Study of Evobrutinib in Participants With RMS (evolutionRMS 2)

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 2)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04338061
• Other study ID #: MS200527_0082
• Secondary ID: 2019-004980-36
• Status: Terminated
• Phase: Phase 3
• Start date: July 2, 2020
• Est. completion date: March 19, 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 19, 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
Belarus	Research Site 144	Gomel
Belarus	Research Site 143	Grodno
Belarus	Research Site 142	Minsk
Belarus	Research Site 141	Vitebsk
Belarus	Research Site 145	Vitebsk
Brazil	Research Site 603	Belo Horizonte
Brazil	Research Site 599	Curitiba
Brazil	Research Site 604	Goiânia
Brazil	Research Site 600	Joinville
Brazil	Research Site 614	Passo Fundo
Brazil	Research Site 591	Porto Alegre
Brazil	Research Site 594	Porto Alegre
Brazil	Research Site 596	Porto Alegre
Brazil	Research Site 609	Vitória
Bulgaria	Research Site 155	Blagoevgrad
Bulgaria	Research Site 156	Dupnitsa
Bulgaria	Research Site 157	Pleven
Bulgaria	Research Site 801	Pleven
Bulgaria	Research Site 804	Pleven
Bulgaria	Research Site 805	Plovdiv
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	Sofia
Bulgaria	Research Site 154	Veliko Tarnovo
Canada	Research Site 106	Burnaby
Canada	Research Site 107	London
Canada	Research Site 105	Montreal
Canada	Research Site 101	Ottawa
France	Research Site 455	Bordeaux Cedex
France	Research Site 459	Brest cedex 2
France	Reserach Site 451	Clermont Ferrand Cedex
France	Research Site 458	Limoges cedex
France	Research Site 456	Nimes
France	Research Site 453	Paris
France	Research Site 457	Pringy cedex
France	Research Site 452	Strasbourg cedex
France	Research Site 454	Tours cedex 9
Germany	Research Site 172	Augsburg
Germany	Research Site 177	Berlin
Germany	Research Site 180	Berlin
Germany	Research Site 178	Bonn
Germany	Research Site 184	Dresden
Germany	Research Site 174	Hamburg
Germany	Research Site 182	Heidelberg
Germany	Research Site 179	Koeln
Germany	Research Site 181	Leipzig
Germany	Research Site 173	Mainz
Germany	Research Site 176	Minden
Germany	Research Site 171	Regensburg
Germany	Research Site 183	Rostock
Germany	Research Site 175	Tuebingen
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	Athens
Greece	Research Site 198	Heraklion
Greece	Research Site 204	Ioannina
Greece	Research Site 192	Larissa
Greece	Research Site 199	Marousi
Greece	Research Site 203	Patra
Greece	Research Site 191	Patras
Greece	Research Site 195	Thessaloniki
India	Research Site 445	Ahmedabad
India	Research Site 444	Bangalore
India	Research Site 443	Mangalore
India	Research Site 442	New Delhi
Italy	Research Site 218	Bari
Italy	Research Site 216	Catania
Italy	Research Site 214	Cefalù
Italy	Research Site 219	Firenze
Italy	Research Site 221	Milano
Italy	Research Site 211	Napoli
Italy	Research Site 215	Napoli
Italy	Research Site 220	Orbassano
Italy	Research Site 217	Palermo
Italy	Research Site 212	Pozzilli
Italy	Research Site 213	Roma
Italy	Research Site 222	Roma
Latvia	Research Site 231	Riga
Latvia	Research Site 232	Riga
Latvia	Research Site 233	Riga
Lithuania	Research site 241	Kaunas
Lithuania	Research site 244	Klaipeda
Lithuania	Research site 243	Siauliai
Lithuania	Research site 242	Vilnius
Malaysia	Research Site 551	Kuala Lumpur
Malaysia	Research Site 554	Kuala Lumpur
Malaysia	Research Site 556	Kuala Lumpur
Malaysia	Research Site 552	Kuching
Malaysia	Research Site 553	Seberang Jaya
Moldova, Republic of	Research Site 251	Chisinau
Moldova, Republic of	Research Site 252	Chisinau
Norway	Research Site 481	Bergen
Norway	Research site 483	Drammen
Norway	Research Site 482	Namsos
Philippines	Research Site 562	Baguio City
Philippines	Research Site 561	Cebu City
Poland	Reserach Site 267	Bydgoszcz
Poland	Reserach Site 268	Bydgoszcz
Poland	Research Site 273	Katowice
Poland	Research site 846	Katowice
Poland	Research site 274	Katowice-Ochojec
Poland	Research Site 276	Krakow
Poland	Research Site 263	Lodz
Poland	Research Site 272	Lódz
Poland	Research Site 266	Nowa Sol
Poland	Research Site 270	Poznan
Poland	Research Site 262	Rzeszow
Poland	Research Site 265	Siemianowice
Poland	Research Site 271	Szczecin
Poland	Research Site 264	Warszawa
Poland	Research Site 277	Warszawa
Poland	Reserach Site 275	Warszawa
Poland	Research Site 261	Zabrze
Poland	Research Site 278	Zamosc
Portugal	Research Site 293	Aveiro
Portugal	Research Site 282	Braga
Portugal	Research Site 289	Coimbra
Portugal	Research Site 281	Lisboa
Portugal	Research Site 283	Lisboa
Portugal	Research Site 287	Lisboa
Portugal	Research SIte 284	Matosinhos
Portugal	Research Site 292	Porto
Portugal	Research Site 288	Pragal
Portugal	Research Site 291	Santa Maria da Feira
Portugal	Research Site 286	Torres Vedras
Puerto Rico	Research Site 791	Guaynabo
Romania	Research Site 314	Brasov
Romania	Research Site 307	Bucure?ti
Romania	Research Site 309	Caracal
Romania	Research Site 302	Targu Mures
Russian Federation	Research Site 325	Kazan
Russian Federation	Research Site 329	Kazan
Russian Federation	Research Site 323	Kemerovo
Russian Federation	Research Site 344	Kirov
Russian Federation	Research Site 340	Krasnodar
Russian Federation	Research Site 334	Krasnoyarsk
Russian Federation	Research Site 341	Moscow
Russian Federation	Research Site 343	Moscow
Russian Federation	Research Site 345	Moscow
Russian Federation	Research Site 332	Nizhniy Novgorod
Russian Federation	Research Site 327	Novosibirsk
Russian Federation	Research Site 330	Novosibirsk
Russian Federation	Research Site 331	Novosibirsk
Russian Federation	Research Site 335	Novosibirsk
Russian Federation	Research Site 328	Rostov-on-Don
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	Saint-Petersburg
Russian Federation	Research Site 326	Saransk
Russian Federation	Research Site 321	Sestroretsk
Russian Federation	Research Site 337	Tyumen
Saudi Arabia	Research Site 493	Riyadh
Singapore	Research Site 571	Singapore
Singapore	Research site 572	Singapore
Slovakia	Research Site 351	Banska Bystrica
Slovakia	Research Site 352	Bratislava
Slovakia	Research Site 353	Bratislava
Slovakia	Research Site 354	Bratislava
Slovakia	Research Site 356	Bratislava
Slovakia	Research Site 359	Dubnica nad Vahom
Slovakia	Research Site 358	Trencin
Slovakia	Research Site 357	Trnava
Slovenia	Research Site 373	Celje
Slovenia	Research Site 372	Ljubljana
Slovenia	Research Site 371	Maribor
South Africa	Research Site 501	Cape Town
South Africa	Research Site 502	Cape Town
South Africa	Research Site 503	Cape Town
South Africa	Research Site 504	Pretoria
Spain	Research Site 384	Alcorcon
Spain	Research Site 391	Barakaldo
Spain	Research Site 390	Barcelona
Spain	Research Site 382	Cordoba
Spain	Research Site 389	El Palmar
Spain	Research Site 388	Madrid
Spain	Research Site 392	Majadahonda
Spain	Research Site 383	Malaga
Spain	Research Site 387	Sevilla
Spain	Research Site 385	Valencia
Spain	Research Site 386	Valencia
Spain	Research Site 381	Vigo
Sweden	Research Site 512	Göteborg
Sweden	Research site 514	Malmö
Sweden	Research Site 511	Stockholm
Sweden	Research Site 513	Uppsala
Switzerland	Research Site 404	Aarau
Switzerland	Research Site 402	Bern
Switzerland	Research Site 403	Lugano
Thailand	Research Site 583	Bangkoknoi
Thailand	Research Site 582	Muang
Turkey	Research Site 538	Ankara
Turkey	Research Site 544	Ankara
Turkey	Research Site 531	Istanbul
Turkey	Research Site 534	Istanbul
Turkey	Research Site 536	Istanbul
Turkey	Research Site 541	Istanbul
Turkey	Research Site 543	Istanbul
Turkey	Research Site 539	Izmir
Turkey	Research Site 533	Kocaeli
Turkey	Research Site 537	Konya
Turkey	Research Site 540	Mersin
Turkey	Research Site 535	Samsun
Turkey	Research Site 532	Trabzon
Ukraine	Research Site 415	Chernihiv
Ukraine	Research Site 417	Chernihiv
Ukraine	Research Site 414	Dnipro
Ukraine	Research Site 416	Dnipro
Ukraine	Research Site 420	Dnipro
Ukraine	Research Site 413	Ivano-Frankivsk
Ukraine	Research Site 624	Kharkiv
Ukraine	Research Site 632	Kharkiv
Ukraine	Research Site 633	Kharkiv
Ukraine	Research Site 419	Kherson
Ukraine	Research Site 411	Kyiv
Ukraine	Research Site 418	Kyiv
Ukraine	Research Site 629	Lutsk
Ukraine	Research Site 627	Lviv
Ukraine	Research Site 622	Poltava
Ukraine	Research Site 625	Rivne
Ukraine	Research Site 628	Ternopil
Ukraine	Research Site 630	Uzhgorod
Ukraine	Research Site 623	Vinnytsia
Ukraine	Research Site 412	Zaporizhzhia
Ukraine	Research Site 621	Zaporizhzhia
Ukraine	Research Site 631	Zaporizhzhia
Ukraine	Research Site 626	Zhytomyr
United States	Research Site 746	Altamonte Springs	Florida
United States	Research Site 724	Amherst	New York
United States	Research Site 736	Asheville	North Carolina
United States	Research Site 711	Canton	Ohio
United States	Research Site 712	Chapel Hill	North Carolina
United States	Research Site 759	Colorado Springs	Colorado
United States	Research Site 757	Columbus	Ohio
United States	Research Site 752	Cullman	Alabama
United States	Research Site 734	Dayton	Ohio
United States	Research Site 738	Detroit	Michigan
United States	Research Site 715	Evanston	Illinois
United States	Research Site 725	Fort Collins	Colorado
United States	Research Site 714	Fort Wayne	Indiana
United States	Research Site 751	Hanford	California
United States	Research Site 742	Honolulu	Hawaii
United States	Research Site 718	Jacksonville	Florida
United States	Research Site 744	Lafayette	Indiana
United States	Research Site 702	Naples	Florida
United States	Research Site 735	Nicholasville	Kentucky
United States	Research Site 721	Norfolk	Virginia
United States	Research Site 740	Orlando	Florida
United States	Research Site 717	Overland Park	Kansas
United States	Research Site 748	Philadelphia	Pennsylvania
United States	Research Site 726	Port Charlotte	Florida
United States	Research Site 723	Saint Louis	Missouri
United States	Research Site 703	San Antonio	Texas
United States	Research Site 719	Sarasota	Florida
United States	Research Site 706	Scarborough	Maine
United States	Research Site 741	Scottsdale	Arizona
United States	Research Site 707	Tampa	Florida
United States	Research Site 743	Tampa	Florida
United States	Research Site 704	Tucson	Arizona
United States	Research Site 732	Vero Beach	Florida
United States	Research Site 705	Weeki Wachee	Florida
United States	Research Site 737	West Hollywood	California
United States	Research Site 753	West Palm Beach	Florida
United States	Research Site 728	Winston-Salem	North Carolina

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,  Belarus,  Brazil,  Bulgaria,  Canada,  France,  Germany,  Greece,  India,  Italy,  Latvia,  Lithuania,  Malaysia,  Moldova, Republic of,  Norway,  Philippines,  Poland,  Portugal,  Puerto Rico,  Romania,  Russian Federation,  Saudi Arabia,  Singapore,  Slovakia,  Slovenia,  South Africa,  Spain,  Sweden,  Switzerland,  Thailand,  Turkey,  Ukraine, 

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