Clinical Trial Results:
A Phase III, Multicenter, Randomized, Parallel Group, Double Blind, Double Dummy, Active Controlled Study of Evobrutinib Compared With Teriflunomide, in Participants With Relapsing Multiple Sclerosis to Evaluate Efficacy and Safety (evolutionRMS 1)
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Summary
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EudraCT number |
2019-004972-20 |
Trial protocol |
DE GB AT HU BE CZ BG ES FI HR IT |
Global end of trial date |
08 Mar 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Mar 2025
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First version publication date |
20 Mar 2025
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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 |
MS200527_0080
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04338022 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Merck Healthcare KGaA, Darmstadt Germany
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Sponsor organisation address |
Street Address: Frankfurter Strasse 250, Darmstadt, Germany, 64293
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Public contact |
Communication Centre, Merck Healthcare KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com
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Scientific contact |
Communication Centre, Merck Healthcare KGaA, Darmstadt Germany, +49 6151725200, service@merckgroup.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 |
08 Mar 2024
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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 |
08 Mar 2024
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The study was to evaluate the efficacy and safety of evobrutinib administered orally twice daily versus Teriflunomide (Aubagio®), administered orally once daily in subjects with Relapsing Multiple Sclerosis (RMS). Subjects who complete the double-blind treatment period (DBTP) and double-blind extension period (DBEP) prior to approval of a separate long-term follow-up study in their country will get an option for evobrutinib treatment continuation through a 96-week open-label extension (OLE) period.
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Protection of trial subjects |
Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
12 Jun 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Bulgaria: 36
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Country: Number of subjects enrolled |
Bosnia and Herzegovina: 4
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Country: Number of subjects enrolled |
Czechia: 66
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Country: Number of subjects enrolled |
Estonia: 19
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Country: Number of subjects enrolled |
Finland: 1
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Country: Number of subjects enrolled |
Georgia: 133
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Country: Number of subjects enrolled |
Croatia: 47
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Country: Number of subjects enrolled |
Hungary: 15
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Country: Number of subjects enrolled |
Poland: 105
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Country: Number of subjects enrolled |
Russian Federation: 163
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Country: Number of subjects enrolled |
Serbia: 29
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Country: Number of subjects enrolled |
Ukraine: 233
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Country: Number of subjects enrolled |
Austria: 3
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Country: Number of subjects enrolled |
Belgium: 5
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Country: Number of subjects enrolled |
Germany: 32
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Country: Number of subjects enrolled |
Spain: 21
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Country: Number of subjects enrolled |
France: 8
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
Italy: 20
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Country: Number of subjects enrolled |
Canada: 4
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Country: Number of subjects enrolled |
United States: 58
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Country: Number of subjects enrolled |
Argentina: 55
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Country: Number of subjects enrolled |
Australia: 9
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Country: Number of subjects enrolled |
Colombia: 4
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Country: Number of subjects enrolled |
Hong Kong: 1
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Country: Number of subjects enrolled |
India: 6
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Country: Number of subjects enrolled |
Israel: 9
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Country: Number of subjects enrolled |
Korea, Republic of: 8
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Country: Number of subjects enrolled |
Mexico: 22
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Country: Number of subjects enrolled |
Taiwan: 6
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Worldwide total number of subjects |
1124
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EEA total number of subjects |
378
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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) |
1124
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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 |
A total of 1561 subjects with relapsing multiple sclerosis (RMS) were screened in this trial. Out of which 1124 subjects were randomized at a ratio of 1:1 (evobrutinib group: 560 and teriflunomide group: 564) in this trial. | ||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
3 subjects were enrolled in the Open Label Extension (OLE) Period after Double Blind Treatment Period (DBTP) Week 96 and they did not enter Double Blind Extension (DBE) period. | ||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Double-blind treatment period: 156 weeks
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Data analyst, Assessor | ||||||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Teriflunomide | ||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received Teriflunomide at a dose of 14 milligrams (mg) orally once daily up to 156 weeks in Double blind treatment period (DBTP) followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in double blind extension (DBE) period and followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in open label extension (OLE) period. | ||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Teriflunomide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received Teriflunomide at a dose of 14 milligrams (mg) orally once daily up to 156 weeks in Double blind treatment period (DBTP).
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Arm title
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Evobrutinib | ||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period and followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in open label extension (OLE) period. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Evobrutinib
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Investigational medicinal product code |
M2951
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP).
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Period 2
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Period 2 title |
Double-blind extension: 96 weeks
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Data analyst, Assessor | ||||||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Teriflunomide | ||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received Teriflunomide at a dose of 14 milligrams (mg) orally once daily up to 156 weeks in Double blind treatment period (DBTP) followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in double blind extension (DBE) period and followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in open label extension (OLE) period. | ||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Teriflunomide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received Teriflunomide at a dose of 14 mg orally once daily up to 96 weeks in double blind extension (DBE) period.
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Arm title
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Evobrutinib | ||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period and followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in open label extension (OLE) period. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Evobrutinib
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Investigational medicinal product code |
M2951
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received Evobrutinib at a dose of 45 mg orally twice daily up to 96 weeks in double blind extension (DBE) period.
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| Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: only 736 subjects (377 in Teriflunomide and 359 in Evobrutinib) started the DBE period. |
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Period 3
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Period 3 title |
Open Label Extension: 96 weeks
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||
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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Evobrutinib | ||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period and followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in open label extension (OLE) period. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Evobrutinib
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Investigational medicinal product code |
M2951
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received Evobrutinib at a dose of 45 mg orally twice daily up to 96 weeks in open label extension (OLE) period.
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| Notes [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: only 3 subjects ("0" in Teriflunomide and "3" in Evobrutinib) started the OLE period. |
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Baseline characteristics reporting groups
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Reporting group title |
Teriflunomide
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Reporting group description |
Subjects received Teriflunomide at a dose of 14 milligrams (mg) orally once daily up to 156 weeks in Double blind treatment period (DBTP) followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in double blind extension (DBE) period and followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in open label extension (OLE) period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Evobrutinib
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Reporting group description |
Subjects received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period and followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in open label extension (OLE) period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Teriflunomide
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Reporting group description |
Subjects received Teriflunomide at a dose of 14 milligrams (mg) orally once daily up to 156 weeks in Double blind treatment period (DBTP) followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in double blind extension (DBE) period and followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in open label extension (OLE) period. | ||
Reporting group title |
Evobrutinib
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Reporting group description |
Subjects received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period and followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in open label extension (OLE) period. | ||
Reporting group title |
Teriflunomide
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Reporting group description |
Subjects received Teriflunomide at a dose of 14 milligrams (mg) orally once daily up to 156 weeks in Double blind treatment period (DBTP) followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in double blind extension (DBE) period and followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in open label extension (OLE) period. | ||
Reporting group title |
Evobrutinib
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Reporting group description |
Subjects received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period and followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in open label extension (OLE) period. | ||
Reporting group title |
Evobrutinib
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Reporting group description |
Subjects received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period and followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in open label extension (OLE) period. | ||
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End point title |
Double Blind Treatment Period (DBTP) and Double Blind Extension (DBE) Period: Annualized Relapse Rate (ARR) [1] | ||||||||||||
End point description |
The qualifying relapse is the occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis (MS) (for more than [>] 24 hours, no fever, infection, injury, adverse events (AEs,) and preceded by a stable or improving neurological state for more than or equal to [>=] 30 days). Full Analysis Set (FAS) included all subjects who were randomized to study treatment.
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End point type |
Primary
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End point timeframe |
From baseline to 172 weeks
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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: Only descriptive data was planned to be reported for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Open Label Extension (OLE) Period: Number of Subjects with Adverse Events (AEs) and Serious AEs [2] [3] | ||||||||||
End point description |
Adverse event (AE): Any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the study drug. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment.
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End point type |
Primary
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End point timeframe |
From OLE Baseline (DBTP Week 96) to OLE Week 52
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be reported for this endpoint. [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint was planned to be reported only OLE period arms. |
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| No statistical analyses for this end point | |||||||||||
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End point title |
DBTP and DBE Period: Percentage of Subjects Without 12-Week Confirmed Disability Progression (CDP) as Measured by Expanded Disability Status Scale (EDSS) | ||||||||||||||||||
End point description |
Disability progression was defined as increase in EDSS of greater than or equal to [>=] 1 point from baseline EDSS score, if EDSS score at baseline is 5.0 or less and an increase of >=0.5 point, if the baseline score is 5.5. Disability progression is considered sustained for 12 weeks when the initial increase in the EDSS is confirmed at a regularly scheduled visit at least 12 weeks after the initial documentation of neurological worsening. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). Kaplan-Meier method was used to estimate the percentage of subjects without 12-week CDP. Full Analysis Set (FAS) included all subjects who were randomized to study treatment. The result reported for this endpoint are the results from data of combined DBTP and DBE periods.
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End point type |
Secondary
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End point timeframe |
Week 96 and Week 156 (combined DBTP and DBE period)
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
DBTP and DBE Period: Percentage of Subjects with 24-Week Confirmed Disability Improvement (CDI) as Measured by Expanded Disability Status Scale (EDSS) | ||||||||||||||||||
End point description |
Disability improvement was defined as a reduction of 1 point from Baseline EDSS score when the Baseline score is >= 2 and less than or equal to [<=] 6 and a reduction of 0.5 point from Baseline EDSS score when the Baseline score is >= 6.5 and <= 9.5. Disability improvement is considered sustained when the initial reduction in the EDSS score is confirmed at a regularly scheduled visit at least 24 weeks after the initial reduction. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). Kaplan-Meier method was used to estimate the percentage of subjects with 12-week CDI. Full Analysis Set (FAS) included all subjects who were randomized to study treatment. The result reported for this endpoint are the results from data of combined DBTP and DBE periods.
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End point type |
Secondary
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End point timeframe |
Week 96 and Week 156 (combined DBTP and DBE period)
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
DBTP and DBE Period: Percentage of Subjects Without 24-Week Confirmed Disability Progression (CDP) as Measured by Expanded Disability Status Scale (EDSS) | ||||||||||||||||||
End point description |
Disability progression was defined as increase in EDSS of greater than or equal to [>=] 1 point from baseline EDSS score, if EDSS score at baseline is 5.0 or less and an increase of >=0.5 point, if the baseline score is 5.5. Disability progression is considered sustained for 24 weeks when the initial increase in the EDSS is confirmed at a regularly scheduled visit at least 24 weeks after the initial documentation of neurological worsening. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). Kaplan-Meier method was used to estimate the percentage of subjects without 24-week CDP. Full Analysis Set (FAS) included all subjects who were randomized to study treatment. The result reported for this endpoint are the results from data of combined DBTP and DBE periods.
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End point type |
Secondary
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End point timeframe |
Week 96 and Week 156 (combined DBTP and DBE period)
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||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
||||||||||||||||||||||||||||
End point title |
DBTP and DBE Period: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Score at Week 48, Week 96, Week 120, Week 144 and Week 156 | |||||||||||||||||||||||||||
End point description |
Physical function was assessed with PROMISnq Short Form v2.0 – Physical Function – Multiple Sclerosis 15a (PROMISnq PF(MS) 15a). PROMISnq PF(MS) 15a assesses a subject's abilities and limitations with respect to everyday physical activities. Results are reported as a T-score. In the general population, T-scores have a mean of 50, standard deviation of 10, and range from 10 to 65. Higher T-scores represent higher physical function. Change from baseline in PROMIS PF score was analyzed using Mixed Effect Model for Repeated Measures (MMRM) to evaluate the result of the 2 periods (DBTP and DBE). Full Analysis Set (FAS) included all subjects who were randomized to study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint. The result reported for this endpoint are the results from data of combined DBTP and DBE periods.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Baseline, Week 48, Week 96, Week 120, Week 144 and Week 156 (combined DBTP and DBE period)
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||
|
|||||||||||||
End point title |
DBTP and DBE Period: Total number of T1 Gadolinium-positive (Gd+) lesions | ||||||||||||
End point description |
Analysis of Gadolinium-positive T1 lesions was done using magnetic resonance imaging (MRI) scans. Full Analysis Set (FAS) included all subjects who were randomized to study treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||||||||||||||
End point title |
DBTP and DBE Period: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Score at Week 48, Week 96, Week 120, Week 144 and Week 156 | |||||||||||||||||||||||||||
End point description |
PROMIS Fatigue score was assessed with PROMIS Short Form v1.0 – Fatigue – Multiple Sclerosis 8a (PROMIS Fatigue (MS) 8a). PROMIS Fatigue (MS) 8a assesses level of fatigue and its interference on daily activities. Results are reported as a T-score. In the general population, T-scores have a mean of 50, standard deviation of 10, and range from 33 to 85. Higher T-scores represent higher fatigue. Change from baseline in PROMIS fatigue score was analyzed using Mixed Effect Model for Repeated Measures (MMRM) to evaluate the result of the 2 periods (DBTP and DBE). Full Analysis Set (FAS) included all subjects who were randomized to study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint. The result reported for this endpoint are the results from data of combined DBTP and DBE periods.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Baseline, Week 48, Week 96, Week 120, Week 144 and Week 156 (combined DBTP and DBE period)
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
DBTP and DBE periods: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) by Severity | ||||||||||||||||||||||||
End point description |
Severity of adverse events (AE) were assessed by the investigator per the National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death. Number of subjects with Grades 1, 2, 3, 4 and 5 were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
||||||||||||||||
End point title |
DBTP and DBE periods: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Adverse Events of Special Interest (AESIs) | |||||||||||||||
End point description |
Adverse event (AE): Any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the study drug. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs: those AEs with an onset date on or after the date of first study intervention administration, or AEs present prior to any study intervention administration but exacerbating after. TEAEs included both Serious TEAEs and non-serious TEAEs. AESIs included liver AEs (possible drug-induced, non-infectious, non-alcoholic, and immune-mediated), infections (serious and opportunistic infections), lipase and amylase elevation, and seizure. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From baseline to 176 weeks
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||
End point title |
DBTP Period: Neurofilament Light Chain Concentration (NfL) at Week 12 | ||||||||||||
End point description |
NfL is a biomarker of neuro-axonal damage whose concentration was assessed in blood at Week 12. Full Analysis Set (FAS) included all subjects who were randomized to study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 12
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DBTP and DBE Period: New or Enlarging T2 Lesions Rate | ||||||||||||
End point description |
Analysis of new or enlarging T2 lesions rate was done using magnetic resonance imaging (MRI) scans. Negative binomial model for lesion count (summed over scans) includes treatment and covariates based on randomization strata and baseline volume of T2 lesion (continuous), with offset equal to the log of the time in years between the last available MRI scan and the baseline scan. Full Analysis Set (FAS) included all subjects who were randomized to study treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Vital Signs: Diastolic Blood Pressure and Systolic Blood Pressure | ||||||||||||||||||
End point description |
Diastolic blood pressure and systolic blood pressure were measured after at least 5 minutes of rest for the subject in a quiet sitting without distractions. Changes in vital signs: diastolic blood pressure and systolic blood pressure from baseline up to 176 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Vital Signs: Pulse Rate | ||||||||||||
End point description |
Pulse rate was measured after at least 5 minutes of rest for the subject in a quiet sitting without distractions. Changes in vital signs: pulse rate from baseline up to baseline up to 176 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Electrocardiograms (ECGs) Parameter: Heart Rate | ||||||||||||
End point description |
Heart rate was measured after at least 5 minutes of rest for the subject in a quiet sitting without distractions. Changes in vital signs: heart rate from baseline up to 176 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Vital Signs: Temperature | ||||||||||||
End point description |
Temperature was measured after at least 5 minutes of rest for the subject in a quiet sitting without distractions. Changes in vital signs: Temperature from baseline up to 176 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Vital Signs: Respiratory Rate | ||||||||||||
End point description |
Respiratory rate was measured after at least 5 minutes of rest for the subject in a quiet sitting without distractions. Changes in vital signs: respiratory rate from baseline up to 176 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Vital Signs: Weight | ||||||||||||
End point description |
Changes in vital signs: weight from baseline up to 176 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Electrocardiograms (ECGs) Parameters: QT Interval - Fridericia's Correction Formula, PR Interval and QRS Duration | |||||||||||||||||||||
End point description |
QT Interval - Fridericia's Correction Formula, PR Interval and QRS Duration was measured after at least 5 minutes of rest for the subject in a quiet sitting without distractions. Changes in vital signs: QT Interval - Fridericia's Correction Formula, PR Interval and QRS Duration from baseline up to 176 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
From baseline to 176 weeks
|
|||||||||||||||||||||
|
||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Hemoglobin and Erythrocytes Mean Corpuscular Hemoglobin (HGB) Concentration [Ery. Mean Corp. HGB conc.] | ||||||||||||||||||
End point description |
Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: erythrocytes mean corpuscular HGB concentration and hemoglobin. Changes in hematology parameters: erythrocytes mean corpuscular HGB concentration and hemoglobin from baseline up to 176 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this outcome measure and “n" = subjects who were evaluable for the specified categories.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes and Reticulocytes | ||||||||||||||||||||||||||||||||||||
End point description |
Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes and Reticulocytes. Changes in hematology parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes and Reticulocytes from baseline up to 176 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint and “n" = subjects who were evaluable for the specified categories.
|
||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Bilirubin and Creatinine | ||||||||||||||||||
End point description |
Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameters: Bilirubin and Creatinine. Changes in biochemistry parameters: Bilirubin and Creatinine from baseline up to 176 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint and “n"= subjects who were evaluable for the specified categories.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume | ||||||||||||
End point description |
Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Erythrocytes Mean Corpuscular Volume. Changes in hematology parameter: Erythrocytes Mean Corpuscular Volume from baseline up to 176 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin | ||||||||||||
End point description |
Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Erythrocytes Mean Corpuscular Hemoglobin. Changes in hematology parameter: Erythrocytes Mean Corpuscular Hemoglobin from baseline to 176 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Hematocrit | ||||||||||||
End point description |
Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Hematocrit. Changes in hematology parameter: Hematocrit from baseline to 176 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||||||||||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase | |||||||||||||||||||||||||||||||||
End point description |
Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase. Changes in biochemistry parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase from baseline up to 176 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint and “n"= subjects who were evaluable for the specified categories.
|
|||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||
End point timeframe |
From baseline to 176 weeks
|
|||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Sodium, Potassium, Calcium, Magnesium, Glucose, Chloride, Urea Nitrogen, Phosphate, Bicarbonate and Corrected Calcium | ||||||||||||||||||||||||||||||||||||||||||
End point description |
Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameters: Sodium, Potassium, Calcium, Magnesium, Glucose, Chloride, Urea Nitrogen, Phosphate, Bicarbonate and Corrected Calcium. Changes in biochemistry parameters: Sodium, Potassium, Calcium, Magnesium, Glucose, Chloride, Urea Nitrogen, Phosphate, Bicarbonate and Corrected Calcium from baseline up to 176 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint and “n"= subjects who were evaluable for the specified categories.
|
||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Total Protein and Albumin | ||||||||||||||||||
End point description |
Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameters: Total Protein and Albumin. Changes in biochemistry parameters: Total Protein and Albumin from baseline to 176 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint and “n”= subjects who were evaluable for the specified categories.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Glomerular Filtration Rate | ||||||||||||
End point description |
Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameter: Glomerular Filtration Rate. Changes in biochemistry parameter: Glomerular Filtration Rate from baseline to 176 weeks were reported. The Glomerular Filtration Rate will be measured as milliliter per minute per 1.73 square meter (mL/min/1.73m^2). Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Urinalyses Parameter: Potential of Hydrogen (pH) of Urine | ||||||||||||
End point description |
Urine samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the urinalyses parameter: pH. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Changes in urinalyses parameter: pH from baseline to 176 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||||||||
End point title |
DBTP and DBE Periods: Absolute Concentrations of Immunoglobulin (Ig) Levels | |||||||||||||||||||||
End point description |
Absolute Concentrations serum levels of IgG, IgA, IgM were assessed. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
At Week 176
|
|||||||||||||||||||||
|
||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||
|
|||||||||||||
End point title |
DBTP and DBE Periods: Change From Baseline in Urinalyses Parameter: Specific Gravity of Urine | ||||||||||||
End point description |
Urine samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the urinalyses parameter: Specific Gravity of Urine. Changes in urinalyses parameter: Specific Gravity of Urine from baseline to 176 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From baseline to 176 weeks
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||
End point title |
OLE Period: Percentage of Subjects with 24-Week Confirmed Disability Improvement (CDI) as Measured by Expanded Disability Status Scale (EDSS) | ||||||||
End point description |
Disability improvement was defined as a reduction of 1 point from Baseline EDSS score when the Baseline score is >= 2 and less than or equal to [<=] 6 and a reduction of 0.5 point from Baseline EDSS score when the Baseline score is >= 6.5 and <= 9.5. Disability improvement is considered sustained when the initial reduction in the EDSS score is confirmed at a regularly scheduled visit at least 24 weeks after the initial reduction. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). Full Analysis Set (FAS) included all subjects who were randomized to study treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From OLE baseline (DBTP Week 96) to OLE Week 52
|
||||||||
|
|||||||||
| Notes [4] - Due to the early termination of the study, data for this endpoint was not collected and analyzed. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
OLE Period: Percentage of Subjects without 24-Week Confirmed Disability Progression (CDP) as Measured by Expanded Disability Status Scale (EDSS) | ||||||||
End point description |
Disability progression was defined as increase in EDSS of greater than or equal to [>=] 1 point from baseline EDSS score, if EDSS score at baseline is 5.0 or less and an increase of >=0.5 point, if the baseline score is 5.5. Disability progression is considered sustained for 24 weeks when the initial increase in the EDSS is confirmed at a regularly scheduled visit at least 24 weeks after the initial documentation of neurological worsening. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). Full Analysis Set (FAS) included all subjects who were randomized to study treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From OLE baseline (DBTP Week 96) to OLE Week 52
|
||||||||
|
|||||||||
| Notes [5] - Due to the early termination of the study, data for this endpoint was not collected and analyzed. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
OLE Period: Annualized Relapse Rate (ARR) | ||||||||
End point description |
The qualifying relapse is the occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis (MS) (for more than [>] 24 hours, no fever, infection, injury, AEs, and preceded by a stable or improving neurological state for more than or equal to [>=] 30 days). Full Analysis Set (FAS) included all subjects who were randomized to study treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From OLE baseline (DBTP Week 96) to OLE Week 52
|
||||||||
|
|||||||||
| Notes [6] - Due to the early termination of the study, data for this endpoint was not collected and analyzed. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
||||||||||||||||||||||
End point title |
DBTP and DBE Periods: Change from Baseline in Immunoglobulin (Ig) Levels | |||||||||||||||||||||
End point description |
Change from baseline serum levels of IgG, IgA, IgM were assessed. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline to 176 weeks
|
|||||||||||||||||||||
|
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| No statistical analyses for this end point | ||||||||||||||||||||||
|
|||||||||
End point title |
OLE Period: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue (MS) 8a Score at Week 52 | ||||||||
End point description |
PROMIS Fatigue score was assessed with PROMIS Short Form v1.0 – Fatigue – Multiple Sclerosis 8a (PROMIS Fatigue (MS) 8a). PROMIS Fatigue (MS) 8a assesses level of fatigue and its interference on daily activities. Results are reported as a T-score. In the general population, T-scores have a mean of 50, standard deviation of 10, and range from 33 to 85. Higher T-scores represent higher fatigue. Full Analysis Set (FAS) included all subjects who were randomized to study treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
OLE Baseline (DBTP Week 96), OLE Week 52
|
||||||||
|
|||||||||
| Notes [7] - Due to the early termination of the study, data for this endpoint was not collected and analyzed. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||
End point title |
OLE Period: Number of Subjects with Abnormalities in Laboratory Parameters | ||||||
End point description |
Laboratory investigation included hematology, biochemistry and coagulation. The number of subjects with abnormalities in laboratory parameters were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
From OLE baseline (DBTP Week 96) to OLE Week 52
|
||||||
|
|||||||
| Notes [8] - Due to the early termination of the study, data for this endpoint was not collected and analyzed. |
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||
End point title |
OLE Period: Number of Subjects with Abnormalities in Vital Signs | ||||||
End point description |
Vital signs included temperature, pulse rate, respiration rate and blood pressure and weight (taken after 5 minutes in the sitting position). The number of subjects with abnormalities in vital signs were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
From OLE baseline (DBTP Week 96) to OLE Week 52
|
||||||
|
|||||||
| Notes [9] - Due to the early termination of the study, data for this endpoint was not collected and analyzed. |
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||
End point title |
OLE Period: Number of Subjects with Abnormalities in Electrocardiograms (ECGs) Findings | ||||||
End point description |
ECG recordings included, heart rate, PR interval and QRS duration. ECG recordings were obtained after the subjects have rested for at least 5 minutes in supine position. The number of subjects with abnormalities in ECG findings were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
From OLE baseline (DBTP Week 96) to OLE Week 52
|
||||||
|
|||||||
| Notes [10] - Due to the early termination of the study, data for this endpoint was not collected and analyzed. |
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||
End point title |
OLE Period: Total Number of New or Enlarging T2 Lesions | ||||||||
End point description |
Analysis of new or enlarging T2 lesions rate was done using magnetic resonance imaging (MRI) scans. Negative binomial model for lesion count (summed over scans) includes treatment and covariates based on randomization strata and baseline volume of T2 lesion (continuous), with offset equal to the log of the time in years between the last available MRI scan and the baseline scan. Full Analysis Set (FAS) included all subjects who were randomized to study treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From OLE baseline (DBTP Week 96) to OLE Week 52
|
||||||||
|
|||||||||
| Notes [11] - Due to the early termination of the study, data for this endpoint was not collected and analyzed. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
OLE Period: Change from Baseline in T2 lesion Volume | ||||||||
End point description |
Change from baseline in T2 lesion volume was reported. Full Analysis Set (FAS) included all subjects who were randomized to study treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From OLE baseline (DBTP Week 96) to OLE Week 52
|
||||||||
|
|||||||||
| Notes [12] - Due to the early termination of the study, data for this endpoint was not collected and analyzed. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
OLE Period: Symbol Digit Modalities Test (SDMT) | ||||||||
End point description |
The SDMT is a test of information processing speed. It consists of 9 abstract symbols. Each symbol is paired with a single digit. The subject is provided with a "key", showing each symbol digit pair. In addition, the subjects are shown several rows of the 9 symbols, which are arranged pseudo-randomly, without the digit. Subjects are asked to voice the digit associated with each symbol as rapidly as possible for 90 seconds. The SDMT score ranges from 0 to 110 where higher scores indicated improvement and lower scores indicated worsening. Full Analysis Set (FAS) included all subjects who were randomized to study treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From OLE baseline (DBTP Week 96) to OLE Week 52
|
||||||||
|
|||||||||
| Notes [13] - Due to the early termination of the study, data for this endpoint was not collected and analyzed. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
OLE Period: Change From Baseline in PROMISnq Physical Function (PF) Multiple Sclerosis (MS) 15a at Week 52 | ||||||||
End point description |
Physical function was assessed with PROMISnq Short Form v2.0 – Physical Function – Multiple Sclerosis 15a (PROMISnq PF(MS) 15a). PROMISnq PF(MS) 15a assesses a subject's abilities and limitations with respect to everyday physical activities. Results are reported as a T-score. In the general population, T-scores have a mean of 50, standard deviation of 10, and range from 10 to 65. Higher T-scores represent higher physical function. Full Analysis Set (FAS) included all subjects who were randomized to study treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
OLE Baseline (DBTP Week 96), OLE Week 52
|
||||||||
|
|||||||||
| Notes [14] - Due to the early termination of the study, data for this endpoint was not collected and analyzed. |
|||||||||
| 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 to 176 weeks
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Safety (SAF) analysis set included all subjects who received at least one dose of study treatment.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.0
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Reporting groups
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Reporting group title |
Evobrutinib
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Reporting group description |
Subjects received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period and followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in open label extension (OLE) period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Teriflunomide
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Reporting group description |
Subjects received Teriflunomide at a dose of 14 milligrams (mg) orally once daily up to 156 weeks in Double blind treatment period (DBTP) followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in double blind extension (DBE) period and followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in open label extension (OLE) period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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27 Nov 2020 |
• To allow sufficient time for repeat laboratory results and other unanticipated events prior to randomization
• To clarify the process in the event of a female subject undergoing AEP
• Medical history is collected at Screening; any changes thereafter are recorded as AEs
• A urine pregnancy test is sufficient at this visit unless there has been a gap of >=1 month since the last test
• Tmax removed from list of PK parameters for evaluation
• Objectives and endpoints added for biomarkers collected during the OLE
• False positive results were not addressed in the original protocol |
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19 May 2021 |
• To be aligned with the inclusion of an optional IA for BSSR.
• Due to unexpectedly rapid enrollment, the trigger for the IA for USSR is projected to occur months after the completion of enrollment, considered too late to implement changes following outcome of IA from an operational perspective. The optional IA for BSSR, triggered prior to completion of enrollment, does not have this disadvantage
• Due to the removal of the IA for USSR, the role played by the IDMC in making the sample size increase recommendation is no longer required.
• Due to removing the IA for USSR, there is no need to control type-1 error in the 12-week CDP analysis using the Cui, Hung, Wang method. Thus, 12-week CDP and 24-week CDP will be analyzed in the same manner. |
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03 Apr 2022 |
• Revision of the treatment duration from fixed 96 weeks to variable duration up to 156 weeks
• CDI endpoint added to secondary endpoints to explore treatment effect on additional clinically relevant endpoint for disability. Week 12 NfL concentration added to investigate early impact of treatment on reducing neuronal damage.
• A new study will allow subjects who completed the double blind treatment period in the current protocol to enroll in a new, single-arm long-term follow-up study, which will also include subjects who completed other RMS studies with evobrutinib. The text of the protocol has been amended to describe a transition opportunity to this long-term follow-up study
• NfL has emerged as a potential biomarker for disease activity and treatment monitoring of patients with MS. Additional information added to support the inclusion of NfL as secondary endpoint. |
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06 Dec 2022 |
• Introduction of an OLE period for subjects completing the DBTP prior to approval of the long-term follow-up study in their country to enable an option for evobrutinib treatment continuation
• Addition of the following exploratory endpoints: Time to PIRA and time to PIRMA (to evaluate the effect of treatment on progression not driven by relapse events or MRI activity); NEP at Weeks 48, 96; Level of anti-SARS-CoV-2 antibodies. |
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26 Apr 2023 |
• To reflect the recent update to the risk profile of evobrutinib (i.e. important identified risk of drug-induced liver injury) by adapting liver-related eligibility criteria, monitoring, and discontinuation criteria as well as language on tolerability and safety of evobrutinib across the protocol.
• To allow subjects to stay on blinded IMP after DBTP in a DBE period to delay the switch of subjects naïve to evobrutinib treatment to the OLE period. This will also allow to generate additional data on efficacy and safety over an extended period of time. |
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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. | |||
| Final Analysis represents analysis of cumulative data collected up to Primary Analysis trigger and beyond through DBE up to final database lock. Therefore, endpoints were evaluated considering a time period from start of DBTP to end of DBE Period. | |||
