Study of Evobrutinib in Participants With RMS (evolutionRMS 2)

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 2)

The study is to evaluate the efficacy and safety of evobrutinib administered orally twice daily versus Teriflunomide (Aubagio®), administered orally once daily in participants with Relapsing Multiple Sclerosis (RMS). Participants 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.

Study Overview

• Status: Terminated
• Conditions: Relapsing Multiple Sclerosis
• Intervention / Treatment: Drug: Teriflunomide; Drug: Evobrutinib

• Study Type: Interventional
• Enrollment (Actual): 1166
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belarus
  • Gomel, Belarus
    • Research Site 144
  • Grodno, Belarus
    • Research Site 143
  • Minsk, Belarus
    • Research Site 142
  • Vitebsk, Belarus
    • Research Site 141
  • Vitebsk, Belarus
    • Research Site 145
• Brazil
  • Belo Horizonte, Brazil
    • Research Site 603
  • Curitiba, Brazil
    • Research Site 599
  • Goiânia, Brazil
    • Research Site 604
  • Joinville, Brazil
    • Research Site 600
  • Passo Fundo, Brazil
    • Research Site 614
  • Porto Alegre, Brazil
    • Research Site 591
  • Porto Alegre, Brazil
    • Research Site 594
  • Porto Alegre, Brazil
    • Research Site 596
  • Vitória, Brazil
    • Research Site 609
• Bulgaria
  • Blagoevgrad, Bulgaria
    • Research Site 155
  • Dupnitsa, Bulgaria
    • Research Site 156
  • Pleven, Bulgaria
    • Research Site 157
  • Pleven, Bulgaria
    • Research Site 801
  • Pleven, Bulgaria
    • Research Site 804
  • Plovdiv, Bulgaria
    • Research Site 805
  • Sofia, Bulgaria
    • Research Site 151
  • Sofia, Bulgaria
    • Research Site 152
  • Sofia, Bulgaria
    • Research Site 153
  • Sofia, Bulgaria
    • Research Site 158
  • Sofia, Bulgaria
    • Research Site 159
  • Sofia, Bulgaria
    • Research Site 160
  • Sofia, Bulgaria
    • Research Site 802
  • Sofia, Bulgaria
    • Research Site 803
  • Sofia, Bulgaria
    • Research Site 808
  • Veliko Tarnovo, Bulgaria
    • Research Site 154
• Canada
  • Burnaby, Canada
    • Research Site 106
  • London, Canada
    • Research Site 107
  • Montreal, Canada
    • Research Site 105
  • Ottawa, Canada
    • Research Site 101
• France
  • Bordeaux Cedex, France
    • Research Site 455
  • Brest cedex 2, France
    • Research Site 459
  • Clermont Ferrand Cedex, France
    • Reserach Site 451
  • Limoges cedex, France
    • Research Site 458
  • Nimes, France
    • Research Site 456
  • Paris, France
    • Research Site 453
  • Pringy cedex, France
    • Research Site 457
  • Strasbourg cedex, France
    • Research Site 452
  • Tours cedex 9, France
    • Research Site 454
• Germany
  • Augsburg, Germany
    • Research Site 172
  • Berlin, Germany
    • Research Site 177
  • Berlin, Germany
    • Research Site 180
  • Bonn, Germany
    • Research Site 178
  • Dresden, Germany
    • Research Site 184
  • Hamburg, Germany
    • Research Site 174
  • Heidelberg, Germany
    • Research Site 182
  • Koeln, Germany
    • Research Site 179
  • Leipzig, Germany
    • Research Site 181
  • Mainz, Germany
    • Research Site 173
  • Minden, Germany
    • Research Site 176
  • Regensburg, Germany
    • Research Site 171
  • Rostock, Germany
    • Research Site 183
  • Tuebingen, Germany
    • Research Site 175
• Greece
  • Athens, Greece
    • Research Site 194
  • Athens, Greece
    • Research Site 196
  • Athens, Greece
    • Research Site 197
  • Athens, Greece
    • Research Site 201
  • Athens, Greece
    • Research Site 202
  • Athens, Greece
    • Research Site 205
  • Athens, Greece
    • Research Site 207
  • Athens, Greece
    • Reserach Site 206
  • Heraklion, Greece
    • Research Site 198
  • Ioannina, Greece
    • Research Site 204
  • Larissa, Greece
    • Research Site 192
  • Marousi, Greece
    • Research Site 199
  • Patra, Greece
    • Research Site 203
  • Patras, Greece
    • Research Site 191
  • Thessaloniki, Greece
    • Research Site 195
• India
  • Ahmedabad, India
    • Research Site 445
  • Bangalore, India
    • Research Site 444
  • Mangalore, India
    • Research Site 443
  • New Delhi, India
    • Research Site 442
• Italy
  • Bari, Italy
    • Research Site 218
  • Catania, Italy
    • Research Site 216
  • Cefalù, Italy
    • Research Site 214
  • Firenze, Italy
    • Research Site 219
  • Milano, Italy
    • Research Site 221
  • Napoli, Italy
    • Research Site 211
  • Napoli, Italy
    • Research Site 215
  • Orbassano, Italy
    • Research Site 220
  • Palermo, Italy
    • Research Site 217
  • Pozzilli, Italy
    • Research Site 212
  • Roma, Italy
    • Research Site 213
  • Roma, Italy
    • Research Site 222
• Latvia
  • Riga, Latvia
    • Research Site 231
  • Riga, Latvia
    • Research Site 232
  • Riga, Latvia
    • Research Site 233
• Lithuania
  • Kaunas, Lithuania
    • Research Site 241
  • Klaipeda, Lithuania
    • Research Site 244
  • Siauliai, Lithuania
    • Research Site 243
  • Vilnius, Lithuania
    • Research Site 242
• Malaysia
  • Kuala Lumpur, Malaysia
    • Research Site 551
  • Kuala Lumpur, Malaysia
    • Research Site 554
  • Kuala Lumpur, Malaysia
    • Research Site 556
  • Kuching, Malaysia
    • Research Site 552
  • Seberang Jaya, Malaysia
    • Research Site 553
• Moldova, Republic of
  • Chisinau, Moldova, Republic of
    • Research Site 251
  • Chisinau, Moldova, Republic of
    • Research Site 252
• Norway
  • Bergen, Norway
    • Research Site 481
  • Drammen, Norway
    • Research site 483
  • Namsos, Norway
    • Research Site 482
• Philippines
  • Baguio City, Philippines
    • Research Site 562
  • Cebu City, Philippines
    • Research Site 561
• Poland
  • Bydgoszcz, Poland
    • Reserach Site 267
  • Bydgoszcz, Poland
    • Reserach Site 268
  • Katowice, Poland
    • Research Site 273
  • Katowice, Poland
    • Research site 846
  • Katowice-Ochojec, Poland
    • Research Site 274
  • Krakow, Poland
    • Research Site 276
  • Lodz, Poland
    • Research Site 263
  • Nowa Sol, Poland
    • Research Site 266
  • Poznan, Poland
    • Research Site 270
  • Rzeszow, Poland
    • Research Site 262
  • Siemianowice, Poland
    • Research Site 265
  • Szczecin, Poland
    • Research Site 271
  • Warszawa, Poland
    • Research Site 264
  • Warszawa, Poland
    • Research Site 277
  • Warszawa, Poland
    • Reserach Site 275
  • Wroclaw, Poland
    • Research Site 269
  • Zabrze, Poland
    • Research Site 261
  • Zamosc, Poland
    • Research Site 278
  • Łódź, Poland
    • Research Site 272
• Portugal
  • Aveiro, Portugal
    • Research Site 293
  • Braga, Portugal
    • Research Site 282
  • Coimbra, Portugal
    • Research Site 289
  • Lisboa, Portugal
    • Research Site 281
  • Lisboa, Portugal
    • Research Site 283
  • Lisboa, Portugal
    • Research Site 287
  • Matosinhos, Portugal
    • Research Site 284
  • Porto, Portugal
    • Research Site 292
  • Pragal, Portugal
    • Research Site 288
  • Santa Maria da Feira, Portugal
    • Research Site 291
  • Torres Vedras, Portugal
    • Research Site 286
• Puerto Rico
  • Guaynabo, Puerto Rico
    • Research Site 791
• Romania
  • Brasov, Romania
    • Research Site 314
  • București, Romania
    • Research Site 307
  • Caracal, Romania
    • Research Site 309
  • Targu Mures, Romania
    • Research Site 302
• Russian Federation
  • Kazan, Russian Federation
    • Research Site 325
  • Kazan, Russian Federation
    • Research Site 329
  • Kemerovo, Russian Federation
    • Research Site 323
  • Kirov, Russian Federation
    • Research Site 344
  • Krasnodar, Russian Federation
    • Research Site 340
  • Krasnoyarsk, Russian Federation
    • Research Site 334
  • Moscow, Russian Federation
    • Research Site 341
  • Moscow, Russian Federation
    • Research Site 343
  • Moscow, Russian Federation
    • Research Site 345
  • Nizhniy Novgorod, Russian Federation
    • Research Site 332
  • Novosibirsk, Russian Federation
    • Research Site 327
  • Novosibirsk, Russian Federation
    • Research Site 330
  • Novosibirsk, Russian Federation
    • Research Site 331
  • Novosibirsk, Russian Federation
    • Research Site 335
  • Rostov-on-Don, Russian Federation
    • Research Site 328
  • Saint Petersburg, Russian Federation
    • Research Site 346
  • Saint-Petersburg, Russian Federation
    • Research Site 324
  • Saint-Petersburg, Russian Federation
    • Research Site 338
  • Saint-Petersburg, Russian Federation
    • Research Site 339
  • Saint-Petersburg, Russian Federation
    • Research Site 342
  • Saransk, Russian Federation
    • Research Site 326
  • Sestroretsk, Russian Federation
    • Research Site 321
  • Tyumen, Russian Federation
    • Research Site 337
• Saudi Arabia
  • Riyadh, Saudi Arabia
    • Research Site 493
• Singapore
  • Singapore, Singapore
    • Research Site 571
  • Singapore, Singapore
    • Research Site 572
• Slovakia
  • Banska Bystrica, Slovakia
    • Research Site 351
  • Bratislava, Slovakia
    • Research Site 352
  • Bratislava, Slovakia
    • Research Site 353
  • Bratislava, Slovakia
    • Research Site 354
  • Bratislava, Slovakia
    • Research Site 356
  • Dubnica nad Vahom, Slovakia
    • Research Site 359
  • Trencin, Slovakia
    • Research Site 358
  • Trnava, Slovakia
    • Research Site 357
• Slovenia
  • Celje, Slovenia
    • Research Site 373
  • Ljubljana, Slovenia
    • Research Site 372
  • Maribor, Slovenia
    • Research Site 371
• South Africa
  • Cape Town, South Africa
    • Research Site 501
  • Cape Town, South Africa
    • Research Site 502
  • Cape Town, South Africa
    • Research Site 503
  • Pretoria, South Africa
    • Research Site 504
• Spain
  • Alcorcon, Spain
    • Research Site 384
  • Barakaldo, Spain
    • Research Site 391
  • Barcelona, Spain
    • Research Site 390
  • Cordoba, Spain
    • Research Site 382
  • El Palmar, Spain
    • Research Site 389
  • Madrid, Spain
    • Research Site 388
  • Majadahonda, Spain
    • Research Site 392
  • Malaga, Spain
    • Research Site 383
  • Sevilla, Spain
    • Research Site 387
  • Valencia, Spain
    • Research Site 385
  • Valencia, Spain
    • Research Site 386
