Clinical Trial Results:
BENEFIT 11 a long-term, follow-up study (16401) of the BENEFIT (304747), BENEFIT Follow-up (305207) Studies and BENEFIT Extension (311129) Study to further evaluate the progress of patients with first demyelinating event suggestive of multiple sclerosis
Summary
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EudraCT number |
2012-005262-35 |
Trial protocol |
BE SE PT HU CZ NO AT FI DK GB ES IT SI PL |
Global end of trial date |
18 Jun 2014
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Results information
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Results version number |
v1 |
This version publication date |
12 Jul 2016
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First version publication date |
26 Jul 2015
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Other versions |
v2 |
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 |
BAY86-5046/16401
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01795872 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Bayer HealthCare AG
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Sponsor organisation address |
Kaiser Wilhelm Allee, D-51368, Leverkusen, Germany,
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Public contact |
Therapeutic Area Head, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.com
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Scientific contact |
Therapeutic Area Head, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.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 |
18 Jun 2014
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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 |
18 Jun 2014
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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 were to describe the disease course (in particular conversion to clinically-definite multiple sclerosis [CDMS]), relapse activity, change in disability, cognitive function, resource use, and employment status, in relation to Interferon beta-1b treatment.
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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 |
20 Sep 2013
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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 |
Norway: 3
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Country: Number of subjects enrolled |
Poland: 42
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Country: Number of subjects enrolled |
Portugal: 1
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Country: Number of subjects enrolled |
Slovenia: 4
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Country: Number of subjects enrolled |
Spain: 30
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Country: Number of subjects enrolled |
Sweden: 5
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Country: Number of subjects enrolled |
United Kingdom: 4
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Country: Number of subjects enrolled |
Austria: 6
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Country: Number of subjects enrolled |
Belgium: 16
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Country: Number of subjects enrolled |
Czech Republic: 36
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Country: Number of subjects enrolled |
Denmark: 2
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Country: Number of subjects enrolled |
Finland: 19
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Country: Number of subjects enrolled |
Germany: 44
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Country: Number of subjects enrolled |
Hungary: 23
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Country: Number of subjects enrolled |
Italy: 8
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Country: Number of subjects enrolled |
Switzerland: 6
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Country: Number of subjects enrolled |
Canada: 11
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Country: Number of subjects enrolled |
France: 15
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Country: Number of subjects enrolled |
Israel: 3
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Worldwide total number of subjects |
278
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EEA total number of subjects |
258
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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) |
278
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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 |
This study was conducted in 19 countries from 20 September 2013 (first subject first visit) to 11 April 2014 (last subject last visit). Subjects who did not participate in a physical/face-to-face visit, had the option of being assessed via telephone on selected key outcomes, in an attempt to keep the subject's ascertainment as high as possible. | ||||||||||||||||||
Pre-assignment
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Screening details |
All subjects who were randomized and treated at least once in the BENEFIT Study NCT00185211 (inclusive of subjects, who prematurely discontinued study participation in that study) and enrolled into the BENEFIT 11 Study 2012-005262-35. Of 468 subjects from original BENEFIT study, a total of 278 subjects were enrolled into the BENEFIT 11 study. | ||||||||||||||||||
Period 1
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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 | ||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) | ||||||||||||||||||
Arm description |
Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 microgram administered subcutaneously every other day in original BENEFIT (304747 / 92012 / NCT00185211) study; continued in BENEFIT Follow-up (305207 / 91031/ NCT00185211) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Interferon Beta-1b (IFNB-1b)
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Investigational medicinal product code |
BAY86-5046
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Other name |
Betaserons, 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 beta-1b, IFNB-1b), 250 microgram administered subcutaneously every other day in original BENEFIT (304747 / 92012 / NCT00185211) study; continued in BENEFIT Follow-up (305207 / 91031) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice.
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Arm title
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Initial Placebo | ||||||||||||||||||
Arm description |
Initial placebo treatment administered in original BENEFIT (304747 / 92012 / NCT00185211) study; Betaferon/Betaseron, 250 microgram administered subcutaneous every other day offered in BENEFIT Follow-up (305207 / 91031) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice. | ||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)
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Reporting group description |
Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 microgram administered subcutaneously every other day in original BENEFIT (304747 / 92012 / NCT00185211) study; continued in BENEFIT Follow-up (305207 / 91031/ NCT00185211) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice. | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Initial Placebo
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Reporting group description |
Initial placebo treatment administered in original BENEFIT (304747 / 92012 / NCT00185211) study; Betaferon/Betaseron, 250 microgram administered subcutaneous every other day offered in BENEFIT Follow-up (305207 / 91031) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice. | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)
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Reporting group description |
Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 microgram administered subcutaneously every other day in original BENEFIT (304747 / 92012 / NCT00185211) study; continued in BENEFIT Follow-up (305207 / 91031/ NCT00185211) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice. | ||
Reporting group title |
Initial Placebo
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Reporting group description |
Initial placebo treatment administered in original BENEFIT (304747 / 92012 / NCT00185211) study; Betaferon/Betaseron, 250 microgram administered subcutaneous every other day offered in BENEFIT Follow-up (305207 / 91031) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice. | ||
Subject analysis set title |
BENEFIT 11 set
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
BENEFIT 11 set is a subset of the FAS and included all subjects who were enrolled in the BENEFIT 11 study (16401) and treated with IFNB-1b (N=167) and Placebo (N=111).
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End point title |
Time to First Relapse by Kaplan-Meier Estimates | ||||||||||||
End point description |
Relapses are key features of the clinical presentation of multiple sclerosis. Relapses were assessed retrospectively based on clinical records and subject history. Time to first relapse is the difference from date of first relapse to the date of the BENEFIT baseline visit +1 or time to first relapse is the difference from date of last clinical visit to the date of the BENEFIT baseline visit + 1 (right censored).
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End point type |
Primary
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End point timeframe |
Up to Year 11 (Day 3960)
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Notes [1] - BENEFIT 11 set [2] - BENEFIT 11 set |
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
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Number of subjects included in analysis |
278
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.1034 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||
Statistical analysis description |
An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is IFNB-1b 250 microgram versus placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 - 4, 5 - 8, >=9).
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Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
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Number of subjects included in analysis |
278
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.0991 | ||||||||||||
Method |
PH regression | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.792
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.6 | ||||||||||||
upper limit |
1.045 |
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End point title |
Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates | ||||||||||||
End point description |
CDMS could be reached due to a qualifying relapse or sustained progression of 1.5 points on the expanded disability status scale (EDSS) as compared to the lowest EDSS obtained during screening or Day 1 and a total EDSS of >=2.5. The validity of CDMS diagnoses was confirmed by a central committee. The EDSS scale quantifies disability in multiple sclerosis (MS) in 8 functional systems, values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on an ordinal scale. Time to CDMS = the difference from date of CDMS to the date of Day 1 + 1 or time to CDMS = the difference from date of last clinical visit to the Day 1+1 (right censored).
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End point type |
Primary
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End point timeframe |
Up to Year 11 (Day 3960)
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Notes [3] - BENEFIT 11 set [4] - BENEFIT 11 set |
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
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Number of subjects included in analysis |
278
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.1307 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||
Statistical analysis description |
An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is, IFNB-1b 250 microgram versus placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on
BENEFIT screening MRI (categorized as 2 - 4, 5 - 8, >=9).
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Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
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Number of subjects included in analysis |
278
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.1204 | ||||||||||||
Method |
PH regression | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.799
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.601 | ||||||||||||
upper limit |
1.061 |
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End point title |
Number of Subjects With Diagnosis of Multiple Sclerosis Within Eleven years after Clinically-Isolated Syndrome (CIS) According to McDonald 2001 and 2010 Criteria [5] | |||||||||||||||||||||||||||
End point description |
MS according to the criteria by McDonald was reached if, in addition to the single clinical demyelinating event, both dissemination in space (DIS) and dissemination in time (DIT) were established by magnetic resonance imaging (MRI) criteria or a new relapse. Number of subjects with diagnosis of MS within 11 years after CIS according to McDonald 2001 and 2010 criteria were reported. In the below table, "n" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
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End point type |
Primary
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End point timeframe |
Year 11
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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: Descriptive statistics were done, no inferential statistical analyses were performed. |
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Notes [6] - BENEFIT 11 set with evaluable subjects [7] - BENEFIT 11 set with evaluable subjects |
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No statistical analyses for this end point |
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End point title |
Disease Course as Assessed at the Time of BENEFIT 11 [8] | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Current diagnosis of MS type were categorized with regard to McDonald 2001 and McDonald 2010 criteria were recorded. CIS and silent disease (no relapse, no sustained EDSS progression and no new MRI lesion), McDonald MS not fulfilling the criteria for CDMS, RRMS (CDMS with relapses without evidence for a secondary disease course), SPMS (CDMS with relapses and evidence for a progressive disease course), Revised diagnosis (other reason than MS found for CIS) and Not assessable. Not assessable means McDonald 2001 and McDonald 2010 criteria could not be judged due to missing MRI scan at BENEFIT 11. Number of subjects with current diagnosis of MS at the time of BENEFIT 11 was assessed.
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End point type |
Primary
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End point timeframe |
Year 11
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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: Descriptive statistics were done, no inferential statistical analyses were performed. |
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Notes [9] - BENEFIT 11 set [10] - BENEFIT 11 set |
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects Converting to Secondary Progressive Multiple Sclerosis (SPMS) [11] | ||||||||||||||||||
End point description |
SPMS was defined for this study as progressive deterioration observed and sustained for at least 6 months with or without superimposed attacks.
Percentage of subjects converting to SPMS were stratified by actual treatment group and baseline EDSS. Baseline EDSS defined as lowest of the EDSS scores obtained during BENEFIT screening or baseline (less than or equal to [<=] median or greater than [>] median). In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
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End point type |
Primary
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End point timeframe |
Year 11
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Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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Notes [12] - BENEFIT 11 set [13] - BENEFIT 11 set |
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No statistical analyses for this end point |
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End point title |
Time to Secondary Progressive Multiple Sclerosis (SPMS) Represented by Kaplan-Meier Estimates | ||||||||||||
End point description |
SPMS was defined for this study as progressive deterioration observed and sustained for at least 6 months with or without superimposed attacks. Time to SPMS was represented by Kaplan-Meier estimates.
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End point type |
Primary
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End point timeframe |
Up to Year 11 (Day 3960)
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Notes [14] - BENEFIT 11 set [15] - BENEFIT 11 set |
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
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Number of subjects included in analysis |
278
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.525 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||
Statistical analysis description |
An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is, IFNB-1b 250 microgram vs. placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 - 4, 5 - 8, >=9).
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Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
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Number of subjects included in analysis |
278
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.504 | ||||||||||||
Method |
PH regression | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.751
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.324 | ||||||||||||
upper limit |
1.741 |
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End point title |
Expanded Disability Status Scale (EDSS) at Year 11 [16] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on a scale. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS.
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End point type |
Primary
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End point timeframe |
Year 11
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Notes [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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Notes [17] - BENEFIT 11 set [18] - BENEFIT 11 set |
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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 Expanded Disability Status Scale (EDSS) Progression at Year 11 [19] | |||||||||||||||
End point description |
The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on a scale. EDSS progression was defined as an increase in the EDSS of at least 1.0 point compared to initial EDSS score or an increase in the EDSS of at least 1.5 points compared to initial EDSS score, if this score was = 0 points. Confirmed EDSS progression status in any of the previous BENEFIT studies (304747, 305207, 311129) was defined as an EDSS progression observed at two consecutive scheduled visits at least 140 days apart from each other. A confirmed EDSS progression is defined as a confirmed EDSS progression in any of the previous BENEFIT studies or EDSS progression in BENEFIT 11. A sustained EDSS progression is defined as a confirmed EDSS progression in any of the previous BENEFIT studies sustained up to and including the BENEFIT 11 visit.
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End point type |
Primary
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End point timeframe |
Year 11
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Notes [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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|
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Notes [20] - BENEFIT 11 set [21] - BENEFIT 11 set |
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of Subjects With Confirmed 2.5-point Expanded Disability Status Scale (EDSS) Progression at Year 11 [22] | |||||||||
End point description |
The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on a scale. EDSS progression was defined as an increase in the EDSS of at least 2.5 points compared to initial EDSS score, if this score was <= 3.5 points, or an increase in the EDSS of at least 2.0 points compared to initial EDSS score, if this score was > 3.5 points. Confirmed EDSS increase status in any of the previous BENEFIT studies (304747, 305207, 311129) was defined as an EDSS increase confirmed at scheduled visits after at least 140 days. A confirmed EDSS increase is defined as a confirmed EDSS increase in any of the previous BENEFIT studies or EDSS increase in BENEFIT 11.
|
|||||||||
End point type |
Primary
|
|||||||||
End point timeframe |
Year 11
|
|||||||||
Notes [22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
||||||||||
|
||||||||||
Notes [23] - BENEFIT 11 set [24] - BENEFIT 11 set |
||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Percentage of Subjects who Ever Reached a Disability Status Scale (DSS) 3 and 6 [25] | ||||||||||||||||||
End point description |
The DSS 3, and DSS 6 are important milestones in the course of disability progression and were documented if reached by the subject.
|
||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||
End point timeframe |
Year 11
|
||||||||||||||||||
Notes [25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
|||||||||||||||||||
|
|||||||||||||||||||
Notes [26] - BENEFIT 11 set [27] - BENEFIT 11 set |
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 3 by Kaplan-Meier Estimates | ||||||||||||
End point description |
The DSS 3 is an important milestones in the course of disability progression and were documented if reached by the subject. The time point of reaching DSS 3 was obtained retrospectively in the BENEFIT 11 study. Time to respective DSS is the difference between the date of respective DSS and the date of the BENEFIT baseline visit +1. Subjects without event at BENEFIT 11 were censored at the BENEFIT 11 visit. This constituted a right-censored observation. Cumulative probability of reaching DSS 3 at Year 11 were estimated by Kaplan-Meier.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Up to Year 11 (Day 3960)
|
||||||||||||
|
|||||||||||||
Notes [28] - BENEFIT 11 set [29] - BENEFIT 11 set |
|||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
||||||||||||
Number of subjects included in analysis |
278
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.5609 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
|||||||||||||
Statistical analysis title |
Statistical analysis 2 | ||||||||||||
Statistical analysis description |
An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is IFNB1b 250 microgram versus placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 4, 5 8, >=9).
|
||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
||||||||||||
Number of subjects included in analysis |
278
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.4768 | ||||||||||||
Method |
PH regression | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.842
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.525 | ||||||||||||
upper limit |
1.351 |
|
|||||||||||||
End point title |
Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 6 by Kaplan-Meier Estimates | ||||||||||||
End point description |
The DSS 6 is an important milestones in the course of disability progression and were documented if reached by the subject. The time point of reaching DSS 6 was obtained retrospectively in the BENEFIT 11 study. Time to respective DSS is the difference between the date of respective DSS and the date of the BENEFIT baseline visit +1. Subjects without event at BENEFIT 11 were censored at the BENEFIT 11 visit. This constituted a right-censored observation. Cumulative probability of reaching DSS 6 at Year 11 were estimated by Kaplan-Meier.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Up to Year 11 (Day 3960)
|
||||||||||||
|
|||||||||||||
Notes [30] - BENEFIT 11 set [31] - BENEFIT 11 set |
|||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
||||||||||||
Number of subjects included in analysis |
278
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.5011 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
Multiple Sclerosis Functional Composite (MSFC) at Year 11 [32] | ||||||||||||
End point description |
The MSFC score consists of three subtests (Timed 25 Foot Walk, 9 Hole Peg Test, 3" Paced Auditory Serial Addition Test [PASAT]) whose Z-standardized results (based on baseline values on Day 1 in Study 304747) were combined into a composite score including upper and lower extremities function, and cognitive function. Standardized results (Z-scores) of the subtests and the overall MSFC Z-score as an average of the three Z-scores were derived using baseline data pooled over both treatment arms as reference population. Higher Z-scores reflect a better neurological status.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Year 11
|
||||||||||||
Notes [32] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
|||||||||||||
|
|||||||||||||
Notes [33] - BENEFIT 11 set with evaluable subjects [34] - BENEFIT 11 set with evaluable subjects |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Multiple Sclerosis Severity Score (MSSS) at Year 11 [35] | ||||||||||||
End point description |
The MSSS added the element of disease duration to the EDSS and was designed to provide a measure of disease severity. It was derived from the EDSS during the data evaluation. The MSSS corrects the EDSS for the duration of disease by using an arithmetical method to compare an individual’s disability with the distribution of scores in case of having equivalent disease duration.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Year 11
|
||||||||||||
Notes [35] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
|||||||||||||
|
|||||||||||||
Notes [36] - BENEFIT 11 set [37] - BENEFIT 11 set |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Cognitive Function: Paced Auditory Serial Addition Test-3 (PASAT-3) at Year 11 | ||||||||||||
End point description |
The Paced Auditory Serial Addition Test (PASAT) is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Year 11
|
||||||||||||
|
|||||||||||||
Notes [38] - BENEFIT 11 set with evaluable subjects [39] - BENEFIT 11 set with evaluable subjects |
|||||||||||||
Statistical analysis title |
Statistical analysis 1: PASAT-3 score at baseline | ||||||||||||
Statistical analysis description |
Parametric longitudinal linear mixed model, including PASAT-3 score at baseline in addition to time and initial treatment. An inferential statistical analysis included subjects with baseline and post-baseline values, hence number of subjects analysed for this analysis were 222. EudraCT database does auto-addition of number of subjects while reporting an explorative analysis of two treatment groups. Due to this format constraint, below table represents number of subjects in this analysis as 223.
|
||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
||||||||||||
Number of subjects included in analysis |
223
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
longitudinal linear mixed model | ||||||||||||
Point estimate |
0.7415
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.6829 | ||||||||||||
upper limit |
0.8001 | ||||||||||||
Statistical analysis title |
Statistical analysis 2: Treatment (IFNB-1b) | ||||||||||||
Statistical analysis description |
Parametric longitudinal linear mixed model, including PASAT-3 score at baseline in addition to time and initial treatment. An inferential statistical analysis included subjects with baseline and post-baseline values, hence number of subjects analysed for this analysis were 222. EudraCT database does auto-addition of number of subjects while reporting an explorative analysis of two treatment groups. Due to this format constraint, below table represents number of subjects in this analysis as 223.
|
||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
||||||||||||
Number of subjects included in analysis |
223
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.0083 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
longitudinal linear mixed model | ||||||||||||
Point estimate |
1.3346
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.3461 | ||||||||||||
upper limit |
2.323 | ||||||||||||
Statistical analysis title |
Statistical analysis 3: Time | ||||||||||||
Statistical analysis description |
Parametric longitudinal linear mixed model, including PASAT-3 score at baseline in addition to time and initial treatment. An inferential statistical analysis included subjects with baseline and post-baseline values, hence number of subjects analysed for this analysis were 222. EudraCT database does auto-addition of number of subjects while reporting an explorative analysis of two treatment groups. Due to this format constraint, below table represents number of subjects in this analysis as 223.
|
||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
||||||||||||
Number of subjects included in analysis |
223
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.016 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
longitudinal linear mixed model | ||||||||||||
Point estimate |
-0.0138
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.0251 | ||||||||||||
upper limit |
-0.0026 | ||||||||||||
Statistical analysis title |
Statistical analysis 4: Time*Treatment (IFNB-1b) | ||||||||||||
Statistical analysis description |
Parametric longitudinal linear mixed model, including PASAT-3 score at baseline in addition to time and initial treatment. An inferential statistical analysis included subjects with baseline and post-baseline values, hence number of subjects analysed for this analysis were 222. EudraCT database does auto-addition of number of subjects while reporting an explorative analysis of two treatment groups. Due to this format constraint, below table represents number of subjects in this analysis as 223.
|
||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
||||||||||||
Number of subjects included in analysis |
223
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.8947 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
longitudinal linear mixed model | ||||||||||||
Point estimate |
-0.001
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.0155 | ||||||||||||
upper limit |
0.0136 | ||||||||||||
Statistical analysis title |
Statistical analysis 5: PASAT-3 at baseline-ANCOVA | ||||||||||||
Statistical analysis description |
Parametric analysis of covariance including PASAT-3 score at baseline in addition to initial treatment. An inferential statistical analysis included subjects with baseline and post-baseline values, hence number of subjects analysed for this analysis were 222. EudraCT database does auto-addition of number of subjects while reporting an explorative analysis of two treatment groups. Due to this format constraint, below table represents number of subjects in this analysis as 223.
|
||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
||||||||||||
Number of subjects included in analysis |
223
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Confidence interval |
|||||||||||||
Statistical analysis title |
Statistical analysis 6: Treatment - ANCOVA | ||||||||||||
Statistical analysis description |
Parametric analysis of covariance including PASAT-3 score at baseline in addition to initial treatment. An inferential statistical analysis included subjects with baseline and post-baseline values, hence number of subjects analysed for this analysis were 222. EudraCT database does auto-addition of number of subjects while reporting an explorative analysis of two treatment groups. Due to this format constraint, below table represents number of subjects in this analysis as 223.
|
||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
||||||||||||
Number of subjects included in analysis |
223
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.422 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Confidence interval |
|
||||||||||||||||||||||
End point title |
Cognitive function: Symbol Digit Modalities Test (SDMT) | |||||||||||||||||||||
End point description |
The Symbol Digit Modalities Test (SDMT) is a cognitive test for sustained attention, concentration, and information-processing speed, with a high sensitivity. Nine different geometrical symbols have one corresponding number each. One-hundred-ten symbols are presented without these numbers; the subject must find the matching number from the top line and verbalize the number to the examiner. The subject is allowed to proceed for 90 seconds, and the number of correct responses in 90 seconds is counted as the total correct score. Also, the numbers of correct responses at 30 and 60 seconds were recorded in this study. Total score ranged from 0 (worst outcome) to best (outcome).
In the below table, "N" signifies number of subjects analysed who were evaluable for the specified parameter for each arm, respectively.
|
|||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||
End point timeframe |
Year 11
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Notes [40] - BENEFIT 11 set [41] - BENEFIT 11 set |
||||||||||||||||||||||
Statistical analysis title |
Time*Treatment (2nd interval, IFNB-1b) | |||||||||||||||||||||
Statistical analysis description |
Parametric linear mixed-effect model including age and education status (categorized as primary school, high school diploma, vocational school diploma, collegial studies, university diploma) at BENFIT 11 in addition to time interval and initial treatment group.
|
|||||||||||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
|||||||||||||||||||||
Number of subjects included in analysis |
278
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
other | |||||||||||||||||||||
P-value |
= 0.7396 | |||||||||||||||||||||
Method |
Parametric linear mixed-effect model | |||||||||||||||||||||
Parameter type |
SDMT scores | |||||||||||||||||||||
Point estimate |
0.228
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.1195 | |||||||||||||||||||||
upper limit |
1.5754 | |||||||||||||||||||||
Statistical analysis title |
Time*Treatment (3rd interval, IFNB-1b) | |||||||||||||||||||||
Statistical analysis description |
Parametric linear mixed-effect model including age and education status (categorized as primary school, high school diploma, vocational school diploma, collegial studies, university diploma) at BENFIT 11 in addition to time interval and initial treatment group.
|
|||||||||||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
|||||||||||||||||||||
Number of subjects included in analysis |
278
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
other | |||||||||||||||||||||
P-value |
= 0.1352 | |||||||||||||||||||||
Method |
Parametric linear mixed-effect model | |||||||||||||||||||||
Parameter type |
SDMT scores | |||||||||||||||||||||
Point estimate |
-1.026
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-2.3734 | |||||||||||||||||||||
upper limit |
0.3215 |
|
|||||||||
End point title |
Relapse-Based Efficacy domain: Hazard Ratio for Recurrent Relapses [42] | ||||||||
End point description |
A relapse was defined as the appearance of a new neurological abnormality or the reappearance of a neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The time to the onset of recurrent relapses was determined for each subject according to the counting process representation for recurrent events. Time to a relapse was right censored if a relapse risk period ended without relapse. Based on the Andersen Gill model the hazard ratio for recurrent relapses was estimated with actual treatment in BENEFIT (304747; i.e. IFNB-1b 250 microgram vs. placebo), steroid use during first event (yes vs. no), onset of disease (multifocal vs. monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2-4, 5-8, >=9) included in the model.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
Year 11
|
||||||||
Notes [42] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: EudraCT database does not allow to report only one treatment group in statistical analyses section. Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below. |
|||||||||
|
|||||||||
Attachments |
Statistical Analysis_HR for Recurrent Relapses |
||||||||
Notes [43] - BENEFIT 11 set |
|||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Relapse Based Efficacy Domain: Annualized Relapse Rate | ||||||||||||
End point description |
The annualized relapse rate is defined as total number of relapses up to Year 11 divided by the total observation time (last clinical visit minus first day of study treatment administration plus 1 of all subjects) in years.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Year 11
|
||||||||||||
|
|||||||||||||
Notes [44] - BENEFIT 11 set [45] - BENEFIT 11 set |
|||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Statistical analysis description |
Relapse rate was analyzed by a generalized linear Poisson regression model with individual relapse counts as dependent variable, covariates: actual treatment in BENEFIT (304747; i.e., IFNB-1b 250 microgram vs. placebo), steroid use during first event (yes vs. no), onset of disease (multifocal vs. monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2-4, 5-8, >=9) and offset variable natural log of time (in years) as difference between last clinical and baseline visits+1.
|
||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
||||||||||||
Number of subjects included in analysis |
278
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.0094 | ||||||||||||
Method |
generalized linear Poisson regression | ||||||||||||
Parameter type |
Risk ratio (RR) | ||||||||||||
Point estimate |
0.8224
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.7096 | ||||||||||||
upper limit |
0.9531 |
|
|||||||||||||
End point title |
Time to use of Ambulatory Device Represented by Kaplan-Meier Estimates | ||||||||||||
End point description |
Date of use of ambulatory device is defined as the retrospectively obtained time point of first use/dependence. Time to use of ambulatory device is the difference between the date of first use/dependence and the date of the BENEFIT baseline visit +1.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Up to Year 11 (Day 3960)
|
||||||||||||
|
|||||||||||||
Notes [46] - BENEFIT 11 set [47] - BENEFIT 11 set |
|||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
||||||||||||
Number of subjects included in analysis |
278
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.2895 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
|||||||||||||
Statistical analysis title |
Statistical analysis 2 | ||||||||||||
Statistical analysis description |
An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is IFNB-1b 250 microgram versus placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 - 4, 5 - 8, >=9).
|
||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
||||||||||||
Number of subjects included in analysis |
278
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.2951 | ||||||||||||
Method |
PH regression | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.581
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.211 | ||||||||||||
upper limit |
1.605 |
|
|||||||||||||
End point title |
Time to Dependence of Ambulatory Device for Walking Represented by Kaplan-Meier Estimates | ||||||||||||
End point description |
Date of dependence from ambulatory device is defined as the retrospectively obtained time point of first use/dependence. Time to dependence from ambulatory device is the difference between the date of first use/dependence and the date of the BENEFIT baseline visit +1. Cumulative probability of dependence of ambulatory device for walking represented by Kaplan-Meier estimates at Year 11.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Up to Year 11 (Day 3960)
|
||||||||||||
|
|||||||||||||
Notes [48] - BENEFIT 11 set [49] - BENEFIT 11 set |
|||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
||||||||||||
Number of subjects included in analysis |
278
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.2904 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
|||||||||||||
Statistical analysis title |
Statistical analysis 2 | ||||||||||||
Statistical analysis description |
An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is IFNB-1b 250 microgram versus placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 - 4, 5 - 8, >=9).
|
||||||||||||
Comparison groups |
Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
|
||||||||||||
Number of subjects included in analysis |
278
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.2957 | ||||||||||||
Method |
PH regression | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.582
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.211 | ||||||||||||
upper limit |
1.606 |
|
||||||||||
End point title |
Number of Subjects With Wheelchair Use After 11 years [50] | |||||||||
End point description |
||||||||||
End point type |
Primary
|
|||||||||
End point timeframe |
Year 11
|
|||||||||
Notes [50] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
||||||||||
|
||||||||||
Notes [51] - BENEFIT 11 set [52] - BENEFIT 11 set |
||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Education Status at Year 11 | |||||||||||||||||||||||||||
End point description |
Subjects with educational status was categorized as primary school, high school diploma, vocational diploma, collegial studies, university diploma, and missing educational status.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Year 11
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
Notes [53] - BENEFIT 11 set [54] - BENEFIT 11 set |
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Living Conditions at Year 11 | ||||||||||||||||||||||||
End point description |
Subjects living condition were categorized as 'living alone', 'long term care facility', living with spouse, partner, family', 'other' and 'missing'.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Year 11
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Notes [55] - BENEFIT 11 set [56] - BENEFIT 11 set |
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||
End point title |
Employment Status at Year 11 | |||||||||||||||||||||||||||||||||
End point description |
Subject's employment status was categorized as 'retired', 'homemaker', 'long term disability', 'employment less than 20 hours (hrs) per week (hrs/week)', employment more than 20 hours per week, 'early retired', 'other', and 'missing'.
|
|||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||
End point timeframe |
Year 11
|
|||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
Notes [57] - BENEFIT 11 set [58] - BENEFIT 11 set |
||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Multiple Sclerosis Impact on Employment at Year 11 | ||||||||||||||||||||||||
End point description |
Subject's MS impact on employment was categorized as, 'unrelated to MS condition', 'ceased work due to MS', 'never worked', 'reduced working hours', or missing.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Year 11
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Notes [59] - BENEFIT 11 set [60] - BENEFIT 11 set |
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Resource Use: Hospitalization During Last 12 months | ||||||||||||||||||||||||
End point description |
Hospitalizations were assessed at year 11 only referring to past 12 months. Number of hospitalizations per subject were categorized as, 'none', '1', '2', '3', and '6'.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Year 11
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Notes [61] - BENEFIT 11 set [62] - BENEFIT 11 set |
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Resource Use: Visits to Other Specialists During Last 12 months | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Visits to Other Specialists were assessed at year 11 only referring to past 12 months. The visits to other specialists were categorized as, 'missing', 'no', 'yes', 'never', and 'unsure'. The other specialists includes, neurologist, nurse clinician, home health aide, visiting nurse, physiotherapist, psychiatrist, psychologist, physician, urologist, social worker and gynecologist.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Year 11
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [63] - BENEFIT 11 set [64] - BENEFIT 11 set |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Resource Use Assessment Questionnaire: Help from Family/Regular Ambulatory Services | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Resources use data was assessed cross-sectionally at 11 years. Supportive care was assessed as “assistance given” for the help from family members or friends with “care given” for the number f hors per week needed, as well as “ambulatory services-yes/no” with sub-categories home care, home help, day care center, meals on wheels and child care for the help from professional caregiver.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Year 11
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [65] - BENEFIT 11 set [66] - BENEFIT 11 set |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Resource Use Assessment Questionnaire: Additional Ambulatory Services During Relapse | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Resources use data was assessed cross-sectionally at 11 years. Additional ambulatory services during relapse were categorized as, 'missing', 'no', and 'yes'. The additional ambulatory services during relapses were home care, home help, day care center, meals on wheels, and child care.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Year 11
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [67] - BENEFIT 11 set [68] - BENEFIT 11 set |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Resource Use Assessment Questionnaire: Adaptions past 6 months | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Resources use data was assessed cross-sectionally at 11 years. The kind of adaptation was categorized as “other part of living”, “star lift”. “ramps”, “alarm”, “work”, “car”, “walking aids”, “wheel chair”, “spectacles”, “special kitchen utensils”, “special hygiene utensils”, “special writing devices” and “ other” with sub-categories as 'missing', 'no', and 'yes'.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Year 11
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [69] - BENEFIT 11 set [70] - BENEFIT 11 set |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Patient-Reported Outcomes (PRO)-based Efficacy Domain: Center of Epidemiological Studies Depression Scale (CES-D) Total Score at Year 11 | ||||||||||||
End point description |
The CES-D is a measure of depressive symptomatology. The CES-D was a self-administered questionnaire for adults comprising 20 items which evaluated the frequency and severity of depressive symptoms. Subjects were asked to recall the previous 7 days. The total score (0-60) was the sum of the scores of the 20 items. A score of >= 16 suggested a mild to moderate level of depressive symptoms; a score >21 suggested major depressive symptoms.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Year 11
|
||||||||||||
|
|||||||||||||
Notes [71] - BENEFIT 11 set with evaluable subjects [72] - BENEFIT 11 set with evaluable subjects |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
PRO-based Efficacy Domain: Fatigue Scale for Sensory and Motor Functions (FSMC) | ||||||||||||
End point description |
The cognitive and physical fatigue was assessed by the FSMC. The scale comprised of 20 questions (10 items for physical and 10 items for cognitive fatigue) and could be completed within 5 minutes. The items are rated on a 5-point Likert scale (1=does not apply at all to 5=applies completely). The FSMC total score ranges from 20 to 100 where a higher score is associated with a higher severity of fatigue.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Year 11
|
||||||||||||
|
|||||||||||||
Notes [73] - BENEFIT 11 set with evaluable subjects [74] - BENEFIT 11 set with evaluable subjects |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Year 11 | ||||||||||||
End point description |
The Functional Assessment of Multiple Sclerosis (FAMS) instrument is a self-reporting, multi-dimensional, health-related QoL index for use in subjects diagnosed with MS. It comprised 58 items on 7 subscales (mobility, symptoms, emotional well-being, general contentment, thinking and fatigue, family/social well-being, and additional concerns). FAMS-TOI is the sum of the subscale scores mobility, symptoms, thinking/fatigue, and additional concerns. The items were rated on a 5-point scale (0 to 4). Score range of FAM-TOI is 0 to 148; the higher the score, the higher the quality of life. The evaluation period was the previous 7 days.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Year 11
|
||||||||||||
|
|||||||||||||
Notes [75] - BENEFIT 11 set with evaluable subjects [76] - BENEFIT 11 set with evaluable subjects |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Functional Assessment of Multiple Sclerosis (FAMS) Total Score at Year 11 | ||||||||||||
End point description |
The Functional Assessment of Multiple Sclerosis (FAMS) instrument is a self-reporting, multi-dimensional, health-related QoL index for use in subjects diagnosed with MS. It comprised 58 items on 7 subscales: mobility, symptoms, emotional well-being, general contentment, thinking and fatigue, family/social well-being, and additional concerns. The items were rated on a 5-point scale (0 to 4). Total score is sum of all sub-scale scores except 14 items for "Additional concerns", ranging 0 to 176; the higher the score, the higher the quality of life. The evaluation period was the previous 7 days.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Year 11
|
||||||||||||
|
|||||||||||||
Notes [77] - BENEFIT 11 set with evaluable subjects [78] - BENEFIT 11 set with evaluable subjects |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
PRO-based Efficacy Domain: European Quality of Life – 5 Dimensions (EQ-5D) Score at Year 11 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The EQ-5D measured five state-of-health dimensions: mobility, self-care, usual activities (work, leisure, etc.), pain/discomfort, and anxiety/depression. Every item had a score of 1 (no problems), 2 (some/moderate problems), or 3 (extreme problems). An individual’s health status was defined in a combination of 5 digits. Subjects with missing answers to all questions were not considered for the respective visit.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Year 11
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [79] - BENEFIT 11 set with evaluable subjects [80] - BENEFIT 11 set with evaluable subjects |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
European Quality of Life – 5 Dimensions (EQ-5D) Health-related quality of life (HRQoL) Score at Year 11 | ||||||||||||
End point description |
Based on large population surveys, an algorithm was developed to combine the recordings of each of these five EQ-5D dimensions in 1 single HRQoL score, ranging from +1 (best imaginable HRQoL score) to -0.59 (worst imaginable HRQoL score). A relatively higher score represents better quality of life.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Year 11
|
||||||||||||
|
|||||||||||||
Notes [81] - BENEFIT 11 set with evaluable subjects [82] - BENEFIT 11 set with evaluable subjects |
|||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of Subjects who Started Second Line Therapy at Year 11 | |||||||||
End point description |
Subjects were treated exclusively at the discretion of their treating physician and according to locally applicable standards and treatment guidelines. Subjects received second line therapy as a MS treatment such as alemtuzumab, cyclophosphamide, ciclosporin, fingolimod, methotrexate, mycophenolate mitoxantrone, natalizumab, etc.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Year 11
|
|||||||||
|
||||||||||
Notes [83] - BENEFIT 11 set [84] - BENEFIT 11 set |
||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of Subjects who Started First Disease-Modifying Treatment (DMT) other than IFNB at Year 11 | |||||||||
End point description |
Subjects were treated exclusively at the discretion of their treating physician and according to locally applicable standards and treatment guidelines. All DMTs other than interferon beta, interferon beta-1a und interferon beta-1b were recorded as DMT other than IFNB.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Year 11
|
|||||||||
|
||||||||||
Notes [85] - BENEFIT 11 set [86] - BENEFIT 11 set |
||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Magnet-Resonance Imaging (MRI): Number of Newly Active Lesions | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Contrast-enhanced MRI (with an extracellular gadolinium-based contrast agent) technique was used for the evaluation of brain lesions in MS. Newly active lesions defined as displaying either new enhancement on T1-weighted scans, or non-enhancing on T1-weighted scan but new on T2-weighted scans.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Year 11
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [87] - BENEFIT 11 set with evaluable subjects [88] - BENEFIT 11 set with evaluable subjects |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Magnet-Resonance Imaging (MRI): Number of Lesions on T1- and T2-Weighted Scans | ||||||||||||||||||
End point description |
Contrast-enhanced MRI (with an extracellular gadolinium-based contrast agent) technique was used for the evaluation of brain lesions in MS. Number of lesions on T1- and T2-Weighted scans were recorded. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Year 11
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [89] - BENEFIT 11 set [90] - BENEFIT 11 set |
|||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Magnet-Resonance Imaging (MRI): Volume of Lesions on T1- and T2-Weighted Scans | |||||||||||||||||||||
End point description |
Contrast-enhanced MRI (with an extracellular gadolinium-based contrast agent) technique was used for the evaluation of brain lesions in MS. Volume of lesions on T1- and T2-Weighted scans were recorded. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Year 11
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Notes [91] - BENEFIT 11 set [92] - BENEFIT 11 set |
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Magnet-Resonance Imaging (MRI): Normalized Brain Volume | ||||||||||||
End point description |
Contrast-enhanced MRI (with an extracellular gadolinium-based contrast agent) technique was used for the evaluation of brain lesions in MS. Brain volume was analysed and reported.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Year 11
|
||||||||||||
|
|||||||||||||
Notes [93] - BENEFIT 11 set with evaluable subjects [94] - BENEFIT 11 set with evaluable subjects |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Optical Coherence Tomography (OCT) Parameter - Retinal Nerve Fiber Layer (RNFL) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
OCT is a noninvasive ocular imaging recognized in MS as a marker of axonal loss. Retinal nerve fiber layer (RNFL) thinning measured by OCT in subjects with MS occurs even in the absence of acute optic neuritis and is associated with worse scores for low-contrast letter acuity and other visual acuity tests. OCT measures peripapillary RNFL.
