Drug-drug Interaction Study of Evobrutinib With Midazolam in Healthy Participants

Sponsor

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany (Industry)

Overall Status

Completed

CT.gov ID

NCT04697511

Collaborator

(none)

Enrollment

Location

Arm

1.5

Actual Duration (Months)

10.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study will investigate the effect of single dose and multiple doses of M2951 on midazolam Pharmacokinetics (PK) in healthy participants.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Midazolam Drug: M2951	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

16 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

A Phase I, Single-Sequence, Open-Label, Single- and Multiple-Dose Study of the Effect of Evobrutinib on Midazolam Pharmacokinetics in Healthy Participants

Actual Study Start Date :

Jan 11, 2021

Actual Primary Completion Date :

Feb 25, 2021

Actual Study Completion Date :

Feb 25, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Midazolam and/or M2951	Drug: Midazolam Participants will receive single oral dose of midazolam on Days 1, 3 and 13 under fed conditions. Drug: M2951 Participants will receive multiple oral doses (twice daily) of M2951 on Day 3 to Day 13 under fed conditions. Other Names: MSC2364447C Evobrutinib

Arm

Intervention/Treatment

Experimental: Midazolam and/or M2951

Drug: Midazolam

Participants will receive single oral dose of midazolam on Days 1, 3 and 13 under fed conditions.

Drug: M2951

Participants will receive multiple oral doses (twice daily) of M2951 on Day 3 to Day 13 under fed conditions.

Other Names:

MSC2364447C

Evobrutinib

Outcome Measures

Primary Outcome Measures

Area Under the Plasma Concentration-Time Curve from Time Zero Extrapolated to Infinity (AUC0-inf) of Midazolam [Pre-dose through 24 hours postdose on Days 1, 3 and 13]
Maximum Observed Plasma Concentration (Cmax) of Midazolam [Pre-dose through 24 hours postdose on Days 1, 3 and 13]

Secondary Outcome Measures

Number of Participants with Treatment-Emergent Adverse Events (TEAEs) [Up to Day 14]
Number of Participants with Treatment-Emergent Adverse Events (TEAEs) by Severity [Up to Day 14]
Number of Participants with Clinically Significant Change From Baseline in Laboratory Parameters, Vital Signs and 12-Lead Electrocardiogram (ECG) Findings [Up to Day 14]
Number of participants with clinically significant change from baseline in laboratory parameters, vital signs and 12- lead ECG findings will be reported.
Area Under the Plasma Concentration-Time Curve from Time Zero Extrapolated to Infinity (AUC0-inf) of 1-hydroxymidazolam [Pre-dose through 24 hours postdose on Days 1, 3 and 13]
Maximum Observed Plasma Concentration (Cmax) of 1-hydroxymidazolam [Pre-dose through 24 hours postdose on Days 1, 3 and 13]
Time to Reach Maximum Plasma Concentration (tmax) of Midazolam and 1-hydroxymidazolam [Pre-dose through 24 hours postdose on Days 1, 3 and 13]
Apparent Terminal Half-life (t1/2) of Midazolam and 1-hydroxymidazolam [Pre-dose through 24 hours postdose on Days 1, 3 and 13]
Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t) of Midazolam and 1-hydroxymidazolam [Pre-dose through 24 hours postdose on Days 1, 3 and 13]
Apparent Total Body Clearance (CL/F) of Midazolam [Pre-dose through 24 hours postdose on Days 1, 3 and 13]
Apparent Volume of Distribution (Vz/F) of Midazolam [Pre-dose through 24 hours postdose on Days 1, 3 and 13]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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