  • Vigo, Spain
    • Research Site 381
• Sweden
  • Göteborg, Sweden
    • Research Site 512
  • Malmö, Sweden
    • Research site 514
  • Stockholm, Sweden
    • Research Site 511
  • Uppsala, Sweden
    • Research Site 513
• Switzerland
  • Aarau, Switzerland
    • Research Site 404
  • Bern, Switzerland
    • Research Site 402
  • Lugano, Switzerland
    • Research Site 403
• Thailand
  • Bangkoknoi, Thailand
    • Research Site 583
  • Muang, Thailand
    • Research Site 582
• Turkey
  • Ankara, Turkey
    • Research Site 538
  • Ankara, Turkey
    • Research Site 544
  • Istanbul, Turkey
    • Research Site 531
  • Istanbul, Turkey
    • Research Site 534
  • Istanbul, Turkey
    • Research Site 536
  • Istanbul, Turkey
    • Research Site 541
  • Istanbul, Turkey
    • Research Site 543
  • Izmir, Turkey
    • Research Site 539
  • Kocaeli, Turkey
    • Research Site 533
  • Konya, Turkey
    • Research Site 537
  • Mersin, Turkey
    • Research Site 540
  • Samsun, Turkey
    • Research Site 535
  • Trabzon, Turkey
    • Research Site 532
• Ukraine
  • Chernihiv, Ukraine
    • Research Site 415
  • Chernihiv, Ukraine
    • Research Site 417
  • Dnipro, Ukraine
    • Research Site 414
  • Dnipro, Ukraine
    • Research Site 416
  • Dnipro, Ukraine
    • Research Site 420
  • Ivano-Frankivsk, Ukraine
    • Research Site 413
  • Kharkiv, Ukraine
    • Research Site 624
  • Kharkiv, Ukraine
    • Research Site 632
  • Kharkiv, Ukraine
    • Research Site 633
  • Kherson, Ukraine
    • Research Site 419
  • Kyiv, Ukraine
    • Research Site 411
  • Kyiv, Ukraine
    • Research Site 418
  • Lutsk, Ukraine
    • Research Site 629
  • Lviv, Ukraine
    • Research Site 627
  • Poltava, Ukraine
    • Research Site 622
  • Rivne, Ukraine
    • Research Site 625
  • Ternopil, Ukraine
    • Research Site 628
  • Uzhgorod, Ukraine
    • Research Site 630
  • Vinnytsia, Ukraine
    • Research Site 623
  • Zaporizhzhia, Ukraine
    • Research Site 412
  • Zaporizhzhia, Ukraine
    • Research Site 621
  • Zaporizhzhia, Ukraine
    • Research Site 631
  • Zhytomyr, Ukraine
    • Research Site 626
• United States
  • Alabama
    • Cullman, Alabama, United States, 35058
      • Research Site 752
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Research Site 741
    • Tucson, Arizona, United States, 85710
      • Research Site 704
  • California
    • Hanford, California, United States, 93230
      • Research Site 751
    • West Hollywood, California, United States, 90048
      • Research Site 737
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Research Site 759
    • Fort Collins, Colorado, United States, 80528
      • Research Site 725
  • Florida
    • Altamonte Springs, Florida, United States, 32714
      • Research Site 746
    • Jacksonville, Florida, United States, 32209
      • Research Site 718
    • Naples, Florida, United States, 34105
      • Research Site 702
    • Orlando, Florida, United States, 32806
      • Research Site 740
    • Port Charlotte, Florida, United States, 33952
      • Research Site 726
    • Sarasota, Florida, United States, 34243
      • Research Site 719
    • Tampa, Florida, United States, 33612
      • Research Site 743
    • Tampa, Florida, United States, 33634
      • Research Site 707
    • Vero Beach, Florida, United States, 32960
      • Research Site 732
    • Weeki Wachee, Florida, United States, 34607
      • Research Site 705
    • West Palm Beach, Florida, United States, 33407
      • Research Site 753
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Research Site 742
  • Illinois
    • Evanston, Illinois, United States, 60201
      • Research site 715
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • Research site 714
    • Lafayette, Indiana, United States, 47904
      • Research Site 744
  • Kansas
    • Overland Park, Kansas, United States, 66212
      • Research Site 717
  • Kentucky
    • Nicholasville, Kentucky, United States, 40356
      • Research Site 735
  • Maine
    • Scarborough, Maine, United States, 04074
      • Research Site 706
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Research Site 738
  • Missouri
    • Saint Louis, Missouri, United States, 63128
      • Research Site 723
  • New York
    • Amherst, New York, United States, 14226
      • Research Site 724
  • North Carolina
    • Asheville, North Carolina, United States, 28006
      • Research Site 736
    • Chapel Hill, North Carolina, United States, 27599
      • Research Site 712
    • Raleigh, North Carolina, United States, 27607
      • Research Site 730
    • Winston-Salem, North Carolina, United States, 27157
      • Research Site 728
  • Ohio
    • Canton, Ohio, United States, 44735
      • Research Site 711
    • Columbus, Ohio, United States, 43214
      • Research Site 757
    • Dayton, Ohio, United States, 45459
      • Research Site 734
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Research Site 748
  • Texas
    • San Antonio, Texas, United States, 78258
      • Research Site 703
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Research Site 721

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants are diagnosed with RMS (relapsing-remitting multiple sclerosis [RRMS] or secondary progressive multiple sclerosis [SPMS] with relapses) in accordance with 2017 Revised McDonald criteria (Thompson 2018)
• Participants with one or more documented relapses within the 2 years before Screening with either: a. one relapse which occurred within the last year prior to randomization, OR b. the presence of at least 1 gadolinium-enhancing (Gd+) T1 lesion within 6 months prior to randomization
• Participants have Expanded Disability Status Scale (EDSS) score of 0 to 5.5 at Screening and Baseline (Day 1). Participants with an EDSS score less than or equal to [<=] 2 at Screening and Baseline (Day 1) are only eligible for participation if their disease duration (time since onset of symptoms) is no more than 10 years
• Participants are neurologically stable for >= 30 days prior to both screening and baseline (Day 1)
• Female participants must be neither pregnant nor breast-feeding or must lack child-bearing potential (as defined by either: post-menopausal or surgically sterile), or use an effective method of contraception for the duration of the study and at least 2 years after study intervention due to the long elimination period for teriflunomide of 2 years, unless the participant undergoes an accelerated elimination procedure
• Male participants must refrain from donating sperm and/or abstain from intercourse with women of child-bearing potential or use an effective method of contraception for the duration of the study and at least 2 years after study intervention due to the long elimination period for teriflunomide of 2 years, unless the participant undergoes an accelerated elimination procedure
• Participants have given written informed consent prior to any study-related procedure
• Other protocol defined inclusion criteria could apply.

Exclusion Criteria:

• Participants diagnosed with Progressive MS, in accordance with the 2017 Revised McDonald criteria as follows: a). Participants with Primary Progressive MS. b) Participants with secondary progressive MS without evidence of relapse
• Disease duration more than (>) 10 years in participants with an EDSS =< 2.0 at screening and Baseline (Day 1)
• Immunologic disorder other than MS, or any other condition requiring oral, intravenous (IV), intramuscular, or intra-articular corticosteroid therapy, with the exception of well-controlled Type 2 diabetes mellitus or well controlled thyroid disease
• Other protocol defined exclusion criteria could apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Evobrutinib	Drug: Evobrutinib; Participants 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.; Other Names: M2951
Active Comparator: Teriflunomide	Drug: Teriflunomide; Participants 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Double Blind Treatment Period (DBTP) and Double Blind Extension (DBE) Period: Annualized Relapse Rate (ARR)	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).	Baseline up to 170 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DBTP and DBE Period: Percentage of Participants Without 12-Week Confirmed Disability Progression (CDP) as Measured by Expanded Disability Status Scale (EDSS)	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 participants without 12-week CDP.	Week 96 and Week 156 (combined DBTP and DBE periods)
DBTP and DBE Period: Percentage of Participants Without 24-Week Confirmed Disability Progression (CDP) as Measured by Expanded Disability Status Scale (EDSS)	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 participants without 24-week CDP.	Week 96 and Week 156 (combined DBTP and DBE periods)
DBTP and DBE Period: Percentage of Participants With 24-Week Confirmed Disability Improvement (CDI) as Measured by Expanded Disability Status Scale (EDSS)	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 participants with 12-week CDI.	Week 96 and Week 156 (combined DBTP and DBE periods)
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	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 participant'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).	Baseline, Week 48, Week 96, Week 120, Week 144 and Week 156 (Combined DBTP and DBE periods)
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	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).	Baseline, Week 48, Week 96, Week 120, Week 144 and Week 156 ((combined DBTP and DBE periods)
DBTP and DBE Period: Total Number of T1 Gadolinium-positive (Gd+) Lesions	Analysis of Gadolinium-positive T1 lesions was done using magnetic resonance imaging (MRI) scans.	Baseline up to 170 weeks
DBTP and DBE Period: New or Enlarging T2 Lesions Rate	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.	Baseline up to 170 weeks
DBTP Period: Neurofilament Light Chain (NfL) Concentration at Week 12	NfL is a biomarker of neuro-axonal damage whose concentration was assessed in blood at Week 12.	Week 12
DBTP and DBE Periods: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Adverse Events of Special Interest (AESIs)	Adverse event (AE): Any untoward medical occurrence in a participant 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.	Baseline up to 170 weeks
DBTP and DBE Periods: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity	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 participants with Grades 1, 2, 3, 4 and 5 were reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Vital Signs: Diastolic Blood Pressure and Systolic Blood Pressure	Diastolic blood pressure and systolic blood pressure were measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Changes in vital signs: diastolic blood pressure and systolic blood pressure from baseline up to 170 weeks were reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Vital Signs: Pulse Rate	Pulse rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Changes in vital signs: pulse rate from baseline up to 170 weeks was reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Vital Signs: Respiratory Rate	Respiratory rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Changes in vital signs: respiratory rate from baseline up to 170 weeks was reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Vital Signs: Weight	Changes in vital signs: weight from baseline up to 170 weeks was reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Vital Signs: Temperature	Temperature was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Changes in vital signs: Temperature from baseline up to 170 weeks was reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Electrocardiograms (ECGs): Heart Rate	Heart rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Changes in vital signs: heart rate from baseline up to 170 weeks was reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Electrocardiograms (ECGs): QT Interval - Fridericia's Correction Formula, PR Interval and QRS Duration	QT Interval - Fridericia's Correction Formula, PR Interval and QRS Duration was measured after at least 5 minutes of rest for the participant 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 170 weeks were reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Hemoglobin and Erythrocytes Mean Corpuscular Hemoglobin (HGB) Concentration	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 170 weeks were reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes and Reticulocytes	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 170 weeks were reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Hematology Parameters: Hematocrit	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 up to 170 weeks was reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin	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 up to 170 weeks was reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume	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 170 weeks was reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Bilirubin and Creatinine	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 170 weeks were reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase	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 170 weeks were reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Sodium, Potassium, Calcium, Magnesium, Glucose, Chloride, Urea Nitrogen, Phosphate, Bicarbonate and Corrected Calcium	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 170 weeks were reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Total Protein and Albumin	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 up to 170 weeks were reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Glomerular Filtration Rate	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 up to 170 weeks were reported. The Glomerular Filtration Rate was measured as milliliter per minute per 1.73 square meter (mL/min/1.73m^2).	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Urinalyses Parameter: Potential of Hydrogen (pH) of Urine	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 up to 170 weeks was reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Change From Baseline in Urinalyses Parameter: Specific Gravity of Urine	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 up to 170 weeks was reported.	Baseline up to 170 weeks
DBTP and DBE Periods: Absolute Concentrations of Immunoglobulin (Ig) Levels	Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.	At Week 170
DBTP and DBE Periods: Change From Baseline in Immunoglobulin (Ig) Levels	Change from baseline serum levels of IgG, IgA, IgM were assessed.	Baseline up to 170 weeks

Collaborators and Investigators

• Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
• Collaborators: EMD Serono Research & Development Institute, Inc.
• Investigators: Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Publications and helpful links

General Publications

• Montalban X, Vermersch P, Arnold DL, Bar-Or A, Cree BAC, Cross AH, Kubala Havrdova E, Kappos L, Stuve O, Wiendl H, Wolinsky JS, Dahlke F, Le Bolay C, Shen Loo L, Gopalakrishnan S, Hyvert Y, Javor A, Guehring H, Tenenbaum N, Tomic D; evolutionRMS investigators. Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): two multicentre, randomised, double-blind, active-controlled, phase 3 trials. Lancet Neurol. 2024 Nov;23(11):1119-1132. doi: 10.1016/S1474-4422(24)00328-4. Epub 2024 Sep 19.

Helpful Links

• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2020
• Primary Completion (Actual): October 2, 2023
• Study Completion (Actual): March 19, 2024

Study Registration Dates

• First Submitted: April 6, 2020
• First Submitted That Met QC Criteria: April 6, 2020
• First Posted (Actual): April 8, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 13, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Evobrutinib; Relapsing Multiple Sclerosis; Teriflunomide; Aubagio®
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis; Sclerosis; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Antirheumatic Agents; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Teriflunomide
• Other Study ID Numbers: MS200527_0082; 2019-004980-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21
• IPD Sharing Time Frame: Within six months after the approval of a new product or a new indication for an approved product in both the United States and the European Union
• IPD Sharing Access Criteria: Qualified scientific and medical researchers can request the data. Such requests must be submitted in writing to the company's portal and will be internally reviewed regarding criteria for researchers' qualification and legitimacy of the research proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No