Trial Outcomes & Findings for DDI Study of Evobrutinib and Carbamazepine (NCT NCT05248945)
NCT ID: NCT05248945
Last Updated: 2026-01-15
Results Overview
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 (LLQ) 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.
COMPLETED
PHASE1
14 participants
Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,16 and 24 hours post dose on Day 1 and Day 19.
2026-01-15
Participant Flow
A total of 18 participants were planned out of which 14 participants received study drug.
Participant milestones
| Measure |
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 mg on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|
|
Overall Study
STARTED
|
14
|
|
Overall Study
COMPLETED
|
12
|
|
Overall Study
NOT COMPLETED
|
2
|
Reasons for withdrawal
| Measure |
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 mg on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|
|
Overall Study
Adverse Event
|
1
|
|
Overall Study
Elevated Gamma-Glutamyl Transferase (GGT)
|
1
|
Baseline Characteristics
DDI Study of Evobrutinib and Carbamazepine
Baseline characteristics by cohort
| Measure |
Evobrutinib + Carbamazepine
n=14 Participants
Participants received a single oral dose of Evobrutinib 45 mg on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|
|
Age, Continuous
|
43 Years
STANDARD_DEVIATION 11.5 • n=14 Participants
|
|
Sex: Female, Male
Female
|
2 Participants
n=14 Participants
|
|
Sex: Female, Male
Male
|
12 Participants
n=14 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
0 Participants
n=14 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
14 Participants
n=14 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=14 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=14 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=14 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=14 Participants
|
|
Race (NIH/OMB)
Black or African American
|
0 Participants
n=14 Participants
|
|
Race (NIH/OMB)
White
|
14 Participants
n=14 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=14 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=14 Participants
|
PRIMARY outcome
Timeframe: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,16 and 24 hours post dose on Day 1 and Day 19.Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. Here 'Overall number of participants analyzed' = number of participants evaluable for this outcome measure.
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 (LLQ) 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.
Outcome measures
| Measure |
Evobrutinib
n=13 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
n=12 Participants
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero Extrapolated to Infinity (AUC0-inf) of Evobrutinib
|
310 Hour*nanograms per milliliter (h*ng/mL)
Geometric Coefficient of Variation 33.2
|
49.2 Hour*nanograms per milliliter (h*ng/mL)
Geometric Coefficient of Variation 23.1
|
PRIMARY outcome
Timeframe: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12, 16 and 24 hours post dose on Day 1 and Day 19.Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
Cmax was obtained from plasma concentration time curve.
Outcome measures
| Measure |
Evobrutinib
n=13 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
n=13 Participants
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Maximum Observed Plasma Concentration (Cmax) of Evobrutinib
|
132 nanogram per milliliter (ng/mL)
Geometric Coefficient of Variation 33.1
|
22.4 nanogram per milliliter (ng/mL)
Geometric Coefficient of Variation 33.1
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
An adverse event (AE) was defined as any untoward medical occurrence in a participant. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a study intervention. A serious adverse event (SAE) was any untoward medical occurrence 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. TEAE's were those events with onset dates on or after the first administration of study intervention. TEAEs include both Serious TEAEs and non-serious TEAEs."
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Serious TEAEs
Any TEAE
|
14 Participants
|
—
|
|
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Serious TEAEs
Any serious TEAE
|
0 Participants
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Blood samples were collected to analyze the hematology parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, and Lymphocytes Values. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline was calculated by subtracting the post-dose visit value from the Baseline value.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Hematology Parameter: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, and Lymphocytes Values
Platelets
|
11 10^9 cells/Liter
Standard Deviation 34.0
|
—
|
|
Absolute Change From Baseline in Hematology Parameter: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, and Lymphocytes Values
Leukocytes
|
-0.23 10^9 cells/Liter
Standard Deviation 0.836
|
—
|
|
Absolute Change From Baseline in Hematology Parameter: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, and Lymphocytes Values
Neutrophils
|
-0.18 10^9 cells/Liter
Standard Deviation 0.857
|
—
|
|
Absolute Change From Baseline in Hematology Parameter: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, and Lymphocytes Values
Eosinophils
|
0.04 10^9 cells/Liter
Standard Deviation 0.064
|
—
|
|
Absolute Change From Baseline in Hematology Parameter: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, and Lymphocytes Values
Basophils
|
0.03 10^9 cells/Liter
Standard Deviation 0.027
|
—
|
|
Absolute Change From Baseline in Hematology Parameter: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, and Lymphocytes Values
Monocytes
|
-0.00 10^9 cells/Liter
Standard Deviation 0.111
|
—
|
|
Absolute Change From Baseline in Hematology Parameter: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, and Lymphocytes Values
Lymphocytes
|
-0.12 10^9 cells/Liter
Standard Deviation 0.541
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Blood samples were collected to analyze the hematology parameter: Hemoglobin levels. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Hematology Parameter: Hemoglobin Levels
|
-5.178 grams per liter (g/L)
Standard Deviation 8.4346
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Blood samples were collected to analyze the hematology parameter: Hematocrit Value. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Hematology Parameter: Hematocrit Values
|
-0.014 litre of cells per litre of blood (L/L)
Standard Deviation 0.0236
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Blood samples were collected to analyze the hematology parameter: Activated Partial Thromboplastin Time. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Hematology Parameter: Activated Partial Thromboplastin Time
|
-0.6 seconds
Standard Deviation 1.29
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Blood samples were collected to analyze the hematology parameter: basophils/leukocytes, eosinophils/leukocytes, lymphocytes/leukocytes, monocytes/ leukocytes, and neutrophils/leukocytes. The data in terms of 'percentage of cells' was calculated as: Count of Basophils (10\^9 cells/L) (or any other defined hematology parameter e.g. Neutrophils, Eosinophils etc.) divided by the total count of Leukocytes (10\^9 cells/L) in the blood multiplied by 100."
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Change From Baseline in Hematology Parameters: Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/ Leukocytes, and Neutrophils/Leukocytes
Basophils/Leukocytes
|
0.5 Percentage of cells
Standard Deviation 0.44
|
—
|
|
Change From Baseline in Hematology Parameters: Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/ Leukocytes, and Neutrophils/Leukocytes
Eosinophils/Leukocytes
|
0.7 Percentage of cells
Standard Deviation 0.98
|
—
|
|
Change From Baseline in Hematology Parameters: Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/ Leukocytes, and Neutrophils/Leukocytes
Lymphocytes/Leukocytes
|
0.1 Percentage of cells
Standard Deviation 7.80
|
—
|
|
Change From Baseline in Hematology Parameters: Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/ Leukocytes, and Neutrophils/Leukocytes
Monocytes/Leukocytes
|
0.3 Percentage of cells
Standard Deviation 2.11
|
—
|
|
Change From Baseline in Hematology Parameters: Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/ Leukocytes, and Neutrophils/Leukocytes
Neutrophils/Leukocytes
|
-1.6 Percentage of cells
Standard Deviation 8.95
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Blood samples were collected to analyze the hematology parameter: Erythrocytes Mean Corpuscular Hemoglobin. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin
|
0.35557 Picograms
Standard Deviation 0.506080
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Blood samples were collected to analyze the hematology parameter: Erythrocytes Mean Corpuscular Volume. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume
|
1.4 Femtoliter
Standard Deviation 0.93
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Blood samples were collected to analyze the hematology parameter: Prothrombin International Normalized Ratio. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value. Percent=Fraction×100
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Hematology Parameter: Prothrombin International Normalized Ratio
|
-0.04 percent
Standard Deviation 0.041
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Blood samples were collected to analyze the Biochemistry Parameter: Bilirubin, Creatinine and Urate. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Biochemistry Parameter: Bilirubin, Creatinine and Urate
Bilirubin
|
-4.9 micromole/liter (umol/L)
Standard Deviation 2.91
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Bilirubin, Creatinine and Urate
Creatinine
|
-1 micromole/liter (umol/L)
Standard Deviation 8.2
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Bilirubin, Creatinine and Urate
Urate
|
-34.6 micromole/liter (umol/L)
Standard Deviation 59.35
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Blood samples were collected to analyze the Biochemistry Parameter: Sodium, Potassium, Calcium, Magnesium and Phosphate Levels. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Biochemistry Parameter: Sodium, Potassium, Calcium, Magnesium and Phosphate Levels
Sodium Levels
|
1 Millimoles per litre (mmol/L)
Standard Deviation 1.6
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Sodium, Potassium, Calcium, Magnesium and Phosphate Levels
Potassium Levels
|
0.49 Millimoles per litre (mmol/L)
Standard Deviation 0.407
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Sodium, Potassium, Calcium, Magnesium and Phosphate Levels
Calcium Levels
|
0.02 Millimoles per litre (mmol/L)
Standard Deviation 0.084
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Sodium, Potassium, Calcium, Magnesium and Phosphate Levels
Magnesium Levels
|
0.05 Millimoles per litre (mmol/L)
Standard Deviation 0.048
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Sodium, Potassium, Calcium, Magnesium and Phosphate Levels
Phosphate Levels
|
0.04 Millimoles per litre (mmol/L)
Standard Deviation 0.210
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Blood samples were collected to analyze the Biochemistry Parameter: Protein and Albumin Levels. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Biochemistry Parameter: Protein and Albumin Levels
Protein
|
-4 g/L
Standard Deviation 4.1
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Protein and Albumin Levels
Albumin
|
2.3 g/L
Standard Deviation 2.61
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Biochemistry Parameter: Alkaline Phosphatase, Amylase, Lipase, Creatinine Kinase, Gamma Glutamyl Transferase Levels, Lactate Dehydrogenase, Aspartate Aminotransferase. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Biochemistry Parameter: Alkaline Phosphatase, Amylase, Lipase, Creatinine Kinase, Gamma Glutamyl Transferase Levels, Lactate Dehydrogenase, Aspartate Aminotransferase
Alkaline Phosphatase
|
8 Units per litre (U/L)
Standard Deviation 11
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Alkaline Phosphatase, Amylase, Lipase, Creatinine Kinase, Gamma Glutamyl Transferase Levels, Lactate Dehydrogenase, Aspartate Aminotransferase
Amylase
|
1 Units per litre (U/L)
Standard Deviation 9.1
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Alkaline Phosphatase, Amylase, Lipase, Creatinine Kinase, Gamma Glutamyl Transferase Levels, Lactate Dehydrogenase, Aspartate Aminotransferase
Lipase
|
2 Units per litre (U/L)
Standard Deviation 3.48
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Alkaline Phosphatase, Amylase, Lipase, Creatinine Kinase, Gamma Glutamyl Transferase Levels, Lactate Dehydrogenase, Aspartate Aminotransferase
Creatine Kinase
|
-33 Units per litre (U/L)
Standard Deviation 69.1
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Alkaline Phosphatase, Amylase, Lipase, Creatinine Kinase, Gamma Glutamyl Transferase Levels, Lactate Dehydrogenase, Aspartate Aminotransferase
Gamma Glutamyl Transferase
|
56 Units per litre (U/L)
Standard Deviation 49.4
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Alkaline Phosphatase, Amylase, Lipase, Creatinine Kinase, Gamma Glutamyl Transferase Levels, Lactate Dehydrogenase, Aspartate Aminotransferase
Lactate Dehydrogenase
|
-1 Units per litre (U/L)
Standard Deviation 22.1
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Alkaline Phosphatase, Amylase, Lipase, Creatinine Kinase, Gamma Glutamyl Transferase Levels, Lactate Dehydrogenase, Aspartate Aminotransferase
Aspartate Aminotransferase
|
9 Units per litre (U/L)
Standard Deviation 14.3
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all subjects, who were administered any dose of any study intervention.
Biochemistry Parameter: Glucose, Chloride, Cholesterol, Triglycerides, Phosphate levels. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Biochemistry Parameter: Glucose, Chloride, Cholesterol, Triglycerides, Phosphate Levels
Triglycerides
|
0.2 mmol/L
Standard Deviation 0.58
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Glucose, Chloride, Cholesterol, Triglycerides, Phosphate Levels
Glucose
|
0.01 mmol/L
Standard Deviation 0.439
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Glucose, Chloride, Cholesterol, Triglycerides, Phosphate Levels
Chloride
|
2 mmol/L
Standard Deviation 1.5
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Glucose, Chloride, Cholesterol, Triglycerides, Phosphate Levels
Cholesterol
|
0.4 mmol/L
Standard Deviation 0.60
|
—
|
|
Absolute Change From Baseline in Biochemistry Parameter: Glucose, Chloride, Cholesterol, Triglycerides, Phosphate Levels
Phosphate
|
0.04 mmol/L
Standard Deviation 0.210
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
12-Lead ECGs were collected after the participants rested quietly for at least 10 minutes in a supine position. 12-Lead ECG Parameter: Heart Rate. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in 12-Lead ECG Parameter: Heart Rate
|
2 beats per minute
Standard Deviation 6.6
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
12-Lead ECGs were collected after the participants rested quietly for at least 10 minutes in a supine position. 12-Lead ECG Parameter: RR Duration. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in 12-Lead ECG Parameter: RR Duration, QT Duration, Fridericia's Formula (QTcF), PR Duration and QRS Duration
PR Duration
|
-2 Millisecond (msec)
Standard Deviation 7.5
|
—
|
|
Absolute Change From Baseline in 12-Lead ECG Parameter: RR Duration, QT Duration, Fridericia's Formula (QTcF), PR Duration and QRS Duration
RR Duration
|
-29 Millisecond (msec)
Standard Deviation 94.9
|
—
|
|
Absolute Change From Baseline in 12-Lead ECG Parameter: RR Duration, QT Duration, Fridericia's Formula (QTcF), PR Duration and QRS Duration
QT Duration
|
-1 Millisecond (msec)
Standard Deviation 8.7
|
—
|
|
Absolute Change From Baseline in 12-Lead ECG Parameter: RR Duration, QT Duration, Fridericia's Formula (QTcF), PR Duration and QRS Duration
QTcF
|
2 Millisecond (msec)
Standard Deviation 8.8
|
—
|
|
Absolute Change From Baseline in 12-Lead ECG Parameter: RR Duration, QT Duration, Fridericia's Formula (QTcF), PR Duration and QRS Duration
QRS Duration
|
-1 Millisecond (msec)
Standard Deviation 3.9
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Blood pressure (systolic and diastolic) was measured after at least 5 minutes resting, with the participant in the seated position without distractions.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Vital Sign: Blood Pressure
Systolic Blood Pressure
|
-2 Millimeters of mercury (mmHg)
Standard Deviation 8.6
|
—
|
|
Absolute Change From Baseline in Vital Sign: Blood Pressure
Diastolic Blood Pressure
|
-2 Millimeters of mercury (mmHg)
Standard Deviation 4.8
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Pulse rate was measured after at least 5 minutes resting, with the subject in the seated position without distractions.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Vital Sign: Pulse Rate
|
2 beats per min
Standard Deviation 7.3
|
—
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
Respiratory Rate was measured after at least 5 minutes resting, with the participant in the seated position without distractions.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Vital Sign: Respiratory Rate
|
-1 breaths per minute
Standard Deviation 3.3
|
—
|
SECONDARY outcome
Timeframe: Baseline Day 1 and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
The absolute changes from baseline in Body Temperature (degree Celsius \[°C\]) were reported.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Absolute Change From Baseline in Vital Sign: Body Temperature
|
0.1 Degree Celsius
Standard Deviation 0.33
|
—
|
SECONDARY outcome
Timeframe: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,16 and 24 hours post dose on Day 1 and Day 19.Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. Here 'Overall number of participants analyzed' = number of participants evaluable for this outcome measure.
CL/f was defined as the apparent total clearance of the drug from plasma after extravascular administration.
Outcome measures
| Measure |
Evobrutinib
n=13 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
n=12 Participants
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Total Body Clearance of Evobrutinib From Plasma (CL/f)
|
145 Litres per hour (L/h)
Geometric Coefficient of Variation 33.2
|
914 Litres per hour (L/h)
Geometric Coefficient of Variation 23.1
|
SECONDARY outcome
Timeframe: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,16 and 24 hours post dose on Day 1 and Day 19.Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. Here 'Overall number of participants analyzed' = number of participants evaluable for this outcome measure.
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. The apparent volume of distribution during the terminal phase following extravascular administration and was calculated by using the formula=Dose/ (AUC0-inf\* λz).
Outcome measures
| Measure |
Evobrutinib
n=13 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
n=12 Participants
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Apparent Volume of Distribution (Vz/f) of Evobrutinib
|
373 Liter
Geometric Coefficient of Variation 20.0
|
1218 Liter
Geometric Coefficient of Variation 28.4
|
SECONDARY outcome
Timeframe: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,16 and 24 hours post dose on Day 1 and Day 19.Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
The AUC from time zero (= dosing time) to the time of the last quantifiable concentration (tlast).
Outcome measures
| Measure |
Evobrutinib
n=13 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
n=13 Participants
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-tlast) of Evobrutinib
|
308 h*ng/mL
Geometric Coefficient of Variation 33.4
|
46.1 h*ng/mL
Geometric Coefficient of Variation 27.1
|
SECONDARY outcome
Timeframe: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,16 and 24 hours post dose on Day 1 and Day 19.Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
Tmax was obtained directly from the concentration versus time curve.
Outcome measures
| Measure |
Evobrutinib
n=13 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
n=13 Participants
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Time to Reach the Maximum Plasma Concentration (Tmax) of Evobrutinib
|
2.00 hours
Interval 0.5 to 4.0
|
2.00 hours
Interval 1.5 to 3.0
|
SECONDARY outcome
Timeframe: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,16 and 24 hours post dose on Day 1 and Day 19.Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. Here 'Overall number of participants analyzed' = number of participants evaluable for this outcome measure.
t1/2 was defined as the time taken for the plasma concentration or the amount of drug in the body to be reduced by half. Terminal half-life calculated by natural log 2 divided by lambda z.
Outcome measures
| Measure |
Evobrutinib
n=13 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
n=12 Participants
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Apparent Terminal Half-Life (t1/2) of Evobrutinib in Plasma
|
1.64 hours
Interval 0.997 to 2.89
|
0.961 hours
Interval 0.652 to 1.22
|
SECONDARY outcome
Timeframe: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,16 and 24 hours post dose on Day 1 and Day 19.Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
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 (LLQ) 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.
Outcome measures
| Measure |
Evobrutinib
n=13 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
n=13 Participants
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Evobrutinib Metabolite (MSC2729909A)
|
115 hour*ng/mL
Geometric Coefficient of Variation 19.6
|
57.1 hour*ng/mL
Geometric Coefficient of Variation 20.1
|
SECONDARY outcome
Timeframe: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,16 and 24 hours post dose on Day 1 and Day 19.Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration was at or above LOQ. Calculated using the mixed log-linear trapezoidal rule (linear up, log down).
Outcome measures
| Measure |
Evobrutinib
n=13 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
n=13 Participants
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (LOQ) (AUC0-tlast) of Evobrutinib Metabolite (MSC2729909A)
|
113 h*ng/mL
Geometric Coefficient of Variation 19.7
|
55.7 h*ng/mL
Geometric Coefficient of Variation 21.3
|
SECONDARY outcome
Timeframe: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,16 and 24 hours post dose on Day 1 and Day 19.Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
Cmax was obtained from plasma concentration time curve.
Outcome measures
| Measure |
Evobrutinib
n=13 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
n=13 Participants
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Maximum Observed Plasma Concentration (Cmax) of Evobrutinib Metabolite (MSC2729909A)
|
30.2 nanograms per milliliters (ng/mL)
Geometric Coefficient of Variation 23.4
|
21.0 nanograms per milliliters (ng/mL)
Geometric Coefficient of Variation 20.0
|
SECONDARY outcome
Timeframe: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,16 and 24 hours post dose on Day 1 and Day 19.Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
Tmax was obtained directly from the concentration versus time curve.
Outcome measures
| Measure |
Evobrutinib
n=13 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
n=13 Participants
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Time to Reach the Maximum Plasma Concentration (Tmax) of Evobrutinib Metabolite (MSC2729909A)
|
2.50 hours
Interval 0.5 to 4.0
|
2.50 hours
Interval 1.5 to 4.0
|
SECONDARY outcome
Timeframe: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,16 and 24 hours post dose on Day 1 and Day 19.Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. Here 'Overall number of participants analyzed' = number of participants evaluable for this outcome measure.
The time prior to the first concentration at or above limit of quantification. It is calculated as last time point at which the concentration is less than (\<) Lower Limit of Quantification (LLOQ) before the occurrence of the first quantifiable concentration.
Outcome measures
| Measure |
Evobrutinib
n=13 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
n=13 Participants
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Time Prior to the First Quantifiable (Non-zero) Concentration (Tlag) of Evobrutinib Metabolite (MSC2729909A) in Plasma
|
0.500 hours
Interval 0.0 to 1.52
|
0.500 hours
Interval 0.0 to 1.5
|
SECONDARY outcome
Timeframe: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,16 and 24 hours post dose on Day 1 and Day 19.Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. Here 'Overall number of participants analyzed' = number of participants evaluable for this outcome measure.
Molecular weight-corrected ratio of metabolite (M) AUC0-inf to parent (P) AUC0-inf: M/P(AUC0-inf) = (AUC0-inf metabolite (MSC2729909A) \*molecular weight (MW) parent) / (AUC0-inf parent\*MW metabolite (MSC2729909A)).
Outcome measures
| Measure |
Evobrutinib
n=13 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
n=12 Participants
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Metabolite to Parent Ratios for Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Evobrutinib Metabolite (MSC2729909A)
|
0.344 Ratio
Geometric Coefficient of Variation 31.0
|
1.11 Ratio
Geometric Coefficient of Variation 21.7
|
SECONDARY outcome
Timeframe: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,16 and 24 hours post dose on Day 1 and Day 19.Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
Molecular weight-corrected ratio of metabolite Cmax to parent Cmax: M/P(Cmax) = (Cmaxmetabolite (MSC2729909A) \* MWparent) / (Cmax parent \* MW metabolite (MSC2729909A)).
Outcome measures
| Measure |
Evobrutinib
n=13 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
n=13 Participants
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Metabolite to Parent Ratios for Maximum Observed Plasma Concentration (Cmax) of Evobrutinib Metabolite (MSC2729909A)
|
0.213 Ratio
Geometric Coefficient of Variation 23.6
|
0.870 Ratio
Geometric Coefficient of Variation 20.9
|
SECONDARY outcome
Timeframe: Baseline (Day 1) and Day 26Population: The safety analysis set included all participants, who were administered any dose of any study intervention.
AE was defined as any untoward medical occurrence in a subject. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a study intervention. SAE was any untoward medical occurrence 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. TEAE's were those events with onset dates on or after the first administration of study intervention. TEAEs include both Serious TEAEs and non-serious TEAEs. Severity of AE were assessed by the investigator as Mild, Moderate, and Severe: An event that prevents normal everyday activities. Severe is a category used to rate the intensity of an event; both AEs and SAEs can be assessed as severe. SAS is used.
Outcome measures
| Measure |
Evobrutinib
n=14 Participants
Participants received a single oral dose of Evobrutinib 45mg on Day 1.
|
Evobrutinib + Carbamazepine
Participants received a single oral dose of Evobrutinib 45 milligram (mg) on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|---|
|
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Based on Severity
Mild
|
14 Participants
|
—
|
|
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Based on Severity
Moderate
|
7 Participants
|
—
|
|
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Based on Severity
Severe
|
0 Participants
|
—
|
Adverse Events
Evobrutinib + Carbamazepine
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Evobrutinib + Carbamazepine
n=14 participants at risk
Participants received a single oral dose of Evobrutinib 45 mg on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
|
|---|---|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Skin and subcutaneous tissue disorders
Hyperhidrosis
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Skin and subcutaneous tissue disorders
Rash papular
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Eye disorders
Diplopia
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Eye disorders
Eyelid ptosis
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Eye disorders
Photophobia
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Eye disorders
Vision blurred
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Gastrointestinal disorders
Abdominal pain upper
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Gastrointestinal disorders
Constipation
|
21.4%
3/14 • Baseline (Day 1) up to Day 26
|
|
Gastrointestinal disorders
Diarrhoea
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Gastrointestinal disorders
Faeces hard
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Gastrointestinal disorders
Nausea
|
42.9%
6/14 • Baseline (Day 1) up to Day 26
|
|
Gastrointestinal disorders
Vomiting
|
21.4%
3/14 • Baseline (Day 1) up to Day 26
|
|
General disorders
Asthenia
|
14.3%
2/14 • Baseline (Day 1) up to Day 26
|
|
General disorders
Fatigue
|
21.4%
3/14 • Baseline (Day 1) up to Day 26
|
|
General disorders
Feeling drunk
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
General disorders
Malaise
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Infections and infestations
Rash pustular
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Investigations
Gamma-glutamyltransferase increased
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Investigations
Platelet count decreased
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Metabolism and nutrition disorders
Decreased appetite
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Metabolism and nutrition disorders
Increased appetite
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Nervous system disorders
Aphasia
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Nervous system disorders
Coordination abnormal
|
14.3%
2/14 • Baseline (Day 1) up to Day 26
|
|
Nervous system disorders
Dizziness
|
50.0%
7/14 • Baseline (Day 1) up to Day 26
|
|
Nervous system disorders
Dysarthria
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Nervous system disorders
Headache
|
42.9%
6/14 • Baseline (Day 1) up to Day 26
|
|
Nervous system disorders
Hypoaesthesia
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Nervous system disorders
Memory impairment
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Nervous system disorders
Sedation
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Nervous system disorders
Somnolence
|
50.0%
7/14 • Baseline (Day 1) up to Day 26
|
|
Psychiatric disorders
Agitation
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Psychiatric disorders
Initial insomnia
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Psychiatric disorders
Listless
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Psychiatric disorders
Terminal insomnia
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Renal and urinary disorders
Urinary incontinence
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
|
Respiratory, thoracic and mediastinal disorders
Nasal congestion
|
7.1%
1/14 • Baseline (Day 1) up to Day 26
|
Additional Information
Communication Center
Merck Healthcare KGaA, Darmstadt Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place