Trial Outcomes & Findings for Relative Bioavailability of Evobrutinib Tablet Batches (NCT NCT07214922)
NCT ID: NCT07214922
Last Updated: 2025-12-23
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 (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.
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
28 participants
Primary outcome timeframe
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
Results posted on
2025-12-23
Participant Flow
Participant milestones
| Measure |
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.
|
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.
|
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.
|
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.
|
|---|---|---|---|---|
|
Overall Study
STARTED
|
7
|
7
|
7
|
7
|
|
Overall Study
COMPLETED
|
7
|
6
|
6
|
7
|
|
Overall Study
NOT COMPLETED
|
0
|
1
|
1
|
0
|
Reasons for withdrawal
| Measure |
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.
|
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.
|
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.
|
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.
|
|---|---|---|---|---|
|
Overall Study
Adverse Event
|
0
|
0
|
1
|
0
|
|
Overall Study
DROPPED OUT ON DAY 5; PRIVATE REASONS
|
0
|
1
|
0
|
0
|
Baseline Characteristics
Relative Bioavailability of Evobrutinib Tablet Batches
Baseline characteristics by cohort
| Measure |
Sequence 1: Treatment A-B-C-D
n=7 Participants
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.
|
Sequence 2: Treatment B-D-A-C
n=7 Participants
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.
|
Sequence 3: Treatment C-A-D-B
n=7 Participants
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.
|
Sequence 4: Treatment D-C-B-A
n=7 Participants
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.
|
Total
n=28 Participants
Total of all reporting groups
|
|---|---|---|---|---|---|
|
Age, Continuous
|
30 Years
STANDARD_DEVIATION 5.6 • n=68 Participants
|
37 Years
STANDARD_DEVIATION 10.1 • n=4 Participants
|
37 Years
STANDARD_DEVIATION 12.8 • n=219 Participants
|
35 Years
STANDARD_DEVIATION 10.4 • n=219 Participants
|
35 Years
STANDARD_DEVIATION 9.9 • n=880 Participants
|
|
Sex: Female, Male
Female
|
4 Participants
n=68 Participants
|
5 Participants
n=4 Participants
|
3 Participants
n=219 Participants
|
5 Participants
n=219 Participants
|
17 Participants
n=880 Participants
|
|
Sex: Female, Male
Male
|
3 Participants
n=68 Participants
|
2 Participants
n=4 Participants
|
4 Participants
n=219 Participants
|
2 Participants
n=219 Participants
|
11 Participants
n=880 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
0 Participants
n=68 Participants
|
1 Participants
n=4 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=219 Participants
|
1 Participants
n=880 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
7 Participants
n=68 Participants
|
6 Participants
n=4 Participants
|
7 Participants
n=219 Participants
|
7 Participants
n=219 Participants
|
27 Participants
n=880 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=68 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=880 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=68 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=880 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=68 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=880 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=68 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=880 Participants
|
|
Race (NIH/OMB)
Black or African American
|
0 Participants
n=68 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=880 Participants
|
|
Race (NIH/OMB)
White
|
7 Participants
n=68 Participants
|
7 Participants
n=4 Participants
|
7 Participants
n=219 Participants
|
7 Participants
n=219 Participants
|
28 Participants
n=880 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=68 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=880 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=68 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=219 Participants
|
0 Participants
n=880 Participants
|
PRIMARY outcome
Timeframe: 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 7Population: 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.
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.
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Evobrutinib
|
205 hour×nanogram per milliliter (h×ng/mL)
Geometric Coefficient of Variation 38.3
|
198 hour×nanogram per milliliter (h×ng/mL)
Geometric Coefficient of Variation 44.0
|
164 hour×nanogram per milliliter (h×ng/mL)
Geometric Coefficient of Variation 45.1
|
207 hour×nanogram per milliliter (h×ng/mL)
Geometric Coefficient of Variation 44.6
|
PRIMARY outcome
Timeframe: 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 7Population: 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.
Cmax was obtained directly from the concentration versus time curve.
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Maximum Observed Plasma Concentration (Cmax) of Evobrutinib
|
121 nanogram per milliliter (ng/mL)
Geometric Coefficient of Variation 64.7
|
111 nanogram per milliliter (ng/mL)
Geometric Coefficient of Variation 69.9
|
84.5 nanogram per milliliter (ng/mL)
Geometric Coefficient of Variation 71.9
|
117 nanogram per milliliter (ng/mL)
Geometric Coefficient of Variation 62.6
|
SECONDARY outcome
Timeframe: Up to 34 daysPopulation: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.
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.
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Number of Participants With Treatment- Emergent Adverse Events (TEAEs)
|
5 Participants
|
2 Participants
|
1 Participants
|
2 Participants
|
SECONDARY outcome
Timeframe: Up to 34 daysPopulation: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.
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.
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Number of Participants With Treatment- Emergent Adverse Events (TEAEs) by Severity
Moderate
|
1 Participants
|
0 Participants
|
1 Participants
|
1 Participants
|
|
Number of Participants With Treatment- Emergent Adverse Events (TEAEs) by Severity
Mild
|
4 Participants
|
2 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Treatment- Emergent Adverse Events (TEAEs) by Severity
Severe
|
0 Participants
|
0 Participants
|
0 Participants
|
1 Participants
|
SECONDARY outcome
Timeframe: Baseline (Pre-dose), 2 hours post-dosePopulation: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.
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.
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Change From Baseline in Vital Signs: Systolic Blood Pressure and Diastolic Blood Pressure
Systolic Blood Pressure
|
-1 millimeters of mercury (mmHg)
Standard Deviation 7.0
|
0 millimeters of mercury (mmHg)
Standard Deviation 10.4
|
-1 millimeters of mercury (mmHg)
Standard Deviation 7.3
|
-1 millimeters of mercury (mmHg)
Standard Deviation 6.9
|
|
Change From Baseline in Vital Signs: Systolic Blood Pressure and Diastolic Blood Pressure
Diastolic Blood Pressure
|
-1 millimeters of mercury (mmHg)
Standard Deviation 4.7
|
-1 millimeters of mercury (mmHg)
Standard Deviation 5.8
|
-1 millimeters of mercury (mmHg)
Standard Deviation 5.8
|
0 millimeters of mercury (mmHg)
Standard Deviation 6.0
|
SECONDARY outcome
Timeframe: Baseline (Pre-dose), 2 hours post-dosePopulation: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.
Temperature was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions.
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Change From Baseline in Vital Signs: Temperature
|
0.0 degree Celsius
Standard Deviation 0.27
|
0.2 degree Celsius
Standard Deviation 0.27
|
0.2 degree Celsius
Standard Deviation 0.34
|
0.0 degree Celsius
Standard Deviation 0.24
|
SECONDARY outcome
Timeframe: Baseline (Pre-dose), 2 hours post-dosePopulation: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.
Pulse rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions.
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Change From Baseline in Vital Signs: Pulse Rate
|
-2 beats per minute
Standard Deviation 7.3
|
-2 beats per minute
Standard Deviation 8.5
|
-1 beats per minute
Standard Deviation 8.6
|
-3 beats per minute
Standard Deviation 8.3
|
SECONDARY outcome
Timeframe: Baseline (Pre-dose), 2 hours post-dosePopulation: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.
Respiratory rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions.
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Change From Baseline in Vital Signs: Respiratory Rate
|
-0 breaths per minute
Standard Deviation 2.0
|
0 breaths per minute
Standard Deviation 2.5
|
-1 breaths per minute
Standard Deviation 2.0
|
-1 breaths per minute
Standard Deviation 1.9
|
SECONDARY outcome
Timeframe: Baseline (Pre-dose), 2 hours post-dosePopulation: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.
Heart rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Change From Baseline in Electrocardiograms (ECGs) Parameter: Heart Rate
|
-1 beats per minute
Standard Deviation 4.7
|
-4 beats per minute
Standard Deviation 6.1
|
-2 beats per minute
Standard Deviation 4.0
|
-2 beats per minute
Standard Deviation 6.6
|
SECONDARY outcome
Timeframe: Baseline (Pre-dose), 2 hours post-dosePopulation: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.
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.
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Change From Baseline in Electrocardiograms (ECGs) Parameter: RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration
RR Duration
|
18 millisecond (msec)
Standard Deviation 70.3
|
52 millisecond (msec)
Standard Deviation 84.6
|
36 millisecond (msec)
Standard Deviation 61.3
|
44 millisecond (msec)
Standard Deviation 106.4
|
|
Change From Baseline in Electrocardiograms (ECGs) Parameter: RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration
QT Duration
|
4 millisecond (msec)
Standard Deviation 10.1
|
9 millisecond (msec)
Standard Deviation 10.9
|
6 millisecond (msec)
Standard Deviation 9.8
|
10 millisecond (msec)
Standard Deviation 10.7
|
|
Change From Baseline in Electrocardiograms (ECGs) Parameter: RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration
QTcF Duration
|
2 millisecond (msec)
Standard Deviation 8.7
|
1 millisecond (msec)
Standard Deviation 11.8
|
1 millisecond (msec)
Standard Deviation 9.5
|
4 millisecond (msec)
Standard Deviation 8.9
|
|
Change From Baseline in Electrocardiograms (ECGs) Parameter: RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration
PR Duration
|
0 millisecond (msec)
Standard Deviation 5.8
|
-5 millisecond (msec)
Standard Deviation 7.8
|
-1 millisecond (msec)
Standard Deviation 6.1
|
-0 millisecond (msec)
Standard Deviation 8.0
|
|
Change From Baseline in Electrocardiograms (ECGs) Parameter: RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration
QRS Duration
|
-1 millisecond (msec)
Standard Deviation 4.6
|
-0 millisecond (msec)
Standard Deviation 4.9
|
-1 millisecond (msec)
Standard Deviation 4.9
|
1 millisecond (msec)
Standard Deviation 4.8
|
SECONDARY outcome
Timeframe: Screening up to Day 8Population: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.
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.
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Number of Participants With Clinically Significant Changes in Laboratory Parameters
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
SECONDARY outcome
Timeframe: 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 7Population: 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.
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).
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Evobrutinib
|
202 h×ng/mL
Geometric Coefficient of Variation 39.2
|
194 h×ng/mL
Geometric Coefficient of Variation 44.5
|
160 h×ng/mL
Geometric Coefficient of Variation 46.3
|
204 h×ng/mL
Geometric Coefficient of Variation 45.1
|
SECONDARY outcome
Timeframe: 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 7Population: 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.
Time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Evobrutinib
|
1.00 hours
Interval 0.5 to 2.0
|
1.00 hours
Interval 0.5 to 1.5
|
1.00 hours
Interval 0.5 to 2.0
|
1.00 hours
Interval 0.25 to 1.5
|
SECONDARY outcome
Timeframe: 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 7Population: 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.
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.
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Terminal Half Life (T1/2) of Evobrutinib
|
1.37 hours
Interval 0.982 to 5.41
|
1.64 hours
Interval 1.01 to 10.8
|
1.78 hours
Interval 1.05 to 13.7
|
1.72 hours
Interval 1.07 to 15.6
|
SECONDARY outcome
Timeframe: 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 7Population: 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.
Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for Evobrutinib.
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Apparent Total Body Clearance (CL/f) of Evobrutinib
|
219 Liter per hour
Geometric Coefficient of Variation 38.3
|
227 Liter per hour
Geometric Coefficient of Variation 44.0
|
275 Liter per hour
Geometric Coefficient of Variation 45.1
|
217 Liter per hour
Geometric Coefficient of Variation 44.6
|
SECONDARY outcome
Timeframe: 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 7Population: 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.
Vz/f is defined as the apparent volume of distribution during the terminal phase following extravascular administration for Evobrutinib.
Outcome measures
| Measure |
Treatment D
n=27 Participants
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=27 Participants
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.
|
Treatment C
n=27 Participants
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.
|
|---|---|---|---|---|
|
Apparent Volume of Distribution During Terminal Phase (VZ/f) of Evobrutinib
|
522 Liters
Geometric Coefficient of Variation 74.2
|
627 Liters
Geometric Coefficient of Variation 84.1
|
843 Liters
Geometric Coefficient of Variation 111.4
|
658 Liters
Geometric Coefficient of Variation 89.2
|
SECONDARY outcome
Timeframe: 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 7Population: 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.
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.
Outcome measures
| Measure |
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.
|
Treatment A
n=26 Participants
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg\]) in treatment period 1, 2, 3 or 4 under fasted conditions.
|
Treatment B
n=26 Participants
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.
|
Treatment C
n=26 Participants
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.
|
|---|---|---|---|---|
|
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
|
—
|
84.0 percentage bioavailability
Interval 75.8 to 93.1
|
105 percentage bioavailability
Interval 98.1 to 112.0
|
106 percentage bioavailability
Interval 98.0 to 115.0
|
Adverse Events
Treatment A
Serious events: 0 serious events
Other events: 2 other events
Deaths: 0 deaths
Treatment B
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Treatment C
Serious events: 1 serious events
Other events: 1 other events
Deaths: 0 deaths
Treatment D
Serious events: 0 serious events
Other events: 5 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Treatment A
n=26 participants at risk
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg) in treatment period 1, 2,3 or 4 under fasted conditions.
|
Treatment B
n=27 participants at risk
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.
|
Treatment C
n=27 participants at risk
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.
|
Treatment D
n=27 participants at risk
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.
|
|---|---|---|---|---|
|
Nervous system disorders
Seizure
|
0.00%
0/26 • Up to 34 days
|
0.00%
0/27 • Up to 34 days
|
3.7%
1/27 • Number of events 1 • Up to 34 days
|
0.00%
0/27 • Up to 34 days
|
Other adverse events
| Measure |
Treatment A
n=26 participants at risk
Participants received single dose of reference treatment (treatment A) of Evobrutinib (45 mg) in treatment period 1, 2,3 or 4 under fasted conditions.
|
Treatment B
n=27 participants at risk
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.
|
Treatment C
n=27 participants at risk
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.
|
Treatment D
n=27 participants at risk
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.
|
|---|---|---|---|---|
|
Nervous system disorders
Dizziness
|
3.8%
1/26 • Number of events 1 • Up to 34 days
|
0.00%
0/27 • Up to 34 days
|
0.00%
0/27 • Up to 34 days
|
3.7%
1/27 • Number of events 1 • Up to 34 days
|
|
Nervous system disorders
Headache
|
0.00%
0/26 • Up to 34 days
|
0.00%
0/27 • Up to 34 days
|
3.7%
1/27 • Number of events 1 • Up to 34 days
|
7.4%
2/27 • Number of events 2 • Up to 34 days
|
|
Immune system disorders
Hypersensitivity
|
0.00%
0/26 • Up to 34 days
|
0.00%
0/27 • Up to 34 days
|
0.00%
0/27 • Up to 34 days
|
3.7%
1/27 • Number of events 1 • Up to 34 days
|
|
Infections and infestations
Nasopharyngitis
|
3.8%
1/26 • Number of events 1 • Up to 34 days
|
0.00%
0/27 • Up to 34 days
|
0.00%
0/27 • Up to 34 days
|
3.7%
1/27 • Number of events 1 • Up to 34 days
|
|
Investigations
Lipase increased
|
0.00%
0/26 • Up to 34 days
|
3.7%
1/27 • Number of events 1 • Up to 34 days
|
0.00%
0/27 • Up to 34 days
|
0.00%
0/27 • Up to 34 days
|
Additional Information
Communication Center
Merck Healthcare KGaA, Darmstadt Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Phone: +49-6151-72-5200
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place