Clinical trial NCT04546789: Effect of Hepatic Impairment on M2951 (BTK Inhibitor) PK
Official title: Phase I Open-label, Single Dose Study to Investigate the Effect of Hepatic Impairment on the PK of Evobrutinib (M2951)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatic Impairment
Keywords: Hepatic Impairment
Pharmacokinetics
Lead sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2020-09-14
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is to investigate the pharmacokinetic (PK) and safety of M2951 (Bruton's tyrosine kinase \[BTK\] inhibitor) in participants with different degrees of hepatic impairment compared to participants with normal hepatic function.


Eligibility criteria: Inclusion Criteria:

* Participants with normal hepatic function only will be 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 OR
* Participants with moderately impaired hepatic function only will be considered to have moderately (Child-Pugh class B and confirmed liver cirrhosis) impaired hepatic function and has been clinically stable for at least 1 month prior to Screening OR
* Participants with mildly impaired hepatic function only will be considered to have mildly (Child-Pugh class A and confirmed liver cirrhosis) impaired hepatic function and has been clinically stable for at least 1 month prior to Screening
* Have a body weight within 50.0 and 120.0 kilogram (kg) and body mass index (BMI) within the range 19.0 and 36.0 kilogram per square meter (kg/m\^2)
* Female participants are not pregnant or breastfeeding, and at least one of the following conditions applies
* Not a woman of childbearing potential (WOCBP)
* Other protocol defined inclusion criteria could apply

Exclusion Criteria:

* Clinical history of autoimmune disorder with hepatic influence (Hashimoto thyroiditis and rheumatic diseases allowed)
* History of any malignancy
* Diseases and surgeries of the gastrointestinal tract, which could influence the gastrointestinal anatomy and mobility. Prior history of cholecystectomy or inflammatory bowel disease, and any clinically relevant surgery within 6 months prior to Screening
* 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 trial per the Investigator's discretion
* Participants with impaired hepatic function will be excluded who had Primary and secondary biliary cirrhosis.
* Participants with impaired hepatic function will be excluded with Clinical evidence of severe ascites.
* Participants with impaired hepatic function will be excluded with Hepatic encephalopathy Grade greater than 1
* Other protocol defined exclusion criteria could apply

Primary outcomes:
measure: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC 0-inf) of M2951 (BTK inhibitor)
timeFrame: Pre-dose up to 32 hours post-dose
measure: Maximum Observed Plasma Concentration (Cmax) of M2951 (BTK inhibitor)
timeFrame: Pre-dose up to 32 hours post-dose
Secondary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Day 1 up to Day 6
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs, Laboratory Parameters and Electrocardiogram Findings
timeFrame: Day 1 up to Day 6
measure: Time to Reach Maximum Plasma Concentration (Tmax) of M2951 (BTK inhibitor)
timeFrame: Pre-dose up to 32 hours post-dose
measure: Apparent Elimination Half Life (t1/2) of M2951 (BTK inhibitor)
timeFrame: Pre-dose up to 32 hours post-dose
measure: Area Under The Plasma Concentration-Time Curve From Time Zero to Time 12 Hours After M2951 (BTK inhibitor) Administration (AUC0-12)
timeFrame: Pre-dose up to 12 hours
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 24 Hours After M2951(BTK inhibitor) Administration (AUC0-24)
timeFrame: Pre-dose up to 24 hours post-dose
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M2951 (BTK inhibitor)
timeFrame: Pre-dose up to 32 hours post-dose
measure: Apparent Total Body Clearance (CL/f) of M2951 (BTK inhibitor)
timeFrame: Pre-dose up to 32 hours post-dose
measure: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M2951 (BTK inhibitor)
timeFrame: Pre-dose up to 32 hours post-dose
measure: Fraction of Unbound Drug (M2951 [BTK inhibitor]) in the Plasma (fu)
timeFrame: Pre-dose up to 32 hours post-dose
measure: Area Under Plasma Concentration for Unbound Drug (M2951 [BTK inhibitor]) From Time Zero to Infinity (AUC0-inf-u)
timeFrame: Pre-dose up to 32 hours post-dose
measure: Maximum Observed Plasma Concentration of Unbound M2951 (BTK inhibitor) (Cmax, u)
timeFrame: Pre-dose up to 32 hours post-dose
measure: Apparent Oral Clearance (CL,u/F) of Unbound M2951 (BTK inhibitor)
timeFrame: Pre-dose up to 32 hours post-dose
Other outcomes:
Locations:
city: Kiel
country: Germany
facility: CRS Clinical Research Services Kiel GmbH
Study officials:
affiliation: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: