Clinical Trial Results:
BENEFIT 15 long-term follow-up study of the BENEFIT and BENEFIT follow-up studies
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Summary
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EudraCT number |
2017-001176-31 |
Trial protocol |
HU ES SE GB AT CZ FI DK BE FR PT IT |
Global end of trial date |
22 May 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
30 May 2019
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First version publication date |
30 May 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
BAY86-5046/19215
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03269175 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Bayer AG
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Sponsor organisation address |
Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
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Public contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Scientific contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
22 May 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
22 May 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objectives are to describe the course of disease over time including, relapse, disability, cognitive function) and the healthcare resource utilization (HRU) (resource use, employment status), in relation to treatment with IFNB-1b.
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Protection of trial subjects |
The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Sep 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Austria: 3
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Country: Number of subjects enrolled |
Belgium: 15
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Country: Number of subjects enrolled |
Canada: 8
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Country: Number of subjects enrolled |
Czech Republic: 42
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Country: Number of subjects enrolled |
Denmark: 2
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Country: Number of subjects enrolled |
Finland: 18
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Country: Number of subjects enrolled |
France: 14
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Country: Number of subjects enrolled |
Germany: 34
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Country: Number of subjects enrolled |
Hungary: 23
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Country: Number of subjects enrolled |
Israel: 3
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Country: Number of subjects enrolled |
Italy: 9
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Country: Number of subjects enrolled |
Norway: 3
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Country: Number of subjects enrolled |
Poland: 36
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Country: Number of subjects enrolled |
Portugal: 1
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Country: Number of subjects enrolled |
Spain: 36
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Country: Number of subjects enrolled |
Sweden: 3
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Country: Number of subjects enrolled |
Switzerland: 6
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Country: Number of subjects enrolled |
United Kingdom: 5
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Worldwide total number of subjects |
261
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EEA total number of subjects |
244
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
261
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Study was conducted in 18 countries between 29 SEP 2017 (FPFV) and 24 MAY 2018 (LPLV). | |||||||||
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Pre-assignment
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Screening details |
Out of the 468 subjects enrolled in the original BENEFIT trial (304747), 261 subjects had been enrolled into the BENEFIT 15 long-term follow-up study with 161 of them in the early IFNB-1b treatment group (treatment received in BENEFIT: IFNB-1b 250 µg) and 100 subjects in the delayed IFNB-1b treatment group (treatment received in BENEFIT: Placebo) | |||||||||
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Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Early IFNB-1b treatment | |||||||||
Arm description |
Initial Betaferon/Betaseron treatment (Interferon beta1b, IFNB1b), 250 microgram administered subcutaneously every other day in original BENEFIT study (304747) study; Different to previous BENEFIT studies, the IFNB-1b group is labelled with “Early IFNB-1b Treatment.” | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Interferon Beta1b
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Investigational medicinal product code |
BAY86-5046
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Other name |
Betaseron, Betaferon
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Initial Betaferon/Betaseron treatment (Interferon beta1b, IFNB1b), 250 microgram administered subcutaneously every other day in original BENEFIT study (304747).
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Arm title
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Delayed IFNB-1b treatment | |||||||||
Arm description |
Initial placebo treatment in original BENEFIT study (304747); Different to previous BENEFIT studies, the placebo group is labelled with “Delayed IFNB-1b Treatment". If and when a patient assigned to this arm developed Clinically Definite Multiple Sclerosis (CDMS), or after 2 years, Betaferon was offered to use. | |||||||||
Arm type |
No intervention | |||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
Early IFNB-1b treatment
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Reporting group description |
Initial Betaferon/Betaseron treatment (Interferon beta1b, IFNB1b), 250 microgram administered subcutaneously every other day in original BENEFIT study (304747) study; Different to previous BENEFIT studies, the IFNB-1b group is labelled with “Early IFNB-1b Treatment.” | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Delayed IFNB-1b treatment
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Reporting group description |
Initial placebo treatment in original BENEFIT study (304747); Different to previous BENEFIT studies, the placebo group is labelled with “Delayed IFNB-1b Treatment". If and when a patient assigned to this arm developed Clinically Definite Multiple Sclerosis (CDMS), or after 2 years, Betaferon was offered to use. | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Early IFNB-1b treatment
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Reporting group description |
Initial Betaferon/Betaseron treatment (Interferon beta1b, IFNB1b), 250 microgram administered subcutaneously every other day in original BENEFIT study (304747) study; Different to previous BENEFIT studies, the IFNB-1b group is labelled with “Early IFNB-1b Treatment.” | ||
Reporting group title |
Delayed IFNB-1b treatment
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Reporting group description |
Initial placebo treatment in original BENEFIT study (304747); Different to previous BENEFIT studies, the placebo group is labelled with “Delayed IFNB-1b Treatment". If and when a patient assigned to this arm developed Clinically Definite Multiple Sclerosis (CDMS), or after 2 years, Betaferon was offered to use. | ||
Subject analysis set title |
BENEFIT 15 set
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This analysis set was a subset of the FAS and included all subjects who were enrolled in the BENEFIT 15 study (19215).
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End point title |
Number of subjects with diagnosis of multiple sclerosis within fifteen years after Clinically-Isolated Syndrome (CIS) according to McDonald 2001 and 2010 Criteria [1] | |||||||||||||||
End point description |
The McDonald criteria (2001 and 2010, respectively) were applied to identify subjects who developed MS according to the respective criteria. Subjects participating in BENEFIT 15 without valid MRI assessment at BENEFIT 15 who did not develop McDonald MS in the previous studies (BENEFIT, BENEFIT follow-up study, BENEFIT extension study, BENEFIT 11) and who did not develop CDMS were excluded from the analysis.
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End point type |
Primary
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End point timeframe |
Over 15 years since the subject´s first clinical event
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Disease course since start of BENEFIT as assessed at the time of BENEFIT 15 [2] | ||||||||||||||||||||||||
End point description |
The disease course was assessed and categorized (CIS without MRI activity, relapses or disability progression after first Event; CIS with MRI activity but no relapses or disability progression after first Event; Relapsing-remitting MS [RRMS] ; Secondary progressive MS [SPMS]; Primary progressive MS [PPMS].
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End point type |
Primary
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End point timeframe |
Over 15 years since the subject`s first clinical event
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Time to first relapse | ||||||||||||
End point description |
Date of the first relapse is defined as the onset date of the first neurological event that is classified as a relapse and has an onset not earlier than the BENEFIT baseline visit. The observed median “Time to first relapse” was reported.
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End point type |
Primary
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End point timeframe |
Over 15 years since the subject´s first clinical event
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Statistical analysis title |
Time to first relapse | ||||||||||||
Comparison groups |
Early IFNB-1b treatment v Delayed IFNB-1b treatment
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Number of subjects included in analysis |
261
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.2239 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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End point title |
Time to recurrent relapse [3] | ||||||||
End point description |
This efficacy variable is based on the temporal occurrence of relapses. In general, there was more than one of such periods per subject, so that each subject is represented as a series of observations (rows of data). The first period starts with the baseline visit in BENEFIT (day 1). Periods that end without a relapse were indicated by a censoring variable (0 indicates censored, 1 indicates relapse); final censoring date is the date of final clinical visit and BENEFIT 15 visit, respectively.
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End point type |
Primary
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End point timeframe |
Over 15 years since the subject´s first clinical event
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Annualized relapse rate [4] | ||||||||||||
End point description |
Relapse rate was analyzed by a generalized linear Poisson regression model, with individual relapse counts as dependent variable, actual treatment group and the set of covariates and offset variable natural log of time (in years) in the period being analyzed.
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End point type |
Primary
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End point timeframe |
Over 15 years since the subject´s first clinical event
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Time to conversion to Clinically-Definite Multiple Sclerosis (CDMS) | ||||||||||||
End point description |
Clinically-definite MS is reached for a patient if either of the following is documented: New neurological event (relapse), i.e., the appearance of new neurologicalabnormality or reappearance of a neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event; OR Sustained progression of 1.5 points on the EDSS and a total EDSS of 2.5.
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End point type |
Primary
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End point timeframe |
Over 15 years since the subject´s first clinical event
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||
Comparison groups |
Early IFNB-1b treatment v Delayed IFNB-1b treatment
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Number of subjects included in analysis |
261
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.2052 | ||||||||||||
Method |
PH regression | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.823
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.609 | ||||||||||||
upper limit |
1.112 | ||||||||||||
Variability estimate |
Standard deviation
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Delayed IFNB-1b treatment v Early IFNB-1b treatment
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Number of subjects included in analysis |
261
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.2555 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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End point title |
Time to conversion to Secondary Progressive Multiple Sclerosis (SPMS) [5] | ||||||||||||
End point description |
The diagnosis of Secondary progressive multiple sclerosis (SPMS) is defined by sustained disability progression in the absence of relapse, with or without superimposed relapses. Specifically, sustained disability progression is defined for this study as an increase in EDSS: by 1 point if the last EDSS before conversion was <= 5.5; OR by 0.5 points if the last EDSS before conversion was above 5.5,
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End point type |
Primary
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End point timeframe |
Over 15 years since the subject´s first clinical event
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Expanded Disability Status Scale these scores (EDSS score) for disability assessed by the investigator during the neurological examination [6] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0="normal neurological examination" and 10="death due to MS" measured in halfpoints on a scale. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS.
