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

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

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

Conditions
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Healthy

Intervention / Treatment
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* Drug: Midazolam
* Drug: M2951


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Midazolam and/or M2951<br> | Drug: Midazolam<br>* Participants will receive single oral dose of midazolam on Days 1, 3 and 13 under fed conditions.<br>Drug: M2951<br>* Participants will receive multiple oral doses (twice daily) of M2951 on Day 3 to Day 13 under fed conditions.<br>* Other names: Evobrutinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Number of participants with clinically significant change from baseline in laboratory parameters, vital signs and 12- lead ECG findings will be reported. | Up to Day 14 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Midazolam, Cytochrome P450, Autoimmune disorders, Inflammatory disorders, Sedative-hypnotic