BENEFIT Study (Betaferon® / Betaseron® in Newly Emerging Multiple Sclerosis for Initial Treatment) and BENEFIT Follow-up Study
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 |
---|---|---|
|
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
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
- Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS at Selected Points in Time [up to 60 months after start of treatment]
CDMS could be reached due to a qualifying relapse or sustained progression of 1.5 points on the expanded disability status scale (EDSS) as compared to the lowest EDSS obtained during screening or Day 1. The validity of CDMS diagnoses was confirmed by a central committee. The EDSS scale quantifies disability in MS in 8 functional systems, values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on an ordinal scale. Time to CDMS = date of CDMS - date of Day 1 + 1 or time to CDMS = date of last clinical visit - date of Day 1 + 1 (right-censored)
- Time to Confirmed Expanded Disability Status Scale (EDSS) Progression Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With Confirmed EDSS Progression at Selected Points in Time [up to 60 months after start of treatment]
EDSS progression was defined as an increase in the expanded disability status scale (EDSS) of 1.0 point compared to the lowest EDSS score obtained during the screening or baseline visit, if this score was <= 5.5. A confirmed EDSS progression status was defined as an EDSS progression observed at two consecutive scheduled visits at least 140 days apart from each other. The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on a scale.
- Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Month 60 [60 months after start of treatment]
As an index of health related quality of life in people diagnosed with MS, the FAMS Trial Outcome Index covers overall physical health (sum of sub-scale scores Mobility, Symptoms, Thinking/Fatigue, Additional Concerns) with a score range from 0 to 148. A higher score reflects a higher overall physical health as reported by patients.
Secondary Outcome Measures
- 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).
- Relapse-based Efficacy Domain: Hazard Ratio for Recurrent Relapses [up to 60 months after start of treatment]
A relapse was defined as the appearance of a new neurological abnormality or the reappearance of a neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The time to the onset of recurrent relapses was determined for each subject according to the counting process representation for recurrent events. Time to a relapse was right-censored if a relapse-risk period ended without relapse. Based on the Andersen-Gill model the hazard ratio for recurrent relapses was estimated. Annualized relapse rates are provided as another outcome measure.
- Relapse-based Efficacy Domain (Supportive): Annualized Relapse Rate [up to 60 months after start of treatment]
The annualized relapse rate is defined as total number of relapses up to month 60 divided by the total observation time (last clinical visit minus first day of study treatment administration plus 1 of all participants) in years.
- Disability-based Efficacy Domain: Multiple Sclerosis Functional Composite (MSFC) at Month 60 [60 months after start of treatment]
The MSFC score consists of three sub-tests (Timed-25-Foot-Walk, 9-Hole-Peg-Test, 3" Paced Auditory Serial Addition Test [PASAT]). Standardized results (Z-scores) of the sub-tests and the overall MSFC Z-score as an average of the three Z-scores were derived using baseline data pooled over both treatment arms as reference population. Higher Z-scores reflect a better neurological status.
- MRI (Magnet-Resonance Imaging)-Based Efficacy Domain: Cumulative Number of Newly Active Lesions at Month 60 [up to 60 months after start of treatment]
Newly active lesions are defined as displaying either new Gadolinium (Gd)-enhancement on T1-weighted scans or non-enhancement on T1-weighted scan but new on T2-weighted scan. The numbers of newly active lesions on yearly MRI scans were summed up to the cumulative number.
- 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.
- MRI-based Efficacy Domain: Absolute Change of Volume of Black Holes From Screening MRI to Month 60 [60 months after start of treatment]
Absolute change of volume of black holes from screening MRI to month 60 was calculated as volume of black holes at month 60 minus volume of black holes at screening.
- MRI-based Efficacy Domain: Percentage Change of Brain Volume From Screening MRI to Month 60 [60 months after start of treatment]
Two-timepoint percentage brain volume change was estimated with Structural Image Evaluation, using Normalisation, of Atrophy (SIENA) software. The measurements describe the percentage change from screening in brain volume at month 60.
Eligibility Criteria
Criteria
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
- Edan G, Kappos L, Montalbán X, Polman CH, Freedman MS, Hartung HP, Miller D, Barkhof F, Herrmann J, Lanius V, Stemper B, Pohl C, Sandbrink R, Pleimes D; BENEFIT Study Group. Long-term impact of interferon beta-1b in patients with CIS: 8-year follow-up of BENEFIT. J Neurol Neurosurg Psychiatry. 2014 Nov;85(11):1183-9. doi: 10.1136/jnnp-2013-306222. Epub 2013 Nov 11.
- Nagtegaal GJ, Pohl C, Wattjes MP, Hulst HE, Freedman MS, Hartung HP, Miller D, Montalban X, Kappos L, Edan G, Pleimes D, Beckman K, Stemper B, Polman CH, Sandbrink R, Barkhof F. Interferon beta-1b reduces black holes in a randomised trial of clinically isolated syndrome. Mult Scler. 2014 Feb;20(2):234-42. doi: 10.1177/1352458513494491. Epub 2013 Jul 10.
- Penner IK, Stemper B, Calabrese P, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalbán X, Barkhof F, Pleimes D, Lanius V, Pohl C, Kappos L, Sandbrink R. Effects of interferon beta-1b on cognitive performance in patients with a first event suggestive of multiple sclerosis. Mult Scler. 2012 Oct;18(10):1466-71. Epub 2012 Apr 4.
- 91031
- 305207
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
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. |
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. |
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 |
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. |
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. |
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. |
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 |
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. |
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 |
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 |
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
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 | |
clinical-trials-contact@bayerhealthcare.com |
- 91031
- 305207