Relapsing-remitting Multiple Sclerosis
Conditions
Keywords
M2951, Relapsing Multiple Sclerosis, Bruton's Tyrosine Kinase inhibitor
Brief summary
The aim of this protocol is to find out about the safety and effectiveness of M2951 in participants with relapsing multiple sclerosis. Participants were placed into 1 of 3 groups to receive M2951, placebo or tecfidera for 24 weeks. After 24 weeks, the participants on placebo were given M2951.
Interventions
DRUGEvobrutinib
Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period received Evobrutinib 75 mg QD orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.
DRUGPlacebo
Placebo were administered for 24 weeks in active treatment period.
DRUGTecfidera
Participants received Tecfidera 120 mg twice daily (BID) for first 7 days followed by 240 mg orally, BID up to Week 48 in active treatment period 1 and BE period received Tecfidera 120 mg BID orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono Research & Development Institute, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Participants with a diagnosis of relapsing multiple sclerosis (may include participants with Secondary Progressive Multiple Sclerosis (SPMS) with superimposed relapses provided they meet the other criteria) in accordance with revised McDonald criteria for MS and Lublin and Reingold * Male or female aged 18 to 65 years * 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-positive (Gd+) T1 lesion within 6 months prior to randomization would make the patient eligible. * Expanded Disability Status Scale score of 0 to 6 at Baseline * Women of childbearing potential must use a supplementary barrier method together with a highly effective method of contraception (according to International Council for Harmonisation \[ICH\] guidance M3\[R2\]) for 4 weeks prior to randomization, throughout the trial, and for 90 days after the last dose of IMP. * Signed and dated informed consent (participant must be able to understand the informed consent) indicating that the participant has been informed of all the pertinent aspects of the trial prior to enrolment and will comply with the requirements of the protocol.
Exclusion criteria
* Progressive MS * Disease duration \> 15 years in participants with EDSS of 2 or less * Use of the following, as determined in the protocol ; rituximab, ocrelizumab, mitoxantrone, or lymphocyte-depleting therapies, lymphocyte trafficking blockers (eg, natalizumab, fingolimod), intravenous (IV) immunoglobulins (Ig), plasmapheresis, immunosuppressive treatments, B-interferons or glatiramer acetate, Systemic glucocorticoids, teriflunomide * Exposure to Tecfidera within 6 months prior to randomization * Any allergy, contraindication, or inability to tolerate Tecfidera * Treatment with dalfampridine (fampridine, Ampyra) unless on a stable dose for ≥ 30 days prior to randomization * Inability to comply with MRI scanning * Immunologic disorder other than MS, with the exception of secondary well-controlled diabetes or thyroid disorder, or any other condition requiring oral, IV, intramuscular, or intra-articular corticosteroid therapy * Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening * Severe drug allergy or history of anaphylaxis, or allergy to the IMP or any of its incipients * Active, clinically significant viral, bacterial, or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks of Screening, or completion of oral anti-infectives within 2 weeks before or during Screening, or a history of recurrent infections (ie, 3 or more of the same type of infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis, and genital or oral herpes simplex virus considered by the Investigator to be sufficiently controlled would not be exclusionary. * History of or positive testing for human immunodeficiency virus (HIV), hepatitis C (HCV) antibody and/or polymerase chain reaction, hepatitis B surface antigen (HBsAg) (+) and/or hepatitis B core total, and/or immunoglobulin M (IgM) antibody (+) at Screening. * The participant: • Has a history of or current diagnosis of active tuberculosis (TB) or • Is currently undergoing treatment for latent TB infection (LTBI) or • Has an untreated LTBI or • Has a positive QuantiFERON®-TB test at Screening. * Indeterminate QuantiFERON® * Participants with current household contacts with active TB will also be excluded * History of splenectomy or any major surgery within 2 months prior to Screening * History of myocardial infarction or cerebrovascular event as per the protocol * History of attempted suicide within 6 months prior to Screening or a positive response to items 4 or 5 of Columbia-Suicide Severity Rating Scale (C-SSRS) * An episode of major depression within the last 6 months prior to Screening * On anticoagulation, fish oil supplements, or antiplatelet therapy other than daily aspirin for cardioprotection and treatment of Tecfidera induced flushing * History of cancer, except adequately treated basal cell or squamous cell carcinoma of the skin * Breastfeeding/lactating or pregnant women * Participation in any investigational drug trial within 1 month or 5 half-lives of the investigational drug, whichever is longest, prior to Screening * Participants currently receiving (or unable to stop using prior to receiving the first dose of IMP) medications or herbal supplements known to be potent inhibitors of cytochrome P450 3A (CYP3A) * History of or current alcohol or substance abuse * Clinically significant abnormality on electrocardiogram or screening chest X-ray * Clinically significant laboratory abnormality
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Gadolinium-Enhancing T1 Lesions | Week 12 to Week 24 | Analysis of T1-Gadolinium enhancing lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Qualified Relapse-Free Status at Week 24 | Week 24 | A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. Percentage of participants with qualified relapse-free status at week 24 were reported. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. |
| Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24 | Baseline, Week 24 | The EDSS is an ordinal clinical rating scale in half-point increments. It assesses the following eight functional systems, areas of the central nervous system that control bodily functions: Pyramidal (ability to walk), Cerebellar (coordination), Brain stem (speech and swallowing), Sensory (touch and pain), Bowel and bladder functions, Visual, Mental, Other (includes any other neurological findings due to Multiple Sclerosis \[MS\]). EDSS overall score ranging from 0 (normal) to 10 (death due to MS). As per planned analysis, Tecfidera treatment group was not included in inferential analysis. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | Baseline up to Safety Follow-up (Week 52) | An adverse event (AE) was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the study drug. An AE was defined as 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. A serious adverse event (SAE) was 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. Treatment-emergent adverse events are defined as any adverse event with a start date on or after the date of first dose and within 28 days after the date of last dose in the study. TEAEs include both Serious TEAEs and non-serious TEAEs. |
| Qualified Relapse-free Status | Week 25 to Week 48 | A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. Percentage of participants with qualified relapse-free status were reported. |
| Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) | Baseline up to Safety Follow-up (Week 52) | Vital signs, including semi supine blood pressure, pulse rate, respiratory rate, weight, and oral temperature were assessed. ECG parameters included rhythm, ventricular rate, PR interval, QRS duration, and QT interval. Number of participants with clinically significant change from baseline in vital signs and ECG were reported. Clinical Significance was decided by the investigator. |
| Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Baseline up to Safety Follow-up (Week 52) | Hematology, biochemistry, and urinalysis values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). For the hematology and biochemistry parameters, participants with a value grade 3 or higher were reported. For the urinalysis parameters, participants with a value grade 3 or higher, or a value \>= 2 upper limit of normal (ULN), or a value classified as ++ Increasing were reported. |
| Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Baseline (Day 1), Weeks 4, 16, and 24 | Absolute Concentrations serum levels of IgG, IgA, IgM were assessed. |
| Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) | Week 48 | Absolute Concentrations serum levels of IgG, IgA, IgM were assessed. |
| Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Baseline (Day 1), Weeks 4, 16, and 24 | Change from baseline in the serum levels of IgG, IgA, IgM were assessed. |
| Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) | Baseline (Week 25), Week 48 | Change from baseline in the serum levels of IgG, IgA, IgM were assessed. |
| Absolute Concentration of B Cells (Active Treatment Period) | Baseline (Day 1), Weeks 4, and 24 | Absolute concentration of B Cells are reported. |
| Absolute Concentration of B Cells (Blinded Extension Period) | Weeks 48 and 52 | Absolute concentration of B Cells were reported. |
| Change From Baseline in Absolute B Cells (Active Treatment Period) | Baseline (Day 1), Weeks 4 and 24 | Change from baseline in absolute B cells are reported. |
| Change From Baseline in Absolute B Cells (Blinded Extension Period) | Baseline (Week 25), Weeks 48 and 52 | Change from baseline in absolute B cells are reported. |
| Total Number of New Gadolinium-positive (Gd+) T1 Lesions | Week 12 to 24 | Analysis of Gadolinium-positive T1 lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. |
| Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions | Week 12 to Week 24 | Analysis of Gadolinium-positive T1 lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. |
| Total Number of New or Enlarging T2 Lesions | Week 12 to Week 24 | Analysis of New or Enlarging T2 lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. |
| Change From Baseline in Volume of T2 Lesions at Week 24 | Baseline, Week 24 | Analysis of volume of T2 lesions was done using magnetic resonance imaging (MRI) scans. Tecfidera treatment group was not included in inferential analysis. |
| Annualized Relapse Rate (ARR) at Week 24 | Week 24 | A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. |
| Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48 | Week 48 | Analysis of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans. |
| Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48 | Week 48 | Analysis of new Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans. |
| Annualized Relapse Rate (ARR) | Week 0 to Week 48 | A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. |
| Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48 | Week 24, Week 48 | The EDSS is an ordinal clinical rating scale in half-point increments. It assesses the following eight functional systems, areas of the central nervous system that control bodily functions: Pyramidal (ability to walk), Cerebellar (coordination), Brain stem (speech and swallowing), Sensory (touch and pain), Bowel and bladder functions, Visual, Mental, Other (includes any other neurological findings due to Multiple Sclerosis \[MS\]). EDSS overall score ranging from 0 (normal) to 10 (death due to MS). |
| Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 24 | Week 24 to Week 48 | Analysis of New or Enlarging T2 lesions was done using magnetic resonance imaging (MRI) scans. |
| Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 48 | Week 24, Week 48 | Analysis of volume of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans. |
| Change From Week 24 in Volume of T2 Lesions at Week 48 | Week 24, Week 48 | Analysis of volume of T2 lesions was done using magnetic resonance imaging (MRI) scans. |
| OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336 | Analysis of T1-Gadolinium enhancing lesions was done using magnetic resonance imaging (MRI) scans. |
| OLE Period: Annualized Relapse Rate (ARR) | OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336 | A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. |
| OLE Period: Percentage of Participants With Qualified Relapse-Free Status | OLE Baseline (BE period Week 48) up to OLE Week 336 | A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. Percentage of participants with qualified relapse-free status from OLE Baseline (BE period Week 48) up to Week 336 were reported. |
| OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336 | The EDSS is an ordinal clinical rating scale in half-point increments. It assesses the following eight functional systems, areas of the central nervous system that control bodily functions: Pyramidal (ability to walk), Cerebellar (coordination), Brain stem (speech and swallowing), Sensory (touch and pain), Bowel and bladder functions, Visual, Mental, Other (includes any other neurological findings due to Multiple Sclerosis \[MS\]). EDSS overall score ranging from 0 (normal) to 10 (death due to MS). |
| OLE Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | OLE Baseline (BE period Week 48) up to OLE Week 336 | An adverse event (AE) was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the study drug. An AE was defined as 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. A serious adverse event (SAE) was 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. Treatment-emergent adverse events are defined as any adverse event with a start date on or after the date of first dose and within 28 days after the date of last dose in the study. TEAEs include both Serious TEAEs and non-serious TEAEs. |
| OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | OLE Baseline (BE period Week 48) up to OLE Week 336 | Vital signs, including semi supine blood pressure, pulse rate, respiratory rate, weight, and oral temperature were assessed. Number of participants with clinically significant change from baseline in vital signs were reported. Clinical Significance was decided by the investigator. |
| OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | OLE Baseline (BE period Week 48) up to OLE Week 336 | Laboratory parameters included hematology, biochemistry, and urinalysis. Number of participants with clinically significant change from baseline in laboratory parameters were reported. Clinical Significance was decided by the investigator. |
| OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECGs) | OLE Baseline (BE period Week 48) up to OLE Week 336 | ECG parameters included rhythm, ventricular rate, PR interval, QRS duration, and QT interval. Number of participants with clinically significant change from baseline in ECG were reported. Clinical Significance was decided by the investigator. |
| OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240 and 288 | Absolute Concentrations serum levels of IgG, IgA, IgM were assessed. |
| OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240 and 288 | Change from baseline in the serum levels of IgG, IgA, IgM were assessed. |
| Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24 | Baseline, Week 24 | Analysis of volume of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. |
Countries
Bulgaria, Czechia, Poland, Russia, Serbia, Slovakia, Spain, Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Period 1) Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. | 53 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period received Evobrutinib 25 mg QD orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period. | 50 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period received Evobrutinib 75 mg QD orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period. | 51 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period received Evobrutinib 75 mg BID orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period. | 53 |
| Tecfidera (Period 1, 2 and 3) Participants received Tecfidera 120 mg twice daily (BID) for first 7 days followed by 240 mg orally, BID up to Week 48 in active treatment period 1 and BE period received Tecfidera 120 mg BID orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period. | 54 |
| Total | 261 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Active Treatment Period (24 Weeks) | Adverse Event | 4 | 0 | 0 | 2 | 2 | 6 | 2 |
| Active Treatment Period (24 Weeks) | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Active Treatment Period (24 Weeks) | Withdrawal by Subject | 0 | 0 | 0 | 3 | 3 | 0 | 0 |
| Blinded Extension Period (24 Weeks) | Adverse Event | 0 | 1 | 0 | 1 | 3 | 1 | 0 |
| Blinded Extension Period (24 Weeks) | Lack of Efficacy | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Blinded Extension Period (24 Weeks) | Progressive Disease | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Blinded Extension Period (24 Weeks) | Withdrawal by Subject | 0 | 5 | 0 | 2 | 1 | 1 | 0 |
| Open-label Extension Period (336 Weeks) | Adverse Event | 0 | 0 | 3 | 2 | 2 | 1 | 2 |
| Open-label Extension Period (336 Weeks) | COVID-19 Related | 0 | 0 | 0 | 1 | 1 | 1 | 2 |
| Open-label Extension Period (336 Weeks) | Death | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Open-label Extension Period (336 Weeks) | Lack of Efficacy | 0 | 0 | 0 | 0 | 2 | 0 | 1 |
| Open-label Extension Period (336 Weeks) | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 1 | 0 |
| Open-label Extension Period (336 Weeks) | Other | 0 | 0 | 3 | 3 | 1 | 2 | 3 |
| Open-label Extension Period (336 Weeks) | Study reached its predefined end | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Open-label Extension Period (336 Weeks) | Withdrawal by Subject | 0 | 0 | 4 | 7 | 2 | 4 | 2 |
Baseline characteristics
| Characteristic | Placebo (Period 1) | Evobrutinib 25 mg QD (Period 1, 2 and 3) | Evobrutinib 75 mg QD (Period 1, 2 and 3) | Evobrutinib 75 mg BID (Period 1, 2 and 3) | Tecfidera (Period 1, 2 and 3) | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 41.6 Years STANDARD_DEVIATION 10.77 | 42.4 Years STANDARD_DEVIATION 9.37 | 42.9 Years STANDARD_DEVIATION 10.07 | 42.2 Years STANDARD_DEVIATION 11.5 | 42.8 Years STANDARD_DEVIATION 11.7 | 42.4 Years STANDARD_DEVIATION 10.67 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 52 Participants | 49 Participants | 51 Participants | 52 Participants | 52 Participants | 256 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 53 Participants | 50 Participants | 51 Participants | 53 Participants | 54 Participants | 261 Participants |
| Sex: Female, Male Female | 39 Participants | 32 Participants | 35 Participants | 36 Participants | 39 Participants | 181 Participants |
| Sex: Female, Male Male | 14 Participants | 18 Participants | 16 Participants | 17 Participants | 15 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 0 / 49 | 0 / 52 | 0 / 53 | 0 / 54 | 0 / 54 | 0 / 39 | 1 / 39 | 0 / 42 | 1 / 44 | 1 / 49 |
| other Total, other adverse events | 14 / 54 | 9 / 49 | 19 / 52 | 19 / 53 | 20 / 54 | 30 / 54 | 30 / 39 | 26 / 39 | 34 / 42 | 31 / 44 | 26 / 49 |
| serious Total, serious adverse events | 2 / 54 | 0 / 49 | 2 / 52 | 2 / 53 | 4 / 54 | 2 / 54 | 7 / 39 | 12 / 39 | 8 / 42 | 5 / 44 | 10 / 49 |
Outcome results
Primary
Total Number of Gadolinium-Enhancing T1 Lesions
Analysis of T1-Gadolinium enhancing lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis.
Time frame: Week 12 to Week 24
Population: Modified Intent-To-Treat (mITT) analysis set included participants who belong to both Intent To Treat (ITT, consisted all participants who randomly allocated to a treatment, based on the intention to treat as randomized principle) and safety analysis sets (consisted all participants who receive at least 1 dose of trial treatment), and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Total Number of Gadolinium-Enhancing T1 Lesions | 3.85 Lesions | Standard Deviation 5.436 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Total Number of Gadolinium-Enhancing T1 Lesions | 4.06 Lesions | Standard Deviation 8.024 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Total Number of Gadolinium-Enhancing T1 Lesions | 1.69 Lesions | Standard Deviation 4.693 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Total Number of Gadolinium-Enhancing T1 Lesions | 1.15 Lesions | Standard Deviation 3.702 |
| Tecfidera (Period 1, 2 and 3) | Total Number of Gadolinium-Enhancing T1 Lesions | 4.78 Lesions | Standard Deviation 22.045 |
p-value: 0.294795% CI: [0.72, 2.91]Negative Binomial model
p-value: 0.001595% CI: [0.14, 0.63]Negative Binomial model
p-value: 0.031395% CI: [0.21, 0.93]Negative Binomial model
Secondary
Absolute Concentration of B Cells (Active Treatment Period)
Absolute concentration of B Cells are reported.
Time frame: Baseline (Day 1), Weeks 4, and 24
Population: The safety analysis set included of all participants who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signified those participants who were evaluable for the specified category at given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Period 1) | Absolute Concentration of B Cells (Active Treatment Period) | Day 1 | 242 cells per micro-liter | Standard Deviation 134.2 |
| Placebo (Period 1) | Absolute Concentration of B Cells (Active Treatment Period) | Week 24 | 264 cells per micro-liter | Standard Deviation 154.9 |
| Placebo (Period 1) | Absolute Concentration of B Cells (Active Treatment Period) | Week 4 | 243 cells per micro-liter | Standard Deviation 130.8 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentration of B Cells (Active Treatment Period) | Week 4 | 220 cells per micro-liter | Standard Deviation 92.7 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentration of B Cells (Active Treatment Period) | Day 1 | 208 cells per micro-liter | Standard Deviation 117.5 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentration of B Cells (Active Treatment Period) | Week 24 | 230 cells per micro-liter | Standard Deviation 119.7 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentration of B Cells (Active Treatment Period) | Week 4 | 277 cells per micro-liter | Standard Deviation 156.2 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentration of B Cells (Active Treatment Period) | Day 1 | 247 cells per micro-liter | Standard Deviation 131.8 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentration of B Cells (Active Treatment Period) | Week 24 | 235 cells per micro-liter | Standard Deviation 115.3 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentration of B Cells (Active Treatment Period) | Day 1 | 219 cells per micro-liter | Standard Deviation 113.7 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentration of B Cells (Active Treatment Period) | Week 24 | 214 cells per micro-liter | Standard Deviation 105 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentration of B Cells (Active Treatment Period) | Week 4 | 270 cells per micro-liter | Standard Deviation 143.2 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentration of B Cells (Active Treatment Period) | Week 4 | 201 cells per micro-liter | Standard Deviation 114.3 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentration of B Cells (Active Treatment Period) | Day 1 | 210 cells per micro-liter | Standard Deviation 97.4 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentration of B Cells (Active Treatment Period) | Week 24 | 180 cells per micro-liter | Standard Deviation 114.3 |
Secondary
Absolute Concentration of B Cells (Blinded Extension Period)
Absolute concentration of B Cells were reported.
Time frame: Weeks 48 and 52
Population: The safety analysis set included of all participants who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signified those participants who were evaluable for the specified category at given time points. Results reported are for blinded extension period only and no participants took placebo during this period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Period 1) | Absolute Concentration of B Cells (Blinded Extension Period) | Week 48 | 203 cells per micro-liter | Standard Deviation 111.9 |
| Placebo (Period 1) | Absolute Concentration of B Cells (Blinded Extension Period) | Week 52 | 227 cells per micro-liter | Standard Deviation 93.7 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentration of B Cells (Blinded Extension Period) | Week 52 | 206 cells per micro-liter | Standard Deviation 140.3 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentration of B Cells (Blinded Extension Period) | Week 48 | 222 cells per micro-liter | Standard Deviation 148.8 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentration of B Cells (Blinded Extension Period) | Week 48 | 187 cells per micro-liter | Standard Deviation 87.1 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentration of B Cells (Blinded Extension Period) | Week 52 | 154 cells per micro-liter | Standard Deviation 73.6 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentration of B Cells (Blinded Extension Period) | Week 48 | 181 cells per micro-liter | Standard Deviation 109.8 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentration of B Cells (Blinded Extension Period) | Week 52 | 135 cells per micro-liter | Standard Deviation 29 |
Secondary
Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period)
Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.
Time frame: Baseline (Day 1), Weeks 4, 16, and 24
Population: The safety analysis set included of all participants who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signified those participants who were evaluable for the specified category at given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 24 | 9.66 Gram per Liter | Standard Deviation 2.081 |
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 16 | 1.43 Gram per Liter | Standard Deviation 0.703 |
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Day 1 | 1.99 Gram per Liter | Standard Deviation 0.777 |
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 24 | 1.99 Gram per Liter | Standard Deviation 0.807 |
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 4 | 9.64 Gram per Liter | Standard Deviation 2.094 |
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 24 | 1.44 Gram per Liter | Standard Deviation 0.748 |
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 4 | 1.40 Gram per Liter | Standard Deviation 0.668 |
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 16 | 2.07 Gram per Liter | Standard Deviation 0.824 |
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Day 1 | 9.61 Gram per Liter | Standard Deviation 1.897 |
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 16 | 9.68 Gram per Liter | Standard Deviation 2.085 |
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 4 | 1.98 Gram per Liter | Standard Deviation 0.777 |
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Day 1 | 1.42 Gram per Liter | Standard Deviation 0.692 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 24 | 1.03 Gram per Liter | Standard Deviation 0.499 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 4 | 9.34 Gram per Liter | Standard Deviation 1.972 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 4 | 1.92 Gram per Liter | Standard Deviation 0.77 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 16 | 9.41 Gram per Liter | Standard Deviation 2.077 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Day 1 | 1.89 Gram per Liter | Standard Deviation 0.764 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 16 | 1.13 Gram per Liter | Standard Deviation 0.558 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 16 | 2.10 Gram per Liter | Standard Deviation 0.813 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 24 | 9.46 Gram per Liter | Standard Deviation 2.123 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 4 | 1.21 Gram per Liter | Standard Deviation 0.526 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 24 | 2.12 Gram per Liter | Standard Deviation 0.833 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Day 1 | 1.27 Gram per Liter | Standard Deviation 0.542 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Day 1 | 9.43 Gram per Liter | Standard Deviation 2.126 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 16 | 1.24 Gram per Liter | Standard Deviation 0.639 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Day 1 | 1.90 Gram per Liter | Standard Deviation 0.722 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 4 | 1.93 Gram per Liter | Standard Deviation 0.762 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 16 | 2.13 Gram per Liter | Standard Deviation 0.832 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 24 | 2.09 Gram per Liter | Standard Deviation 0.838 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Day 1 | 9.81 Gram per Liter | Standard Deviation 1.841 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 4 | 9.79 Gram per Liter | Standard Deviation 1.91 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 16 | 9.70 Gram per Liter | Standard Deviation 1.991 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 24 | 9.62 Gram per Liter | Standard Deviation 2.048 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Day 1 | 1.44 Gram per Liter | Standard Deviation 0.716 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 4 | 1.32 Gram per Liter | Standard Deviation 0.654 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 24 | 1.20 Gram per Liter | Standard Deviation 0.672 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 4 | 9.64 Gram per Liter | Standard Deviation 1.987 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Day 1 | 1.87 Gram per Liter | Standard Deviation 0.675 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 24 | 9.36 Gram per Liter | Standard Deviation 1.988 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Day 1 | 9.62 Gram per Liter | Standard Deviation 1.96 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Day 1 | 1.33 Gram per Liter | Standard Deviation 0.684 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 24 | 2.09 Gram per Liter | Standard Deviation 0.793 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 24 | 1.08 Gram per Liter | Standard Deviation 0.494 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 4 | 1.28 Gram per Liter | Standard Deviation 0.656 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 16 | 2.08 Gram per Liter | Standard Deviation 0.753 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 4 | 1.94 Gram per Liter | Standard Deviation 0.748 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 16 | 1.20 Gram per Liter | Standard Deviation 0.689 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 16 | 9.56 Gram per Liter | Standard Deviation 2.129 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 4 | 9.05 Gram per Liter | Standard Deviation 1.922 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 4 | 1.23 Gram per Liter | Standard Deviation 0.603 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Day 1 | 2.03 Gram per Liter | Standard Deviation 0.763 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 24 | 9.27 Gram per Liter | Standard Deviation 1.866 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 4 | 1.90 Gram per Liter | Standard Deviation 0.699 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 24 | 1.97 Gram per Liter | Standard Deviation 0.757 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 24 | 1.29 Gram per Liter | Standard Deviation 0.667 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Day 1 | 9.47 Gram per Liter | Standard Deviation 1.839 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Day 1 | 1.27 Gram per Liter | Standard Deviation 0.589 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 16 | 9.58 Gram per Liter | Standard Deviation 1.85 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 16 | 2.03 Gram per Liter | Standard Deviation 0.752 |
| Tecfidera (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 16 | 1.28 Gram per Liter | Standard Deviation 0.678 |
Secondary
Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period)
Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.
Time frame: Week 48
Population: The safety analysis set included of all participants who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure. Results reported are for blinded extension period only and no participants took placebo during this period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgA | 2.13 Gram per Liter | Standard Deviation 0.807 |
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgM | 1.08 Gram per Liter | Standard Deviation 0.557 |
| Placebo (Period 1) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgG | 9.53 Gram per Liter | Standard Deviation 2.07 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgA | 2.18 Gram per Liter | Standard Deviation 0.79 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgM | 1.13 Gram per Liter | Standard Deviation 0.639 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgG | 9.74 Gram per Liter | Standard Deviation 1.902 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgG | 9.38 Gram per Liter | Standard Deviation 2.189 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgA | 2.23 Gram per Liter | Standard Deviation 0.838 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgM | 1.10 Gram per Liter | Standard Deviation 0.692 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgA | 2.06 Gram per Liter | Standard Deviation 0.695 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgM | 1.28 Gram per Liter | Standard Deviation 0.635 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgG | 9.60 Gram per Liter | Standard Deviation 1.968 |
Secondary
Annualized Relapse Rate (ARR)
A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days.
Time frame: Week 0 to Week 48
Population: mITT analysis set consists of all participants who belong to both the ITT and safety analysis sets, and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo (Period 1) | Annualized Relapse Rate (ARR) | 0.37 relapses per year |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Annualized Relapse Rate (ARR) | 0.52 relapses per year |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Annualized Relapse Rate (ARR) | 0.25 relapses per year |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Annualized Relapse Rate (ARR) | 0.11 relapses per year |
| Tecfidera (Period 1, 2 and 3) | Annualized Relapse Rate (ARR) | 0.14 relapses per year |
Secondary
Annualized Relapse Rate (ARR) at Week 24
A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. As per planned analysis, Tecfidera treatment group was not included in inferential analysis.
Time frame: Week 24
Population: The modified ITT (mITT) analysis set consists of all participants who belong to both the ITT and safety analysis sets, and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo (Period 1) | Annualized Relapse Rate (ARR) at Week 24 | 0.37 relapses per year |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Annualized Relapse Rate (ARR) at Week 24 | 0.57 relapses per year |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Annualized Relapse Rate (ARR) at Week 24 | 0.13 relapses per year |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Annualized Relapse Rate (ARR) at Week 24 | 0.08 relapses per year |
| Tecfidera (Period 1, 2 and 3) | Annualized Relapse Rate (ARR) at Week 24 | 0.20 relapses per year |
p-value: 0.269295% CI: [0.67, 4.09]Negative Binomial model
p-value: 0.089695% CI: [0.08, 1.2]Negative Binomial model
p-value: 0.063395% CI: [0.05, 1.09]Negative Binomial model
Secondary
Change From Baseline in Absolute B Cells (Active Treatment Period)
Change from baseline in absolute B cells are reported.
Time frame: Baseline (Day 1), Weeks 4 and 24
Population: The safety analysis set included of all participants who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signified those participants who were evaluable for the specified category at given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Absolute B Cells (Active Treatment Period) | Week 4 | -5 cells per micro-liter | Standard Deviation 94.5 |
| Placebo (Period 1) | Change From Baseline in Absolute B Cells (Active Treatment Period) | Week 24 | 7 cells per micro-liter | Standard Deviation 135.8 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Absolute B Cells (Active Treatment Period) | Week 4 | 9 cells per micro-liter | Standard Deviation 112.2 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Absolute B Cells (Active Treatment Period) | Week 24 | 13 cells per micro-liter | Standard Deviation 98.2 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Absolute B Cells (Active Treatment Period) | Week 4 | 31 cells per micro-liter | Standard Deviation 114.2 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Absolute B Cells (Active Treatment Period) | Week 24 | -15 cells per micro-liter | Standard Deviation 128.5 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Absolute B Cells (Active Treatment Period) | Week 24 | -9 cells per micro-liter | Standard Deviation 85.1 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Absolute B Cells (Active Treatment Period) | Week 4 | 50 cells per micro-liter | Standard Deviation 86.7 |
| Tecfidera (Period 1, 2 and 3) | Change From Baseline in Absolute B Cells (Active Treatment Period) | Week 4 | -3 cells per micro-liter | Standard Deviation 111 |
| Tecfidera (Period 1, 2 and 3) | Change From Baseline in Absolute B Cells (Active Treatment Period) | Week 24 | -26 cells per micro-liter | Standard Deviation 113.9 |
Secondary
Change From Baseline in Absolute B Cells (Blinded Extension Period)
Change from baseline in absolute B cells are reported.
Time frame: Baseline (Week 25), Weeks 48 and 52
Population: The safety analysis set included of all participants who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signified those participants who were evaluable for the specified category at given time points. Results reported are for blinded extension period only and no participants took placebo during this period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Absolute B Cells (Blinded Extension Period) | Week 48 | -5 cells per micro-liter | Standard Deviation 116.1 |
| Placebo (Period 1) | Change From Baseline in Absolute B Cells (Blinded Extension Period) | Week 52 | -28 cells per micro-liter | Standard Deviation 209.8 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Absolute B Cells (Blinded Extension Period) | Week 52 | -25 cells per micro-liter | Standard Deviation 65.5 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Absolute B Cells (Blinded Extension Period) | Week 48 | -30 cells per micro-liter | Standard Deviation 148.2 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Absolute B Cells (Blinded Extension Period) | Week 48 | -32 cells per micro-liter | Standard Deviation 97.9 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Absolute B Cells (Blinded Extension Period) | Week 52 | -81 cells per micro-liter | Standard Deviation 119 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Absolute B Cells (Blinded Extension Period) | Week 48 | -15 cells per micro-liter | Standard Deviation 105.7 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Absolute B Cells (Blinded Extension Period) | Week 52 | 15 cells per micro-liter | Standard Deviation 22.6 |
Secondary
Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24
The EDSS is an ordinal clinical rating scale in half-point increments. It assesses the following eight functional systems, areas of the central nervous system that control bodily functions: Pyramidal (ability to walk), Cerebellar (coordination), Brain stem (speech and swallowing), Sensory (touch and pain), Bowel and bladder functions, Visual, Mental, Other (includes any other neurological findings due to Multiple Sclerosis \[MS\]). EDSS overall score ranging from 0 (normal) to 10 (death due to MS). As per planned analysis, Tecfidera treatment group was not included in inferential analysis.
Time frame: Baseline, Week 24
Population: Modified Intent-To-Treat (mITT) analysis set included participants who belong to both Intent To Treat (ITT, consisted all participants who randomly allocated to a treatment, based on the intention to treat as randomized principle) and safety analysis sets (consisted all participants who receive at least 1 dose of trial treatment), and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24 | -0.03 Units on a scale | Standard Deviation 0.301 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24 | 0.02 Units on a scale | Standard Deviation 0.622 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24 | -0.14 Units on a scale | Standard Deviation 0.664 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24 | 0.04 Units on a scale | Standard Deviation 0.216 |
| Tecfidera (Period 1, 2 and 3) | Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24 | 0.02 Units on a scale | Standard Deviation 0.274 |
p-value: 0.40795% CI: [0, 0]Wilcoxon rank-sum test
p-value: 0.582995% CI: [0, 0]Wilcoxon rank-sum test
p-value: 0.273295% CI: [0, 0]Wilcoxon rank-sum test
Secondary
Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period)
Change from baseline in the serum levels of IgG, IgA, IgM were assessed.
Time frame: Baseline (Day 1), Weeks 4, 16, and 24
Population: The safety analysis set included of all participants who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signified those participants who were evaluable for the specified category at given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 24 | 0.04 Gram per Liter | Standard Deviation 0.163 |
| Placebo (Period 1) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 16 | 0.04 Gram per Liter | Standard Deviation 0.747 |
| Placebo (Period 1) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 16 | 0.10 Gram per Liter | Standard Deviation 0.188 |
| Placebo (Period 1) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 24 | 0.06 Gram per Liter | Standard Deviation 0.682 |
| Placebo (Period 1) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 16 | 0.02 Gram per Liter | Standard Deviation 0.177 |
| Placebo (Period 1) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 24 | 0.06 Gram per Liter | Standard Deviation 0.25 |
| Placebo (Period 1) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 4 | -0.01 Gram per Liter | Standard Deviation 0.21 |
| Placebo (Period 1) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 4 | 0.02 Gram per Liter | Standard Deviation 0.758 |
| Placebo (Period 1) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 4 | -0.02 Gram per Liter | Standard Deviation 0.201 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 4 | -0.06 Gram per Liter | Standard Deviation 0.1 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 24 | 0.00 Gram per Liter | Standard Deviation 1.228 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 4 | -0.10 Gram per Liter | Standard Deviation 0.697 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 16 | -0.07 Gram per Liter | Standard Deviation 0.964 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 24 | 0.21 Gram per Liter | Standard Deviation 0.283 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 24 | -0.14 Gram per Liter | Standard Deviation 0.286 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 16 | 0.18 Gram per Liter | Standard Deviation 0.245 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 4 | 0.02 Gram per Liter | Standard Deviation 0.165 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 16 | -0.12 Gram per Liter | Standard Deviation 0.184 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 24 | -0.15 Gram per Liter | Standard Deviation 1.058 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 4 | 0.04 Gram per Liter | Standard Deviation 0.169 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 16 | 0.21 Gram per Liter | Standard Deviation 0.313 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 24 | 0.18 Gram per Liter | Standard Deviation 0.416 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 4 | -0.02 Gram per Liter | Standard Deviation 0.688 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 16 | -0.10 Gram per Liter | Standard Deviation 1.068 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 4 | -0.12 Gram per Liter | Standard Deviation 0.233 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 16 | -0.18 Gram per Liter | Standard Deviation 0.244 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 24 | -0.20 Gram per Liter | Standard Deviation 0.289 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 4 | 0.02 Gram per Liter | Standard Deviation 0.581 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 24 | -0.28 Gram per Liter | Standard Deviation 0.774 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 24 | 0.22 Gram per Liter | Standard Deviation 0.229 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 4 | -0.05 Gram per Liter | Standard Deviation 0.133 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 16 | 0.22 Gram per Liter | Standard Deviation 0.209 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 24 | -0.21 Gram per Liter | Standard Deviation 0.167 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 16 | -0.14 Gram per Liter | Standard Deviation 0.189 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 4 | 0.07 Gram per Liter | Standard Deviation 0.195 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 16 | -0.05 Gram per Liter | Standard Deviation 0.71 |
| Tecfidera (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 4 | -0.13 Gram per Liter | Standard Deviation 0.238 |
| Tecfidera (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 4 | -0.42 Gram per Liter | Standard Deviation 0.926 |
| Tecfidera (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 24 | -0.23 Gram per Liter | Standard Deviation 0.882 |
| Tecfidera (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 24 | -0.06 Gram per Liter | Standard Deviation 0.207 |
| Tecfidera (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig G, Week 16 | 0.07 Gram per Liter | Standard Deviation 0.961 |
| Tecfidera (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 24 | -0.00 Gram per Liter | Standard Deviation 0.186 |
| Tecfidera (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 16 | -0.00 Gram per Liter | Standard Deviation 0.184 |
| Tecfidera (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig M, Week 4 | -0.04 Gram per Liter | Standard Deviation 0.132 |
| Tecfidera (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Ig A, Week 16 | -0.02 Gram per Liter | Standard Deviation 0.274 |
Secondary
Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period)
Change from baseline in the serum levels of IgG, IgA, IgM were assessed.
Time frame: Baseline (Week 25), Week 48
Population: The safety analysis set included of all participants who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure. Results reported are for blinded extension period only and no participants took placebo during this period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgG | 0.11 Gram per Liter | Standard Deviation 1.024 |
| Placebo (Period 1) | Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgM | -0.18 Gram per Liter | Standard Deviation 0.211 |
| Placebo (Period 1) | Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgA | 0.26 Gram per Liter | Standard Deviation 0.248 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgA | 0.28 Gram per Liter | Standard Deviation 0.275 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgG | -0.08 Gram per Liter | Standard Deviation 0.94 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgM | -0.27 Gram per Liter | Standard Deviation 0.287 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgG | -0.24 Gram per Liter | Standard Deviation 0.883 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgA | 0.36 Gram per Liter | Standard Deviation 0.32 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgM | -0.23 Gram per Liter | Standard Deviation 0.218 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgA | 0.03 Gram per Liter | Standard Deviation 0.316 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgM | -0.01 Gram per Liter | Standard Deviation 0.198 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) | IgG | 0.10 Gram per Liter | Standard Deviation 1.244 |
Secondary
Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24
Analysis of volume of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis.
Time frame: Baseline, Week 24
Population: mITT analysis set consists of all participants who belong to both the ITT and safety analysis sets, and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24 | -0.023 cc | Standard Deviation 0.222 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24 | 0.057 cc | Standard Deviation 0.3479 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24 | -0.111 cc | Standard Deviation 0.5416 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24 | -0.051 cc | Standard Deviation 0.1032 |
| Tecfidera (Period 1, 2 and 3) | Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24 | -0.050 cc | Standard Deviation 0.4771 |
p-value: 0.931595% CI: [-0.004, 0.009]Wilcoxon rank-sum test
p-value: 0.000895% CI: [-0.05, 0]Wilcoxon rank-sum test
p-value: 0.001495% CI: [-0.042, 0]Wilcoxon rank-sum test
Secondary
Change From Baseline in Volume of T2 Lesions at Week 24
Analysis of volume of T2 lesions was done using magnetic resonance imaging (MRI) scans. Tecfidera treatment group was not included in inferential analysis.
Time frame: Baseline, Week 24
Population: mITT analysis set consists of all participants who belong to both the ITT and safety analysis sets, and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Volume of T2 Lesions at Week 24 | 0.42 cubic centimeter (cc) | Standard Deviation 1.009 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Baseline in Volume of T2 Lesions at Week 24 | 0.93 cubic centimeter (cc) | Standard Deviation 1.853 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Baseline in Volume of T2 Lesions at Week 24 | -0.01 cubic centimeter (cc) | Standard Deviation 0.562 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Baseline in Volume of T2 Lesions at Week 24 | 0.09 cubic centimeter (cc) | Standard Deviation 0.463 |
| Tecfidera (Period 1, 2 and 3) | Change From Baseline in Volume of T2 Lesions at Week 24 | 0.47 cubic centimeter (cc) | Standard Deviation 2.964 |
p-value: 0.877695% CI: [-0.24, 0.28]Mixed Effect Model for Repeat Measures
p-value: 0.001995% CI: [-0.66, -0.15]Mixed Effect Model for Repeat Measures
p-value: 0.006395% CI: [-0.62, -0.1]Mixed Effect Model for Repeat Measures
Secondary
Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48
The EDSS is an ordinal clinical rating scale in half-point increments. It assesses the following eight functional systems, areas of the central nervous system that control bodily functions: Pyramidal (ability to walk), Cerebellar (coordination), Brain stem (speech and swallowing), Sensory (touch and pain), Bowel and bladder functions, Visual, Mental, Other (includes any other neurological findings due to Multiple Sclerosis \[MS\]). EDSS overall score ranging from 0 (normal) to 10 (death due to MS).
Time frame: Week 24, Week 48
Population: mITT BE analysis set included all participants who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48 | -0.05 Units on a scale | Standard Deviation 0.26 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48 | -0.10 Units on a scale | Standard Deviation 0.351 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48 | -0.01 Units on a scale | Standard Deviation 0.619 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48 | 0.00 Units on a scale | Standard Deviation 0.238 |
| Tecfidera (Period 1, 2 and 3) | Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48 | -0.10 Units on a scale | Standard Deviation 0.404 |
Secondary
Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 48
Analysis of volume of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.
Time frame: Week 24, Week 48
Population: mITT BE analysis set included all participants who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 48 | 0.092 cc | Standard Deviation 0.4626 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 48 | 0.088 cc | Standard Deviation 0.4006 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 48 | 0.045 cc | Standard Deviation 0.2285 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 48 | 0.024 cc | Standard Deviation 0.1981 |
| Tecfidera (Period 1, 2 and 3) | Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 48 | -0.203 cc | Standard Deviation 1.1073 |
Secondary
Change From Week 24 in Volume of T2 Lesions at Week 48
Analysis of volume of T2 lesions was done using magnetic resonance imaging (MRI) scans.
Time frame: Week 24, Week 48
Population: mITT BE analysis set included all participants who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Change From Week 24 in Volume of T2 Lesions at Week 48 | 0.53 cc | Standard Deviation 1.36 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Change From Week 24 in Volume of T2 Lesions at Week 48 | 0.67 cc | Standard Deviation 1.865 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Change From Week 24 in Volume of T2 Lesions at Week 48 | 0.35 cc | Standard Deviation 1.083 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Change From Week 24 in Volume of T2 Lesions at Week 48 | -0.03 cc | Standard Deviation 1.031 |
| Tecfidera (Period 1, 2 and 3) | Change From Week 24 in Volume of T2 Lesions at Week 48 | -0.57 cc | Standard Deviation 2.699 |
Secondary
Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions
Analysis of Gadolinium-positive T1 lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis.
Time frame: Week 12 to Week 24
Population: mITT analysis set consists of all participants who belong to both the ITT and safety analysis sets, and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions | 1.02 Lesions | Standard Deviation 1.439 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions | 1.31 Lesions | Standard Deviation 3.13 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions | 0.42 Lesions | Standard Deviation 1.173 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions | 0.34 Lesions | Standard Deviation 0.96 |
| Tecfidera (Period 1, 2 and 3) | Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions | 1.45 Lesions | Standard Deviation 7.293 |
p-value: 0.973195% CI: [-0.25, 0.25]Wilcoxon rank-sum test
p-value: 0.001795% CI: [-0.5, 0]Wilcoxon rank-sum test
p-value: <0.000195% CI: [-0.75, -0.25]Wilcoxon rank-sum test
Secondary
Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48
Analysis of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.
Time frame: Week 48
Population: mITT BE analysis set included all participants who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48 | 1.00 Lesions | Standard Deviation 1.614 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48 | 1.91 Lesions | Standard Deviation 4.296 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48 | 0.85 Lesions | Standard Deviation 2.867 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48 | 0.49 Lesions | Standard Deviation 1.218 |
| Tecfidera (Period 1, 2 and 3) | Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48 | 0.42 Lesions | Standard Deviation 1.444 |
Secondary
Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48
Analysis of new Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.
Time frame: Week 48
Population: mITT BE analysis set included all participants who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48 | 0.95 Lesions | Standard Deviation 1.569 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48 | 1.84 Lesions | Standard Deviation 4.154 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48 | 0.85 Lesions | Standard Deviation 2.867 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48 | 0.49 Lesions | Standard Deviation 1.218 |
| Tecfidera (Period 1, 2 and 3) | Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48 | 0.42 Lesions | Standard Deviation 1.444 |
Secondary
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs)
Vital signs, including semi supine blood pressure, pulse rate, respiratory rate, weight, and oral temperature were assessed. ECG parameters included rhythm, ventricular rate, PR interval, QRS duration, and QT interval. Number of participants with clinically significant change from baseline in vital signs and ECG were reported. Clinical Significance was decided by the investigator.
Time frame: Baseline up to Safety Follow-up (Week 52)
Population: The safety analysis set included of all participants who received at least 1 dose of evobrutinib or placebo or Tecfidera.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo (Period 1) | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) | Vital Sign Abnormalities | 0 Participants |
| Placebo (Period 1) | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) | ECG Abnormalities | 0 Participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) | Vital Sign Abnormalities | 0 Participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) | ECG Abnormalities | 0 Participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) | Vital Sign Abnormalities | 0 Participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) | ECG Abnormalities | 0 Participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) | Vital Sign Abnormalities | 0 Participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) | ECG Abnormalities | 0 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) | Vital Sign Abnormalities | 0 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) | ECG Abnormalities | 0 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) | Vital Sign Abnormalities | 0 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) | ECG Abnormalities | 0 Participants |
Secondary
Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values
Hematology, biochemistry, and urinalysis values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). For the hematology and biochemistry parameters, participants with a value grade 3 or higher were reported. For the urinalysis parameters, participants with a value grade 3 or higher, or a value \>= 2 upper limit of normal (ULN), or a value classified as ++ Increasing were reported.
Time frame: Baseline up to Safety Follow-up (Week 52)
Population: The safety analysis set included of all participants who received at least 1 dose of evobrutinib or placebo or Tecfidera.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo (Period 1) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 or value >= 2 ULN or ++ Increasing urinalysis values | 0 Participants |
| Placebo (Period 1) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 biochemistry values | 2 Participants |
| Placebo (Period 1) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 hematology values | 0 Participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 hematology values | 2 Participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 biochemistry values | 8 Participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 or value >= 2 ULN or ++ Increasing urinalysis values | 2 Participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 or value >= 2 ULN or ++ Increasing urinalysis values | 1 Participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 hematology values | 0 Participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 biochemistry values | 6 Participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 hematology values | 1 Participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 or value >= 2 ULN or ++ Increasing urinalysis values | 2 Participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 biochemistry values | 9 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 or value >= 2 ULN or ++ Increasing urinalysis values | 2 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 hematology values | 0 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 biochemistry values | 16 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 biochemistry values | 9 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 hematology values | 1 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Grade >= 3 or value >= 2 ULN or ++ Increasing urinalysis values | 6 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death
An adverse event (AE) was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the study drug. An AE was defined as 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. A serious adverse event (SAE) was 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. Treatment-emergent adverse events are defined as any adverse event with a start date on or after the date of first dose and within 28 days after the date of last dose in the study. TEAEs include both Serious TEAEs and non-serious TEAEs.
Time frame: Baseline up to Safety Follow-up (Week 52)
Population: The safety analysis set included of all participants who received at least 1 dose of evobrutinib or placebo or Tecfidera.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo (Period 1) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | Serious TEAEs | 2 Participants |
| Placebo (Period 1) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | TEAEs | 24 Participants |
| Placebo (Period 1) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | TEAEs Leading to Death | 0 Participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | Serious TEAEs | 0 Participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | TEAEs | 19 Participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | TEAEs Leading to Death | 0 Participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | Serious TEAEs | 2 Participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | TEAEs | 28 Participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | TEAEs Leading to Death | 0 Participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | Serious TEAEs | 2 Participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | TEAEs | 35 Participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | TEAEs Leading to Death | 0 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | Serious TEAEs | 4 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | TEAEs | 34 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | TEAEs Leading to Death | 0 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | TEAEs | 35 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | TEAEs Leading to Death | 0 Participants |
| Tecfidera (Period 1, 2 and 3) | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | Serious TEAEs | 2 Participants |
Secondary
OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels
Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.
Time frame: OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240 and 288
Population: The Safety OLE Analysis Set included all participants who receive at least 1 dose of Evobrutinib during the OLE. Overall Number of Participants Analyzed= Participants evaluable for this outcome measure and Number analyzed = participants who were evaluable for the specified category. Results reported are for OLE period only and no participants took placebo during this period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, OLE Baseline (BE period Week 48) | 2.31 Gram per Liter | Standard Deviation 0.966 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 72 | 2.38 Gram per Liter | Standard Deviation 1.084 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 96 | 2.42 Gram per Liter | Standard Deviation 1.173 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 96 | 1.01 Gram per Liter | Standard Deviation 0.556 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 240 | 2.71 Gram per Liter | Standard Deviation 1.28 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 96 | 9.46 Gram per Liter | Standard Deviation 2.49 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 192 | 9.37 Gram per Liter | Standard Deviation 2.156 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 192 | 0.89 Gram per Liter | Standard Deviation 0.492 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 72 | 1.03 Gram per Liter | Standard Deviation 0.551 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 288 | 2.68 Gram per Liter | Standard Deviation 1.305 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 144 | 2.57 Gram per Liter | Standard Deviation 1.274 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 144 | 9.48 Gram per Liter | Standard Deviation 2.294 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 288 | 0.85 Gram per Liter | Standard Deviation 0.405 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, OLE Baseline (BE period Week 48) | 1.06 Gram per Liter | Standard Deviation 0.55 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, OLE Baseline (BE period Week 48) | 9.75 Gram per Liter | Standard Deviation 2.253 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 240 | 9.28 Gram per Liter | Standard Deviation 2.081 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 144 | 0.88 Gram per Liter | Standard Deviation 0.463 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 192 | 2.60 Gram per Liter | Standard Deviation 1.242 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 288 | 9.46 Gram per Liter | Standard Deviation 2.068 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 72 | 9.63 Gram per Liter | Standard Deviation 2.335 |
| Placebo (Period 1) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 240 | 0.85 Gram per Liter | Standard Deviation 0.42 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 72 | 10.47 Gram per Liter | Standard Deviation 2.509 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 240 | 10.33 Gram per Liter | Standard Deviation 2.422 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 96 | 10.10 Gram per Liter | Standard Deviation 2.461 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 192 | 9.99 Gram per Liter | Standard Deviation 2.197 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 144 | 10.43 Gram per Liter | Standard Deviation 2.304 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 96 | 2.69 Gram per Liter | Standard Deviation 1.026 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 288 | 0.90 Gram per Liter | Standard Deviation 0.49 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 192 | 0.87 Gram per Liter | Standard Deviation 0.461 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 144 | 2.73 Gram per Liter | Standard Deviation 0.918 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 144 | 0.88 Gram per Liter | Standard Deviation 0.468 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 192 | 2.71 Gram per Liter | Standard Deviation 0.987 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 96 | 0.87 Gram per Liter | Standard Deviation 0.413 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 240 | 2.85 Gram per Liter | Standard Deviation 1.095 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 72 | 2.53 Gram per Liter | Standard Deviation 1.075 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 72 | 0.87 Gram per Liter | Standard Deviation 0.397 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 288 | 3.08 Gram per Liter | Standard Deviation 1.276 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, OLE Baseline (BE period Week 48) | 2.44 Gram per Liter | Standard Deviation 0.897 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, OLE Baseline (BE period Week 48) | 0.89 Gram per Liter | Standard Deviation 0.403 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, OLE Baseline (BE period Week 48) | 10.37 Gram per Liter | Standard Deviation 2.512 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 240 | 0.83 Gram per Liter | Standard Deviation 0.419 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 288 | 10.48 Gram per Liter | Standard Deviation 2.541 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 144 | 10.38 Gram per Liter | Standard Deviation 2.638 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, OLE Baseline (BE period Week 48) | 2.49 Gram per Liter | Standard Deviation 0.953 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 72 | 2.72 Gram per Liter | Standard Deviation 1.137 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 96 | 2.91 Gram per Liter | Standard Deviation 1.181 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 144 | 2.82 Gram per Liter | Standard Deviation 1.326 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 192 | 2.86 Gram per Liter | Standard Deviation 1.255 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 240 | 3.05 Gram per Liter | Standard Deviation 1.314 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 288 | 3.12 Gram per Liter | Standard Deviation 1.306 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, OLE Baseline (BE period Week 48) | 10.73 Gram per Liter | Standard Deviation 2.479 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 72 | 10.69 Gram per Liter | Standard Deviation 2.515 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 96 | 10.76 Gram per Liter | Standard Deviation 2.413 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 192 | 10.36 Gram per Liter | Standard Deviation 2.548 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 240 | 10.47 Gram per Liter | Standard Deviation 2.562 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 288 | 10.64 Gram per Liter | Standard Deviation 2.566 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, OLE Baseline (BE period Week 48) | 1.08 Gram per Liter | Standard Deviation 0.68 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 72 | 1.05 Gram per Liter | Standard Deviation 0.758 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 96 | 1.05 Gram per Liter | Standard Deviation 0.747 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 144 | 0.94 Gram per Liter | Standard Deviation 0.614 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 192 | 0.90 Gram per Liter | Standard Deviation 0.462 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 240 | 0.87 Gram per Liter | Standard Deviation 0.468 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 288 | 0.94 Gram per Liter | Standard Deviation 0.544 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 288 | 10.36 Gram per Liter | Standard Deviation 2.273 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, OLE Baseline (BE period Week 48) | 10.44 Gram per Liter | Standard Deviation 2.291 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 144 | 2.91 Gram per Liter | Standard Deviation 1.233 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, OLE Baseline (BE period Week 48) | 2.52 Gram per Liter | Standard Deviation 0.97 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 144 | 0.89 Gram per Liter | Standard Deviation 0.377 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 240 | 3.13 Gram per Liter | Standard Deviation 1.269 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 288 | 0.87 Gram per Liter | Standard Deviation 0.397 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 96 | 2.82 Gram per Liter | Standard Deviation 1.113 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 72 | 0.91 Gram per Liter | Standard Deviation 0.425 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 192 | 0.84 Gram per Liter | Standard Deviation 0.32 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 288 | 3.30 Gram per Liter | Standard Deviation 1.347 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 144 | 10.21 Gram per Liter | Standard Deviation 2.552 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 240 | 0.88 Gram per Liter | Standard Deviation 0.369 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 192 | 3.15 Gram per Liter | Standard Deviation 1.185 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 96 | 10.29 Gram per Liter | Standard Deviation 2.172 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 240 | 10.47 Gram per Liter | Standard Deviation 2.562 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 192 | 10.46 Gram per Liter | Standard Deviation 2.135 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, OLE Baseline (BE period Week 48) | 0.92 Gram per Liter | Standard Deviation 0.422 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 96 | 0.92 Gram per Liter | Standard Deviation 0.46 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 72 | 10.42 Gram per Liter | Standard Deviation 2.116 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 72 | 2.65 Gram per Liter | Standard Deviation 1.062 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 72 | 2.43 Gram per Liter | Standard Deviation 0.865 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 240 | 9.58 Gram per Liter | Standard Deviation 2.245 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, OLE Baseline (BE period Week 48) | 9.65 Gram per Liter | Standard Deviation 2.165 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 288 | 9.72 Gram per Liter | Standard Deviation 2.7 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 288 | 2.92 Gram per Liter | Standard Deviation 1.108 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, OLE Baseline (BE period Week 48) | 0.99 Gram per Liter | Standard Deviation 0.586 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 240 | 2.65 Gram per Liter | Standard Deviation 0.984 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 240 | 0.87 Gram per Liter | Standard Deviation 0.611 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 72 | 0.94 Gram per Liter | Standard Deviation 0.561 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgA, Week 192 | 2.70 Gram per Liter | Standard Deviation 1.055 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, OLE Baseline (BE period Week 48) | 2.31 Gram per Liter | Standard Deviation 0.906 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 96 | 0.91 Gram per Liter | Standard Deviation 0.525 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 144 | 2.57 Gram per Liter | Standard Deviation 1.025 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 144 | 0.90 Gram per Liter | Standard Deviation 0.519 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig A, Week 96 | 2.62 Gram per Liter | Standard Deviation 1.072 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 288 | 1.03 Gram per Liter | Standard Deviation 0.568 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig M, Week 192 | 0.90 Gram per Liter | Standard Deviation 0.585 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 144 | 9.32 Gram per Liter | Standard Deviation 2.115 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 96 | 9.93 Gram per Liter | Standard Deviation 2.285 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | IgG, Week 192 | 9.56 Gram per Liter | Standard Deviation 2.094 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels | Ig G, Week 72 | 9.93 Gram per Liter | Standard Deviation 2.131 |
Secondary
OLE Period: Annualized Relapse Rate (ARR)
A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days.
Time frame: OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336
Population: modified ITT OLE Analysis Set (mITT-OLE) Analysis Set: participants randomly allocated to a treatment who belong to Safety OLE Analysis Set, and who have at least 1 Magnetic Resonance Imaging (MRI) assessment on or after OLE Week 0. Here, Number analyzed signifies those participants who were evaluable for the specified category. Results reported are for OLE period only and no participants took placebo during this period.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo (Period 1) | OLE Period: Annualized Relapse Rate (ARR) | Week 144 | 0.07 relapses per year |
| Placebo (Period 1) | OLE Period: Annualized Relapse Rate (ARR) | Week 96 | 0.16 relapses per year |
| Placebo (Period 1) | OLE Period: Annualized Relapse Rate (ARR) | OLE Baseline (BE period Week 48) | 0.29 relapses per year |
| Placebo (Period 1) | OLE Period: Annualized Relapse Rate (ARR) | Week 240 | 0.16 relapses per year |
| Placebo (Period 1) | OLE Period: Annualized Relapse Rate (ARR) | Week 192 | 0.04 relapses per year |
| Placebo (Period 1) | OLE Period: Annualized Relapse Rate (ARR) | Week 288 | 0.13 relapses per year |
| Placebo (Period 1) | OLE Period: Annualized Relapse Rate (ARR) | Week 336 | 0.00 relapses per year |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 336 | 0.00 relapses per year |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 288 | 0.05 relapses per year |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 192 | 0.08 relapses per year |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 144 | 0.11 relapses per year |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | OLE Baseline (BE period Week 48) | 0.18 relapses per year |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 240 | 0.04 relapses per year |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 96 | 0.13 relapses per year |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 288 | 0.07 relapses per year |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 144 | 0.03 relapses per year |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 192 | 0.22 relapses per year |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 240 | 0.10 relapses per year |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 336 | 0.31 relapses per year |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | OLE Baseline (BE period Week 48) | 0.14 relapses per year |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 96 | 0.09 relapses per year |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 240 | 0.13 relapses per year |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 336 | 0.00 relapses per year |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 192 | 0.16 relapses per year |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 96 | 0.08 relapses per year |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | OLE Baseline (BE period Week 48) | 0.17 relapses per year |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 144 | 0.15 relapses per year |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 288 | 0.00 relapses per year |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 240 | 0.00 relapses per year |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 96 | 0.03 relapses per year |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | OLE Baseline (BE period Week 48) | 0.12 relapses per year |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 336 | 0.00 relapses per year |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 192 | 0.04 relapses per year |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 144 | 0.16 relapses per year |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Annualized Relapse Rate (ARR) | Week 288 | 0.04 relapses per year |
Secondary
OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336
The EDSS is an ordinal clinical rating scale in half-point increments. It assesses the following eight functional systems, areas of the central nervous system that control bodily functions: Pyramidal (ability to walk), Cerebellar (coordination), Brain stem (speech and swallowing), Sensory (touch and pain), Bowel and bladder functions, Visual, Mental, Other (includes any other neurological findings due to Multiple Sclerosis \[MS\]). EDSS overall score ranging from 0 (normal) to 10 (death due to MS).
Time frame: OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336
Population: modified ITT OLE Analysis Set (mITT-OLE) Analysis Set: participants randomly allocated to a treatment who belong to Safety OLE Analysis Set, and who have at least 1 Magnetic Resonance Imaging (MRI) assessment on or after OLE Week 0. Overall Number of Participants Analyzed= Participants evaluable for this outcome measure and Number analyzed = participants who were evaluable for the specified category. Results reported are for OLE period only and no participants took placebo during this period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Period 1) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 96 | 0.1 units on a scale | Standard Deviation 0.4 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 240 | 0.3 units on a scale | Standard Deviation 0.72 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 336 | 0.0 units on a scale | Standard Deviation 0.52 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 288 | 0.4 units on a scale | Standard Deviation 0.8 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 144 | 0.1 units on a scale | Standard Deviation 0.79 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | OLE Baseline (BE period Week 48) | 0.1 units on a scale | Standard Deviation 0.39 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 192 | 0.2 units on a scale | Standard Deviation 0.64 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 96 | 0.1 units on a scale | Standard Deviation 0.46 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 144 | 0.1 units on a scale | Standard Deviation 0.61 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | OLE Baseline (BE period Week 48) | 0.0 units on a scale | Standard Deviation 0.69 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 192 | 0.1 units on a scale | Standard Deviation 0.61 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 240 | 0.3 units on a scale | Standard Deviation 0.5 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 288 | 0.1 units on a scale | Standard Deviation 0.87 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 336 | 0.5 units on a scale | Standard Deviation 1.36 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 336 | 0.7 units on a scale | Standard Deviation 1.38 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 288 | 0.4 units on a scale | Standard Deviation 0.58 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 144 | 0.2 units on a scale | Standard Deviation 0.79 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 192 | 0.2 units on a scale | Standard Deviation 0.35 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 96 | 0.2 units on a scale | Standard Deviation 0.71 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | OLE Baseline (BE period Week 48) | 0.1 units on a scale | Standard Deviation 0.46 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 240 | 0.2 units on a scale | Standard Deviation 0.46 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 96 | 0.0 units on a scale | Standard Deviation 0.42 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 144 | 0.0 units on a scale | Standard Deviation 0.44 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 240 | 0.2 units on a scale | Standard Deviation 0.93 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 192 | 0.2 units on a scale | Standard Deviation 0.72 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 288 | 0.4 units on a scale | Standard Deviation 0.81 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 336 | -0.2 units on a scale | Standard Deviation 0.57 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | OLE Baseline (BE period Week 48) | 0.0 units on a scale | Standard Deviation 0.27 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 336 | 0.0 units on a scale | Standard Deviation 0.52 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 240 | 0.1 units on a scale | Standard Deviation 0.4 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | OLE Baseline (BE period Week 48) | 0.0 units on a scale | Standard Deviation 0.34 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 288 | 0.2 units on a scale | Standard Deviation 0.45 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 192 | 0.0 units on a scale | Standard Deviation 0.29 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 144 | 0.0 units on a scale | Standard Deviation 0.28 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 | Week 96 | 0.0 units on a scale | Standard Deviation 0.32 |
Secondary
OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels
Change from baseline in the serum levels of IgG, IgA, IgM were assessed.
Time frame: OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240 and 288
Population: The Safety OLE Analysis Set included all participants who receive at least 1 dose of Evobrutinib during the OLE. Overall Number of Participants Analyzed= Participants evaluable for this outcome measure and Number analyzed = participants who were evaluable for the specified category. Results reported are for OLE period only and no participants took placebo during this period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 72 | -0.19 Gram per Liter | Standard Deviation 0.17 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 288 | 0.18 Gram per Liter | Standard Deviation 1.492 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 96 | -0.23 Gram per Liter | Standard Deviation 0.146 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig M, OLE Baseline (BE period Week 48) | -0.18 Gram per Liter | Standard Deviation 0.152 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 144 | -0.28 Gram per Liter | Standard Deviation 0.323 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 192 | 0.60 Gram per Liter | Standard Deviation 0.597 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 72 | 0.40 Gram per Liter | Standard Deviation 1.019 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 144 | 0.58 Gram per Liter | Standard Deviation 0.594 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 96 | 0.17 Gram per Liter | Standard Deviation 1.359 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 288 | 0.68 Gram per Liter | Standard Deviation 0.934 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 144 | 0.35 Gram per Liter | Standard Deviation 1.367 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 240 | -0.29 Gram per Liter | Standard Deviation 0.282 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 96 | 0.44 Gram per Liter | Standard Deviation 0.491 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 192 | 0.14 Gram per Liter | Standard Deviation 1.227 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 72 | 0.40 Gram per Liter | Standard Deviation 0.398 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 240 | -0.01 Gram per Liter | Standard Deviation 1.336 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 240 | 0.67 Gram per Liter | Standard Deviation 0.605 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, OLE Baseline (BE period Week 48) | 0.26 Gram per Liter | Standard Deviation 0.237 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, OLE Baseline (BE period Week 48) | 0.39 Gram per Liter | Standard Deviation 0.96 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 192 | -0.28 Gram per Liter | Standard Deviation 0.254 |
| Placebo (Period 1) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 288 | -0.29 Gram per Liter | Standard Deviation 0.284 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 240 | -0.20 Gram per Liter | Standard Deviation 0.187 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 96 | -0.13 Gram per Liter | Standard Deviation 0.141 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 144 | 0.17 Gram per Liter | Standard Deviation 1.451 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 288 | 0.48 Gram per Liter | Standard Deviation 1.465 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 288 | -0.11 Gram per Liter | Standard Deviation 0.313 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 240 | 0.10 Gram per Liter | Standard Deviation 1.557 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 72 | -0.11 Gram per Liter | Standard Deviation 0.119 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 144 | -0.14 Gram per Liter | Standard Deviation 0.195 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig M, OLE Baseline (BE period Week 48) | -0.10 Gram per Liter | Standard Deviation 0.12 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 192 | 0.38 Gram per Liter | Standard Deviation 0.443 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 72 | 0.36 Gram per Liter | Standard Deviation 0.515 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, OLE Baseline (BE period Week 48) | 0.54 Gram per Liter | Standard Deviation 1.463 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 192 | -0.13 Gram per Liter | Standard Deviation 1.141 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 72 | 0.56 Gram per Liter | Standard Deviation 1.364 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 288 | 0.75 Gram per Liter | Standard Deviation 0.68 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 144 | 0.41 Gram per Liter | Standard Deviation 0.347 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 240 | 0.55 Gram per Liter | Standard Deviation 0.471 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 192 | -0.16 Gram per Liter | Standard Deviation 0.204 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 96 | 0.18 Gram per Liter | Standard Deviation 1.228 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, OLE Baseline (BE period Week 48) | 0.17 Gram per Liter | Standard Deviation 0.333 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 96 | 0.45 Gram per Liter | Standard Deviation 0.407 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 288 | 0.91 Gram per Liter | Standard Deviation 0.915 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, OLE Baseline (BE period Week 48) | 0.69 Gram per Liter | Standard Deviation 1.147 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 72 | 0.79 Gram per Liter | Standard Deviation 1.236 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 96 | 0.64 Gram per Liter | Standard Deviation 1.178 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 144 | 0.31 Gram per Liter | Standard Deviation 1.356 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 192 | 0.18 Gram per Liter | Standard Deviation 1.625 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 240 | 0.37 Gram per Liter | Standard Deviation 1.596 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 240 | -0.19 Gram per Liter | Standard Deviation 0.205 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 288 | -0.15 Gram per Liter | Standard Deviation 0.315 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 288 | 0.37 Gram per Liter | Standard Deviation 2.203 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig M, OLE Baseline (BE period Week 48) | -0.09 Gram per Liter | Standard Deviation 0.122 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 72 | -0.10 Gram per Liter | Standard Deviation 0.147 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 96 | -0.09 Gram per Liter | Standard Deviation 0.199 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 144 | -0.17 Gram per Liter | Standard Deviation 0.174 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 192 | -0.19 Gram per Liter | Standard Deviation 0.186 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, OLE Baseline (BE period Week 48) | 0.19 Gram per Liter | Standard Deviation 0.283 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 72 | 0.41 Gram per Liter | Standard Deviation 0.417 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 96 | 0.58 Gram per Liter | Standard Deviation 0.485 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 144 | 0.50 Gram per Liter | Standard Deviation 0.67 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 192 | 0.55 Gram per Liter | Standard Deviation 0.667 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 240 | 0.74 Gram per Liter | Standard Deviation 0.682 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 288 | -0.17 Gram per Liter | Standard Deviation 0.178 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 96 | 0.54 Gram per Liter | Standard Deviation 0.446 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 240 | -0.16 Gram per Liter | Standard Deviation 0.254 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, OLE Baseline (BE period Week 48) | 0.26 Gram per Liter | Standard Deviation 0.291 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 72 | 1.07 Gram per Liter | Standard Deviation 0.994 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 144 | -0.11 Gram per Liter | Standard Deviation 0.149 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 144 | 0.57 Gram per Liter | Standard Deviation 0.589 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 192 | 0.84 Gram per Liter | Standard Deviation 1.384 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 288 | 1.02 Gram per Liter | Standard Deviation 0.637 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, OLE Baseline (BE period Week 48) | 1.11 Gram per Liter | Standard Deviation 1.15 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 192 | -0.18 Gram per Liter | Standard Deviation 0.197 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 240 | 0.78 Gram per Liter | Standard Deviation 0.621 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig M, OLE Baseline (BE period Week 48) | -0.05 Gram per Liter | Standard Deviation 0.099 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 72 | 0.38 Gram per Liter | Standard Deviation 0.453 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 192 | 0.82 Gram per Liter | Standard Deviation 0.53 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 72 | -0.07 Gram per Liter | Standard Deviation 0.104 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 240 | 0.75 Gram per Liter | Standard Deviation 1.362 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 288 | 1.01 Gram per Liter | Standard Deviation 1.57 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 144 | 0.68 Gram per Liter | Standard Deviation 1.458 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 96 | 0.84 Gram per Liter | Standard Deviation 1.073 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 96 | -0.08 Gram per Liter | Standard Deviation 0.127 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 192 | -0.46 Gram per Liter | Standard Deviation 0.33 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 240 | -0.53 Gram per Liter | Standard Deviation 0.348 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 288 | 0.93 Gram per Liter | Standard Deviation 0.724 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 144 | -0.40 Gram per Liter | Standard Deviation 0.327 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 240 | 0.19 Gram per Liter | Standard Deviation 1.314 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 192 | 0.09 Gram per Liter | Standard Deviation 1.324 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 96 | 0.47 Gram per Liter | Standard Deviation 1.355 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, OLE Baseline (BE period Week 48) | 0.28 Gram per Liter | Standard Deviation 0.355 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 144 | -0.09 Gram per Liter | Standard Deviation 1.176 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 72 | 0.42 Gram per Liter | Standard Deviation 0.368 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 240 | 0.68 Gram per Liter | Standard Deviation 0.52 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 96 | 0.59 Gram per Liter | Standard Deviation 0.545 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, Week 72 | 0.48 Gram per Liter | Standard Deviation 1.288 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 96 | -0.35 Gram per Liter | Standard Deviation 0.301 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig A, Week 144 | 0.54 Gram per Liter | Standard Deviation 0.452 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig G, OLE Baseline (BE period Week 48) | 0.23 Gram per Liter | Standard Deviation 1.216 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | Ig M, OLE Baseline (BE period Week 48) | -0.28 Gram per Liter | Standard Deviation 0.28 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgG, Week 288 | 0.36 Gram per Liter | Standard Deviation 1.44 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 72 | -0.34 Gram per Liter | Standard Deviation 0.264 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgM, Week 288 | -0.39 Gram per Liter | Standard Deviation 0.472 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels | IgA, Week 192 | 0.67 Gram per Liter | Standard Deviation 0.492 |
Secondary
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECGs)
ECG parameters included rhythm, ventricular rate, PR interval, QRS duration, and QT interval. Number of participants with clinically significant change from baseline in ECG were reported. Clinical Significance was decided by the investigator.
Time frame: OLE Baseline (BE period Week 48) up to OLE Week 336
Population: The Safety OLE Analysis Set included all participants who receive at least 1 dose of Evobrutinib during the OLE. Results reported are for OLE period only and no participants took placebo during this period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (Period 1) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECGs) | 0 Participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECGs) | 0 Participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECGs) | 0 Participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECGs) | 0 Participants |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECGs) | 0 Participants |
Secondary
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters
Laboratory parameters included hematology, biochemistry, and urinalysis. Number of participants with clinically significant change from baseline in laboratory parameters were reported. Clinical Significance was decided by the investigator.
Time frame: OLE Baseline (BE period Week 48) up to OLE Week 336
Population: The Safety OLE Analysis Set included all participants who receive at least 1 dose of Evobrutinib during the OLE. Results reported are for OLE period only and no participants took placebo during this period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (Period 1) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | 0 Participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | 0 Participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | 0 Participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | 0 Participants |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | 0 Participants |
Secondary
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
Vital signs, including semi supine blood pressure, pulse rate, respiratory rate, weight, and oral temperature were assessed. Number of participants with clinically significant change from baseline in vital signs were reported. Clinical Significance was decided by the investigator.
Time frame: OLE Baseline (BE period Week 48) up to OLE Week 336
Population: The Safety OLE Analysis Set included all participants who receive at least 1 dose of Evobrutinib during the OLE. Results reported are for OLE period only and no participants took placebo during this period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (Period 1) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
Secondary
OLE Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the study drug. An AE was defined as 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. A serious adverse event (SAE) was 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. Treatment-emergent adverse events are defined as any adverse event with a start date on or after the date of first dose and within 28 days after the date of last dose in the study. TEAEs include both Serious TEAEs and non-serious TEAEs.
Time frame: OLE Baseline (BE period Week 48) up to OLE Week 336
Population: The Safety OLE Analysis Set included all participants who receive at least 1 dose of Evobrutinib during the OLE. Results reported are for OLE period only and no participants took placebo during this period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (Period 1) | OLE Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 35 Participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 29 Participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 41 Participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 40 Participants |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 37 Participants |
Secondary
OLE Period: Percentage of Participants With Qualified Relapse-Free Status
A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. Percentage of participants with qualified relapse-free status from OLE Baseline (BE period Week 48) up to Week 336 were reported.
Time frame: OLE Baseline (BE period Week 48) up to OLE Week 336
Population: modified ITT OLE Analysis Set (mITT-OLE) Analysis Set: participants randomly allocated to a treatment who belong to Safety OLE Analysis Set, and who have at least 1 Magnetic Resonance Imaging (MRI) assessment on or after OLE Week 0. Overall Number of Participants Analyzed= Participants evaluable for this outcome measure. Results reported are for OLE period only and no participants took placebo during this period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Period 1) | OLE Period: Percentage of Participants With Qualified Relapse-Free Status | 66.7 percentage of participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Percentage of Participants With Qualified Relapse-Free Status | 68.4 percentage of participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Percentage of Participants With Qualified Relapse-Free Status | 71.4 percentage of participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Percentage of Participants With Qualified Relapse-Free Status | 65.9 percentage of participants |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Percentage of Participants With Qualified Relapse-Free Status | 83.3 percentage of participants |
Secondary
OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions
Analysis of T1-Gadolinium enhancing lesions was done using magnetic resonance imaging (MRI) scans.
Time frame: OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336
Population: modified ITT OLE Analysis Set (mITT-OLE) Analysis Set: participants randomly allocated to a treatment who belong to Safety OLE Analysis Set, and who have at least 1 Magnetic Resonance Imaging (MRI) assessment on or after OLE Week 0. Overall Number of Participants Analyzed= Participants evaluable for this outcome measure and Number analyzed= participants who were evaluable for the specified category. Results reported are for OLE period only and no participants took placebo during this period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Period 1) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 192 | 1.00 Lesions | Standard Deviation 3.367 |
| Placebo (Period 1) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 336 | 0.83 Lesions | Standard Deviation 1.602 |
| Placebo (Period 1) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | OLE Baseline (BE period Week 48) | 0.82 Lesions | Standard Deviation 2.668 |
| Placebo (Period 1) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 240 | 1.68 Lesions | Standard Deviation 5.8 |
| Placebo (Period 1) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 144 | 0.76 Lesions | Standard Deviation 2.294 |
| Placebo (Period 1) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 288 | 0.35 Lesions | Standard Deviation 0.671 |
| Placebo (Period 1) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 96 | 0.13 Lesions | Standard Deviation 0.341 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 336 | 3.00 Lesions | Standard Deviation 5.745 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 240 | 0.63 Lesions | Standard Deviation 1.996 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 288 | 0.35 Lesions | Standard Deviation 0.786 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 96 | 0.63 Lesions | Standard Deviation 1.822 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | OLE Baseline (BE period Week 48) | 1.74 Lesions | Standard Deviation 4.395 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 144 | 0.41 Lesions | Standard Deviation 1.217 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 192 | 0.64 Lesions | Standard Deviation 1.89 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | OLE Baseline (BE period Week 48) | 1.46 Lesions | Standard Deviation 4.519 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 96 | 0.49 Lesions | Standard Deviation 1.121 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 336 | 1.17 Lesions | Standard Deviation 2.858 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 288 | 0.32 Lesions | Standard Deviation 1.09 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 192 | 0.81 Lesions | Standard Deviation 2.206 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 240 | 0.37 Lesions | Standard Deviation 1.189 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 144 | 0.82 Lesions | Standard Deviation 3.512 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 336 | 0.29 Lesions | Standard Deviation 0.756 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | OLE Baseline (BE period Week 48) | 1.16 Lesions | Standard Deviation 3.05 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 96 | 0.69 Lesions | Standard Deviation 1.411 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 144 | 0.54 Lesions | Standard Deviation 1.146 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 192 | 0.84 Lesions | Standard Deviation 1.798 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 240 | 0.77 Lesions | Standard Deviation 2.417 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 288 | 1.04 Lesions | Standard Deviation 2.946 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 192 | 0.96 Lesions | Standard Deviation 3.13 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 336 | 5.60 Lesions | Standard Deviation 18.31 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 288 | 0.35 Lesions | Standard Deviation 1.265 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 144 | 1.29 Lesions | Standard Deviation 5.94 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 96 | 0.67 Lesions | Standard Deviation 2.255 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | OLE Baseline (BE period Week 48) | 2.03 Lesions | Standard Deviation 11.829 |
| Tecfidera (Period 1, 2 and 3) | OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions | Week 240 | 0.88 Lesions | Standard Deviation 3.204 |
Secondary
Qualified Relapse-free Status
A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. Percentage of participants with qualified relapse-free status were reported.
Time frame: Week 25 to Week 48
Population: mITT BE analysis set included all participants who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Period 1) | Qualified Relapse-free Status | 84.1 percentage of participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Qualified Relapse-free Status | 86.4 percentage of participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Qualified Relapse-free Status | 78.3 percentage of participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Qualified Relapse-free Status | 91.1 percentage of participants |
| Tecfidera (Period 1, 2 and 3) | Qualified Relapse-free Status | 96.0 percentage of participants |
Secondary
Qualified Relapse-Free Status at Week 24
A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. Percentage of participants with qualified relapse-free status at week 24 were reported. As per planned analysis, Tecfidera treatment group was not included in inferential analysis.
Time frame: Week 24
Population: mITT analysis set consists of all participants who belong to both the ITT and safety analysis sets, and who have at least one baseline and one post-baseline MRI assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Period 1) | Qualified Relapse-Free Status at Week 24 | 77.4 percentage of participants |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Qualified Relapse-Free Status at Week 24 | 74.0 percentage of participants |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Qualified Relapse-Free Status at Week 24 | 88.2 percentage of participants |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Qualified Relapse-Free Status at Week 24 | 86.8 percentage of participants |
| Tecfidera (Period 1, 2 and 3) | Qualified Relapse-Free Status at Week 24 | 88.9 percentage of participants |
p-value: 0.560995% CI: [0.29, 1.95]Logistic model
p-value: 0.068995% CI: [0.92, 8.41]Logistic model
p-value: 0.176795% CI: [0.72, 5.99]Logistic model
Secondary
Total Number of New Gadolinium-positive (Gd+) T1 Lesions
Analysis of Gadolinium-positive T1 lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis.
Time frame: Week 12 to 24
Population: Modified Intent-To-Treat (mITT) analysis set included participants who belong to both Intent To Treat (ITT, consisted all participants who randomly allocated to a treatment, based on the intention to treat as randomized principle) and safety analysis sets (consisted all participants who receive at least 1 dose of trial treatment), and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Total Number of New Gadolinium-positive (Gd+) T1 Lesions | 3.08 Lesions | Standard Deviation 4.371 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Total Number of New Gadolinium-positive (Gd+) T1 Lesions | 3.44 Lesions | Standard Deviation 6.846 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Total Number of New Gadolinium-positive (Gd+) T1 Lesions | 1.20 Lesions | Standard Deviation 3.499 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Total Number of New Gadolinium-positive (Gd+) T1 Lesions | 0.98 Lesions | Standard Deviation 3.273 |
| Tecfidera (Period 1, 2 and 3) | Total Number of New Gadolinium-positive (Gd+) T1 Lesions | 3.24 Lesions | Standard Deviation 15.32 |
p-value: 0.367695% CI: [0.7, 2.65]Negative Binomial
p-value: 0.000595% CI: [0.13, 0.57]Negative Binomial
p-value: 0.015795% CI: [0.2, 0.85]Negative Binomial
Secondary
Total Number of New or Enlarging T2 Lesions
Analysis of New or Enlarging T2 lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis.
Time frame: Week 12 to Week 24
Population: mITT analysis set consists of all participants who belong to both the ITT and safety analysis sets, and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Total Number of New or Enlarging T2 Lesions | 5.96 Lesions | Standard Deviation 6.994 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Total Number of New or Enlarging T2 Lesions | 6.52 Lesions | Standard Deviation 11.569 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Total Number of New or Enlarging T2 Lesions | 3.41 Lesions | Standard Deviation 10.752 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Total Number of New or Enlarging T2 Lesions | 2.19 Lesions | Standard Deviation 4.719 |
| Tecfidera (Period 1, 2 and 3) | Total Number of New or Enlarging T2 Lesions | 5.35 Lesions | Standard Deviation 16.667 |
p-value: 0.480795% CI: [0.63, 2.65]Negative Binomial
p-value: 0.06295% CI: [0.24, 1.04]Negative Binomial
p-value: 0.018995% CI: [0.2, 0.87]Negative Binomial
Secondary
Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 24
Analysis of New or Enlarging T2 lesions was done using magnetic resonance imaging (MRI) scans.
Time frame: Week 24 to Week 48
Population: mITT BE analysis set included all participants who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period. Here, Number of Participants Analyzed signified those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 24 | 3.57 Lesions | Standard Deviation 4.346 |
| Evobrutinib 25 mg QD (Period 1, 2 and 3) | Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 24 | 5.86 Lesions | Standard Deviation 11.33 |
| Evobrutinib 75 mg QD (Period 1, 2 and 3) | Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 24 | 3.84 Lesions | Standard Deviation 10.083 |
| Evobrutinib 75 mg BID (Period 1, 2 and 3) | Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 24 | 1.60 Lesions | Standard Deviation 3.799 |
| Tecfidera (Period 1, 2 and 3) | Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 24 | 1.88 Lesions | Standard Deviation 4.796 |