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End point type |
Primary
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End point timeframe |
15 years after the subject´s first clinical event
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of subjects with confirmed and sustained 1-point EDSS progression (Disability progression) [7] | |||||||||||||||
End point description |
The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0="normal neurological examination" and 10="death due to MS" measured in halfpoints on a scale. EDSS progression was defined as an increase in the EDSS of at least 1.0 Point compared to initial EDSS score or an increase in the EDSS of at least 1.5 points compared to initial EDSS score, if this score was = 0 points. A confirmed EDSS progression is defined as a confirmed EDSS progression in any of the previous BENEFIT studies or EDSS progression in BENEFIT 15. A sustained EDSS progression is defined as a confirmed EDSS progression in any of the previous BENEFIT studies sustained up to and including the BENEFIT 15 visit.
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End point type |
Primary
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End point timeframe |
Over 15 years since the subject´s first clinical event
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Number of subjects with confirmed 2.5-point EDSS progression (Disability progression) [8] | |||||||||
End point description |
The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0="normal neurological examination" and 10="death due to MS" measured in halfpoints on a scale. EDSS progression was defined as an increase in the EDSS of at least 2.5 Points compared to initial EDSS score, if this score was <= 3.5 points, or an increase in the EDSS of at least 2.0 points compared to initial EDSS score, if this score was > 3.5 points. A confirmed EDSS increase is defined as a confirmed EDSS increase in any of the previous BENEFIT studies or EDSS increase in BENEFIT 15.
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End point type |
Primary
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End point timeframe |
Over 15 years since the subject´s first clinical event
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| Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Multiple Sclerosis Functional Composite (MSFC) score (Neurological status) [9] | ||||||||||||
End point description |
The MSFC score consists of three subtests (Timed 25 Foot Walk, 9 Hole Peg Test, 3" Paced Auditory Serial Addition Test [PASAT]) whose Z-standardized results (based on baseline values on Day 1 in Study 304747) were combined into a composite score including upper and lower extremities function, and cognitive function. Standardized results (Z-scores) of the subtests and the overall MSFC Z-score as an average of the three Z-scores were derived using baseline data pooled over both treatment arms as reference population. Higher Z-scores reflect a better neurological Status.
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End point type |
Primary
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End point timeframe |
Over 15 years since the subject´s first clinical event
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| Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Paced Auditory Serial Addition Test (PASAT-3) score (Cognitive function) [10] | ||||||||||||
End point description |
The Paced Auditory Serial Addition Test (PASAT) is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability.
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End point type |
Primary
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End point timeframe |
Over 15 years since the subject´s first clinical event
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| Notes [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Time to use of ambulatory device | ||||||||||||
End point description |
Date of use of ambulatory device is defined as the retrospectively obtained time point of first use/dependence. Time to use of ambulatory device is the difference between the date of first use/dependence and the date of the BENEFIT baseline visit +1.
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End point type |
Primary
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End point timeframe |
Over 15 years since the subject´s first clinical event
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Early IFNB-1b treatment v Delayed IFNB-1b treatment
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Number of subjects included in analysis |
261
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.4918 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||
Comparison groups |
Early IFNB-1b treatment v Delayed IFNB-1b treatment
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Number of subjects included in analysis |
261
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.8257 | ||||||||||||
Method |
PH regression | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.097
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.482 | ||||||||||||
upper limit |
2.494 | ||||||||||||
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End point title |
Time to dependence on ambulatory device | ||||||||||||
End point description |
Date of dependence from ambulatory device is defined as the retrospectively obtained time point of first use/dependence. Time to dependence from ambulatory device is the difference between the date of first use/dependence and the date of the BENEFIT baseline visit +1. Cumulative probability of dependence of ambulatory device for walking represented by Kaplan-Meier estimates at Year 15.
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End point type |
Primary
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End point timeframe |
Over 15 years since the subject´s first clinical event
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||
Comparison groups |
Early IFNB-1b treatment v Delayed IFNB-1b treatment
|
||||||||||||
Number of subjects included in analysis |
261
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.6811 | ||||||||||||
Method |
PH Regression | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.834
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.351 | ||||||||||||
upper limit |
1.98 | ||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Early IFNB-1b treatment v Delayed IFNB-1b treatment
|
||||||||||||
Number of subjects included in analysis |
261
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.9479 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
|||||||||||||
|
||||||||||
End point title |
Time to use of wheelchair [11] | |||||||||
End point description |
Date of use of wheelchair is defined as the retrospectively obtained time point of first use/dependence. Time to use of wheelchair is the difference between the date of first use/dependence and the date of the BENEFIT baseline visit +1.
|
|||||||||
End point type |
Primary
|
|||||||||
End point timeframe |
Over 15 years since the subject´s first clinical event
|
|||||||||
| Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
||||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
|||||||||||||||||||||||||||||||||||||
End point title |
Employment status (Standardized questions) [12] | ||||||||||||||||||||||||||||||||||||
End point description |
Subject's employment status was categorized as 'missing', 'unemployed', 'retired', 'homemaker', 'long term disability', 'employment less than 20 hours (hrs) per week (hrs/week)', employment more than 20 hours per week, 'early retired' and 'other'.
|
||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
At one single visit, 15 years after the subject’s first clinical event
|
||||||||||||||||||||||||||||||||||||
| Notes [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
|||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Multiple sclerosis impact on employment [13] | ||||||||||||||||||||||||
End point description |
Subject's MS impact on employment was categorized as, 'unrelated to MS condition', 'ceased work due to MS', 'never worked', 'reduced working hours', or missing.
|
||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
At one single visit, 15 years after the subject’s first clinical event
|
||||||||||||||||||||||||
| Notes [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Resource use assessment questions: Help from family/regular ambulatory services [14] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Resources use data was assessed cross-sectionally at 15 years. Supportive care was assessed as “assistance given” for the help from family members or friends with “care given” for the number of hours per week needed, as well as “ambulatory services-yes/no” with sub-categories home care, home help, day care center, meals on wheels and child care for the help from professional caregiver.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At one single visit, 15 years after the subject’s first clinical event
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Resource use assessment questions: Additional ambulatory services during relapse [15] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Resources use data was assessed cross-sectionally at 15 years. Additional ambulatory services during relapse were categorized as, 'missing', 'no', and 'yes'. The additional ambulatory services during relapses were home care, home help, day care center, meals on wheels, and child care.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At one single visit, 15 years after the subject’s first clinical event
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Resource use assessment questions: Adaptions (past 6 months) [16] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Resources use data was assessed cross-sectionally at 15 years using diferent categories "adaptations", “other part of living”, “stair lift”, “ramps”, “alarm”, “work”, “car”, “walking aids”, “wheel chair”, “spectacles”, “special kitchen utensils”, “special hygiene utensils”, “special writing devices” and “ other” with sub-categories as 'missing', 'no', and 'yes'.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At one single visit, 15 years after the subject’s first clinical event
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical Analysis for this endpoint. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Symbol Digit Modalities Test score (SDMT score) | ||||||||||||||||||
End point description |
The Symbol Digit Modalities Test (SDMT) is a cognitive test for sustained attention, concentration, and information processing speed. The numbers of correct responses after 90 seconds were reported, and standardized results (Z-scores) for the number of correct responses after 90 seconds were calculated.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
At one single visit, 15 years after the subject’s first clinical event
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
||||||||||||||||
End point title |
Relation of SDMT and FSMC (Fatigue Scale for Motor and Cognitive Functions) | |||||||||||||||
End point description |
SDMT number of correct responses in 90 seconds and Fatigue Scale for Motor and Cognitive Functions (FSMC) Cognitive scale were summarized for the subjects who had non-missing values for both, SDMT in 90 seconds and FSMC Cognitive scale. Spearman partial rank-order correlation of SDMT number of correct responses with FSMC cognitive scale score while adjusting for age and sex were estimated.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
At one single visit, 15 years after the subject’s first clinical event
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Relation of mental processing speed and MRI parameters | ||||||||||||||||||||||||||||||
End point description |
