Study of Evobrutinib in Participants With RMS (evolutionRMS 1)

Relapsing Multiple Sclerosis Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04338022
• Other study ID #: MS200527_0080
• Secondary ID: 2019-004972-20
• Status: Terminated
• Phase: Phase 3
• Start date: June 12, 2020
• Est. completion date: March 8, 2024

Study information

• Verified date: April 2024
• Source: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1124
• Est. completion date: March 8, 2024
• Est. primary completion date: October 2, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Multiple Sclerosis
• Relapsing Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Evobrutinib
Evobrutinib twice daily (BID) in DBTP.
• Placebo (match to Teriflunomide)
Placebo match to Teriflunomide once daily in DBTP.
• Teriflunomide
Teriflunomide once daily in DBTP.
• Placebo (match to Evobrutinib)
Placebo match to Evobrutinib BID in DBTP.

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany	EMD Serono Research & Development Institute, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Bosnia and Herzegovina,  Bulgaria,  Canada,  Colombia,  Croatia,  Czechia,  Estonia,  Finland,  France,  Georgia,  Germany,  Hong Kong,  Hungary,  India,  Israel,  Italy,  Korea, Republic of,  Mexico,  Netherlands,  Poland,  Russian Federation,  Serbia,  Spain,  Taiwan,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	DBTP: Annualized Relapse Rate (ARR)	The annualized relapse rates up to 156 weeks will be calculated based on qualified relapses. Qualifying relapse is defined as occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis (MS) (for more than 24 hours, no fever, infection, injury, adverse events, and preceded by a stable or improving neurological state for greater than or equal to (=>) 30 days).	Up to 156 weeks
Primary	DBE Period: ARR	The annualized relapse rates up to 96 weeks will be calculated based on qualified relapses. Qualifying relapse is defined as occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis (MS) (for more than 24 hours, no fever, infection, injury, adverse events, and preceded by a stable or improving neurological state for greater than or equal to (=>) 30 days).	Up to 96 weeks
Primary	OLE Period: Number of Participants with Adverse Events and Serious Adverse Events (SAE)s		Baseline OLE up to 96 weeks
Secondary	DBTP: Time to First Occurrence of 12-Week Confirmed Disability Progression (CDP) as measured by Expanded Disability Status Scale (EDSS) Progression		Up to 156 weeks
Secondary	DBTP: Time to First Occurrence of 24-Week CDP as measured by EDSS Progression		Up to 156 weeks
Secondary	DBTP: Time to First Occurrence of 24-Week Confirmed Disability Improvement (CDI) as measured by EDSS Improvement		Up to 156 weeks
Secondary	DBTP: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) MS Physical Function (PF) Short Form Score		Baseline up to 96 weeks
Secondary	DBTP: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) MS Fatigue Short Form Score		Baseline up to 96 weeks
Secondary	DBTP: Total Number of Gadolinium-Enhancing (Gd+) T1 Lesions Assessed by all Available Magnetic Resonance Imaging (MRI) Scans		Up to Week 156
Secondary	DBTP: Total Number of New or Enlarging T2 Lesions Assessed by the Last Available Magnetic Resonance Imaging (MRI) Scan Relative to Baseline MRI Scan		Up to Week 156
Secondary	DBTP: Neurofilament light chain (NfL) Serum Concentration		At Week 12
Secondary	DBTP: Number of Participants With Adverse Events (AEs) and Adverse Events of Special Interest (AESIs)	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment.	Baseline up to 156 weeks
Secondary	DBTP: Number of Participants With Clinically Significant Change From Baseline in Vital Signs, Laboratory Parameters and Electrocardiogram Findings	Number of participants with clinically significant change from baseline in vital signs, laboratory parameters and electrocardiogram findings will be reported.	Baseline up to 156 weeks
Secondary	DBTP: Absolute Concentrations of Immunoglobulin (Ig) Levels		Baseline up to 156 weeks
Secondary	DBTP: Change From Baseline in Immunoglobulin (Ig) Levels		Baseline up to 156 weeks
Secondary	DBE Period: Time to First Occurrence of 12-Week CDP as measured by EDSS Progression		Up to 96 weeks
Secondary	DBE Period: Time to First Occurrence of 24-Week CDP as measured by EDSS Progression		Up to 96 weeks
Secondary	DBE Period: Time to First Occurrence of 24-Week CDI as measured by EDSS Improvement		Up to 96 weeks
Secondary	DBE Period: Change From Baseline in PROMIS MS PF Short Form Score		Baseline up to 96 weeks
Secondary	DBE Period: Change From Baseline in PROMIS MS Fatigue Short Form Score		Baseline up to 96 weeks
Secondary	DBE Period: Total Number of Gd+ T1 Lesions Assessed by all Available MRI Scans		Up to Week 96
Secondary	DBE Period: Total Number of New or Enlarging T2 Lesions Assessed on the Last Available MRI Scans Relative to Baseline MRI Scan		Up to Week 96
Secondary	DBE Period: Number of Participants With Adverse Events (AEs) and Adverse Events of Special Interest (AESIs)	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment.	Baseline up to 96 weeks
Secondary	DBE Period: Number of Participants With Clinically Significant Change From Baseline in Vital Signs, Laboratory Parameters and Electrocardiogram Findings	Number of participants with clinically significant change from baseline in vital signs, laboratory parameters and electrocardiogram findings will be reported.	Baseline up to 96 weeks
Secondary	DBE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels		Baseline up to 96 weeks
Secondary	DBE Period: Change From Baseline in Immunoglobulin (Ig) Levels		Baseline up to 96 weeks
Secondary	OLE Period: ARR based on protocol-defined qualified relapses		Baseline OLE up to 96 weeks
Secondary	OLE Period: Time to first occurrence of 24-week CDP as measured by EDSS		Baseline OLE up to 96 weeks
Secondary	OLE Period: Time to first occurrence of 24-week CDI as measured by EDSS		Baseline OLE up to 96 weeks
Secondary	OLE Period: Symbol Digital Modalities Test Over time		Baseline OLE up to 96 weeks
Secondary	OLE Period: PROMISnq PF (MS) 15a score change over time		Baseline OLE up to 96 weeks
Secondary	OLE Period: PROMIS Fatigue (MS) 8a Score Change Over Time		Baseline OLE up to 96 weeks
Secondary	OLE Period: Number of Participants With Clinically Significant Change From Baseline in Vital Signs, Electrocardiogram (ECG) and Laboratory Findings		Baseline OLE up to 96 weeks
Secondary	OLE: Total Number of New or Enlarging T2 Lesions Assessed on the Last Available Magnetic Resonance Imaging (MRI) Scans		Baseline OLE up to 96 weeks
Secondary	OLE: Change from Baseline in T2 lesion Volume Over Time		Baseline OLE up to 96 weeks

External Links

•   Trial Awareness and Transparency website