Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| 2022-002755-19 | EudraCT Number |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
The main purpose of the study is to compare the Pharmacokinetics (PK), safety and tolerability of different manufacturing batches of M2951 tablet formulation relative to a reference batch under fasted conditions in healthy participants.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Evobrutinib: Treatment Sequence 1: ABCD | Experimental | Participants will receive single oral dose of Treatment A on Day 1 in period 1, followed by single oral dose of Treatment B on Day 3 in period 2, followed by Treatment C on Day 5 in period 3 and followed by single oral dose of Treatment D on Day 7 under fasted condition in period 4. There will be 48 hours washout period between each treatment period. |
|
| Evobrutinib: Treatment Sequence 2: BDAC | Experimental | Participants will receive single oral dose of Treatment B on Day 1 in period 1, followed by single oral dose of Treatment D on Day 3 in period 2, followed by Treatment A on Day 5 in period 3 and followed by single oral dose of Treatment C on Day 7 under fasted condition in period 4. There will be 48 hours washout period between each treatment period. |
|
| Evobrutinib: Treatment Sequence 3: CADB | Experimental | Participants will receive single oral dose of Treatment C on Day 1 in period 1, followed by single oral dose of Treatment A on Day 3 in period 2, followed by Treatment D on Day 5 in period 3 and followed by single oral dose of Treatment B on Day 7 under fasted condition in period 4. There will be 48 hours washout period between each treatment period. |
|
| Evobrutinib: Treatment Sequence 4: DCBA |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Treatment A | Drug | Participants will receive single dose of Treatment A in treatment period 1, 2, 3 or 4 under fasted conditions. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Evobrutinib | AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
| Maximum Observed Plasma Concentration (Cmax) of Evobrutinib | Cmax was obtained directly from the concentration versus time curve. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Treatment- Emergent Adverse Events (TEAEs) | An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE 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. TEAEs were defined as events with onset date or worsening during the on-treatment period. TEAEs included both serious and non-serious TEAEs. |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Participants with history or presence of clinically relevant respiratory, gastrointestinal, renal, hepatic, hematological, lymphatic, neurological, cardiovascular, musculoskeletal, genitourinary, immunological, dermatological, connective tissue, psychiatric (due to rare risk of hallucinations, agitation and activation of psychosis), and other diseases or disorders, and epilepsy, as determined by medical evaluation
Participants with diagnosis of hemochromatosis, Wilson´s disease, alpha 1 antitrypsin deficiency, or any other chronic liver disease including Gilbert's disease will be excluded from the study
Participants with prior history of cholecystectomy or splenectomy, and any clinically relevant surgery within 6 months prior to the first administration of study intervention
Participants with history of any malignancy
Participants with history of seizures
Participants with history of pharmacologically treated psychiatric disease
Participants with history of chronic or recurrent acute infection or any bacterial, viral, parasitic or fungal infections within 30 days prior to Screening and at any time between Screening and admission, or hospitalization due to infection within 6 months prior to the first administration of study intervention
Participants with history of shingles within 12 months prior to Screening
Participants with history of drug hypersensitivity
Participants with history of residential exposure to tuberculosis, or a positive QuantiFERON® test within 4 weeks prior to or at the time of Screening
Participants positive for
Participants with any condition, including findings in the laboratory tests, medical history (example heart failure, hypokalemia, family history of Long QT Syndrome), or other Screening assessments, that in the opinion of the Investigator constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study's objectives, conduct, or evaluation
Participants with history of administration of live vaccines or live-attenuated virus vaccines within 3 months prior to Day 1.
Participants with history of administration of other types of vaccines is allowed until 14 days before the first administration of study intervention, thereafter it is prohibited until the end of the study.
Participants with Moderate or strong inhibitors or inducers of Cytochrome P450 3A4 (CYP3A4)/5 or Pgp within 4 weeks prior to the first administration of study intervention
Participants with use of any prescribed medicine or over-the-counter drug or dietary supplement, including herbal remedies, vitamins, and minerals, antacids and dietary supplements such as fish oils within 2 weeks or 5 times the half-life of the respective drug, whichever is longer, prior to the first administration of study intervention
Participants with use of any investigational drug in any clinical study within 60 days prior to Day 1 administration, or have used an experimental monoclonal antibody within the past 1 year prior to Day 1, or have participated in a study evaluating a Bruton Tyrosine Kinase (BTK) inhibitor within 60 days, or are on extended follow-up in a clinical study, even if last administration of a study intervention was more than 60 days ago, or 5 half-lives of the investigational drug, whichever is longer, prior to the first administration of study intervention
Participants with a medical history and physical examination results that include any ongoing clinically relevant findings as judged by the Investigator
Participants with clinically relevant findings (excluding minor, not clinically relevant excursions from normal ranges, as judged by the Investigator) at Screening in biochemistry, hematology, coagulation, and urinalysis examinations for the age of the participant, as judged by the Investigator:
Participants with estimated glomerular rate (eGFR) according to the Chronic Kidney Disease Epidemiology Collaboration Creatinine Equation (2009) < 90 milliliters/minute(mL/min) at Screening. In case of a borderline result between ≥ 80 and < 90 mL/min, Cystatin C will be determined in addition, and the participant will only be included if the Cystatin C value is below the upper limit of normal
Participants with semi-supine systolic blood pressure > 140 mmHg or < 90 millimeters of mercury (mmHg), diastolic blood pressure > 90 mmHg or < 50 mmHg, and pulse rate > 90 or < 50 beats per minute (bpm) at Screening.
Participants with consumption of alcohol from 48 hours prior to first administration of study intervention.
Other protocol defined exclusion criteria could apply
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Nuvisan GmbH | Neu-Ulm | 89231 | Germany |
Not provided
| Label | URL |
|---|---|
| Trial Awareness and Transparency website | View source |
| Medical Information Location Map - Med Info Contacts | View source |
Not provided
We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Sequence 1: Treatment A-B-C-D | Participants received single oral dose of reference treatment (treatment A) of Evobrutinib (45 milligrams [mg]) on Day 1 in period 1, followed by single oral dose of lower dissolution bound batch (treatment B) of Evobrutinib (45 mg) on Day 3 in period 2, followed by single oral dose of upper dissolution bound batch (treatment C) of Evobrutinib (45 mg) on Day 5 in period 3 and followed by single oral dose of hammer milled batch (treatment D) of Evobrutinib (45 mg) on Day 7 under fasted condition in period 4. A washout period of 48 hours was maintained between 4 treatment periods. |
| FG001 | Sequence 2: Treatment B-D-A-C | Participants received single oral dose of lower dissolution bound batch (treatment B) of Evobrutinib (45 mg) on Day 1 in period 1, followed by single oral dose of hammer milled batch (treatment D) of Evobrutinib (45 mg) on Day 3 in period 2, followed by single oral dose of reference treatment (treatment A) of Evobrutinib (45 (mg) on Day 5 in period 3 and followed by single oral dose of upper dissolution bound batch (treatment C) of Evobrutinib (45 mg) on Day 7 under fasted condition in period 4. A washout period of 48 hours was maintained between 4 treatment periods. |
| FG002 | Sequence 3: Treatment C-A-D-B | Participants received single oral dose of upper dissolution bound batch (treatment C) of Evobrutinib (45 mg) on Day 1 in period 1, followed by single oral dose of reference treatment (treatment A) of Evobrutinib (45 (mg) on Day 3 in period 2, followed by single oral dose of hammer milled batch (treatment D) of Evobrutinib (45 mg) on Day 5 in period 3 and followed by single oral dose of lower dissolution bound batch (treatment B) of Evobrutinib (45 mg) on Day 7 under fasted condition in period 4. A washout period of 48 hours was maintained between 4 treatment periods. |
| FG003 | Sequence 4: Treatment D-C-B-A | Participants received single oral dose of hammer milled batch (treatment D) of Evobrutinib (45 mg) on Day 1 in period 1, followed by single oral dose of upper dissolution bound batch (treatment C) of Evobrutinib (45 mg) on Day 3 in period 2, followed by single oral dose of lower dissolution bound batch (treatment B) of Evobrutinib (45 mg) on Day 5 in period 3 and followed by single oral dose of reference treatment (treatment A) of Evobrutinib (45 (mg) on Day 7 under fasted condition in period 4. A washout period of 48 hours was maintained between 4 treatment periods. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Sequence 1: Treatment A-B-C-D | Participants received single oral dose of reference treatment (treatment A) of Evobrutinib (45 milligrams [mg]) on Day 1 in period 1, followed by single oral dose of lower dissolution bound batch (treatment B) of Evobrutinib (45 mg) on Day 3 in period 2, followed by single oral dose of upper dissolution bound batch (treatment C) of Evobrutinib (45 mg) on Day 5 in period 3 and followed by single oral dose of hammer milled batch (treatment D) of Evobrutinib (45 mg) on Day 7 under fasted condition in period 4. A washout period of 48 hours was maintained between 4 treatment periods. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Evobrutinib | AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. | Pharmacokinetic (PK) Analysis Set was a subset of the Safety Analysis Set and included all participants who receive at least one dose of active investigational medicinal product (IMP) and provide at least one measurable post-dose concentration. | Posted | Geometric Mean | Geometric Coefficient of Variation | hour×nanogram per milliliter (h×ng/mL) | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
|
Up to 34 days
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Treatment A | Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg) in treatment period 1, 2,3 or 4 under fasted conditions. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Seizure | Nervous system disorders | MedDRA 25.1 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypersensitivity | Immune system disorders | meddra 25.1 | Non-systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Communication Center | Merck Healthcare KGaA, Darmstadt Germany, an affiliate of Merck KGaA, Darmstadt, Germany | +49-6151-72-5200 | service@emdgroup.com |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Sep 8, 2022 | Oct 24, 2025 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 6, 2023 | Oct 24, 2025 | SAP_001.pdf |
Not provided
| ID | Term |
|---|---|
| C000632111 | evobrutinib |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Participants will receive single oral dose of Treatment D on Day 1 in period 1, followed by single oral dose of Treatment C on Day 3 in period 2, followed by Treatment B on Day 5 in period 3 and followed by single oral dose of Treatment A on Day 7 under fasted condition in period 4. There will be 48 hours washout period between each treatment period. |
|
|
| Treatment B | Drug | Participants will receive single dose of Treatment B in treatment period 1, 2, 3 or 4 under fasted conditions. |
|
|
| Treatment C | Drug | Participants will receive single dose of Treatment C in treatment period 1, 2, 3 or 4 under fasted conditions. |
|
|
| Treatment D | Drug | Participants will receive single dose of Treatment D in treatment period 1, 2, 3 or 4 under fasted conditions. |
|
|
| Up to 34 days |
| Number of Participants With Treatment- Emergent Adverse Events (TEAEs) by Severity | The Investigator assessed the severity of each AE and SAE reported during the study and assign it to one of the following categories: Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities; Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities; Severe: An event that prevents normal everyday activities. Do not confuse an AE that is assessed as severe with a SAE. Severe is a category used to rate the intensity of an event; both AEs and SAEs can be assessed as severe. | Up to 34 days |
| Change From Baseline in Vital Signs: Systolic Blood Pressure and Diastolic Blood Pressure | Diastolic blood pressure and systolic blood pressure were measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. | Baseline (Pre-dose), 2 hours post-dose |
| Change From Baseline in Vital Signs: Temperature | Temperature was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. | Baseline (Pre-dose), 2 hours post-dose |
| Change From Baseline in Vital Signs: Pulse Rate | Pulse rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. | Baseline (Pre-dose), 2 hours post-dose |
| Change From Baseline in Vital Signs: Respiratory Rate | Respiratory rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. | Baseline (Pre-dose), 2 hours post-dose |
| Change From Baseline in Electrocardiograms (ECGs) Parameter: Heart Rate | Heart rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions | Baseline (Pre-dose), 2 hours post-dose |
| Change From Baseline in Electrocardiograms (ECGs) Parameter: RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration | RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. | Baseline (Pre-dose), 2 hours post-dose |
| Number of Participants With Clinically Significant Changes in Laboratory Parameters | Laboratory investigation included hematology, biochemistry and urinalysis. The number of participants with clinically significant changes from baseline in laboratory parameters were reported. Clinical significance was determined by the investigator. | Screening up to Day 8 |
| Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Evobrutinib | The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ). Calculated using the mixed log-linear trapezoidal rule (linear up, log down). | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Evobrutinib | Time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
| Terminal Half Life (T1/2) of Evobrutinib | Terminal half-life was calculated as log2 divided by lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
| Apparent Total Body Clearance (CL/f) of Evobrutinib | Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for Evobrutinib. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
| Apparent Volume of Distribution During Terminal Phase (VZ/f) of Evobrutinib | Vz/f is defined as the apparent volume of distribution during the terminal phase following extravascular administration for Evobrutinib. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
| Relative Bioavailability Based on Area Under the Plasma Concentration Curve From Time Zero Extrapolated to Infinity [Frel(AUC0-inf)] of Evobrutinib (Treatment B, C and D) Compared to Evobrutinib Reference Treatment A | Relative Bioavailability in percentage of each treatment (B, C, and D) in relation to the reference Treatment (A) was calculated as Frel = 100 multiplied by (AUC0-inf [treatment B, C, D]) multiplied by Dose [treatment A] divided by (AUC0-inf [treatment A]) multiplied by Dose [treatment B, C, D]. Treatment A to determine relative bioavailability. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
| DROPPED OUT ON DAY 5; PRIVATE REASONS |
|
| BG001 | Sequence 2: Treatment B-D-A-C | Participants received single oral dose of lower dissolution bound batch (treatment B) of Evobrutinib (45 mg) on Day 1 in period 1, followed by single oral dose of hammer milled batch (treatment D) of Evobrutinib (45 mg) on Day 3 in period 2, followed by single oral dose of reference treatment (treatment A) of Evobrutinib (45 (mg) on Day 5 in period 3 and followed by single oral dose of upper dissolution bound batch (treatment C) of Evobrutinib (45 mg) on Day 7 under fasted condition in period 4. A washout period of 48 hours was maintained between 4 treatment periods. |
| BG002 | Sequence 3: Treatment C-A-D-B | Participants received single oral dose of upper dissolution bound batch (treatment C) of Evobrutinib (45 mg) on Day 1 in period 1, followed by single oral dose of reference treatment (treatment A) of Evobrutinib (45 (mg) on Day 3 in period 2, followed by single oral dose of hammer milled batch (treatment D) of Evobrutinib (45 mg) on Day 5 in period 3 and followed by single oral dose of lower dissolution bound batch (treatment B) of Evobrutinib (45 mg) on Day 7 under fasted condition in period 4. A washout period of 48 hours was maintained between 4 treatment periods. |
| BG003 | Sequence 4: Treatment D-C-B-A | Participants received single oral dose of hammer milled batch (treatment D) of Evobrutinib (45 mg) on Day 1 in period 1, followed by single oral dose of upper dissolution bound batch (treatment C) of Evobrutinib (45 mg) on Day 3 in period 2, followed by single oral dose of lower dissolution bound batch (treatment B) of Evobrutinib (45 mg) on Day 5 in period 3 and followed by single oral dose of reference treatment (treatment A) of Evobrutinib (45 (mg) on Day 7 under fasted condition in period 4. A washout period of 48 hours was maintained between 4 treatment periods. |
| BG004 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG000 |
| Treatment A |
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg]) in treatment period 1, 2, 3 or 4 under fasted conditions. |
| OG001 | Treatment B | Participants received single dose of lower dissolution bound formulation (treatment B) of Evobrutinib (45 mg) in treatment period 1, 2, 3 or 4 under fasted conditions. |
| OG002 | Treatment C | Participants received single dose of upper dissolution bound formulation (treatment C) of Evobrutinib (45 mg) in treatment period 1, 2, 3 or 4 under fasted conditions. |
| OG003 | Treatment D | Participants received single dose of hammer milled formulation (treatment D) of Evobrutinib (45 mg) in treatment period 1, 2, 3 or 4 under fasted conditions. |
|
|
| Primary | Maximum Observed Plasma Concentration (Cmax) of Evobrutinib | Cmax was obtained directly from the concentration versus time curve. | Pharmacokinetic (PK) Analysis Set was a subset of the Safety Analysis Set and included all participants who receive at least one dose of active investigational medicinal product (IMP) and provide at least one measurable post-dose concentration. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram per milliliter (ng/mL) | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
|
|
|
| Secondary | Number of Participants With Treatment- Emergent Adverse Events (TEAEs) | An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE 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. TEAEs were defined as events with onset date or worsening during the on-treatment period. TEAEs included both serious and non-serious TEAEs. | Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention. | Posted | Count of Participants | Participants | Up to 34 days |
|
|
|
| Secondary | Number of Participants With Treatment- Emergent Adverse Events (TEAEs) by Severity | The Investigator assessed the severity of each AE and SAE reported during the study and assign it to one of the following categories: Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities; Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities; Severe: An event that prevents normal everyday activities. Do not confuse an AE that is assessed as severe with a SAE. Severe is a category used to rate the intensity of an event; both AEs and SAEs can be assessed as severe. | Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention. | Posted | Count of Participants | Participants | Up to 34 days |
|
|
|
| Secondary | Change From Baseline in Vital Signs: Systolic Blood Pressure and Diastolic Blood Pressure | Diastolic blood pressure and systolic blood pressure were measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. | Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention. | Posted | Mean | Standard Deviation | millimeters of mercury (mmHg) | Baseline (Pre-dose), 2 hours post-dose |
|
|
|
| Secondary | Change From Baseline in Vital Signs: Temperature | Temperature was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. | Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention. | Posted | Mean | Standard Deviation | degree Celsius | Baseline (Pre-dose), 2 hours post-dose |
|
|
|
| Secondary | Change From Baseline in Vital Signs: Pulse Rate | Pulse rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. | Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention. | Posted | Mean | Standard Deviation | beats per minute | Baseline (Pre-dose), 2 hours post-dose |
|
|
|
| Secondary | Change From Baseline in Vital Signs: Respiratory Rate | Respiratory rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. | Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention. | Posted | Mean | Standard Deviation | breaths per minute | Baseline (Pre-dose), 2 hours post-dose |
|
|
|
| Secondary | Change From Baseline in Electrocardiograms (ECGs) Parameter: Heart Rate | Heart rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions | Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention. | Posted | Mean | Standard Deviation | beats per minute | Baseline (Pre-dose), 2 hours post-dose |
|
|
|
| Secondary | Change From Baseline in Electrocardiograms (ECGs) Parameter: RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration | RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. | Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention. | Posted | Mean | Standard Deviation | millisecond (msec) | Baseline (Pre-dose), 2 hours post-dose |
|
|
|
| Secondary | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Laboratory investigation included hematology, biochemistry and urinalysis. The number of participants with clinically significant changes from baseline in laboratory parameters were reported. Clinical significance was determined by the investigator. | Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention. | Posted | Count of Participants | Participants | Screening up to Day 8 |
|
|
|
| Secondary | Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Evobrutinib | The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ). Calculated using the mixed log-linear trapezoidal rule (linear up, log down). | Pharmacokinetic (PK) Analysis Set was a subset of the Safety Analysis Set and included all participants who receive at least one dose of active investigational medicinal product (IMP) and provide at least one measurable post-dose concentration. | Posted | Geometric Mean | Geometric Coefficient of Variation | h×ng/mL | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
|
|
|
| Secondary | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Evobrutinib | Time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve. | Pharmacokinetic (PK) Analysis Set was a subset of the Safety Analysis Set and included all participants who receive at least one dose of active investigational medicinal product (IMP) and provide at least one measurable post-dose concentration. | Posted | Median | Full Range | hours | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
|
|
|
| Secondary | Terminal Half Life (T1/2) of Evobrutinib | Terminal half-life was calculated as log2 divided by lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve. | Pharmacokinetic (PK) Analysis Set was a subset of the Safety Analysis Set and included all participants who receive at least one dose of active investigational medicinal product (IMP) and provide at least one measurable post-dose concentration. | Posted | Median | Full Range | hours | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
|
|
|
| Secondary | Apparent Total Body Clearance (CL/f) of Evobrutinib | Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for Evobrutinib. | Pharmacokinetic (PK) Analysis Set was a subset of the Safety Analysis Set and included all participants who receive at least one dose of active investigational medicinal product (IMP) and provide at least one measurable post-dose concentration. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter per hour | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
|
|
|
| Secondary | Apparent Volume of Distribution During Terminal Phase (VZ/f) of Evobrutinib | Vz/f is defined as the apparent volume of distribution during the terminal phase following extravascular administration for Evobrutinib. | Pharmacokinetic (PK) Analysis Set was a subset of the Safety Analysis Set and included all participants who receive at least one dose of active investigational medicinal product (IMP) and provide at least one measurable post-dose concentration. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liters | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
|
|
|
| Secondary | Relative Bioavailability Based on Area Under the Plasma Concentration Curve From Time Zero Extrapolated to Infinity [Frel(AUC0-inf)] of Evobrutinib (Treatment B, C and D) Compared to Evobrutinib Reference Treatment A | Relative Bioavailability in percentage of each treatment (B, C, and D) in relation to the reference Treatment (A) was calculated as Frel = 100 multiplied by (AUC0-inf [treatment B, C, D]) multiplied by Dose [treatment A] divided by (AUC0-inf [treatment A]) multiplied by Dose [treatment B, C, D]. Treatment A to determine relative bioavailability. | Pharmacokinetic (PK) Analysis Set was a subset of the Safety Analysis Set and included all participants who receive at least one dose of active investigational medicinal product (IMP) and provide at least one measurable post-dose concentration. | Posted | Geometric Mean | 95% Confidence Interval | percentage bioavailability | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7 |
|
|
|
| 0 |
| 26 |
| 0 |
| 26 |
| 2 |
| 26 |
| EG001 | Treatment B | Participants received single dose of lower dissolution bound formulation (treatment B) of Evobrutinib (45 mg) in treatment period 1, 2, 3 or 4 under fasted conditions. | 0 | 27 | 0 | 27 | 1 | 27 |
| EG002 | Treatment C | Participants received single dose of upper dissolution bound formulation (treatment C) of Evobrutinib (45 mg) in treatment period 1, 2, 3 or 4 under fasted conditions. | 0 | 27 | 1 | 27 | 1 | 27 |
| EG003 | Treatment D | Participants received single dose of hammer milled formulation (treatment D) of Evobrutinib (45 mg) in treatment period 1, 2, 3 or 4 under fasted conditions. | 0 | 27 | 0 | 27 | 5 | 27 |
| Nasopharyngitis | Infections and infestations | meddra 25.1 | Non-systematic Assessment |
|
| Lipase increased | Investigations | meddra 25.1 | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | meddra 25.1 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | meddra 25.1 | Non-systematic Assessment |
|
Not provided
Not provided
| Moderate |
|
| Severe |
|
| Diastolic Blood Pressure |
|
| QT Duration |
|
| QTcF Duration |
|
| PR Duration |
|
| QRS Duration |
|