Trial Outcomes & Findings for Effect of Evobrutinib on Pharmacokinetics of a Combined Oral Contraceptive (NCT NCT07215806)

NCT ID: NCT07215806

Last Updated: 2025-11-14

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 serum concentration at the last sampling time point at which the measured serum 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 serum concentrations of the terminal log-linear phase.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 20 participants
• Primary outcome timeframe: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18
• Results posted on: 2025-11-14

Participant Flow

Participant milestones

Measure	COC + Evobrutinib Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Overall Study STARTED	20
Overall Study COMPLETED	20
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Effect of Evobrutinib on Pharmacokinetics of a Combined Oral Contraceptive

Baseline characteristics by cohort

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Age, Continuous	57 Years STANDARD_DEVIATION 6.8 • n=10 Participants
Sex: Female, Male Female	20 Participants n=10 Participants
Sex: Female, Male Male	0 Participants n=10 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=10 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	20 Participants n=10 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=10 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=10 Participants
Race (NIH/OMB) Asian	0 Participants n=10 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=10 Participants
Race (NIH/OMB) Black or African American	0 Participants n=10 Participants
Race (NIH/OMB) White	20 Participants n=10 Participants
Race (NIH/OMB) More than one race	0 Participants n=10 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=10 Participants

PRIMARY outcome

Timeframe: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18

Population: Pharmacokinetics (PK) Analysis set included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results; with adequate study intervention compliance; with evaluable PK data, i.e., no missing values for primary endpoints at each PK profile/assessment day (Day 1, Day 15).

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 serum concentration at the last sampling time point at which the measured serum 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 serum concentrations of the terminal log-linear phase.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Ethinyl Estradiol and Norethisterone Norethisterone	36000 hour × picogram per milliliter (h×pg/mL) Geometric Coefficient of Variation 35.9
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Ethinyl Estradiol and Norethisterone Ethinyl Estradiol	1090 hour × picogram per milliliter (h×pg/mL) Geometric Coefficient of Variation 26.7

PRIMARY outcome

Timeframe: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18

Population: Pharmacokinetics (PK) Analysis set included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results; with adequate study intervention compliance; with evaluable PK data, i.e., no missing values for primary endpoints at each PK profile/assessment day (Day 1, Day 15).

Cmax was obtained directly from the concentration versus time curve.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethisterone Ethinyl Estradiol	51.8 pg/mL Geometric Coefficient of Variation 30.1
Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethisterone Norethisterone	4620 pg/mL Geometric Coefficient of Variation 34.0

SECONDARY outcome

Timeframe: Up to 46 days

Population: 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	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Number of Participants With Treatment- Emergent Adverse Events (TEAEs)	9 Participants

SECONDARY outcome

Timeframe: Up to 46 days

Population: 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	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Number of Participants With Treatment- Emergent Adverse Events (TEAEs) by Severity Mild	8 Participants
Number of Participants With Treatment- Emergent Adverse Events (TEAEs) by Severity Moderate	1 Participants
Number of Participants With Treatment- Emergent Adverse Events (TEAEs) by Severity Severe	0 Participants

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: hemoglobin.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Hematology Parameter: Hemoglobin at Day 18	-8.780 gram per liter (g/L) Standard Deviation 7.7256

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Erythrocytes.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Hematology Parameter: Erythrocytes at Day 18	-0.29 10^12 cells per liter Standard Deviation 0.263

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes and Lymphocytes.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Hematology Parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes and Lymphocytes at Day 18 Platelets	-18 10^9 cells per liter Standard Deviation 38.0
Change From Baseline in Hematology Parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes and Lymphocytes at Day 18 Leukocytes	-0.08 10^9 cells per liter Standard Deviation 1.395
Change From Baseline in Hematology Parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes and Lymphocytes at Day 18 Neutrophils	-0.21 10^9 cells per liter Standard Deviation 1.390
Change From Baseline in Hematology Parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes and Lymphocytes at Day 18 Eosinophils	-0.00 10^9 cells per liter Standard Deviation 0.050
Change From Baseline in Hematology Parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes and Lymphocytes at Day 18 Basophils	0.00 10^9 cells per liter Standard Deviation 0.017
Change From Baseline in Hematology Parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes and Lymphocytes at Day 18 Monocytes	-0.02 10^9 cells per liter Standard Deviation 0.110
Change From Baseline in Hematology Parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes and Lymphocytes at Day 18 Lymphocytes	0.16 10^9 cells per liter Standard Deviation 0.338

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: Hematocrit, Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Hematology Parameters: Hematocrit, Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes at Day 18 Monocytes/Leukocytes	-0.2 percentage of cells Standard Deviation 1.34
Change From Baseline in Hematology Parameters: Hematocrit, Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes at Day 18 Neutrophils/Leukocytes	-3.0 percentage of cells Standard Deviation 9.30
Change From Baseline in Hematology Parameters: Hematocrit, Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes at Day 18 Hematocrit	-0.029 percentage of cells Standard Deviation 0.0227
Change From Baseline in Hematology Parameters: Hematocrit, Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes at Day 18 Basophils/Leukocytes	0.0 percentage of cells Standard Deviation 0.30
Change From Baseline in Hematology Parameters: Hematocrit, Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes at Day 18 Eosinophils/Leukocytes	0.0 percentage of cells Standard Deviation 0.63
Change From Baseline in Hematology Parameters: Hematocrit, Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes at Day 18 Lymphocytes/Leukocytes	3.2 percentage of cells Standard Deviation 8.44

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the coagulation parameter: Activated Partial Thromboplastin Time.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Coagulation Parameter: Activated Partial Thromboplastin Time at Day 18	-1.6 seconds Standard Deviation 0.84

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Erythrocytes Mean Corpuscular Hemoglobin.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin at Day 18	-0.06283 picogram Standard Deviation 0.541316

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Erythrocytes Mean Corpuscular Volume.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume at Day 18	-0.7 femtoliters Standard Deviation 0.95

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the coagulation parameter: Prothrombin Intl. Normalized Ratio.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Coagulation Parameter: Prothrombin Intl. Normalized Ratio at Day 18	-0.02 ratio Standard Deviation 0.042

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameter: bilirubin, creatinine and urate.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Chemistry Parameters: Bilirubin, Creatinine and Urate at Day 18 Bilirubin	-0.8 micromole per liter (mcmol/L) Standard Deviation 3.11
Change From Baseline in Chemistry Parameters: Bilirubin, Creatinine and Urate at Day 18 Creatinine	-4 micromole per liter (mcmol/L) Standard Deviation 6.2
Change From Baseline in Chemistry Parameters: Bilirubin, Creatinine and Urate at Day 18 Urate	4.1 micromole per liter (mcmol/L) Standard Deviation 31.48

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameter: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Chemistry Parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase at Day 18 Gamma Glutamyl Transferase	0 units per liter (U/L) Standard Deviation 5.4
Change From Baseline in Chemistry Parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase at Day 18 Lactate Dehydrogenase	-35 units per liter (U/L) Standard Deviation 19.7
Change From Baseline in Chemistry Parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase at Day 18 Aspartate Aminotransferase	-2 units per liter (U/L) Standard Deviation 6.2
Change From Baseline in Chemistry Parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase at Day 18 Alanine Aminotransferase	3 units per liter (U/L) Standard Deviation 11.8
Change From Baseline in Chemistry Parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase at Day 18 Alkaline Phosphatase	-4 units per liter (U/L) Standard Deviation 10.1
Change From Baseline in Chemistry Parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase at Day 18 Amylase	-1 units per liter (U/L) Standard Deviation 7.5
Change From Baseline in Chemistry Parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase at Day 18 Lipase	-2.0 units per liter (U/L) Standard Deviation 7.77

