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NCT04338061

Study of Evobrutinib in Participants With RMS (evolutionRMS 2)

Terminated Phase 3 Results posted Last updated 21 March 2025
What this trial tests

Phase 3 trial testing Teriflunomide in Relapsing Multiple Sclerosis in 1,166 participants. Terminated before completion.

Timeline
2 July 2020
Primary endpoint
2 October 2023
19 March 2024

Quick facts

Lead sponsorMerck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
PhasePhase 3
StatusTerminated
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment1,166
Start date2 July 2020
Primary completion2 October 2023
Estimated completion19 March 2024
Sites278 locations across Italy, Malaysia, Poland, Philippines, Russia, Sweden, Lithuania, Bulgaria

Drugs / interventions tested

Conditions studied

Sponsor

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany — full company profile →

Who can join

Adults 18 to 55, any sex, with Relapsing Multiple Sclerosis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Double Blind Treatment Period (DBTP) and Double Blind Extension (DBE) Period: Annualized Relapse Rate (ARR) Primary · Baseline up to 170 weeks

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).

GroupValue95% CI
Teriflunomide0.110.09 – 0.13
Evobrutinib0.110.09 – 0.13
DBTP and DBE Period: Percentage of Participants Without 12-Week Confirmed Disability Progression (CDP) as Measured by Expanded Disability Status Scale (EDSS) Secondary · Week 96 and Week 156 (combined DBTP and DBE periods)

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 particip

Week 96
GroupValue95% CI
Teriflunomide88.985.7 – 91.4
Evobrutinib91.888.9 – 93.9
Week 156
GroupValue95% CI
Teriflunomide82.376.0 – 87.1
Evobrutinib85.077.8 – 90.0
DBTP and DBE Period: Percentage of Participants Without 24-Week Confirmed Disability Progression (CDP) as Measured by Expanded Disability Status Scale (EDSS) Secondary · Week 96 and Week 156 (combined DBTP and DBE periods)

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 particip

Week 96
GroupValue95% CI
Teriflunomide91.688.7 – 93.8
Evobrutinib93.691.0 – 95.5
Week 156
GroupValue95% CI
Teriflunomide89.786.5 – 92.2
Evobrutinib90.987.8 – 93.3
DBTP and DBE Period: Percentage of Participants With 24-Week Confirmed Disability Improvement (CDI) as Measured by Expanded Disability Status Scale (EDSS) Secondary · Week 96 and Week 156 (combined DBTP and DBE periods)

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 wit

Week 96
GroupValue95% CI
Teriflunomide11.48.6 – 15.0
Evobrutinib7.65.4 – 10.7
Week 156
GroupValue95% CI
Teriflunomide12.59.5 – 16.4
Evobrutinib8.46.0 – 11.6
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 Secondary · Baseline, Week 48, Week 96, Week 120, Week 144 and Week 156 (Combined DBTP and DBE periods)

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)

Week 48
GroupValue95% CI
Teriflunomide0.25-0.22 – 0.72
Evobrutinib0.31-0.16 – 0.78
Week 96
GroupValue95% CI
Teriflunomide-0.31-0.88 – 0.26
Evobrutinib-0.45-1.03 – 0.13
Week 120
GroupValue95% CI
Teriflunomide-0.56-1.23 – 0.11
Evobrutinib-0.19-0.86 – 0.48
Week 144
GroupValue95% CI
Teriflunomide-0.38-1.12 – 0.35
Evobrutinib-0.57-1.31 – 0.17
Week 156
GroupValue95% CI
TeriflunomideNANA – NA
EvobrutinibNANA – NA
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 Secondary · Baseline, Week 48, Week 96, Week 120, Week 144 and Week 156 ((combined DBTP and DBE periods)

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).

Week 48
GroupValue95% CI
Teriflunomide-2.20-2.81 – -1.60
Evobrutinib-2.59-3.19 – -1.98
Week 96
GroupValue95% CI
Teriflunomide-2.17-2.85 – -1.49
Evobrutinib-2.12-2.81 – -1.44
Week 120
GroupValue95% CI
Teriflunomide-2.24-3.00 – -1.48
Evobrutinib-2.59-3.35 – -1.83
Week 144
GroupValue95% CI
Teriflunomide-2.41-3.35 – -1.48
Evobrutinib-2.16-3.10 – -1.22
Week 156
GroupValue95% CI
Teriflunomide-2.21-3.62 – -0.81
Evobrutinib-2.34-3.83 – -0.86
DBTP and DBE Period: Total Number of T1 Gadolinium-positive (Gd+) Lesions Secondary · Baseline up to 170 weeks

Analysis of Gadolinium-positive T1 lesions was done using magnetic resonance imaging (MRI) scans.

GroupValue95% CI
Teriflunomide0.290.24 – 0.34
Evobrutinib0.510.43 – 0.60
DBTP and DBE Period: New or Enlarging T2 Lesions Rate Secondary · Baseline up to 170 weeks

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.

GroupValue95% CI
Teriflunomide6.886.01 – 7.87
Evobrutinib6.175.38 – 7.07
DBTP Period: Neurofilament Light Chain (NfL) Concentration at Week 12 Secondary · Week 12

NfL is a biomarker of neuro-axonal damage whose concentration was assessed in blood at Week 12.

GroupValue95% CI
Teriflunomide13.0912.69 – 13.50
Evobrutinib12.5112.13 – 12.90
DBTP and DBE Periods: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Adverse Events of Special Interest (AESIs) Secondary · Baseline up to 170 weeks

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. TEA

Participants with TEAEs
GroupValue95% CI
Teriflunomide524
Evobrutinib508
Participants with AESIs
GroupValue95% CI
Teriflunomide144
Evobrutinib135
DBTP and DBE Periods: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity Secondary · Baseline up to 170 weeks

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.

Participants with Grade 1
GroupValue95% CI
Teriflunomide41
Evobrutinib59
Participants with Grade 2
GroupValue95% CI
Teriflunomide389
Evobrutinib351
Participants with Grade 3
GroupValue95% CI
Teriflunomide87
Evobrutinib92
Participants with Grade 4
GroupValue95% CI
Teriflunomide7
Evobrutinib6
Participants with Grade 5
GroupValue95% CI
Teriflunomide0
Evobrutinib0
DBTP and DBE Periods: Change From Baseline in Vital Signs: Diastolic Blood Pressure and Systolic Blood Pressure Secondary · Baseline up to 170 weeks

Diastolic blood pressure and systolic blood pressure were measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Changes in vital signs: diastolic blood pressure and systolic blood pressure from baseline up to 170 weeks were reported.

Systolic Blood Pressure
GroupValue95% CI
Teriflunomide2.4± 11.0
Evobrutinib1.0± 11.50
Diastolic Blood Pressure
GroupValue95% CI
Teriflunomide1.4± 8.73
Evobrutinib-0.5± 8.38

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline up to 170 weeks. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Teriflunomide
Serious: 37/583 (6%)
Deaths: 0/583
Evobrutinib
Serious: 51/581 (9%)
Deaths: 0/581

Serious adverse events (85 terms)

ReactionSystemTeriflunomideEvobrutinib
Alanine aminotransferase increasedInvestigations——
Uterine leiomyomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)——
Aspartate aminotransferase increasedInvestigations——
Multiple sclerosis relapseNervous system disorders——
AppendicitisInfections and infestations——
COVID-19Infections and infestations——
COVID-19 pneumoniaInfections and infestations——
Urinary tract infectionInfections and infestations——
Accidental overdoseInjury, poisoning and procedural complications——
Papillary thyroid cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)——
Lumbosacral radiculopathyNervous system disorders——
Acute myocardial infarctionCardiac disorders——
Myocardial infarctionCardiac disorders——
ChalazionEye disorders——
Ileus spasticGastrointestinal disorders——
Cholecystitis acuteHepatobiliary disorders——
CholelithiasisHepatobiliary disorders——
Drug-induced liver injuryHepatobiliary disorders——
HepatitisHepatobiliary disorders——
HyperbilirubinaemiaHepatobiliary disorders——
Acute sinusitisInfections and infestations——
Cholecystitis infectiveInfections and infestations——
Chronic tonsillitisInfections and infestations——
Pyelonephritis acuteInfections and infestations——
Renal abscessInfections and infestations——
Other adverse events (21 terms — click to expand)

ReactionSystemTeriflunomideEvobrutinib
Alanine aminotransferase increasedInvestigations——
COVID-19Infections and infestations——
HeadacheNervous system disorders——
Neutrophil count decreasedInvestigations——
AlopeciaSkin and subcutaneous tissue disorders——
Aspartate aminotransferase increasedInvestigations——
NasopharyngitisInfections and infestations——
White blood cell count decreasedInvestigations——
Back painMusculoskeletal and connective tissue disorders——
Upper respiratory tract infectionInfections and infestations——
NeutropeniaBlood and lymphatic system disorders——
DiarrhoeaGastrointestinal disorders——
FatigueGeneral disorders——
Urinary tract infectionInfections and infestations——
Lymphocyte count decreasedInvestigations——
Respiratory tract infection viralInfections and infestations——
NauseaGastrointestinal disorders——
AnaemiaBlood and lymphatic system disorders——
Lipase increasedInvestigations——
Pain in extremityMusculoskeletal and connective tissue disorders——
Gamma-glutamyltransferase increasedInvestigations——

Most-reported serious reactions: Alanine aminotransferase increased, Uterine leiomyoma, Aspartate aminotransferase increased, Multiple sclerosis relapse, Appendicitis, COVID-19, COVID-19 pneumonia, Urinary tract infection.

Data from ClinicalTrials.gov NCT04338061 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. B cell depletion therapies in autoimmune disease: advances and mechanistic insights.
    Lee DSW, Rojas OL, Gommerman JL. · · 2021 · cited 496× · PMID 33324003 · DOI 10.1038/s41573-020-00092-2
  2. Secondary Progressive Multiple Sclerosis: New Insights.
    Cree BAC, Arnold DL, Chataway J, Chitnis T, et al · · 2021 · cited 159× · PMID 34088878 · DOI 10.1212/wnl.0000000000012323
  3. Bruton tyrosine kinase inhibitors for multiple sclerosis.
    Krämer J, Bar-Or A, Turner TJ, Wiendl H. · · 2023 · cited 119× · PMID 37055617 · DOI 10.1038/s41582-023-00800-7
  4. Targeted Immunotherapy for Autoimmune Disease.
    Jung SM, Kim WU. · · 2022 · cited 113× · PMID 35291650 · DOI 10.4110/in.2022.22.e9
  5. Updates and advances in multiple sclerosis neurotherapeutics.
    Amin M, Hersh CM. · · 2023 · cited 89× · PMID 36314777 · DOI 10.2217/nmt-2021-0058
  6. BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies.
    Alu A, Lei H, Han X, Wei Y, et al · · 2022 · cited 88× · PMID 36183125 · DOI 10.1186/s13045-022-01353-w
  7. Neurodegeneration and demyelination in multiple sclerosis.
    Garton T, Gadani SP, Gill AJ, Calabresi PA. · · 2024 · cited 63× · PMID 38889714 · DOI 10.1016/j.neuron.2024.05.025
  8. Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases.
    Zhang D, Gong H, Meng F. · · 2021 · cited 45× · PMID 34443496 · DOI 10.3390/molecules26164907

Verify or expand the search:

Other trials of Teriflunomide

Trials testing the same drug.

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Currently open trials in the same condition.

Other Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany trials

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Data sources for this page

Drug Landscape aggregates and links these public records for informational use only. Always verify against the primary source before clinical or regulatory decisions. Canonical URL: https://druglandscape.com/trial/NCT04338061.

Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing