Drug-Drug Interaction Study of Evobrutinib and Transporter Substrates

Healthy Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05064488
• Other study ID #: MS200527_0078
• Secondary ID: 2021-001923-42
• Status: Completed
• Phase: Phase 1
• Start date: October 4, 2021
• Est. completion date: December 10, 2021

Study information

• Verified date: January 2022
• Source: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: December 10, 2021
• Est. primary completion date: December 10, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• Evobrutinib
Participants will receive evobrutinib film-coated tablet, twice daily under fed conditions from Days 4 to 12 in Part 1 and from Days 2 to 8 in Part 2 of the study.
• Digoxin
Participants will receive digoxin tablet under fed conditions, once a day on Day 1 and Day 10 in Part 1.
• Metformin
Participants will receive metformin oral solution under fed conditions, once a day on Day 1 and Day 10 in Part 1.
• Rosuvastatin
Participants will receive rosuvastatin tablet under fed conditions, once a day on Day 1 and Day 10 in Part 1.
• Sumatriptan
Participants will receive sumatriptan tablet under fed conditions, once a day on Day 1 and Day 8 in Part 2.

Locations

Country	Name	City	State
Germany	Nuvisan GmbH	Neu-Ulm

Sponsors (1)

Lead Sponsor	Collaborator
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Transporter Cocktail	The transporter cocktail includes digoxin, metformin, and rosuvastatin.	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
Primary	Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Evobrutinib		Day 10, 11 and 12: 1 hours post-dose
Primary	Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Sumatriptan		Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9
Primary	Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Evobrutinib		Day 6, 7 and 8: 1 hours post-dose
Primary	Part 1: Maximum Observed Plasma Concentration (Cmax) of Transporter Cocktail		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
Primary	Part 1: Maximum Observed Plasma Concentration (Cmax) of Evobrutinib		Day 10, 11 and 12: 1 hours post-dose
Primary	Part 2: Maximum Observed Plasma Concentration (Cmax) of Sumatriptan		Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9
Primary	Part 2: Maximum Observed Plasma Concentration (Cmax) of Evobrutinib		Day 6, 7 and 8: 1 hours post-dose
Secondary	Part 1 and Part 2: Number of Participants with Treatment Emergent Adverse Events (TEAEs)		Part 1: Up to Day 13; Part 2: Up to Day 9
Secondary	Part 1 and Part 2: Number of Participants with Treatment Emergent Adverse Events (TEAEs) by Severity		Part 1: Up to Day 13; Part 2: Up to Day 9
Secondary	Part 1 and Part 2: Number of Participants With Abnormal Changes From Baseline in Laboratory Parameters, Vital Signs and 12-Lead Electrocardiogram (ECG) Findings	Number of participants with abnormal changes from baseline in laboratory parameters, vital signs and 12-Lead electrocardiogram (ECG) findings will be reported.	Part 1: Baseline up to Day 13; Part 2: Baseline up to Day 9
Secondary	Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Transporter Cocktail		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
Secondary	Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Evobrutinib		Day 10, 11 and 12: 1 hours post-dose
Secondary	Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of Sumatriptan		Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9
Secondary	Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of Evobrutinib		Day 6, 7 and 8: 1 hours post-dose
Secondary	Part 1: Apparent Terminal Half-Life (t1/2) of Transporter Cocktail		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
Secondary	Part 1: Apparent Terminal Half-Life (t1/2) of Evobrutinib		Day 10, 11 and 12: 1 hours post-dose
Secondary	Part 2: Apparent Terminal Half-Life (t1/2) of Sumatriptan		Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9
Secondary	Part 2: Apparent Terminal Half-Life (t1/2) of Evobrutinib		Day 6, 7 and 8: 1 hours post-dose
Secondary	Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Transporter Cocktail		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
Secondary	Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Evobrutinib		Day 10, 11 and 12: 1 hours post-dose
Secondary	Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Sumatriptan		Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9
Secondary	Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Evobrutinib		Day 6, 7 and 8: 1 hours post-dose
Secondary	Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Transporter Cocktail		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
Secondary	Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Evobrutinib		Day 10, 11 and 12: 1 hours post-dose
Secondary	Part 2: Apparent Total Body Clearance From Plasma (CL/F) of Sumatriptan		Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9
Secondary	Part 2: Apparent Total Body Clearance From Plasma (CL/F) of Evobrutinib		Day 6, 7 and 8: 1 hours post-dose
Secondary	Part 1: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Transporter Cocktail		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
Secondary	Part 1: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Evobrutinib		Day 10, 11 and 12: 1 hours post-dose
Secondary	Part 2: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Sumatriptan		Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9
Secondary	Part 2: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Evobrutinib		Day 6, 7 and 8: 1 hours post-dose
Secondary	Part 1: Cumulative Amount Excreted From Time Zero to the End of the Collection Interval After Dosing Dosing (Ae0-36) of Merformin		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
Secondary	Part 1: Renal Clearance (CLR) of Metformin		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

External Links

•   Trial Awareness and Transparency website