Open-label, Multi-center Phase III Extension of the Double-blind, Placebo-controlled BENEFIT Study (no. 92012/304747) to Obtain Long-term Follow-up Data of Patients With Clinically Definite Multiple Sclerosis (MS) and Patients With a First Demyelinating Event Suggestive of MS Treated With 8 MIU (250 µg) Interferon Beta-1b (Betaferon® / Betaseron®) Given Subcutaneously Every Other Day for at Least 36 Months.
Study Start Date :
Aug 1, 2002
Actual Primary Completion Date :
May 1, 2008
Actual Study Completion Date :
May 1, 2008

Arms and Interventions

Arm Intervention/Treatment
Experimental: Initial IFNB-1b (Interferon beta-1b)

Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase

Drug: Interferon beta-1b (Betaseron, BAY86-5046)
Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase

Experimental: Initial Placebo

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

Drug: Interferon beta-1b (Betaseron, BAY86-5046)
Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)

Outcome Measures

Primary Outcome Measures

  1. Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS at Selected Points in Time [up to 60 months after start of treatment]

    CDMS could be reached due to a qualifying relapse or sustained progression of 1.5 points on the expanded disability status scale (EDSS) as compared to the lowest EDSS obtained during screening or Day 1. The validity of CDMS diagnoses was confirmed by a central committee. The EDSS scale quantifies disability in MS in 8 functional systems, values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on an ordinal scale. Time to CDMS = date of CDMS - date of Day 1 + 1 or time to CDMS = date of last clinical visit - date of Day 1 + 1 (right-censored)

  2. Time to Confirmed Expanded Disability Status Scale (EDSS) Progression Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With Confirmed EDSS Progression at Selected Points in Time [up to 60 months after start of treatment]

    EDSS progression was defined as an increase in the expanded disability status scale (EDSS) of 1.0 point compared to the lowest EDSS score obtained during the screening or baseline visit, if this score was <= 5.5. A confirmed EDSS progression status was defined as an EDSS progression observed at two consecutive scheduled visits at least 140 days apart from each other. The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on a scale.

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

    As an index of health related quality of life in people diagnosed with MS, the FAMS Trial Outcome Index covers overall physical health (sum of sub-scale scores Mobility, Symptoms, Thinking/Fatigue, Additional Concerns) with a score range from 0 to 148. A higher score reflects a higher overall physical health as reported by patients.

Secondary Outcome Measures

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

    MS according to the criteria by McDonald was reached if, in addition to the single clinical demyelinating event, both dissemination in space and dissemination in time were established by MRI-criteria or a new relapse. Time to McDonald MS is the difference of date of McDonald MS to the date of Day 1 + 1. For subjects without McDonald MS, time to McDonald MS is the difference from the maximum (date of last magnetic resonance imaging scan, date of last clinical visit) to the date of Day 1 + 1 (right-censored observation).

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

    A relapse was defined as the appearance of a new neurological abnormality or the reappearance of a neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The time to the onset of recurrent relapses was determined for each subject according to the counting process representation for recurrent events. Time to a relapse was right-censored if a relapse-risk period ended without relapse. Based on the Andersen-Gill model the hazard ratio for recurrent relapses was estimated. Annualized relapse rates are provided as another outcome measure.

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

    The annualized relapse rate is defined as total number of relapses up to month 60 divided by the total observation time (last clinical visit minus first day of study treatment administration plus 1 of all participants) in years.

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

    The MSFC score consists of three sub-tests (Timed-25-Foot-Walk, 9-Hole-Peg-Test, 3" Paced Auditory Serial Addition Test [PASAT]). Standardized results (Z-scores) of the sub-tests and the overall MSFC Z-score as an average of the three Z-scores were derived using baseline data pooled over both treatment arms as reference population. Higher Z-scores reflect a better neurological status.

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

    Newly active lesions are defined as displaying either new Gadolinium (Gd)-enhancement on T1-weighted scans or non-enhancement on T1-weighted scan but new on T2-weighted scan. The numbers of newly active lesions on yearly MRI scans were summed up to the cumulative number.

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

    Absolute change of T2 lesion volume from screening MRI to month 60 was calculated as T2 lesion volume at month 60 minus T2 lesion volume at screening.

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

    Absolute change of volume of black holes from screening MRI to month 60 was calculated as volume of black holes at month 60 minus volume of black holes at screening.

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

    Two-timepoint percentage brain volume change was estimated with Structural Image Evaluation, using Normalisation, of Atrophy (SIENA) software. The measurements describe the percentage change from screening in brain volume at month 60.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 48 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Patients who have reached scheduled end of study in BENEFIT, either by developing CDMS or by completing 24 months
Exclusion Criteria:
  • No participation in the initial BENEFIT study

Contacts and Locations

Locations

Site City State Country Postal Code
1 Graz Austria 8036
2 Innsbruck Austria 6020
3 Wien Austria 1090
4 Bruxelles Belgium 1200
5 Gent Belgium 9000
6 Leuven Belgium 3000
7 Liège 1 Belgium 4000
8 Calgary Alberta Canada T2N 2T9
9 Vancouver British Columbia Canada V6T 2B5
10 London Ontario Canada N6A 5A5
11 Ottawa Ontario Canada K1H 8L6
12 Toronto Ontario Canada M5B 1W8
13 Montreal Quebec Canada H2L 4M1
14 Brno Czech Republic 63900
15 Hradec Kralove Czech Republic 50005
16 Ostrava Czech Republic 70852
17 Plzen Czech Republic 30460
18 Prag Czech Republic 10034
19 Prag Czech Republic 12808
20 Glostrup Denmark 2600
21 Helsinki Finland 00100
22 Kuopio Finland 70210
23 Oulu Finland 90029
24 Seinäjoki Finland 60220
25 Tampere Finland 33521
26 Turku Finland 20100
27 Rennes Bretagne France 35038
28 Bordeaux Gironde France 33076
29 Clermont ferrand France 63003
30 Dijon France 21033
31 Lille France 59037
32 Nancy France 54035
33 Nice France 06000
34 Paris France 75019
35 Toulouse France 31059
36 Ulm Baden-Württemberg Germany 89081
37 München Bayern Germany 81377
38 Regensburg Bayern Germany 93053
39 Würzburg Bayern Germany 97080
40 Hennigsdorf Brandenburg Germany 16761
41 Gießen Hessen Germany 35392
42 Marburg Hessen Germany 35039
43 Offenbach Hessen Germany 63069
44 Greifswald Mecklenburg-Vorpommern Germany 17475
45 Braunschweig Niedersachsen Germany 38126
46 Göttingen Niedersachsen Germany 37099
47 Düsseldorf Nordrhein-Westfalen Germany 40225
48 Düsseldorf Nordrhein-Westfalen Germany 40479
49 Köln Nordrhein-Westfalen Germany 50931
50 Münster Nordrhein-Westfalen Germany 48149
51 Mainz Rheinland-Pfalz Germany 55101
52 Homburg Saarland Germany 66424
53 Halle Sachsen-Anhalt Germany 06120
54 Magdeburg Sachsen-Anhalt Germany 39120
55 Erfurt Thüringen Germany 99089
56 Berlin Germany 12200
57 Berlin Germany 13585
58 Szeged Csongrad Hungary 6720
59 Budapest Hungary 1076
60 Budapest Hungary 1145
61 Budapest Hungary 1204
62 Debrecen Hungary 4032
63 Haifa Israel 34362
64 Tel Hashomer Israel 52621
65 Gallarate Varese Italy 21013
66 Milano Italy 20132
67 Padova Italy 35128
68 Pavia Italy 27100
69 Torino Italy 10126
70 Sittard Netherlands 6131 BK
71 Tilburg Netherlands 5022 GC
72 Bergen Norway N-5021
73 Bydgoszcz Poland 85681
74 Krakow Poland 31503
75 Lodz Poland 90153
76 Lublin Poland 20090
77 Wroclaw Poland 50420
78 Coimbra Portugal 3000
79 Lubljana Slovenia 1525
80 Hospitalet de Llobregat Barcelona Spain 08907
81 Barakaldo Vizcaya Spain 48903
82 Barcelona Spain 08035
83 Barcelona Spain 08036
84 Madrid Spain 28040
85 Malaga Spain 29010
86 Sevilla Spain 41071
87 Valencia Spain 46026
88 Göteborg Sweden 41685
89 Basel Basel-Stadt Switzerland 4031
90 St. Gallen Switzerland 9007
91 Dundee Scotland United Kingdom DD1 9SY
92 Aberdeen United Kingdom AB25 2ZN
93 London United Kingdom W6 8RF
94 Sheffield United Kingdom S10 2JF

Sponsors and Collaborators

  • Bayer

Investigators

  • Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:
Bayer
ClinicalTrials.gov Identifier:
NCT00185211
Other Study ID Numbers:
  • 91031
  • 305207
First Posted:
Sep 16, 2005
Last Update Posted:
Dec 30, 2013
Last Verified:
Dec 1, 2013

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail The full analysis set includes all 468 participants (particip.) with at least one administration of study drug in the placebo-controlled original study 92012, using treatment groups as randomized according to the minimization procedure regardless of the kind of study treatment (IFNB-1b/placebo) received. 19 subjects did not consent to the Follow-up
Arm/Group Title Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Arm/Group Description Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)
Period Title: Placebo-controlled Study (92012)
STARTED 292 176
COMPLETED 271 166
NOT COMPLETED 21 10
Period Title: Placebo-controlled Study (92012)
STARTED 261 157
COMPLETED 235 123
NOT COMPLETED 26 34

Baseline Characteristics

Arm/Group Title Initial IFNB-1b (Interferon Beta-1b) Initial Placebo Total
Arm/Group Description Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial) Total of all reporting groups
Overall Participants 292 176 468
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
30.8
(7.6)
30.7
(7.1)
30.7
(7.4)
Sex: Female, Male (Count of Participants)
Female
207
70.9%
124
70.5%
331
70.7%
Male
85
29.1%
52
29.5%
137
29.3%
Number of T2 lesions detected in screening MRI (Magnet-Resonance Imaging) (participants) [Number]
2 to 4 T2 lesions
42
14.4%
25
14.2%
67
14.3%
5 to 8 T2 lesions
43
14.7%
28
15.9%
71
15.2%
at least 9 T2 lesions
207
70.9%
123
69.9%
330
70.5%
Number of participants with steroid use during the first clinical demyelinating event (participants) [Number]
Steroid Use
209
71.6%
123
69.9%
332
70.9%
No Steroid Use
83
28.4%
53
30.1%
136
29.1%
Type of onset of disease (classification of first demyelinating event) (participants) [Number]
monofocal disease
153
52.4%
93
52.8%
246
52.6%
multifocal disease
139
47.6%
83
47.2%
222
47.4%

Outcome Measures

1. Primary Outcome
Title Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS at Selected Points in Time
Description CDMS could be reached due to a qualifying relapse or sustained progression of 1.5 points on the expanded disability status scale (EDSS) as compared to the lowest EDSS obtained during screening or Day 1. The validity of CDMS diagnoses was confirmed by a central committee. The EDSS scale quantifies disability in MS in 8 functional systems, values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on an ordinal scale. Time to CDMS = date of CDMS - date of Day 1 + 1 or time to CDMS = date of last clinical visit - date of Day 1 + 1 (right-censored)
Time Frame up to 60 months after start of treatment

Outcome Measure Data

Analysis Population Description
The analysis followed the intention to treat (ITT) principle. After five years, in the initial placebo arm 94 participants and in the initial IFNB-1b arm 124 participants had reached CDMS diagnosis.
Arm/Group Title Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Arm/Group Description Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)
Measure Participants 292 176
Kaplan-Meier estimate at year 2
26.9
45.0
Kaplan-Meier estimate at year 3
36.7
51.2
Kaplan-Meier estimate at year 5
46.2
57.3
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments The null hypothesis for comparison of initial IFNB-1b versus initial placebo treatment was: H0: The survival functions (i.e., the probability that time to CDMS is ≥ t) are identical for both treatment arms for all points in time t>0. The two-sided alternative hypothesis was: H1: The survival functions (i.e., the probability that time to CDMS is ≥ t) are not identical for both treatment arms for some points in time t>0.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0027
Comments A 2-sided error level of 0.0253 was used for analyses at month 36 and 60 in order to keep the study-wise error level at 0.05. A conditional sequential testing approach was used for the family of null hypotheses of the primary efficacy variables.
Method Log Rank
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments Time to CDMS was modelled by a Cox proportional hazards regression model with the following covariates: treatment group, steroid use during first event (yes vs. no), onset of disease (monofocal vs. multifocal) and number of T2 lesions at screening (categories: 2-4, 5-8 and at least 9 T2 lesions). The null hypothesis was: Initial IFNB-1b and initial placebo do not differ with regard to the hazard for CDMS, i.e. hazard ratio = 1.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0028
Comments
Method Regression, Cox
Comments covariate adjustment: steroid use during first event, onset of disease, categorized number of T2 lesions at screening
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.663
Confidence Interval () 97.47%
0.488 to 0.902
Parameter Dispersion Type:
Value:
Estimation Comments The direction of comparison is initial IFNB-1b (numerator) versus initial placebo (denominator), i.e. the Hazard Ratio represents the relative risk of initial IFNB-1b treatment compared to initial placebo treatment.
2. Primary Outcome
Title Time to Confirmed Expanded Disability Status Scale (EDSS) Progression Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With Confirmed EDSS Progression at Selected Points in Time
Description EDSS progression was defined as an increase in the expanded disability status scale (EDSS) of 1.0 point compared to the lowest EDSS score obtained during the screening or baseline visit, if this score was <= 5.5. A confirmed EDSS progression status was defined as an EDSS progression observed at two consecutive scheduled visits at least 140 days apart from each other. The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on a scale.
Time Frame up to 60 months after start of treatment

Outcome Measure Data

Analysis Population Description
The analysis followed the ITT principle. The 25%-percentile for time to confirmed EDSS progression was 908 days in the initial placebo arm but was not estimable in the initial IFNB-1b arm. After five years, in the initial placebo arm 47 participants and in the initial IFNB-1b arm 65 participants had reached confirmed EDSS progression.
Arm/Group Title Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Arm/Group Description Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)
Measure Participants 292 176
Kaplan-Meier estimate at year 2
12.8
19.9
Kaplan-Meier estimate at year 3
16.8
25.3
Kaplan-Meier estimate at year 5
24.9
28.9
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments The null hypothesis for comparison of initial IFNB-1b versus initial placebo treatment was: H0: The survival functions (i.e., the probability that time to confirmed EDSS progression is ≥ t) are not identical for both treatment arms for some points in time t>0. The two-sided alternative hypothesis was: H1: The survival functions (i.e., the probability that time to confirmed EDSS progression is ≥ t) are identical for both treatment arms for some points in time t>0.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.1768
Comments A 2-sided error level of 0.0253 was used for analyses at month 36 and 60 in order to keep the study-wise error level at 0.05. A conditional sequential testing approach was used for the family of null hypotheses of the primary efficacy variables.
Method Log Rank
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments Time to confirmed EDSS progression was modelled by a Cox proportional hazards regression model with the following covariates: treatment group and volume of T2 lesions on screening MRI. The null hypothesis was: Initial IFNB-1b and initial placebo do not differ with regard to the hazard for confirmed EDSS progression, i.e. hazard ratio = 1.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.1604
Comments
Method Regression, Cox
Comments The variable used as additional covariate adjustment was volume of T2 lesions on screening MRI.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.764
Confidence Interval () 97.47%
0.497 to 1.174
Parameter Dispersion Type:
Value:
Estimation Comments The direction of comparison is initial IFNB-1b (numerator) versus initial placebo (denominator), i.e. the Hazard Ratio represents the relative risk of initial IFNB-1b treatment compared to initial placebo treatment.
3. Primary Outcome
Title Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Month 60
Description As an index of health related quality of life in people diagnosed with MS, the FAMS Trial Outcome Index covers overall physical health (sum of sub-scale scores Mobility, Symptoms, Thinking/Fatigue, Additional Concerns) with a score range from 0 to 148. A higher score reflects a higher overall physical health as reported by patients.
Time Frame 60 months after start of treatment

Outcome Measure Data

Analysis Population Description
The analysis followed the ITT principle. Not all patients who completed the follow-up study could be included at month 60 as subject to copyright constraints and to the availability of validated language versions, FAMS assessments could not be conducted in all patients.
Arm/Group Title Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Arm/Group Description Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)
Measure Participants 169 91
Median (Inter-Quartile Range) [units on a scale]
125
125
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments The null hypothesis H0: "The distribution of FAMS TOI at month 60, adjusted for baseline FAMS TOI, is identical for both treatment arms" was tested against the alternative hypothesis HA: "The distribution of FAMS TOI at month 60, adjusted for baseline FAMS TOI, is not the same in the two treatment arms" using a non-parametric analysis of covariance (ANCOVA).
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.8880
Comments A 2-sided error level of 0.0253 was used for analyses at month 36 and 60 in order to keep the study-wise error level at 0.05. A conditional sequential testing approach was used for the family of null hypotheses of the primary efficacy variables.
Method non-parametric ANCOVA
Comments Variable used as covariate: FAMS TOI measured at baseline
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments The null hypothesis H0: "The mean FAMS TOI at month 60, adjusted for baseline FAMS TOI, is identical for both treatment arms" was tested against the alternative hypothesis HA: "The mean FAMS TOI at month 60, adjusted for baseline FAMS TOI, is not the same in the two treatment arms" using a parametric analysis of covariance (ANCOVA).
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.3832
Comments
Method ANCOVA
Comments Variable used as covariate: FAMS TOI measured at baseline
4. Secondary Outcome
Title Relapse-based Efficacy Domain: Time to Multiple Sclerosis (MS) According to McDonald Criteria
Description MS according to the criteria by McDonald was reached if, in addition to the single clinical demyelinating event, both dissemination in space and dissemination in time were established by MRI-criteria or a new relapse. Time to McDonald MS is the difference of date of McDonald MS to the date of Day 1 + 1. For subjects without McDonald MS, time to McDonald MS is the difference from the maximum (date of last magnetic resonance imaging scan, date of last clinical visit) to the date of Day 1 + 1 (right-censored observation).
Time Frame up to 60 months after start of treatment

Outcome Measure Data

Analysis Population Description
The analysis followed the ITT principle. After five years, in the initial placebo arm 151 participants and in the initial IFNB-1b arm 224 participants had reached McDonald MS diagnosis.
Arm/Group Title Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Arm/Group Description Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)
Measure Participants 292 176
Median (95% Confidence Interval) [months]
9.4
6
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments The null hypothesis for comparison of initial IFNB-1b versus initial placebo treatment was: H0: The survival functions (i.e., the probability that time to McDonald MS is ≥ t) are identical for both treatment arms for all points in time t>0. The two-sided alternative hypothesis was: H1: The survival functions (i.e., the probability that time to McDonald MS is ≥ t) are not identical for both treatment arms for some points in time t>0.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.000006
Comments The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
Method Log Rank
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments Time to McDonald MS was modelled by a Cox proportional hazards regression model with the following covariates: treatment group, steroid use during first event (yes vs. no), onset of disease (monofocal vs. multifocal) and number of T2 lesions at screening (categories: 2-4, 5-8 and at least 9 T2 lesions). The null hypothesis was: Initial IFNB-1b and initial placebo do not differ with regard to the hazard for McDonald MS, i.e. hazard ratio = 1.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.000001
Comments
Method Regression, Cox
Comments covariate adjustment: steroid use during first event, onset of disease, categorized number of T2 lesions at screening
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.583
Confidence Interval () 95%
0.474 to 0.718
Parameter Dispersion Type:
Value:
Estimation Comments The direction of comparison is initial IFNB-1b versus initial placebo, i.e. the Hazard Ratio represents the relative risk of initial IFNB-1b treatment compared to initial placebo treatment.
5. Secondary Outcome
Title Relapse-based Efficacy Domain: Hazard Ratio for Recurrent Relapses
Description A relapse was defined as the appearance of a new neurological abnormality or the reappearance of a neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The time to the onset of recurrent relapses was determined for each subject according to the counting process representation for recurrent events. Time to a relapse was right-censored if a relapse-risk period ended without relapse. Based on the Andersen-Gill model the hazard ratio for recurrent relapses was estimated. Annualized relapse rates are provided as another outcome measure.
Time Frame up to 60 months after start of treatment

Outcome Measure Data

Analysis Population Description
The analysis followed the Intention-To-Treat (ITT) principle. The hazard for recurrent relapses was modelled by an extension of the Cox Proportional Hazards (PH) regression model (Andersen-Gill Model).
Arm/Group Title All Subjects
Arm/Group Description All subjects part of Intention-To-Treat (ITT) Population
Measure Participants 468
Number [Ratio]
0.797
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b)
Comments The time to recurrent relapses was modelled by an extension of Cox's PH regression model (Andersen-Gill Model) for recurrent events with the following covariates: treatment group, steroid use during first event (yes vs. no), onset of disease (monofocal vs. multifocal) and number of T2 lesions at screening (2-4, 5-8 and at least 9 T2 lesions). The null hypothesis was: Initial IFNB-1b and initial placebo do not differ with regard to the hazard for recurrent relapses, i.e. hazard ratio = 1.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.1265
Comments The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
Method Andersen-Gill Model
Comments Covariate adjustment: steroid use during first event, onset of disease, categorized number of T2 lesions at screening
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.797
Confidence Interval () 95%
0.595 to 1.066
Parameter Dispersion Type:
Value:
Estimation Comments The direction of comparison is initial IFNB-1b (numerator) versus initial placebo (denominator), i.e. the Hazard Ratio represents the relative risk of initial IFNB-1b treatment compared to initial placebo treatment.
6. Secondary Outcome
Title Relapse-based Efficacy Domain (Supportive): Annualized Relapse Rate
Description The annualized relapse rate is defined as total number of relapses up to month 60 divided by the total observation time (last clinical visit minus first day of study treatment administration plus 1 of all participants) in years.
Time Frame up to 60 months after start of treatment

Outcome Measure Data

Analysis Population Description
The analysis followed the ITT principle. For each treatment arm, the relapse rate is defined as total number of relapses up to month 60 divided by the total observation time in years.
Arm/Group Title Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Arm/Group Description Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)
Measure Participants 292 176
Mean (95% Confidence Interval) [number of relapses per patient and year]
0.2139
0.2695
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments Relapse rate was analyzed by a generalized linear Poisson regression model with individual relapse counts as dependent variable, covariates: treatment arm, steroid use during first event, onset of disease and categorized number of T2 lesions at screening and offset variable natural log of time (in years) as difference between last clinical visit and baseline visit. The treatment effect on the relapse rate was of primary interest.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0141
Comments The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
Method generalized linear Poisson regression
Comments covariate adjustment: steroid use during first event, onset of disease, categorized number of T2 lesions at screening
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.7971
Confidence Interval () 95%
0.6650 to 0.9554
Parameter Dispersion Type:
Value:
Estimation Comments The direction of comparison is initial IFNB-1b (numerator) versus initial placebo (denominator), i.e. the Risk Ratio represents the relative risk of initial IFNB-1b treatment compared to initial placebo treatment.
7. Secondary Outcome
Title Disability-based Efficacy Domain: Multiple Sclerosis Functional Composite (MSFC) at Month 60
Description The MSFC score consists of three sub-tests (Timed-25-Foot-Walk, 9-Hole-Peg-Test, 3" Paced Auditory Serial Addition Test [PASAT]). Standardized results (Z-scores) of the sub-tests and the overall MSFC Z-score as an average of the three Z-scores were derived using baseline data pooled over both treatment arms as reference population. Higher Z-scores reflect a better neurological status.
Time Frame 60 months after start of treatment

Outcome Measure Data

Analysis Population Description
The analysis followed the ITT principle. Not all FAS patients completed the follow-up study or had MSFC results at month 60 available.
Arm/Group Title Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Arm/Group Description Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)
Measure Participants 228 120
Median (Inter-Quartile Range) [Z-scores]
0.226
0.225
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments The null hypothesis H0: "The distribution of MSFC Z-scores at month 60 adjusted for baseline MSFC Z-score is identical for both treatment arms" was tested against the alternative hypothesis HA: "The distribution of MSFC Z-scores at month 60 adjusted for baseline MSFC Z-score is not the same in the two treatment groups" based on a non-parametric analysis of covariance (ANCOVA).
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.6078
Comments The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
Method non-parametric ANCOVA
Comments Variable used as covariate: MSFC Z-scores measured at baseline
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments The null hypothesis H0: "The mean MSFC Z-scores at month 60 adjusted for baseline MSFC Z-score are identical for both treatment arms" was tested against the alternative hypothesis HA: "The mean MSFC Z-scores at month 60 adjusted for baseline MSFC Z-score are not the same in the two treatment groups" based on a non-parametric analysis of covariance (ANCOVA).
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.8245
Comments The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
Method ANCOVA
Comments Variable used as covariate: MSFC Z-scores measured at baseline
8. Secondary Outcome
Title MRI (Magnet-Resonance Imaging)-Based Efficacy Domain: Cumulative Number of Newly Active Lesions at Month 60
Description Newly active lesions are defined as displaying either new Gadolinium (Gd)-enhancement on T1-weighted scans or non-enhancement on T1-weighted scan but new on T2-weighted scan. The numbers of newly active lesions on yearly MRI scans were summed up to the cumulative number.
Time Frame up to 60 months after start of treatment

Outcome Measure Data

Analysis Population Description
The analysis followed the ITT principle. Not all patients in the full analysis set completed the follow-up study or had MRI scan readings at month 60 available.
Arm/Group Title Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Arm/Group Description Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)
Measure Participants 219 114
Median (Inter-Quartile Range) [cumulative number of lesions]
4
7
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments The null hypothesis H0: "The distribution of the cumulative number of newly active lesions at month 60 adjusted for the number of Gadolinium (Gd)-enhancing lesions on T1 at screening is identical for both treatment arms." was tested against the corresponding two-sided alternative hypothesis based on a non-parametric analysis of covariance (ANCOVA).
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0062
Comments The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
Method non-parametric ANCOVA
Comments Variable used as covariate: number of Gd-enhancing lesions on T1 at screening
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments Assuming that the cumulative number of newly active lesions at month 60 follows a negative binomial distribution, a generalized linear model (logarithmic link function, covariate: number of Gd-enhancing lesions on T1 at BENEFIT screening) was set up in order to analyze the treatment effect on that MRI outcome.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0435
Comments The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
Method generalized linear model
Comments Distribution: negative binomial distribution; covariate: number of Gd-enhancing lesions on T1 at screening
Method of Estimation Estimation Parameter Relative effect size
Estimated Value 0.7351
Confidence Interval () 95%
0.5436 to 0.9940
Parameter Dispersion Type:
Value:
Estimation Comments The direction of comparison is initial IFNB-1b versus initial placebo.
9. Secondary Outcome
Title MRI-based Efficacy Domain: Absolute Change of T2 Lesion Volume From Screening MRI to Month 60
Description Absolute change of T2 lesion volume from screening MRI to month 60 was calculated as T2 lesion volume at month 60 minus T2 lesion volume at screening.
Time Frame 60 months after start of treatment

Outcome Measure Data

Analysis Population Description
The analysis followed the ITT principle. Not all FAS patients completed the follow-up study or had MRI scan readings at month 60 available.
Arm/Group Title Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Arm/Group Description Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)
Measure Participants 215 112
Median (Inter-Quartile Range) [cubic millimeter]
-123.0
-194.5
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments The null hypothesis H0: "The distribution of the absolute change of T2 lesion volume at month 60 adjusted for the T2 lesion volume at screening is identical for both treatment arms." was tested against the corresponding two-sided alternative hypothesis based on a non-parametric analysis of covariance (ANCOVA).
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.7801
Comments The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
Method non-parametric ANCOVA
Comments Variable used as covariate: T2 lesion volume at screening
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments The null hypothesis H0: "The mean absolute change of T2 lesion volume at month 60 adjusted for the T2 lesion volume at screening is identical for both treatment arms." was tested against the corresponding two-sided alternative hypothesis based on a parametric analysis of covariance (ANCOVA).
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.9408
Comments The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
Method ANCOVA
Comments Variable used as covariate: T2 lesion volume at screening
10. Secondary Outcome
Title MRI-based Efficacy Domain: Absolute Change of Volume of Black Holes From Screening MRI to Month 60
Description Absolute change of volume of black holes from screening MRI to month 60 was calculated as volume of black holes at month 60 minus volume of black holes at screening.
Time Frame 60 months after start of treatment

Outcome Measure Data

Analysis Population Description
The analysis followed the ITT principle. Not all FAS patients completed the follow-up study or had MRI scan readings at month 60 available.
Arm/Group Title Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Arm/Group Description Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)
Measure Participants 217 114
Median (Inter-Quartile Range) [cubic millimeter]
0
0
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments The null hypothesis H0: "The distribution of the absolute change of volume of black holes at month 60 adjusted for the volume of black holes at screening is identical for both treatment arms." was tested against the corresponding two-sided alternative hypothesis based on a non-parametric analysis of covariance (ANCOVA).
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.6619
Comments The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
Method non-parametric ANCOVA
Comments Variable used as covariate: Volume of black holes at screening
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments The null hypothesis H0: "The mean absolute change of volume of black holes at month 60 adjusted for the volume of black holes at screening is identical for both treatment arms." was tested against the corresponding two-sided alternative hypothesis based on a parametric analysis of covariance (ANCOVA).
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.8558
Comments The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
Method ANCOVA
Comments Variable used as covariate: Volume of black holes at screening
11. Secondary Outcome
Title MRI-based Efficacy Domain: Percentage Change of Brain Volume From Screening MRI to Month 60
Description Two-timepoint percentage brain volume change was estimated with Structural Image Evaluation, using Normalisation, of Atrophy (SIENA) software. The measurements describe the percentage change from screening in brain volume at month 60.
Time Frame 60 months after start of treatment

Outcome Measure Data

Analysis Population Description
The analysis followed the ITT principle. Not all patients in the full analysis set completed the follow-up study or had MRI scan readings at month 60 available. There were several missing values in both treatment arms regarding the percentage brain volume change.
Arm/Group Title Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Arm/Group Description Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)
Measure Participants 141 80
Median (Inter-Quartile Range) [Percentage of brain volume]
-2.281
-1.771
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments The null hypothesis H0: "The distribution of the percentage change of brain volume at month 60 adjusted for the brain volume at screening is identical for both treatment arms." was tested against the corresponding two-sided alternative hypothesis based on a non-parametric analysis of covariance (ANCOVA).
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.1208
Comments The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
Method non-parametric ANCOVA
Comments Variable used as covariate: Brain volume at screening
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Initial IFNB-1b (Interferon Beta-1b), Initial Placebo
Comments The null hypothesis H0: "The mean percentage change of brain volume at month 60 adjusted for the brain volume at screening is identical for both treatment arms." was tested against the corresponding two-sided alternative hypothesis based on a parametric analysis of covariance (ANCOVA).
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0719
Comments The two-sided error level for the exploratory analysis of the secondary outcome measures was of 0.05.
Method ANCOVA
Comments Variable used as covariate: Brain volume at screening

Adverse Events

Time Frame
Adverse Event Reporting Description
Arm/Group Title Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Arm/Group Description Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)
All Cause Mortality
Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN)
Serious Adverse Events
Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 61/292 (20.9%) 42/176 (23.9%)
Blood and lymphatic system disorders
Leukopenia 1/292 (0.3%) 0/176 (0%)
Cardiac disorders
Myocardial infarct 1/292 (0.3%) 0/176 (0%)
Cardiovascular disorder 0/292 (0%) 1/176 (0.6%)
Endocrine disorders
Goiter 0/292 (0%) 1/176 (0.6%)
Eye disorders
Eye disorder 0/292 (0%) 1/176 (0.6%)
Gastrointestinal disorders
Abdominal pain 0/292 (0%) 1/176 (0.6%)
Colitis 1/292 (0.3%) 2/176 (1.1%)
Gastrointestinal Disorder 1/292 (0.3%) 0/176 (0%)
Gastrointestinal Hemorrhage 0/292 (0%) 1/176 (0.6%)
Nausea 0/292 (0%) 1/176 (0.6%)
General disorders
Cyst 1/292 (0.3%) 0/176 (0%)
Fever 0/292 (0%) 1/176 (0.6%)
Hernia 0/292 (0%) 1/176 (0.6%)
Mucous membrane disorder 1/292 (0.3%) 0/176 (0%)
Unevaluable reaction 10/292 (3.4%) 8/176 (4.5%)
Injection site necrosis 2/292 (0.7%) 0/176 (0%)
Injection site reaction 1/292 (0.3%) 0/176 (0%)
Hepatobiliary disorders
Cholelithiasis 1/292 (0.3%) 0/176 (0%)
Hepatitis 1/292 (0.3%) 0/176 (0%)
Jaundice 1/292 (0.3%) 0/176 (0%)
Immune system disorders
Allergic reaction 1/292 (0.3%) 0/176 (0%)
Infections and infestations
Cellulitis 0/292 (0%) 1/176 (0.6%)
Infection 0/292 (0%) 1/176 (0.6%)
Pneumonia 1/292 (0.3%) 1/176 (0.6%)
Pharyngitis 1/292 (0.3%) 0/176 (0%)
Sinusitis 1/292 (0.3%) 2/176 (1.1%)
Cystitis 1/292 (0.3%) 0/176 (0%)
Urinary tract infection 0/292 (0%) 1/176 (0.6%)
Pyelonephritis 1/292 (0.3%) 0/176 (0%)
Injury, poisoning and procedural complications
Accidental injury 3/292 (1%) 1/176 (0.6%)
Bone fracture (not spontaneous) 3/292 (1%) 1/176 (0.6%)
Investigations
Liver function test abnormal 2/292 (0.7%) 0/176 (0%)
Weight gain 1/292 (0.3%) 0/176 (0%)
Metabolism and nutrition disorders
Hyponatremia 1/292 (0.3%) 0/176 (0%)
Musculoskeletal and connective tissue disorders
Back pain 3/292 (1%) 0/176 (0%)
Arthralgia 1/292 (0.3%) 0/176 (0%)
Tendon disorder 0/292 (0%) 1/176 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm 1/292 (0.3%) 0/176 (0%)
Thyroid carcinoma 0/292 (0%) 1/176 (0.6%)
Breast carcinoma 1/292 (0.3%) 0/176 (0%)
Breast neoplasm 0/292 (0%) 1/176 (0.6%)
Nervous system disorders
Migraine 0/292 (0%) 1/176 (0.6%)
Convulsion 0/292 (0%) 1/176 (0.6%)
Grand mal convulsion 0/292 (0%) 1/176 (0.6%)
Myoclonus 1/292 (0.3%) 0/176 (0%)
Headache 0/292 (0%) 1/176 (0.6%)
Multiple sclerosis 11/292 (3.8%) 5/176 (2.8%)
Pregnancy, puerperium and perinatal conditions
Abortion 1/292 (0.3%) 1/176 (0.6%)
Unintended pregnancy 0/292 (0%) 1/176 (0.6%)
Psychiatric disorders
Suicide attemp other than overdose 0/292 (0%) 1/176 (0.6%)
Anxiety 0/292 (0%) 1/176 (0.6%)
Depression 2/292 (0.7%) 2/176 (1.1%)
Emotional lability 0/292 (0%) 1/176 (0.6%)
Personality disorder 0/292 (0%) 1/176 (0.6%)
Psychosis 1/292 (0.3%) 0/176 (0%)
Psychotic depression 1/292 (0.3%) 0/176 (0%)
Reproductive system and breast disorders
Ovarian cyst 0/292 (0%) 2/176 (1.1%)
Endometrial disorder 0/292 (0%) 1/176 (0.6%)
Vaginal hemorrhage 1/292 (0.3%) 0/176 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma 0/292 (0%) 1/176 (0.6%)
Epistaxis 1/292 (0.3%) 0/176 (0%)
Skin and subcutaneous tissue disorders
Skin necrosis 0/292 (0%) 1/176 (0.6%)
Skin ulcer 1/292 (0.3%) 0/176 (0%)
Surgical and medical procedures
Surgery 12/292 (4.1%) 6/176 (3.4%)
Vascular disorders
Thrombosis 0/292 (0%) 1/176 (0.6%)
Other (Not Including Serious) Adverse Events
Initial IFNB-1b (Interferon Beta-1b) Initial Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 283/292 (96.9%) 169/176 (96%)
Blood and lymphatic system disorders
Leukopenia 73/292 (25%) 26/176 (14.8%)
Ear and labyrinth disorders
Vertigo 10/292 (3.4%) 10/176 (5.7%)
Eye disorders
Eye pain 18/292 (6.2%) 7/176 (4%)
Abnormal vision 17/292 (5.8%) 8/176 (4.5%)
Blurred vision 17/292 (5.8%) 4/176 (2.3%)
Gastrointestinal disorders
Abdominal pain 22/292 (7.5%) 14/176 (8%)
Tooth disorder 19/292 (6.5%) 9/176 (5.1%)
Diarrhea 21/292 (7.2%) 9/176 (5.1%)
Nausea 21/292 (7.2%) 10/176 (5.7%)
Vomiting 23/292 (7.9%) 7/176 (4%)
General disorders
Asthenia 89/292 (30.5%) 53/176 (30.1%)
Fever 48/292 (16.4%) 18/176 (10.2%)
Pain 36/292 (12.3%) 15/176 (8.5%)
Injection site reaction 163/292 (55.8%) 71/176 (40.3%)
Chills 17/292 (5.8%) 5/176 (2.8%)
Injection site pain 24/292 (8.2%) 9/176 (5.1%)
Hepatobiliary disorders
Bilirubinemia 29/292 (9.9%) 20/176 (11.4%)
Immune system disorders
Allergic reaction 23/292 (7.9%) 11/176 (6.3%)
Infections and infestations
Flu syndrome 152/292 (52.1%) 90/176 (51.1%)
Upper respiratory infection 96/292 (32.9%) 59/176 (33.5%)
Pharyngitis 47/292 (16.1%) 26/176 (14.8%)
Infection 29/292 (9.9%) 11/176 (6.3%)
Gastroenteritis 19/292 (6.5%) 14/176 (8%)
Bronchitis 27/292 (9.2%) 15/176 (8.5%)
Rhinitis 18/292 (6.2%) 9/176 (5.1%)
Sinusitis 19/292 (6.5%) 16/176 (9.1%)
Urinary tract infection 14/292 (4.8%) 13/176 (7.4%)
Injury, poisoning and procedural complications
Accidental injury 26/292 (8.9%) 14/176 (8%)
Investigations
SGOT increased 34/292 (11.6%) 7/176 (4%)
SGPT increased 50/292 (17.1%) 14/176 (8%)
Liver function test abnormal 19/292 (6.5%) 6/176 (3.4%)
Metabolism and nutrition disorders
Hyperglycemia 12/292 (4.1%) 11/176 (6.3%)
Musculoskeletal and connective tissue disorders
Back pain 49/292 (16.8%) 20/176 (11.4%)
Pain in extremity 33/292 (11.3%) 15/176 (8.5%)
Myalgia 29/292 (9.9%) 20/176 (11.4%)
Neck pain 11/292 (3.8%) 9/176 (5.1%)
Arthralgia 21/292 (7.2%) 15/176 (8.5%)
Muscle cramps 15/292 (5.1%) 8/176 (4.5%)
Myasthenia 16/292 (5.5%) 10/176 (5.7%)
Nervous system disorders
Headache 98/292 (33.6%) 54/176 (30.7%)
Multiple sclerosis 112/292 (38.4%) 82/176 (46.6%)
Paresthesia 82/292 (28.1%) 53/176 (30.1%)
Dizziness 14/292 (4.8%) 10/176 (5.7%)
Hypertonia 15/292 (5.1%) 5/176 (2.8%)
Hypesthesia 15/292 (5.1%) 10/176 (5.7%)
Pregnancy, puerperium and perinatal conditions
Unintended pregnancy 15/292 (5.1%) 12/176 (6.8%)
Psychiatric disorders
Anxiety 33/292 (11.3%) 18/176 (10.2%)
Depression 56/292 (19.2%) 41/176 (23.3%)
Insomnia 37/292 (12.7%) 21/176 (11.9%)
Respiratory, thoracic and mediastinal disorders
Sore throat 19/292 (6.5%) 11/176 (6.3%)
Skin and subcutaneous tissue disorders
Rash 39/292 (13.4%) 15/176 (8.5%)
Surgical and medical procedures
Surgery 22/292 (7.5%) 14/176 (8%)
Vascular disorders
Hypertension 13/292 (4.5%) 9/176 (5.1%)

Limitations/Caveats

Participant Flow: Subject with "Other" as reason for not completing a study period are presented according to the NIH pre-specified categories as far as possible.

More Information

Certain Agreements

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

Submit for review any manuscript / abstract related to the Study at least 90 days prior to publication.The proposed publication / presentation shall only be made after BSP has obtained adequate patent protection for the Results, or after the patentable information has been taken out of the publication/presentation.

Results Point of Contact

Name/Title Therapeutic Area Head
Organization BAYER
Phone
Email clinical-trials-contact@bayerhealthcare.com
Responsible Party:
Bayer
ClinicalTrials.gov Identifier:
NCT00185211
Other Study ID Numbers:
  • 91031
  • 305207
First Posted:
Sep 16, 2005
Last Update Posted:
Dec 30, 2013
Last Verified:
Dec 1, 2013