Drug-Drug Interaction Study of Evobrutinib and Transporter Substrates

• Evobrutinib (45mg) (Drug), also known as M2951: Participants received film-coated Evobrutinib tablet at a dose of 45 milligrams (mg), orally twice daily on Days 4 to 12 in Part 1 and Days 2 to 8 in Part 2 under fed conditions.
• Digoxin (0.25mg) (Drug): Participants received single oral dose of digoxin tablet (0.25 mg) on Day 1 and Day 10 in Part 1 under fed conditions.
• Metformin (10mg) (Drug): Participants received single oral dose of metformin 10 mg solution on Day 1 and Day 10 in Part 1 under fed conditions.
• Rosuvastatin (10mg) (Drug): Participants received single oral dose of rosuvastatin tablet (10 mg) on Day 1 and Day 10 in Part 1 under fed conditions.
• Sumatriptan (25mg) (Drug): Participants received single dose of sumatriptan tablet (25 mg) on Day 1 and Day 8 in Part 2 under fed conditions.

Primary outcomes

• Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Digoxin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
• Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
• Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Rosuvastatin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
• Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Sumatriptan [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8]: The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
• Part 1: Maximum Observed Plasma Concentration (Cmax) of Digoxin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: Cmax was obtained directly from the concentration versus time curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
• Part 1: Maximum Observed Plasma Concentration (Cmax) of Metformin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: Cmax was obtained directly from the concentration versus time curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
• Part 1: Maximum Observed Plasma Concentration (Cmax) of Rosuvastatin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: Cmax was obtained directly from the concentration versus time curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
• Part 2: Maximum Observed Plasma Concentration (Cmax) of Sumatriptan [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8]: Cmax was obtained directly from the concentration versus time curve. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.

Secondary outcomes

• Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs [Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8]: An adverse event (AE) was 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. Serious AE: 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. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs.
• Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity [Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8]: Severity of TEAEs were graded using Qualitative Toxicity Scale, as follows: Mild: Participant is aware of the event or symptom, but the event or symptom is easily tolerated; Moderate: Participant experiences sufficient discomfort to interfere with or reduce his or her usual level of activity; Severe: Significant impairment of functioning: the participant is unable to carry out his or her usual activities. Number of participants with TEAEs by severity were reported.
• Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Laboratory Parameters [Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8]: Laboratory investigation included hematology, biochemistry and urinalysis. Clinical meaningful changes were determined by the investigator. The number of participants with clinically relevant changes from baseline in laboratory parameters were reported.
• Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs [Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8]: Vital signs included body temperature, systolic and diastolic blood pressure and pulse rate. Clinical relevance was determined by the investigator. The number of participants with clinically relevant changes from baseline in vital signs were reported.
• Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings [Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8]: 12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration and QT interval. The corrected QT interval (QTcF) was calculated using Fridericia's formula. 12-lead ECG recordings were obtained after the participants have rested for at least 10 minutes in semisupine position. Clinical relevance was determined by the investigator. The number of participants with clinically relevant changes from baseline in 12-Lead ECG findings were reported.
• Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Digoxin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: Tmax was the time to reach the maximum observed concentration collected during a dosing interval. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
• Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: Tmax was the time to reach the maximum observed concentration collected during a dosing interval. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
• Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Rosuvastatin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: Tmax was the time to reach the maximum observed concentration collected during a dosing interval. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
• Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of Sumatriptan [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8]: Tmax was the time to reach the maximum observed concentration collected during a dosing interval. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
• Part 1: Apparent Terminal Half-Life (t1/2) of Digoxin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
• Part 1: Apparent Terminal Half-Life (t1/2) of Metformin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
• Part 1: Apparent Terminal Half-Life (t1/2) of Rosuvastatin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
• Part 2: Apparent Terminal Half-Life (t1/2) of Sumatriptan [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8]: T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
• Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Digoxin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: 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 was calculated using the mixed log-linear trapezoidal rule (linear up, log down). The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
• Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Metformin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: 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 was calculated using the mixed log-linear trapezoidal rule (linear up, log down). The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
• Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Rosuvastatin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: 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 was calculated using the mixed log-linear trapezoidal rule (linear up, log down). The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
• Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Sumatriptan [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8]: 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 was calculated using the mixed log-linear trapezoidal rule (linear up, log down). As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
• Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Digoxin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-tlast + Clast pred/Lambda Z, where AUC0-tlast was 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; Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
• Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Metformin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-tlast + Clast pred/Lambda Z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
• Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Rosuvastatin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-tlast + Clast pred/Lambda Z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
• Part 2: Apparent Total Body Clearance From Plasma (CL/F) of Sumatriptan [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8]: CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-tlast + Clast pred/Lambda Z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
• Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Digoxin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf*Lambda Z), where AUC0-inf = (AUC0-tlast + Clast pred/Lambda Z), where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
• Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Metformin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf*Lambda Z), where AUC0-inf = (AUC0-tlast + Clast pred/Lambda Z), where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
• Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Rosuvastatin [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10]: Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf*Lambda Z), where AUC0-inf = (AUC0-tlast + Clast pred/Lambda Z), where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
• Part 2: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Sumatriptan [Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8]: Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf*Lambda Z), where AUC0-inf = (AUC0-tlast + Clast pred/Lambda Z), where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
• Part 1: Cumulative Amount Excreted (CAE) From Time Zero to the End of the Collection Interval After Dosing Dosing (Ae0-36) of Metformin [Pre-dose, 0 to 4, 4 to 8, 8 to 12; 12 to 24 hours post-dose on Days 1 and 10]: Ae0-36 was calculated as the cumulative amount excreted from time zero (= dosing time) to the end of the collection interval after dosing, for metformin only. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
• Part 1: Renal Clearance (CLr) of Metformin [Pre-dose, 0 to 4, 4 to 8, 8 to 12; 12 to 24 hours post-dose on Days 1 and 10]: CLr was calculated as Ae0-36 divided by AUC0-36, for metformin only. AUC0-36: AUC from time zero (= dosing time) to 36 hours post-dose (metformin only) calculated using the mixed log-linear trapezoidal rule (linear up, log down). The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.

Sex: All, ages: 18 Years to 55 Years, accepts healthy volunteers

Inclusion Criteria:

* Participants were overtly healthy as determined by medical evaluation, including no clinically significant abnormality identified on physical examination or laboratory evaluation and no active clinically significant disorder, condition, infection or disease that would pose a risk to participant safety or interfere with the study evaluation, procedures, or completion
* Participants had a body weight within 50.0 and 100.0 kilograms \[kg\] (inclusive) and body mass index within the range of 19.0 and 30.0 kilograms per square meter \[kg/m\^2\] (inclusive)
* Other protocol defined inclusion criteria could apply

Exclusion Criteria:

* History or presence of clinically relevant respiratory, gastrointestinal, renal, hepatic, hematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, connective tissue diseases or disorders, as determined by medical evaluation
* Individuals with diagnosis of hemochromatosis, Wilson´s disease, alpha 1 antitrypsin deficiency, or any other chronic liver disease including Gilbert's disease were excluded from the study
* Prior history of cholecystectomy or splenectomy, and any clinically relevant surgery within 6 months prior to Screening
* History of any malignancy
* History of chronic or recurrent acute infection or any bacterial, viral, parasitic or fungal infections within 30 days prior to Screening and at any time between Screening and admission, or hospitalization due to infection within 6 months prior to Screening
* History of shingles within 12 months prior to Screening
* History of drug hypersensitivity, ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or formulation ingredients; history of serious allergic reactions leading to hospitalization or any other hypersensitivity reaction in general, which may affect the safety of the participant and/or outcome of the study per the Investigator's discretion
* History of alcoholism or drug abuse within 2 years prior to Screening, or positive for drugs of abuse, nicotine/cotinine or alcohol by the laboratory assays conducted during Screening and Day -1
* History of residential exposure to tuberculosis, or a positive QuantiFERON® test within 4 weeks prior to or at the time of Screening
* Administration of live vaccines or live-attenuated virus vaccines within 3 months prior to Screening
* Moderate or strong inhibitors or inducers of Cytochrome P450, family 3, subfamily A (CYP3A4/5) within 4 weeks prior to the first administration of study intervention
* Other protocol defined exclusion criteria could apply

Participant flow

Outcome results

• Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Digoxin (Primary), Geometric mean, Hour*nanogram per milliliter (h*ng/mL): Part 1: Cocktail 15.8 +/- 21.5; Part 1: Evobrutinib + Cocktail 18.7 +/- 23.7
• Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin (Primary), Geometric mean, h*ng/mL: Part 1: Cocktail 20.2 +/- 23.3; Part 1: Evobrutinib + Cocktail 42.2 +/- 77.1
• Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Rosuvastatin (Primary), Geometric mean, h*ng/mL: Part 1: Cocktail 34.6 +/- 64.3; Part 1: Evobrutinib + Cocktail 34.3 +/- 74.7
• Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Sumatriptan (Primary), Geometric mean, h*ng/mL: Part 2: Sumatriptan 52.5 +/- 43.7; Part 2: Evobrutinib + Sumatriptan 46.9 +/- 41.0
• Part 1: Maximum Observed Plasma Concentration (Cmax) of Digoxin (Primary), Geometric mean, Nanogram per milliliter (ng/mL): Part 1: Cocktail 1.15 +/- 31.7; Part 1: Evobrutinib + Cocktail 1.15 +/- 34.8
• Part 1: Maximum Observed Plasma Concentration (Cmax) of Metformin (Primary), Geometric mean, ng/mL: Part 1: Cocktail 3.24 +/- 23.1; Part 1: Evobrutinib + Cocktail 6.58 +/- 76.5
• Part 1: Maximum Observed Plasma Concentration (Cmax) of Rosuvastatin (Primary), Geometric mean, ng/mL: Part 1: Cocktail 2.35 +/- 60.3; Part 1: Evobrutinib + Cocktail 2.16 +/- 66.5
• Part 2: Maximum Observed Plasma Concentration (Cmax) of Sumatriptan (Primary), Geometric mean, ng/mL: Part 2: Sumatriptan 13.4 +/- 39.7; Part 2: Evobrutinib + Sumatriptan 10.9 +/- 38.6
• Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs (Secondary), Count of participants, Participants: Part 1: Cocktail 7; Part 1: Evobrutinib 9; Part 1: Evobrutinib + Cocktail 6; Part 2: Sumatriptan 6; Part 2: Evobrutinib 10; Part 2: Evobrutinib + Sumatriptan 8
• Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity (Secondary), Count of participants, Participants: Part 1: Cocktail 5; Part 1: Evobrutinib 9; Part 1: Evobrutinib + Cocktail 6; Part 2: Sumatriptan 4; Part 2: Evobrutinib 10; Part 2: Evobrutinib + Sumatriptan 7
• Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Laboratory Parameters (Secondary), Count of participants, Participants: Part 1: Cocktail 0; Part 1: Evobrutinib 0; Part 1: Evobrutinib + Cocktail 0; Part 2: Sumatriptan 0; Part 2: Evobrutinib 0; Part 2: Evobrutinib + Sumatriptan 0
• Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs (Secondary), Count of participants, Participants: Part 1: Cocktail 0; Part 1: Evobrutinib 0; Part 1: Evobrutinib + Cocktail 0; Part 2: Sumatriptan 0; Part 2: Evobrutinib 0; Part 2: Evobrutinib + Sumatriptan 0
• Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings (Secondary), Count of participants, Participants: Part 1: Cocktail 0; Part 1: Evobrutinib 0; Part 1: Evobrutinib + Cocktail 0; Part 2: Sumatriptan 0; Part 2: Evobrutinib 0; Part 2: Evobrutinib + Sumatriptan 0
• Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Digoxin (Secondary), Median, Hours: Part 1: Cocktail 1.50 (0.333 to 2.00); Part 1: Evobrutinib + Cocktail 2.00 (0.667 to 4.00)
• Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin (Secondary), Median, Hours: Part 1: Cocktail 3.00 (3.00 to 4.02); Part 1: Evobrutinib + Cocktail 4.00 (2.00 to 4.02)
• Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Rosuvastatin (Secondary), Median, Hours: Part 1: Cocktail 4.00 (1.50 to 8.00); Part 1: Evobrutinib + Cocktail 4.00 (1.50 to 6.02)
• Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of Sumatriptan (Secondary), Median, Hours: Part 2: Sumatriptan 2.00 (1.50 to 3.05); Part 2: Evobrutinib + Sumatriptan 2.00 (1.50 to 4.00)
• Part 1: Apparent Terminal Half-Life (t1/2) of Digoxin (Secondary), Median, Hours: Part 1: Cocktail 31.0 (24.1 to 67.9); Part 1: Evobrutinib + Cocktail 46.9 (24.6 to 69.4)
• Part 1: Apparent Terminal Half-Life (t1/2) of Metformin (Secondary), Median, Hours: Part 1: Cocktail 3.02 (2.52 to 5.24); Part 1: Evobrutinib + Cocktail 3.50 (2.23 to 13.8)
• Part 1: Apparent Terminal Half-Life (t1/2) of Rosuvastatin (Secondary), Median, Hours: Part 1: Cocktail 15.5 (12.5 to 29.1); Part 1: Evobrutinib + Cocktail 15.5 (9.60 to 19.0)
• 15 more outcome measures not shown.

Adverse events

Time frame: Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8

Other adverse events by term

• Study Protocol (PDF, 2021-08-24)
• Statistical Analysis Plan (PDF, 2021-12-07)

• Medical Responsible, Study director, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany