Clinical trial NCT05064488: Drug-Drug Interaction Study of Evobrutinib and Transporter Substrates
Official title: A Phase I, Open-Label, Two-Part Study of the Effect of Multiple-Dose Evobrutinib on Transporter Substrates Digoxin, Metformin, Rosuvastatin, and Sumatriptan Pharmacokinetics in Healthy Participants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Clinical Pharmacology
Drug interaction
Evobrutinib
Digoxin
Metformin
Rosuvastatin
Sumatriptan
Lead sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2021-10-01
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study consists of 2 parts: Part 1 and 2. The purpose of this study is to evaluate the pharmacokinetic, safety and tolerability of multiple doses of evobrutinib on single doses of digoxin, metformin and rosuvastatin in Part-1 and sumatriptan in Part-2 of the study.


Eligibility criteria: Inclusion Criteria:

* Participants are 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 have 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 will be 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

Primary outcomes:
measure: Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Transporter Cocktail
timeFrame: Pre-dose through 16 hours post-dose on Days 1 and 10; 24, 36 hours post-dose on Day 2 and Day 11; 48, 60 hours post-dose on Day 3 and Day 12; 72 hours post-dose on Day 4 and Day 13
measure: Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Evobrutinib
timeFrame: Day 10, 11 and 12: 1 hours post-dose
measure: Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Sumatriptan
timeFrame: Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9
measure: Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Evobrutinib
timeFrame: Day 6, 7 and 8: 1 hours post-dose
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of Transporter Cocktail
timeFrame: Pre-dose through 16 hours post-dose on Days 1 and 10; 24, 36 hours post-dose on Day 2 and Day 11; 48, 60 hours post-dose on Day 3 and Day 12; 72 hours post-dose on Day 4 and Day 13
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of Evobrutinib
timeFrame: Day 10, 11 and 12: 1 hours post-dose
measure: Part 2: Maximum Observed Plasma Concentration (Cmax) of Sumatriptan
timeFrame: Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9
measure: Part 2: Maximum Observed Plasma Concentration (Cmax) of Evobrutinib
timeFrame: Day 6, 7 and 8: 1 hours post-dose
Secondary outcomes:
measure: Part 1 and Part 2: Number of Participants with Treatment Emergent Adverse Events (TEAEs)
timeFrame: Part 1: Up to Day 13; Part 2: Up to Day 9
measure: Part 1 and Part 2: Number of Participants with Treatment Emergent Adverse Events (TEAEs) by Severity
timeFrame: Part 1: Up to Day 13; Part 2: Up to Day 9
measure: Part 1 and Part 2: Number of Participants With Abnormal Changes From Baseline in Laboratory Parameters, Vital Signs and 12-Lead Electrocardiogram (ECG) Findings
timeFrame: Part 1: Baseline up to Day 13; Part 2: Baseline up to Day 9
measure: Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Transporter Cocktail
timeFrame: Pre-dose through 16 hours post-dose on Days 1 and 10; 24, 36 hours post-dose on Day 2 and Day 11; 48, 60 hours post-dose on Day 3 and Day 12; 72 hours post-dose on Day 4 and Day 13
measure: Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Evobrutinib
timeFrame: Day 10, 11 and 12: 1 hours post-dose
measure: Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of Sumatriptan
timeFrame: Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9
measure: Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of Evobrutinib
timeFrame: Day 6, 7 and 8: 1 hours post-dose
measure: Part 1: Apparent Terminal Half-Life (t1/2) of Transporter Cocktail
timeFrame: Pre-dose through 16 hours post-dose on Days 1 and 10; 24, 36 hours post-dose on Day 2 and Day 11; 48, 60 hours post-dose on Day 3 and Day 12; 72 hours post-dose on Day 4 and Day 13
measure: Part 1: Apparent Terminal Half-Life (t1/2) of Evobrutinib
timeFrame: Day 10, 11 and 12: 1 hours post-dose
measure: Part 2: Apparent Terminal Half-Life (t1/2) of Sumatriptan
timeFrame: Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9
measure: Part 2: Apparent Terminal Half-Life (t1/2) of Evobrutinib
timeFrame: Day 6, 7 and 8: 1 hours post-dose
measure: Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Transporter Cocktail
timeFrame: Pre-dose through 16 hours post-dose on Days 1 and 10; 24, 36 hours post-dose on Day 2 and Day 11; 48, 60 hours post-dose on Day 3 and Day 12; 72 hours post-dose on Day 4 and Day 13
measure: Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Evobrutinib
timeFrame: Day 10, 11 and 12: 1 hours post-dose
measure: Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Sumatriptan
timeFrame: Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9
measure: Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Evobrutinib
timeFrame: Day 6, 7 and 8: 1 hours post-dose
measure: Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Transporter Cocktail
timeFrame: Pre-dose through 16 hours post-dose on Days 1 and 10; 24, 36 hours post-dose on Day 2 and Day 11; 48, 60 hours post-dose on Day 3 and Day 12; 72 hours post-dose on Day 4 and Day 13
measure: Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Evobrutinib
timeFrame: Day 10, 11 and 12: 1 hours post-dose
measure: Part 2: Apparent Total Body Clearance From Plasma (CL/F) of Sumatriptan
timeFrame: Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9
measure: Part 2: Apparent Total Body Clearance From Plasma (CL/F) of Evobrutinib
timeFrame: Day 6, 7 and 8: 1 hours post-dose
measure: Part 1: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Transporter Cocktail
timeFrame: Pre-dose through 16 hours post-dose on Days 1 and 10; 24, 36 hours post-dose on Day 2 and Day 11; 48, 60 hours post-dose on Day 3 and Day 12; 72 hours post-dose on Day 4 and Day 13
measure: Part 1: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Evobrutinib
timeFrame: Day 10, 11 and 12: 1 hours post-dose
measure: Part 2: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Sumatriptan
timeFrame: Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9
measure: Part 2: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Evobrutinib
timeFrame: Day 6, 7 and 8: 1 hours post-dose
measure: Part 1: Cumulative Amount Excreted From Time Zero to the End of the Collection Interval After Dosing Dosing (Ae0-36) of Merformin
timeFrame: Pre-dose, 0 to 4, 4 to 8, 8 to 12 hours post-dose on Day 1 and Day 10; 12 to 24, 24 to 36 hours post-dose on Day 2 and Day 11
measure: Part 1: Renal Clearance (CLR) of Metformin
timeFrame: Pre-dose, 0 to 4, 4 to 8, 8 to 12 hours post-dose on Day 1 and Day 10; 12 to 24, 24 to 36 hours post-dose on Day 2 and Day 11
Other outcomes:
Locations:
city: Neu-Ulm
country: Germany
facility: Nuvisan GmbH
Study officials:
affiliation: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: