The main purpose of the study is to compare the Pharmacokinetics (PK), safety and tolerability of different manufacturing batches of M2951 tablet formulation relative to a reference batch under fasted conditions in healthy participants.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
28
Participants will receive single dose of Treatment A in treatment period 1, 2, 3 or 4 under fasted conditions.
Participants will receive single dose of Treatment B in treatment period 1, 2, 3 or 4 under fasted conditions.
Participants will receive single dose of Treatment C in treatment period 1, 2, 3 or 4 under fasted conditions.
Nuvisan GmbH
Neu-Ulm, Germany
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Evobrutinib
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7
Maximum Observed Plasma Concentration (Cmax) of Evobrutinib
Cmax was obtained directly from the concentration versus time curve.
Time frame: 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
Number of Participants With Treatment- Emergent Adverse Events (TEAEs)
An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as events with onset date or worsening during the on-treatment period. TEAEs included both serious and non-serious TEAEs.
Time frame: Up to 34 days
Number of Participants With Treatment- Emergent Adverse Events (TEAEs) by Severity
The Investigator assessed the severity of each AE and SAE reported during the study and assign it to one of the following categories: Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities; Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities; Severe: An event that prevents normal everyday activities. Do not confuse an AE that is assessed as severe with a SAE. Severe is a category used to rate the intensity of an event; both AEs and SAEs can be assessed as severe.
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Participants will receive single dose of Treatment D in treatment period 1, 2, 3 or 4 under fasted conditions.
Time frame: Up to 34 days
Change From Baseline in Vital Signs: Systolic Blood Pressure and Diastolic Blood Pressure
Diastolic blood pressure and systolic blood pressure were measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions.
Time frame: Baseline (Pre-dose), 2 hours post-dose
Change From Baseline in Vital Signs: Temperature
Temperature was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions.
Time frame: Baseline (Pre-dose), 2 hours post-dose
Change From Baseline in Vital Signs: Pulse Rate
Pulse rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions.
Time frame: Baseline (Pre-dose), 2 hours post-dose
Change From Baseline in Vital Signs: Respiratory Rate
Respiratory rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions.
Time frame: Baseline (Pre-dose), 2 hours post-dose
Change From Baseline in Electrocardiograms (ECGs) Parameter: Heart Rate
Heart rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions
Time frame: Baseline (Pre-dose), 2 hours post-dose
Change From Baseline in Electrocardiograms (ECGs) Parameter: RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration
RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions.
Time frame: Baseline (Pre-dose), 2 hours post-dose
Number of Participants With Clinically Significant Changes in Laboratory Parameters
Laboratory investigation included hematology, biochemistry and urinalysis. The number of participants with clinically significant changes from baseline in laboratory parameters were reported. Clinical significance was determined by the investigator.
Time frame: Screening up to Day 8
Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Evobrutinib
The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ). Calculated using the mixed log-linear trapezoidal rule (linear up, log down).
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Evobrutinib
Time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7
Terminal Half Life (T1/2) of Evobrutinib
Terminal half-life was calculated as log2 divided by lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7
Apparent Total Body Clearance (CL/f) of Evobrutinib
Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for Evobrutinib.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7
Apparent Volume of Distribution During Terminal Phase (VZ/f) of Evobrutinib
Vz/f is defined as the apparent volume of distribution during the terminal phase following extravascular administration for Evobrutinib.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose on Days 1, 3, 5 and 7
Relative Bioavailability Based on Area Under the Plasma Concentration Curve From Time Zero Extrapolated to Infinity [Frel(AUC0-inf)] of Evobrutinib (Treatment B, C and D) Compared to Evobrutinib Reference Treatment A
Relative Bioavailability in percentage of each treatment (B, C, and D) in relation to the reference Treatment (A) was calculated as Frel = 100 multiplied by (AUC0-inf \[treatment B, C, D\]) multiplied by Dose \[treatment A\] divided by (AUC0-inf \[treatment A\]) multiplied by Dose \[treatment B, C, D\]. Treatment A to determine relative bioavailability.
Time frame: 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