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameter: Sodium, Potassium, Calcium, Glucose, Chloride and Triglycerides.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Chemistry Parameters: Sodium, Potassium, Calcium, Glucose, Chloride and Triglycerides at Day 18 Potassium	-0.03 millimoles per liter (mmol/L) Standard Deviation 0.397
Change From Baseline in Chemistry Parameters: Sodium, Potassium, Calcium, Glucose, Chloride and Triglycerides at Day 18 Calcium	-0.04 millimoles per liter (mmol/L) Standard Deviation 0.077
Change From Baseline in Chemistry Parameters: Sodium, Potassium, Calcium, Glucose, Chloride and Triglycerides at Day 18 Glucose	-0.10 millimoles per liter (mmol/L) Standard Deviation 0.385
Change From Baseline in Chemistry Parameters: Sodium, Potassium, Calcium, Glucose, Chloride and Triglycerides at Day 18 Chloride	2 millimoles per liter (mmol/L) Standard Deviation 2.4
Change From Baseline in Chemistry Parameters: Sodium, Potassium, Calcium, Glucose, Chloride and Triglycerides at Day 18 Triglycerides	0.2 millimoles per liter (mmol/L) Standard Deviation 0.29
Change From Baseline in Chemistry Parameters: Sodium, Potassium, Calcium, Glucose, Chloride and Triglycerides at Day 18 Sodium	1 millimoles per liter (mmol/L) Standard Deviation 2.6

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameter: Total Protein.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Chemistry Parameters: Total Protein at Day 18	-2 gram per liter (g/L) Standard Deviation 3.5

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: Safety (SAF) analysis set included all participants, who were administered any dose of any study intervention.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameter: C Reactive Protein.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Chemistry Parameters: C Reactive Protein at Day 18	4 milligram per liter (g/L) Standard Deviation 8.2

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: 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	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Vital Signs: Systolic Blood Pressure and Diastolic Blood Pressure at Day 18 Systolic Blood Pressure	4 millimeters of mercury (mmHg) Standard Deviation 12.5
Change From Baseline in Vital Signs: Systolic Blood Pressure and Diastolic Blood Pressure at Day 18 Diastolic Blood Pressure	3 millimeters of mercury (mmHg) Standard Deviation 9.7

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: 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	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Vital Signs: Pulse Rate at Day 18	4 beats per minute Standard Deviation 10.6

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: 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	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Vital Signs: Respiratory Rate at Day 18	0 breaths per minute Standard Deviation 1.5

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: 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	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Vital Signs: Temperature at Day 18	0.2 degree Celsius Standard Deviation 0.49

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: 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	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Electrocardiograms (ECGs) Parameter: Heart Rate at Day 18	-4 beats per minute Standard Deviation 7.5

SECONDARY outcome

Timeframe: Baseline, Day 18

Population: 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	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Change From Baseline in Electrocardiograms (ECGs) Parameter: RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration at Day 18 RR Duration	51 milliseconds (msec) Standard Deviation 98.4
Change From Baseline in Electrocardiograms (ECGs) Parameter: RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration at Day 18 QT Duration	3 milliseconds (msec) Standard Deviation 17.8
Change From Baseline in Electrocardiograms (ECGs) Parameter: RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration at Day 18 QTcF Duration	-5 milliseconds (msec) Standard Deviation 11.0
Change From Baseline in Electrocardiograms (ECGs) Parameter: RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration at Day 18 PR Duration	3 milliseconds (msec) Standard Deviation 15.3
Change From Baseline in Electrocardiograms (ECGs) Parameter: RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration at Day 18 QRS Duration	-2 milliseconds (msec) Standard Deviation 9.6

SECONDARY outcome

Timeframe: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18

Population: Pharmacokinetics (PK) Analysis set included all participants: who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results; with adequate study intervention compliance; with evaluable PK data, i.e., no missing values for primary endpoints at each PK profile/assessment day (Day 1, Day 15).

Time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethisterone Ethinyl Estradiol	3.00 hours Interval 1.5 to 6.02
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethisterone Norethisterone	2.00 hours Interval 0.667 to 3.0

SECONDARY outcome

Timeframe: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18

Population: Pharmacokinetics (PK) Analysis set included all participants: who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results; with adequate study intervention compliance; with evaluable PK data, i.e., no missing values for primary endpoints at each PK profile/assessment day (Day 1, Day 15).

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	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Terminal Half Life (T1/2) of Ethinyl Estradiol and Norethisterone Ethinyl Estradiol	21.5 hours Interval 10.5 to 32.1
Terminal Half Life (T1/2) of Ethinyl Estradiol and Norethisterone Norethisterone	12.7 hours Interval 7.58 to 20.9

SECONDARY outcome

Timeframe: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18

Population: Pharmacokinetics (PK) Analysis set included all participants: who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results; with adequate study intervention compliance; with evaluable PK data, i.e., no missing values for primary endpoints at each PK profile/assessment day (Day 1, Day 15).

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	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Ethinyl Estradiol and Norethisterone Ethinyl Estradiol	964 h×pg/mL Geometric Coefficient of Variation 26.9
Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Ethinyl Estradiol and Norethisterone Norethisterone	35100 h×pg/mL Geometric Coefficient of Variation 36.4

SECONDARY outcome

Timeframe: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18

Population: Pharmacokinetics (PK) Analysis set included all participants: who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results; with adequate study intervention compliance; with evaluable PK data, i.e., no missing values for primary endpoints at each PK profile/assessment day (Day 1, Day 15).

Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for Ethinyl Estradiol/Norethisterone.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Apparent Total Body Clearance (CL/f) of Ethinyl Estradiol and Norethisterone Norethisterone	13.9 Liter per hour Geometric Coefficient of Variation 35.9
Apparent Total Body Clearance (CL/f) of Ethinyl Estradiol and Norethisterone Ethinyl Estradiol	27.6 Liter per hour Geometric Coefficient of Variation 26.7

SECONDARY outcome

Timeframe: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18

Population: Pharmacokinetics (PK) Analysis set included all participants: who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results; with adequate study intervention compliance; with evaluable PK data, i.e., no missing values for primary endpoints at each PK profile/assessment day (Day 1, Day 15).

Vz/f is defined as the apparent volume of distribution during the terminal phase following extravascular administration for Ethinyl Estradiol/Norethisterone.

Outcome measures

Measure	COC + Evobrutinib n=20 Participants Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Apparent Volume of Distribution During Terminal Phase (VZ/f) of Ethinyl Estradiol and Norethisterone Ethinyl Estradiol	816 Liter Geometric Coefficient of Variation 26.0
Apparent Volume of Distribution During Terminal Phase (VZ/f) of Ethinyl Estradiol and Norethisterone Norethisterone	252 Liter Geometric Coefficient of Variation 46.7

Adverse Events

COC + Evobrutinib

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	COC + Evobrutinib n=20 participants at risk Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15 in combination with Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.
Skin and subcutaneous tissue disorders Dry skin	5.0% 1/20 • Number of events 1 • Up to 46 days
Gastrointestinal disorders Abnormal faeces	5.0% 1/20 • Number of events 1 • Up to 46 days
Gastrointestinal disorders Defaecation urgency	5.0% 1/20 • Number of events 1 • Up to 46 days
Gastrointestinal disorders Flatulence	5.0% 1/20 • Number of events 1 • Up to 46 days
Gastrointestinal disorders Gastrointestinal disorder	5.0% 1/20 • Number of events 1 • Up to 46 days
General disorders Fatigue	5.0% 1/20 • Number of events 1 • Up to 46 days
Infections and infestations Nasopharyngitis	5.0% 1/20 • Number of events 1 • Up to 46 days
Musculoskeletal and connective tissue disorders Arthralgia	5.0% 1/20 • Number of events 1 • Up to 46 days
Musculoskeletal and connective tissue disorders Pain in extremity	5.0% 1/20 • Number of events 1 • Up to 46 days
Nervous system disorders Headache	5.0% 1/20 • Number of events 2 • Up to 46 days
Nervous system disorders Restless legs syndrome	5.0% 1/20 • Number of events 1 • Up to 46 days
Renal and urinary disorders Pollakiuria	30.0% 6/20 • Number of events 6 • Up to 46 days
Reproductive system and breast disorders Polymenorrhoea	5.0% 1/20 • Number of events 1 • Up to 46 days
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.0% 1/20 • Number of events 1 • Up to 46 days

Additional Information

Communication Center

Merck Healthcare KGaA, Darmstadt Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Phone: +49-6151-72-5200

Email: service@emdgroup.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place