Clinical trial NCT04697511: Drug-drug Interaction Study of Evobrutinib With Midazolam in Healthy Participants
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Midazolam
Cytochrome P450
Autoimmune disorders
Inflammatory disorders
Sedative-hypnotic
Lead sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2021-01-06
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: OTHER

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


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: Area Under the Plasma Concentration-Time Curve from Time Zero Extrapolated to Infinity (AUC0-inf) of Midazolam
timeFrame: Pre-dose through 24 hours postdose on Days 1, 3 and 13
measure: Maximum Observed Plasma Concentration (Cmax) of Midazolam
timeFrame: Pre-dose through 24 hours postdose on Days 1, 3 and 13
Secondary outcomes:
measure: Number of Participants with Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Up to Day 14
measure: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) by Severity
timeFrame: Up to Day 14
measure: Number of Participants with Clinically Significant Change From Baseline in Laboratory Parameters, Vital Signs and 12-Lead Electrocardiogram (ECG) Findings
timeFrame: Up to Day 14
measure: Area Under the Plasma Concentration-Time Curve from Time Zero Extrapolated to Infinity (AUC0-inf) of 1-hydroxymidazolam
timeFrame: Pre-dose through 24 hours postdose on Days 1, 3 and 13
measure: Maximum Observed Plasma Concentration (Cmax) of 1-hydroxymidazolam
timeFrame: Pre-dose through 24 hours postdose on Days 1, 3 and 13
measure: Time to Reach Maximum Plasma Concentration (tmax) of Midazolam and 1-hydroxymidazolam
timeFrame: Pre-dose through 24 hours postdose on Days 1, 3 and 13
measure: Apparent Terminal Half-life (t1/2) of Midazolam and 1-hydroxymidazolam
timeFrame: Pre-dose through 24 hours postdose on Days 1, 3 and 13
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t) of Midazolam and 1-hydroxymidazolam
timeFrame: Pre-dose through 24 hours postdose on Days 1, 3 and 13
measure: Apparent Total Body Clearance (CL/F) of Midazolam
timeFrame: Pre-dose through 24 hours postdose on Days 1, 3 and 13
measure: Apparent Volume of Distribution (Vz/F) of Midazolam
timeFrame: Pre-dose through 24 hours postdose on Days 1, 3 and 13
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: