Clinical Trial Results:
A Multicenter, Open-Label Study Evaluating the Effectiveness of Oral Tecfidera® (Dimethyl Fumarate) on Multiple Sclerosis Disease Activity and Patient-Reported Outcomes in Subjects with Relapsing-Remitting Multiple Sclerosis in the Real-World Setting (PROTEC)
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Summary
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EudraCT number |
2013-001656-35 |
Trial protocol |
AT HU BE PT IT CZ SK ES SI FR |
Global end of trial date |
09 Jan 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
24 Jan 2021
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First version publication date |
24 Jan 2021
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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 |
109MS408
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01930708 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Biogen MA Inc.
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Sponsor organisation address |
225 Binney Street, Cambridge, Massachusetts, United States, 02142
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Public contact |
Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
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Scientific contact |
Biogen Study Medical Director, Biogen, clinicaltrials@biogen.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 |
09 Jan 2020
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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 |
09 Jan 2020
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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 objective of the study was to estimate the annualised relapse rate (ARR) in subjects with relapsing-remitting multiple sclerosis (RRMS) who were treated with dimethyl fumarate (DMF) over a 12-month period.
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Protection of trial subjects |
Written informed consent was obtained from each subject or subject’s legally authorised representative (e.g., parent or legal guardian), as applicable, prior to evaluations performed for eligibility. Subjects or the subject’s legally authorised representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
31 Oct 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 |
Austria: 114
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Country: Number of subjects enrolled |
Belgium: 47
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Country: Number of subjects enrolled |
Canada: 109
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Country: Number of subjects enrolled |
Czechia: 86
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Country: Number of subjects enrolled |
France: 199
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Country: Number of subjects enrolled |
Hungary: 54
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Country: Number of subjects enrolled |
Italy: 208
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Country: Number of subjects enrolled |
Portugal: 134
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Country: Number of subjects enrolled |
Slovakia: 21
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Country: Number of subjects enrolled |
Slovenia: 21
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Country: Number of subjects enrolled |
Spain: 121
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Worldwide total number of subjects |
1114
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EEA total number of subjects |
1005
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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) |
1107
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From 65 to 84 years |
7
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects were enrolled at 93 investigational sites in Australia, Austria, Belgium, Czech Republic, France, Hungary, Italy, Portugal, Slovakia, Slovenia, Spain, and Canada from 31 October 2013 to 20 March 2015. | ||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 1114 subjects with Relapsing-Remitting Multiple Sclerosis (RRMS) were enrolled in this study. Of which, 1106 subjects received at least 1 dose of study drug (Dimethyl Fumarate {DMF}). Subjects started were subjects who were enrolled in study. Subjects treated were subjects who received at least 1 dose of DMF. | ||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (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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Arm title
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BG00012 240 mg BID | ||||||||||||||||||||
Arm description |
Subjects received BG00012 capsules, 120 milligrams (mg), orally, twice daily (BID) on Days 1 through 7 followed by BG00012 capsules, 240 mg, orally, BID, thereafter for up to 12 months. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
BG00012
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Investigational medicinal product code |
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Other name |
Dimethyl fumarate DMF
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Pharmaceutical forms |
Gastro-resistant capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
BG00012 was administered as capsules, 120 mg, orally, BID on Day 1 through 7 followed by BG00012 capsules, 240 mg, orally, BID thereafter up to 12 months.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
Subjects received BG00012 capsules, 120 milligrams (mg), orally, twice daily (BID) on Days 1 through 7 followed by BG00012 capsules, 240 mg, orally, BID, thereafter up to 12 months. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
BG00012 240 mg BID
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Reporting group description |
Subjects received BG00012 capsules, 120 milligrams (mg), orally, twice daily (BID) on Days 1 through 7 followed by BG00012 capsules, 240 mg, orally, BID, thereafter for up to 12 months. | ||
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End point title |
Annualised Relapse Rate (ARR) at Month 12 [1] | ||||||||
End point description |
A multiple sclerosis (MS) relapse was defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurologic findings upon examination by the investigator, and followed by a period of 30 days of stability or improvement. The annualised relapse rate for a period was calculated as the total number of relapses that occurred during the period for all subjects, divided by the total number of subject-years followed in that period. Relapses and follow-up times that occurred after treatment discontinuation were excluded from the calculations. Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF.
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End point type |
Primary
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End point timeframe |
Month 12
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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: The statistical analysis is not added to the primary endpoint as the study is single arm study and per EudraCT format only statistical analysis between two comparison arms can be added to the database. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from Baseline to Month 12 in Multiple Sclerosis Impact Scale (MSIS-29) Score | ||||||||||||||||
End point description |
MSIS-29 was a validated, 29-item, MS-specific HRQoL scale which included 2 sub-scales that measured the physical and psychological impact of MS on the subject’s day-to-day life: the 20-item physical impact scale and the 9-item psychological impact scale. For each item, the subject was asked to circle the number that best described his or her situation. The numbers for each item ranged from 1 (not at all) to 5 (extremely). The total score range ranged from 0-100, where lower scores indicated a better outcome. Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF. A negative number of change from baseline (CFB) value indicates an improvement in MSIS-29. Here, 'n' signifies the number of subjects analysed at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change from Baseline to Month 12 in Modified Fatigue Impact Scale-5 Item (MFIS-5) Score | ||||||||||||
End point description |
MFIS-5 scale consisted of 5 statements that described how fatigue affected a person. It assessed the effects of fatigue on physical, cognitive, and psychosocial functioning. For each statement, the subject was asked to circle the number that best indicated how often fatigue had affected him or her during the previous 4 weeks. The numbers for each question ranged from 0 (never) to 4 (almost always). The total scores ranged from 0 to 20. A lower MFIS-5 score indicated a lower impact of fatigue and therefore a better outcome. Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF. A negative number of CFB value indicates an improvement in MFIS-5. Here, 'n' signifies the number of subjects analysed at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from Baseline to Month 12 in Treatment Satisfaction Questionnaire for Medication (TSQM) Score | ||||||||||||||||||||||||
End point description |
TSQM was a validated, 14-item questionnaire that measured a subject’s level of satisfaction/dissatisfaction with medication. It consisted of four scales: effectiveness scale (questions 1 to 3), side effects scale (questions 4 to 8), convenience scale (questions 9 to 11) and global satisfaction scale (questions 12 to 14). The scores were computed by adding items for each domain. The lowest possible score was subtracted from this composite score and divided by the greatest possible score minus the lowest possible score. This provided a transformed score between 0 and 1 that was then multiplied by 100. The total score ranged from 0 to 100, where a higher TSQM score indicated greater satisfaction with medication. Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF. A positive number of CFB value indicates an improvement in TSQM. Here, 'n' signifies the number of subjects analysed at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change from Baseline to Month 12 in EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index Score | ||||||||||||
End point description |
EQ-5D-5L include 2 components, EuroQol-5D (EQ-5D) descriptive system and EuroQol visual analogue scale (EQ VAS). EQ-5D descriptive system provided a profile of the subject’s health state in 5 dimensions (mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the subject was instructed to indicate whether they had “no problems” (level 1), “slight problems” (level 2), “moderate problems” (level 3), “severe problems (level 4), or “extreme problems/inability” (level 5) on that day. EQ-5D-5L scores were derived based on value sets for England. EQ-5D descriptive system score had a possible range from -0.109 to 1.00, with higher scores indicating a better outcome. Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF. Positive number of CFB value indicates an improvement in EQ-5D descriptive system. 'n' signifies number of subjects analysed at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from Baseline to Month 12 in EuroQol Visual Analogue Scale (EQ VAS) Score | ||||||||||||
End point description |
EQ-5D-5L included 2 components, the EuroQol-5D (EQ-5D) descriptive system and the EuroQol visual analogue scale (EQ VAS). For the EQ VAS, the subject was instructed to mark an “x” on a vertical scale at the point that best described his or her own health on that day, where 0 represented the “worst health” he or she could imagine and 100 the “best health” he or she could imagine. Higher scores indicated a better outcome. Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF. Positive number of CFB value indicates an improvement in EQ-5D VAS. Here, 'n' signifies the number of subjects analysed at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from Baseline to Month 12 in Patient-Reported Indices for Multiple Sclerosis-Activity Limitations (PRIMUS-Activity Limitations) Score | ||||||||||||
End point description |
This 15-item component of the PRIMUS assessed a subject's ability to carry out various activities of daily living during the previous week without the use of aids (e.g., cane, walker, or wheelchair) or assistance. For each item, the subject was asked whether he or she could perform the activity without difficulty (scoring 0) or with difficulty (scoring 1), or was unable to perform the activity (scoring 2). The possible total scores ranged from 0 to 30. Higher scores indicated a worse outcome. Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF. A negative number of CFB value indicates an improvement in PRIMUS. Here, 'n' signifies the number of subjects analysed at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Work Productivity and Activity Impairment-Multiple Sclerosis Version (WPAI-MS): Change from Baseline to Month 12 in Number of Subjects Who Were Employed | ||||||||||
End point description |
This 6-item instrument assesses employment status, and, during the previous 7 days, hours of missed work due to MS or other reasons, hours worked (if employed), effect on productivity due to MS while working, and activity impairment attributable to health problems. Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF. Here, 'n' signifies the number of subjects analysed at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||||
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End point title |
Change from Baseline to Month 12 in WPAI-MS Scores | ||||||||||||||||||||||||
End point description |
The WPAI measured impairments in work and activities due to MS. It included 1. work time missed, 2. impairment while working, 3. overall work impairment, and 4. activity impairment. The scores were reported as percentage. A higher score indicates higher impairment and lower productivity. A negative number of CFB value indicates an improvement in WPAI-MS. Here, 'n' signifies the number of subjects analysed at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change from Baseline to Month 12 in Beck Depression Inventory-Fast Screen (BDI-Fast Screen) Score | ||||||||||||
End point description |
This was a 7-item scale that evaluated depression in subjects with medical illness during the prior 2 weeks. It had been validated in subjects with MS. It assessed depressive symptoms, and possible scores ranged from 0 to 21, where 0 to 3 = minimal depression symptoms, 4 to 6 = mild depression symptoms, 7 to 9 = moderate depression symptoms, and 10 or higher = severe depression symptoms. A lower BDI-Fast Screen score indicated fewer depressive symptoms and therefore a better outcome. Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF. A negative number of CFB value indicates an improvement in BDI-Fast Screen. Here, 'n' signifies the number of subjects analysed at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Subjects with Confirmed (24-week) Expanded Disability Status Scale (EDSS) Progression at Month 12 | ||||||||
End point description |
Confirmed EDSS disability progression was defined as at least a 1.0 point increase in EDSS from a baseline EDSS >=1.0 or at least a 1.5 point increase from a baseline EDSS of 0 or at least 0.5 point increase from a baseline EDSS >= 6 and confirmed at 6 months (154 days) after initial progression. Progression could start at a scheduled assessment or relapse assessment during the treatment period but could be confirmed at during either the treatment and/or follow up 24-week period. EDSS assessments during relapse assessments were not used for confirmation. Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF.
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End point type |
Secondary
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End point timeframe |
Month 12
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| No statistical analyses for this end point | |||||||||
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End point title |
ARR at Baseline and Month 6 | ||||||||||||
End point description |
An MS relapse was defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurologic findings upon examination by the investigator, and followed by a period of 30 days of stability or improvement. The annualised relapse rate for a period was calculated as the total number of relapses that occurred during the period for all subjects, divided by the total number of subject-years followed in that period. Relapses and follow-up times that occurred after treatment discontinuation were excluded from the calculations. Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF.
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End point type |
Secondary
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End point timeframe |
Baseline and Month 6
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Subjects Relapsed at Month 12 | ||||||||
End point description |
An MS relapse was defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurologic findings upon examination by the investigator, and followed by a period of 30 days of stability or improvement. Relapses and follow-up times that occurred after treatment discontinuation were excluded from the calculations. Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF.
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End point type |
Secondary
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End point timeframe |
Month 12
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects Who Are Hospitalised Due to MS Relapses | ||||||
End point description |
Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF.
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End point type |
Secondary
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End point timeframe |
Up to Month 12
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Subjects Who Have Emergency Room Visits due to MS Relapses | ||||||
End point description |
Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF.
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End point type |
Secondary
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End point timeframe |
Up to Month 12
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| Notes [2] - Data on emergency room visits was not collected in the study. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Subjects Who Have Relapses Requiring Intravenous (IV) Steroid Treatment During the Study | ||||||||||||||||
End point description |
The rate of relapses requiring IV steroid therapy is calculated as the total number of relapses requiring IV therapy divided by number of subject-years followed within 12 months. Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF.
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End point type |
Secondary
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End point timeframe |
Up to Month 12
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Number of Subjects Who Make Visits to Neurologists or Other Specialists Due to MS Over a 12-Month Period | ||||||
End point description |
Enrolled population included all subjects who were eligible, signed informed consent and were enrolled in the study.
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End point type |
Secondary
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End point timeframe |
Up to Month 12
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| No statistical analyses for this end point | |||||||
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End point title |
Percentage of Subjects Who Reported Not Taking the Full Prescribed DMF Dose | ||||||||
End point description |
Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF.
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End point type |
Secondary
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End point timeframe |
Up to Month 12
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Overall Adherence | ||||||||
End point description |
Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF. Here, 'number of subjects analysed' are subjects assessed in this endpoint.
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End point type |
Secondary
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End point timeframe |
Up to Month 12
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects Who Had Reasons for Not Taking Full Dose Over a 12-Month Period | ||||||||||||||||||||||||
End point description |
Primary analysis population included all subjects who were eligible, signed informed consent, enrolled, and took at least 1 dose of DMF.
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End point type |
Secondary
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End point timeframe |
Up to Month 12
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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 |
From Baseline (Day 1) up to end of treatment (Month 12)
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Adverse event reporting additional description |
The safety population is defined as all subjects who received at least 1 dose of DMF.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
BG00012 240 mg BID
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Reporting group description |
Subjects received BG00012 capsules, 120 milligrams (mg), orally, twice daily (BID) on Days 1 through 7 followed by BG00012 capsules, 240 mg, orally, BID, thereafter up to 12 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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20 Jun 2013 |
The primary reason for this amendment is to address the following: 1) Validated translations for the Patient-Reported Indices for Multiple Sclerosis (PRIMUS) Activity Limitations instrument were not available for all languages. As a result, this instrument was administered only in countries where translations were available (Austria, Canada, France, Italy, and Spain). 2) Austrian Drug Law allows clinical trials to be conducted in women of childbearing potential only if it is confirmed that they are not pregnant. Therefore, pregnancy tests must be performed on a monthly basis during the study (including 4 to 5 half-life times after the last dose) by a physician who is not necessarily the investigator. |
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Interruptions (globally) |
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| 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. | |||
| None reported | |||