In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Year 11
|
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Notes [95] - BENEFIT 11 set [96] - BENEFIT 11 set |
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No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Optical Coherence Tomography (OCT) Parameter - Total Macular Volume (TMV) | ||||||||||||||||||
End point description |
OCT is a noninvasive ocular imaging recognized in MS as a marker of axonal loss. OCT is a potential method for capturing neuronal in addition to axonal degeneration in MS. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
|
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End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Year 11
|
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|
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Notes [97] - BENEFIT 11 set [98] - BENEFIT 11 set |
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No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Optical Coherence Tomography (OCT) Parameter - Pupillo Macular Bundle (PMB) | ||||||||||||||||||
End point description |
OCT is a noninvasive ocular imaging recognized in MS as a marker of axonal loss. OCT is a potential method for capturing neuronal in addition to axonal degeneration in MS. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
|
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End point type |
Secondary
|
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End point timeframe |
Year 11
|
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|
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Notes [99] - BENEFIT 11 set [100] - BENEFIT 11 set |
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No statistical analyses for this end point |
|
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End point title |
Optical Coherence Tomography (OCT) Parameter – Ganglion Cell Inner Plexiform Layer | ||||||||||||||||||
End point description |
OCT is a noninvasive ocular imaging recognized in MS as a marker of axonal loss. OCT is a potential method for capturing neuronal in addition to axonal degeneration in MS. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
|
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End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Year 11
|
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|
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Notes [101] - BENEFIT 11 set [102] - BENEFIT 11 set |
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No statistical analyses for this end point |
|
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End point title |
Ophthalmological examination – Optic Nerve Head | |||||||||||||||||||||
End point description |
Standard clinical ophthalmic examination and test were applied for visual assessment and the differential diagnosis of OCT-related findings.
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End point type |
Secondary
|
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End point timeframe |
Year 11
|
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|
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Notes [103] - BENEFIT 11 set with evaluable subjects [104] - BENEFIT 11 set with evaluable subjects |
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No statistical analyses for this end point |
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End point title |
Ophthalmological examination - Slit lamp Biomicroscopy | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Standard clinical ophthalmic examination and test were applied for visual assessment and the differential diagnosis of OCT-related findings. Ocular medical and surgical history, visual acuity (Early Treatment Diabetic Retinopathy Study Chart), low-contrast letter acuity (Sloan charts), and eye examination through slit-lamp biomicroscopy were assessed.
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End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Year 11
|
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Notes [105] - Subjects with ophthalmological examination from BENEFIT 11 set. [106] - Subjects with ophthalmological examination from BENEFIT 11 set. |
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No statistical analyses for this end point |
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End point title |
Ophthalmological examination - Visual Acuity | ||||||||||||||||||
End point description |
Standard clinical ophthalmic examination and test were applied for visual assessment and the differential diagnosis of OCT-related findings. Ocular medical and surgical history, visual acuity (Early Treatment Diabetic Retinopathy Study Chart), low-contrast letter acuity (Sloan charts), and eye examination through slit-lamp biomicroscopy were assessed.
|
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End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Year 11
|
||||||||||||||||||
|
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Notes [107] - Subjects with ophthalmological examination from BENEFIT 11 set. [108] - Subjects with ophthalmological examination from BENEFIT 11 set. |
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No statistical analyses for this end point |
|
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End point title |
Number of Subjects with Vitamin D Intake | |||||||||||||||||||||||||||
End point description |
Number of subjects with intake of Vitamin D were categorized as, 'since beginning of the BENEFIT study', and 'within the past 12 months'.
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End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Year 11
|
|||||||||||||||||||||||||||
|
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Notes [109] - BENEFIT 11 set [110] - BENEFIT 11 set |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
After signing the informed consent form up to the end of study (approximately 1 year)
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Adverse event reporting additional description |
The death reported in this study was not considered an AE or an SAE as per the definitions provided in the protocol, but rather was categorized under “Medical history.”
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
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Reporting groups
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Reporting group title |
Overall
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Reporting group description |
This overall reporting group includes both of the reporting groups below: Initial Interferon Beta-1b: Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 microgram administered subcutaneously every other day in original BENEFIT (304747 / 92012 / NCT00185211) study. Initial Placebo: Initial placebo treatment administered in original BENEFIT study; Betaferon/Betaseron, 250 microgram administered subcutaneous every other day offered in BENEFIT Follow-up (305207 / 91031) phase. At the time of study 16401 subjects were on any MS disease modifying or on no therapy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
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Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
22 Jan 2013 |
This amendment was included following change:
- modifications were made to provide clearer study procedures and provide greater consistency; generalized contrast agent procedure guidance instead of confining to Gadobutrol administration; removed references to magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) imaging procedures; clarification of Adverse events reporting details |
||
05 Dec 2013 |
The enrollment date as extended to increase the number of subjects. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
Results of the DNA, RNA and Biomarkers were not reported as they would be reported in a separate report, as planned. |