Mental processing speed was defined as the sum of the adjusted PASAT-3 Z-scores and SDMT Z-scores (for number of correct responses in 90 seconds). MRI parameters of interest included: volume of hyperintense lesions on T2 (mm^3), volume of hypointense lesions on T1 (mm^3), normalized brain volume (cm^3), mean cortical thickness (mm), normalized thalamic volume (mm^3), mean upper spinal cord area (mm^2). Spearman partial rank-order correlation coefficients were estimated.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
At one single visit, 15 years after the subject’s first clinical event
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||
End point title |
European Quality of Life – 5 Dimensions Health-related Quality of life (EQ-5D HRQoL) Score | ||||||||||||
End point description |
The EQ-5D measures 5 state-of-health dimensions: mobility, self-care, usual activities (work, leisure, etc.), pain/discomfort, and anxiety/depression. Every item has a score of 1 (no problems), 2 (some/moderate problems), or 3 (extreme problems). Accordingly, the individual’s health status was defined in a combination of 5 digits.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over 15 years since the subject´s first clinical event
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
European Quality of Life-5 Dimensions Visual Analog Scale (EQ-5D VAS) score | ||||||||||||
End point description |
A second assessment recorded the perception of the subject’s overall health on a 100-mm visual analog scale (VAS), with 0 denoting death and 100 denoting perfect health. The VAS was only used in subjects who attended a clinical visit in BENEFIT 15 (i.e. regular assessment), but not in subjects with a phone assessment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over 15 years since the subject`s first clinical event
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Functional Assessment of Multiple Sclerosis (FAMS score) | ||||||||||||
End point description |
The Functional Assessment of Multiple Sclerosis (FAMS) instrument is a self-reporting, multi-dimensional, health-related QoL index for use in subjects diagnosed with MS. It comprises 58 items and has 7 subscales: mobility, symptoms, emotional well-being, general contentment, thinking, fatigue, and family/social well-being. The FAMS total score (range 0-176) is the sum of all subscales except the 14 items from the subscale additional concerns. A higher FAMS total score reflects a higher quality of life.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over 15 years since the subject´s first clinical event
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Fatigue Scale for Motor and Cognitive Functions (FSMC score) | ||||||||||||
End point description |
Fatigue Scale for Motor and Cognitive Functions (FSMC) measures both, cognitive and physical fatigue, equally. The Scale comprises 20 questions (10 items for physical and 10 items for cognitive fatigue). The FSMC total score ranges from 20 to 100 where a higher score is associated with a higher severity of fatigue.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At one single visit, 15 years after the subject’s first clinical event
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Center of Epidemiological Studies for Depression (CES-D) score | ||||||||||||
End point description |
The Center of Epidemiological Studies for Depression Scale (CES-D) is a measure of depressive symptomatology. The CES-D is a self-administered questionnaire for adults comprising 20 items which evaluate the frequency and severity of depressive symptoms. The total score (0-60) is the sum of the scores of the 20 items. A score of ≥16 suggests a mild to moderate level of depressive symptoms.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At one single visit, 15 years after the subject’s first clinical event
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Time to second line therapy | ||||||||||||
End point description |
Time to second line therapy is the difference between the date of second line therapy and the date of the BENEFIT baseline visit + 1. This constitutes an uncensored observation. Number of subjects with 2nd line therapy at Year 15 (5400 days) was reported.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over 15 years since the subject´s first clinical event
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Time to 2nd line therapy | ||||||||||||
Comparison groups |
Early IFNB-1b treatment v Delayed IFNB-1b treatment
|
||||||||||||
Number of subjects included in analysis |
181
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.4203 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||
End point title |
Time to first Disease-Modifying Therapies (DMT) other than IFNB-1b | ||||||||||||
End point description |
Time to first DMT other than IFNB is the difference between the date of first DMT other than IFNB and the date of the BENEFIT baseline visit + 1. This constitutes an uncensored observation. Number of subjects with DMT other than IFNB at Year 15 (5400 days) was reported.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over 15 years since the subject´s first clinical event
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Time to first DMT other than IFNB | ||||||||||||
Comparison groups |
Early IFNB-1b treatment v Delayed IFNB-1b treatment
|
||||||||||||
Number of subjects included in analysis |
132
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.8409 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Adverse event data were collected after signing the informed consent until 30 days after end of the BENEFIT 15 study
|
||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
|
||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Overall
|
||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
This overall reporting group includes both of the reporting groups below: Interferon Beta-1b: Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 microgram administered subcutaneously every other day in original BENEFIT (304747 / 92012 / NCT00185211) study. Placebo: Initial placebo treatment administered in original BENEFIT study; Betaferon/Betaseron, 250 microgram administered subcutaneous every other day offered in BENEFIT Follow-up (305207 / 91031) phase. At the time of study 19215 subjects were on any MS disease modifying or on no therapy. | ||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| An integrated statistical analysis was performed according to the study protocol, including 468 subjects from the previous studies 304747, 305207, 311129, 16401 and the present study 19215. | |||
