Evobrutinib compared to Teriflunomide in participants with Relapsing Multiple Sclerosis

• Register: EUCTR
• Last refreshed on: 3 June 2024
• Main ID: EUCTR2019-004980-36-BG
• Date of registration: 19/06/2020
• Prospective Registration: Yes
• Primary sponsor: Merck Healthcare KGaA
• Public title: Evobrutinib compared to Teriflunomide in participants with Relapsing Multiple Sclerosis
• Scientific 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. - Phase III Study of Evobrutinib in RMS (EVOLUTION RMS 2)
• Date of first enrolment: 12/10/2020
• Target sample size: 930
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-004980-36
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: Active comparator (Aubagio), double-dummy If controlled, specify comparator, Other Medicinial Product: yes Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

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

Contacts

• Name: Communication Center
• Affiliation: Merck Healthcare KGaA

• Name: Communication Center
• Affiliation: Merck Healthcare KGaA

Key inclusion & exclusion criteria

Inclusion criteria:
For DBTP:
- 18 years to 55 years female and male participants
- 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
- 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.
For DBE period:
- Participants need to be able and willing to provide written informed
consent for the DBE period before the first procedure in DBE.
- Participant does not fulfill any permanent discontinuation criteria
based on Week 156/EODBTP assessments.
For OLE period:
- participants have completed the DBE Period, or are still under study
treatment when enrollment into OLE is opened - but not into the longterm
follow-up study -,and who, in the opinion of the Investigator, may
benefit from treatment with evobrutinib.
- participants are able and willing to provide written informed consent
for the OLE period (e.g., before the first OLE procedure on OLE Day 1)
and to comply with the study protocol.
- participants have documentation of completed AEP (confirmed blood
concentration level of < 0.02 µg/mL of teriflunomide as defined in
protocol) before Day 1/Baseline visit (applicable to all participants
previously treated with teriflunomide, or with an unknown exposure
status during the DBTP and DBE period).
- Women of childbearing potential are willing to continue to use the
contraceptive methods as described in protocol
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 930
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
For DBTP:
- 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.
- 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.
For OLE period:
- Participants who did not complete study intervention in DBE period.
- Treatment with injectable (e.g., IV, intramuscular, intra-articular) or
oral glucocorticoids, or ACTH (e.g., Acthar gel) within 30 days before
OLE Day 1, with the exception of rescue treatment for MS relapse
specified by the study protocol.
- History of suicidal ideation or an episode of clinically severe depression
(as determined by the Investigator) within 12 weeks prior to OLE Day 1.
- History of abnormal laboratory results that, in the opinion of the
Investigator, are indicative of a significant cardiac, endocrine,
hematologic, immunologic, metabolic urologic, pulmonary,
gastrointestinal, dermatologic, psychiatric, renal, neurologic (other than
MS), and/or other major diseases.
- Any of the following abnormal blood tests during the DBE Period
requiring discontinuation of study intervention, and/or at End of DBE
visit, with a week before OLE Day 1: ALT/serum glutamate pyruvate
transaminase, AST/serum glutamic oxaloacetic transaminase, Total
Bilirubin, amylase, or lipase, eGFR.
- Female participants who have a positive pregnancy test result, are
pregnant, or are currently breast feeding.
- Inability to comply with study requirements.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Relapsing Multiple Sclerosis
MedDRA version: 20.0 Level: PT Classification code 10048393 Term: Multiple sclerosis relapse System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 21.1 Level: PT Classification code 10063399 Term: Relapsing-remitting multiple sclerosis System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

Product Name: Evobrutinib
Product Code: M2951
Pharmaceutical Form: Tablet
INN or Proposed INN: EVOBRUTINIB
CAS Number: 1415823-73-2
Current Sponsor code: M2951
Other descriptive name: MSC2364447C
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 45-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Trade Name: Aubagio
Product Name: Aubagio
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: TERIFLUNOMIDE
CAS Number: 108605-62-5
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 14-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: DBTP-to demonstrate the efficacy of evobrutinib relative to that of Teriflunomide: a.on disability progression (DP); b.on disability improvement; c.on patient reported symptoms and functional status; d.on magnetic resonance imaging (MRI) lesion parameters; e.by evaluating response on Neurofilament light chain (NfL) concentrations in serum; and f.to characterize the safety and tolerability of evobrutinib.
DBE Period-to further evaluate the efficacy of evobrutinib relative to that of teriflunomide: a.on DP; b.on disability improvement; c.on patient reported symptoms and functional status; d.on MRI lesion parameters; and e.to further characterize the safety and tolerability of evobrutinib.
OLE Period-to evaluate the long-term efficacy of evobrutinib 45mg BID: a.in participants with RMS; b.in participants with RMS on patient reported symptoms and functional status; c.to further evaluate the longterm safety and tolerability of evobrutinib 45mg BID in participants with RMS over time.

Main Objective: For the Double-blind Treatment Period (DBTP): To demonstrate superior efficacy with evobrutinib compared to Teriflunomide in terms of Annualized Relapse Rate (ARR)
For the the Double-Blind Extension (DBE) Period: To further evaluate the
efficacy with evobrutinib compared to teriflunomide in terms of
Annualized Relapse Rate (ARR)
For the Open Label Extension (OLE) Period: To evaluate the long-term safety and tolerability of evobrutinib 45 mg twice daily (BID) in participants with Relapsing Multiple Sclerosis (RMS) over time

Primary end point(s): For DBTP: ARR based on qualified relapses at up to 156 weeks in participants with RMS
For DBE Period: ARR based on qualified relapses in participants with RMS
For OLE period: Occurrence of AEs and SAEs

Timepoint(s) of evaluation of this end point: For DBTP: up to 156 weeks
For DBE Period: up to 96 weeks
For OLE period: Entire OLE duration

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: For DBTP:
a. 12 week up to 156 weeks
b.c. 24-week up to 156 weeks
d.e. over 96 weeks
f: Total number of T1 Gd+ lesions based on all available MRI scans
g. Number of new or enlarging T2 lesions on the last available MRI scan relative to the baseline MRI scan
h. at 12 weeks
i. end of the Safety Follow-up period
For DBE period:
a. at 12 weeks
b., c. at 24 weeks
d., e., f., g., h. for up to 96 weeks
For OLE period:
a., d., e., f., g. for up to 96 weeks
b., c. 24-weeks

Secondary end point(s): For DBTP:
a. Time to first occurrence of 12-week confirmed disability progression (CDP) as measured by the Expanded Disability Status Scale (EDSS) up to 156 weeks
b. Time to first occurrence of 24-week CDP as measured by EDSS up to 156 weeks
c. Time to first occurrence of 24-week Confirmed Disability Improvement (CDI) as measured by the EDSS up to 156 weeks
d. Change from Baseline (CFB) in Patient Reported Outcomes Measurement Information System [PROMIS] PF score over 96 weeks
e. CFB in PROMIS Fatigue score over 96 weeks
f. Total number of T1 Gd+ lesions on all available MRI scans
g. Number of new or enlarging T2 lesions on the last available MRI scan relative to the baseline MRI scan
h. NfL concentration at 12 weeks
g. Safety as assessed by the nature, severity, and occurrence of adverse events (AEs) and adverse events of special interest (AESIs); vital signs; electrocardiograms (ECGs); absolute concentrations and change from Baseline in immunoglobulin (Ig) levels; and clinical laboratory safety parameters up to the end of the Safety Follow-up period
For DBE Period:
a. Time to first occurrence of 12-week CDP as measured by EDSS
b. Time to first occurrence of 24-week CDP as measured by EDSS
c. Time to first occurrence of 24-week CDP as measured by the EDSS
d. CFB in PROMIS PF score over time
e. CFB in PROMIS Fatigue score over time
f. Total number of T1 Gd+ lesions based on all available MRI scans
g. Number of new or enlarging T2 lesions on the last available MRI scan
relative to the baseline MRI scan
h. Safety as assessed by the nature, severity, and occurrence of AEs and
AESIs; vital signs; ECGs; absolute concentrations and CFB in Ig levels;
and clinical laboratory safety parameters up to the end of the Safety
Follow-up period.
For OLE period:
a. ARR based on protocol defined qualified relapses
b. Time to first occurrence of 24-week CDP as measured by EDSS
c. Time to first occurrence of 24-week CDI as measured by EDSS
d. SDMT over time
e. PROMISnq PF (MS) 15a score change over time
f. PROMIS Fatigue (MS) 8a score change over time
g. Safety Laboratory Parameters including Blood Chemistry, Hematology, Coagulation, Vitals, ECGs

Secondary ID(s)

Evolution RMS 2

MS200527_0082

2019-004980-36-PT

Source(s) of Monetary Support

Merck Healthcare KGaA

Ethics review

Status: Approved
Approval date: 12/10/2020
Contact: