Study of Evobrutinib in Participants With RMS (evolutionRMS 1)

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)

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): 1124
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Ciudad Autonoma Buenos Aires, Argentina
    • Research Site 566
  • Ciudad Autonoma Buenos Aires, Argentina
    • Research Site 567
  • Ciudad Autonoma Buenos Aires, Argentina
    • Research Site 574
  • Ciudad Autonoma Buenos Aires, Argentina
    • Research Site 579
  • Ciudad Autonoma de Buenos Aires, Argentina
    • Research Site 561
  • Ciudad Autonoma de Buenos Aires, Argentina
    • Research Site 562
  • Ciudad Autonoma de Buenos Aires, Argentina
    • Research Site 577
  • Cordoba, Argentina
    • Research Site 564
  • Godoy Cruz, Argentina
    • Research Site 568
  • Guaymallen, Argentina
    • Research Site 576
  • Rosario, Argentina
    • Research Site 565
  • Rosario, Argentina
    • Research Site 569
  • Salta, Argentina
    • Research Site 571
  • San Juan, Argentina
    • Research Site 572
  • San Miguel de Tucuman, Argentina
    • Research Site 563
• Australia
  • Auchenflower, Australia
    • Research Site 104
  • Concord, Australia
    • Research Site 107
  • Hobart, Australia
    • Research Site 109
  • Liverpool, Australia
    • Research Site 101
  • New Lambton Heights, Australia
    • Research Site 102
  • St Leonards, Australia
    • Research Site 103
• Austria
  • Innsbruck, Austria
    • Research Site 151
  • Linz, Austria
    • Research Site 156
  • Salzburg, Austria
    • Research Site 154
  • Vienna, Austria
    • Research Site 153
• Belgium
  • Bruxelles, Belgium
    • Research Site 474
  • Bruxelles, Belgium
    • Research Site 475
  • Kortrijk, Belgium
    • Research Site 473
  • La Louvière, Belgium
    • Research Site 471
  • Liège, Belgium
    • Research Site 472
  • Overpelt, Belgium
    • Research Site 478
  • Roeselare, Belgium
    • Research Site 476
• Bosnia and Herzegovina
  • Bihac, Bosnia and Herzegovina
    • Research Site 161
  • Mostar, Bosnia and Herzegovina
    • Research Site 163
  • Sarajevo, Bosnia and Herzegovina
    • Research Site 162
• Bulgaria
  • Pleven, Bulgaria
    • Research Site 171
  • Pleven, Bulgaria
    • Research Site 174
  • Plovdiv, Bulgaria
    • Reasearch Site 175
  • Plovdiv, Bulgaria
    • Research Site 177
  • Sofia, Bulgaria
    • Research Site 172
  • Sofia, Bulgaria
    • Research Site 173
  • Sofia, Bulgaria
    • Research Site 176
  • Sofia, Bulgaria
    • Research Site 178
  • Sofia, Bulgaria
    • Research Site 179
  • Sofia, Bulgaria
    • Research Site 180
• Canada
  • Greenfield Park, Canada
    • Research Site 126
  • Levis, Canada
    • Research Site 125
  • Moncton, Canada
    • Research Site 128
  • Montreal, Canada
    • Research Site 129
  • Toronto, Canada
    • Research Site 124
• Colombia
  • Barranquilla, Colombia
    • Research Site 591
  • Barranquilla, Colombia
    • Research Site 597
  • Medellin, Colombia
    • Research Site 592
  • Medellin, Colombia
    • Research Site 600
• Croatia
  • Osijek, Croatia
    • Research Site 193
  • Rijeka, Croatia
    • Research Site 197
  • Varazdin, Croatia
    • Research Site 195
  • Zagreb, Croatia
    • Research Site 192
  • Zagreb, Croatia
    • Research Site 194
• Czechia
  • Brno, Czechia
    • Research Site 212
  • Brno, Czechia
    • Research Site 218
  • Hradec Kralove, Czechia
    • Research Site 219
  • Hradec Kralove, Czechia
    • Research Site 222
  • Jihlava, Czechia
    • Research Site 211
  • Ostrava, Czechia
    • Research Site 223
  • Pardubice, Czechia
    • Research Site 215
  • Plzen-Bory, Czechia
    • Research Site 216
  • Praha 10, Czechia
    • Research Site 217
  • Praha 2, Czechia
    • Research Site 220
  • Praha 4 - Krc, Czechia
    • Research Site 213
  • Praha 5, Czechia
    • Research Site 224
• Estonia
  • Tallinn, Estonia
    • Research Site 231
  • Tartu, Estonia
    • Research Site 232
• Finland
  • Turku, Finland
    • Research Site 491
• France
  • Bron cedex, France
    • Research Site 510
  • Caen cedex 9, France
    • Research Site 509
  • Grenoble cedex 09, France
    • Research Site 502
  • Lille, France
    • Research Site 508
  • Lille cedex, France
    • Research Site 504
  • Montpellier, France
    • Reserach Site 505
  • Nantes cedex 1, France
    • Research Site 511
  • Nice Cedex 1, France
    • Research Site 506
  • Rennes cedex 09, France
    • Research Site 507
  • Rouen Cedex, France
    • Research Site 501
  • Toulouse cedex 9, France
    • Research Site 503
• Georgia
  • Tbilisi, Georgia
    • Research Site 241
  • Tbilisi, Georgia
    • Research Site 242
  • Tbilisi, Georgia
    • Research Site 243
  • Tbilisi, Georgia
    • Research Site 244
  • Tbilisi, Georgia
    • Research Site 245
  • Tbilisi, Georgia
    • Research Site 246
  • Tbilisi, Georgia
    • Research Site 247
  • Tbilisi, Georgia
    • Research Site 248
  • Tbilisi, Georgia
    • Research Site 249
  • Tbilisi, Georgia
    • Research Site 250
• Germany
  • Bamberg, Germany
    • Research Site 265
  • Bayreuth, Germany
    • Research Site 267
  • Berlin, Germany
    • Research Site 271
  • Bochum, Germany
    • Research Site 264
  • Bonn, Germany
    • Research Site 274
  • Erbach, Germany
    • Research Site 270
  • Essen, Germany
    • Research Site 268
  • Frankfurt, Germany
    • Research Site 263
  • Hannover, Germany
    • Research Site 275
  • Mannheim, Germany
    • Research Site 272
  • Muenchen, Germany
    • Research Site 262
  • Muenster, Germany
    • Research Site 266
  • Potsdam, Germany
    • Research Site 261
  • Siegen, Germany
    • Research Site 273
  • Ulm, Germany
    • Research Site 269
• Hong Kong
  • Hong Kong, Hong Kong
    • Research Site 700
  • Hongkong, Hong Kong
    • Research Site 704
  • Shatin, Hong Kong
    • Research Site 701
• Hungary
  • Budapest, Hungary
    • Research Site 282
  • Budapest, Hungary
    • Research Site 285
  • Budapest, Hungary
    • Research Site 286
  • Budapest, Hungary
    • Research Site 288
  • Budapest, Hungary
    • Research Site 290
  • Kistarcsa, Hungary
    • Research Site 281
  • Pecs, Hungary
    • Research Site 284
  • Tatabanya, Hungary
    • Research Site 289
  • Vac, Hungary
    • Research Site 291
• India
  • Hyderabad, India
    • Research Site 457
  • Nashik, India
    • Research Site 456
  • New Delhi, India
    • Research Site 451
• Israel
  • Ashkelon, Israel
    • Research Site 303
  • Jerusalem, Israel
    • Research Site 305
  • Petah Tikva, Israel
    • Research Site 307
  • Ramat Gan, Israel
    • Research Site 308
  • Rechovot, Israel
    • Research Site 301
  • Safed, Israel
    • Research Site 304
• Italy
  • Bologna, Italy
    • Research Site 319
  • Chieti, Italy
    • Research Site 321
  • Genova, Italy
    • Research Site 322
  • Messina, Italy
    • Research Site 320
  • Milano, Italy
    • Research Site 315
  • Montichiari, Italy
    • Research Site 314
  • Napoli, Italy
    • Research Site 316
  • Napoli, Italy
    • Research Site 317
  • Reggio Calabria, Italy
    • Research Site 311
  • Roma, Italy
    • Research Site 318
  • Salerno, Italy
    • Research Site 312
  • Verona, Italy
    • Research Site 313
• Korea, Republic of
  • Goyang-si, Korea, Republic of
    • Research Site 462
  • Seoul, Korea, Republic of
    • Research Site 461
  • Seoul, Korea, Republic of
    • Research Site 463
  • Seoul, Korea, Republic of
    • Research Site 464
  • Seoul, Korea, Republic of
    • Research Site 465
  • Seoul, Korea, Republic of
    • Research Site 466
  • Seoul, Korea, Republic of
    • Research Site 467
• Mexico
  • Aguascalientes, Mexico
    • Research Site 133
  • Culiacan, Mexico
    • Research Site 134
• Netherlands
  • Hoorn, Netherlands
    • Research Site 534
  • Nieuwegein, Netherlands
    • Research Site 531
  • Rotterdam, Netherlands
    • Research Site 535
  • Sittard-Geleen, Netherlands
    • Research Site 532
• Poland
  • Bydgoszcz, Poland
    • Research Site 332
  • Gdansk, Poland
    • Research Site 335
  • Katowice, Poland
    • Research Site 336
  • Knurow, Poland
    • Research Site 340
  • Lodz, Poland
    • Research Site 339
  • Lublin, Poland
    • Research Site 337
  • Oswiecim, Poland
    • Research Site 331
  • Rzeszów, Poland
    • Research Site 338
  • Warszawa, Poland
    • Research Site 341
  • Warszawa, Poland
    • Research Site 342
• Russian Federation
  • Barnaul, Russian Federation
    • Research Site 365
  • Ekaterinburg, Russian Federation
    • Research site 368
  • Kaluga, Russian Federation
    • Research Site 355
  • Kazan, Russian Federation
    • Research Site 358
  • Kirov, Russian Federation
    • Research Site 354
  • Krasnoyarsk, Russian Federation
    • Research Site 363
  • Moscow, Russian Federation
    • Research Site 353
  • Moscow, Russian Federation
    • Research Site 359
  • Nizhniy Novgorod, Russian Federation
    • Research Site 352
  • Perm, Russian Federation
    • Research site 367
  • Pyatigorsk, Russian Federation
    • Research Site 362
  • Saint-Petersburg, Russian Federation
    • Research site 369
  • Saratov, Russian Federation
    • Research Site 360
  • Smolensk, Russian Federation
    • Research Site 361
  • St.Petersburg, Russian Federation
    • Research Site 356
  • Tomsk, Russian Federation
    • Research Site 370
  • Ufa, Russian Federation
    • Research Site 351
  • Ulyanovsk, Russian Federation
    • Research Site 357
  • Yaroslavl, Russian Federation
    • Research Site 366
• Serbia
  • Belgrade, Serbia
    • Research Site 382
  • Belgrade, Serbia
    • Research Site 383
  • Belgrade, Serbia
    • Research Site 385
  • Kragujevac, Serbia
    • Research Site 389
  • Nis, Serbia
    • Research Site 390
  • Novi Sad, Serbia
    • Research Site 388
  • Uzice, Serbia
    • Research Site 384
  • Valjevo, Serbia
    • Research Site 381
• Spain
  • Barcelona, Spain
    • Research Site 406
  • Barcelona, Spain
    • Research Site 407
  • Cadiz, Spain
    • Research Site 405
  • Lleida, Spain
    • Research Site 401
  • Madrid, Spain
    • Research Site 403
  • Madrid, Spain
    • Research Site 408
  • Madrid, Spain
    • Research Site 409
  • Pozuelo de Alarcon, Spain
    • Research Site 411
  • Salt, Spain
    • Research Site 410
  • San Sebastian, Spain
    • Research Site 402
  • Sevilla, Spain
    • Research Site 404
• Taiwan
  • Kaohsiung, Taiwan
    • Research site 713
  • Taichung, Taiwan
    • Research Site 711
  • Taipei, Taiwan
    • Research site 714
  • Taipei, Taiwan
    • Research site 715
• Ukraine
  • Chernivtsi, Ukraine
    • Research Site 432
  • Kharkiv, Ukraine
    • Research Site 425
  • Kharkiv, Ukraine
    • Research Site 429
  • Kharkiv, Ukraine
    • Research Site 430
  • Kharkiv, Ukraine
    • Research Site 435
  • Kharkiv, Ukraine
    • Research Site 436
  • Kharkiv, Ukraine
    • Research Site 437
  • Kropyvnytskyi, Ukraine
    • Research Site 422
  • Kyiv, Ukraine
    • Research Site 438
  • Lviv, Ukraine
    • Research Site 426
  • Odesa, Ukraine
    • Research Site 424
  • Poltava, Ukraine
    • Research Site 423
  • Sumy, Ukraine
    • Research Site 427
  • Vinnytsia, Ukraine
    • Research Site 431
  • Zaporizhzhia, Ukraine
    • Research Site 421
  • Zaporizhzhia, Ukraine
    • Research Site 428
• United Kingdom
  • Exeter, United Kingdom
    • Research Site 544
  • Glasgow, United Kingdom
    • Research Site 549
  • Newcastle, United Kingdom
    • Research Site 552
  • Swansea, United Kingdom
    • Research Site 547
• United States
  • Alabama
    • Mobile, Alabama, United States, 36693-7003
      • Research Site 629
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Research Site 614
    • Phoenix, Arizona, United States, 85018
      • Research Site 677
  • California
    • Long Beach, California, United States, 90806
      • Research Site 642
    • Pasadena, California, United States, 91105
      • Research Site 644
    • San Diego, California, United States, 92121
      • Research Site 672
  • Connecticut
    • Stamford, Connecticut, United States, 06905
      • Research Site 634
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Research Site 656
  • Florida
    • Boca Raton, Florida, United States, 33428
      • Research Site 616
    • Maitland, Florida, United States, 32751
      • Research Site 625
    • Miami, Florida, United States, 33136
      • Research Site 617
    • Ormond Beach, Florida, United States, 32174
      • Research Site 643
    • Saint Petersburg, Florida, United States, 33713
      • Research site 645
    • Tallahassee, Florida, United States, 32308
      • Research Site 652
  • Illinois
    • Elk Grove Village, Illinois, United States, 60007
      • Research Site 621
    • Northbrook, Illinois, United States, 60062
      • Research Site 649
    • Peoria, Illinois, United States, 61637
      • Research Site 675
    • Rolling Meadows, Illinois, United States, 60008
      • Research Site 628
  • Indiana
    • Indianapolis, Indiana, United States, 46256
      • Research Site 624
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Research Site 632
  • Louisiana
    • New Orleans, Louisiana, United States, 70115
      • Research Site 653
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Research Site 623
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Research Site 633
    • Foxboro, Massachusetts, United States, 02035
      • Research Site 639
    • Lawrence, Massachusetts, United States, 01843
      • Research Site 635
    • Worcester, Massachusetts, United States, 01655
      • Research Site 636
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Research Site 613
    • Farmington Hills, Michigan, United States, 48334
      • Research Site 612
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Research Site 638
    • Saint Louis, Missouri, United States, 63131
      • Research Site 664
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Research Site 668
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Research Site 626
  • New Jersey
    • Audubon, New Jersey, United States, 08106
      • Research Site 667
  • New York
    • Patchogue, New York, United States, 11772
      • Research Site 620
  • Ohio
    • Akron, Ohio, United States, 44320
      • Research Site 663
    • Toledo, Ohio, United States, 43614-2598
      • Research Site 630
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Research Site 611
    • Oklahoma City, Oklahoma, United States, 73104
      • Research Site 641
  • Oregon
    • Springfield, Oregon, United States, 97477
      • Research Site 615
  • Pennsylvania
    • Willow Grove, Pennsylvania, United States, 19090
      • Research Site 647
  • Tennessee
    • Knoxville, Tennessee, United States, 37922
      • Research Site 648
    • Nashville, Tennessee, United States, 37205
      • Research Site 627
    • Nashville, Tennessee, United States, 37215
      • Research Site 637
  • Texas
    • Dallas, Texas, United States, 75214
      • Research Site 662
    • Houston, Texas, United States, 77030
      • Research Site 631
    • Lubbock, Texas, United States, 79410
      • Research Site 650
    • Round Rock, Texas, United States, 78681
      • Research Site 619
  • Utah
    • Layton, Utah, United States, 84041
      • Research Site 676
  • Virginia
    • Alexandria, Virginia, United States, 22310
      • Research Site 673
    • Virginia Beach, Virginia, United States, 23456
      • Research Site 654
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226-3596
      • Research Site 651

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 <= 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 and followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in open label extension (OLE) 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 and followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in open label extension (OLE) 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).	From baseline to 172 weeks
Open Label Extension (OLE) Period: Number of Participants With Adverse Events (AEs) and Serious AEs	Adverse event (AE): Any untoward medical occurrence in a participant 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.	From OLE Baseline (DBTP Week 96) to OLE Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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: 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 period)
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.	From baseline to 176 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.	From baseline to 176 weeks
DBTP Period: Neurofilament Light Chain Concentration (NfL) 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.	From baseline to 176 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.	From baseline to 176 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 176 weeks were reported.	From baseline to 176 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 baseline up to 176 weeks was reported.	From baseline to 176 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 176 weeks was reported.	From baseline to 176 weeks
DBTP and DBE Periods: Change From Baseline in Vital Signs: Weight	Changes in vital signs: weight from baseline up to 176 weeks was reported.	From baseline to 176 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 176 weeks was reported.	From baseline to 176 weeks
DBTP and DBE Periods: Change From Baseline in Electrocardiograms (ECGs) Parameter: Heart Rate	Heart rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Changes in ECG parameter: heart rate from baseline up to 176 weeks was reported.	From baseline to 176 weeks
DBTP and DBE Periods: Change From Baseline in Electrocardiograms (ECGs) Parameters: 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 ECG parameter: QT Interval - Fridericia's Correction Formula, PR Interval and QRS Duration from baseline up to 176 weeks were reported.	From baseline to 176 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 176 weeks were reported.	From baseline to 176 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 176 weeks were reported.	From baseline to 176 weeks
DBTP and DBE Periods: Change From Baseline in Hematology Parameter: 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 176 weeks was reported.	From baseline to 176 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 176 weeks was reported.	From baseline to 176 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 176 weeks was reported.	From baseline to 176 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 176 weeks were reported.	From baseline to 176 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 176 weeks were reported.	From baseline to 176 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 176 weeks were reported.	From baseline to 176 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 176 weeks were reported.	From baseline to 176 weeks
DBTP and DBE Periods: Change From Baseline in Biochemistry Parameter: 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 176 weeks was reported. The Glomerular Filtration Rate will be measured as milliliter per minute per 1.73 square meter (mL/min/1.73m^2).	From baseline to 176 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 176 weeks was reported.	From baseline to 176 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 176 weeks was reported.	From baseline to 176 weeks
DBTP and DBE Periods: Absolute Concentrations of Immunoglobulin (Ig) Levels	Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.	At Week 176
DBTP and DBE Periods: Change From Baseline in Immunoglobulin (Ig) Levels	Change from baseline serum levels of IgG, IgA, IgM were assessed.	Baseline to 176 weeks
OLE 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, AEs, and preceded by a stable or improving neurological state for more than or equal to [>=] 30 days).	From OLE baseline (DBTP Week 96) to OLE Week 52
OLE 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).	From OLE baseline (DBTP Week 96) to OLE Week 52
OLE 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).	From OLE baseline (DBTP Week 96) to OLE Week 52
OLE Period: Symbol Digit Modalities Test (SDMT)	The SDMT is a test of information processing speed. It consists of 9 abstract symbols. Each symbol is paired with a single digit. The participant is provided with a "key", showing each symbol digit pair. In addition, the participants are shown several rows of the 9 symbols, which are arranged pseudo-randomly, without the digit. Participants 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. Participant wise data was reported for this outcome measure.	Assessed from OLE baseline to OLE Week 96; OLE Week 48 were reported for Participants 1 and 2 and OLE Week 12 were reported for Participant 3
OLE Period: Change From Baseline in PROMISnq Physical Function (PF) Multiple Sclerosis (MS) 15a at Week 52	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 ranges from 10 to 65. Higher T-scores represent higher physical function. Participant wise data was reported for this outcome measure.	OLE Baseline (DBTP Week 96), OLE Week 52
OLE Period: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue (MS) 8a Score at Week 52	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 general, T-scores have a mean of 50, standard deviation of 10, and range from 33 to 85. Higher T-scores represent higher fatigue. Participant wise data was reported for this outcome measure.	OLE baseline (DBTP Week 96), OLE Week 52
OLE Period: Number of Participants With Abnormalities in Laboratory Parameters	Laboratory investigation included hematology, biochemistry and coagulation. The number of participants with abnormalities in laboratory parameters were reported.	From OLE baseline (DBTP Week 96) to OLE Week 52
OLE Period: Number of Participants With Abnormalities in Vital Signs	Vital signs included temperature, pulse rate, respiration rate and blood pressure and weight (taken after 5 minutes in the sitting position). The number of participants with abnormalities in vital signs were reported.	From OLE baseline (DBTP Week 96) to OLE Week 52
OLE Period: Number of Participants With Abnormalities in Electrocardiograms (ECGs) Findings	ECG recordings included, heart rate, PR interval and QRS duration. ECG recordings were obtained after the participants have rested for at least 5 minutes in supine position. The number of participants with abnormalities in ECG findings were reported.	From OLE baseline (DBTP Week 96) to OLE Week 52
OLE Period: Number of New or Enlarging T2 Lesions	Analysis of number of new or enlarging T2 lesions 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. Participant wise data was reported for this outcome measure.	From OLE baseline (DBTP Week 96) to OLE Week 52
OLE Period: Change From Baseline in T2 Lesion Volume	Change from baseline in T2 lesion volume was reported. Participant wise data was reported for this outcome measure.	From OLE baseline (DBTP Week 96) to OLE Week 52

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): June 12, 2020
• Primary Completion (Actual): October 2, 2023
• Study Completion (Actual): March 8, 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): June 12, 2025
• Last Update Submitted That Met QC Criteria: May 26, 2025
• Last Verified: May 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_0080; 2019-004972-20 (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