Effect of Hepatic Impairment on M2951 (BTK Inhibitor) PK

Phase I Open-label, Single Dose Study to Investigate the Effect of Hepatic Impairment on the PK of Evobrutinib (M2951)

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.

Study Overview

• Status: Completed
• Conditions: Hepatic Impairment
• Intervention / Treatment: Drug: M2951 (BTK inhibitor)

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Kiel, Germany
    • CRS Clinical Research Services Kiel GmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1: Normal Hepatic Function; Healthy participants who have normal hepatic function with sex, age (± 10 years; >= 18 years old and =< 79 years old), and weight (± 10 percent; >= 50 kilogram (kg) and =< 120 kg) matching with the mild and moderate hepatic impairment cohorts will receive single oral dose of M2951 (BTK inhibitor).	Drug: M2951 (BTK inhibitor); Participants will receive a single oral dose of M2951 (BTK inhibitor).; Other Names: Evobrutinib
Experimental: Group 2: Mild Hepatic Impairment; Participants with mild hepatic impairment based on Child-Pugh Class A score of 5 or 6 will receive single oral dose of M2951 (BTK inhibitor).	Drug: M2951 (BTK inhibitor); Participants will receive a single oral dose of M2951 (BTK inhibitor).; Other Names: Evobrutinib
Experimental: Group 3: Moderate Hepatic Impairment; Participants with moderate hepatic impairment based on Child-Pugh Class B score of 7 to 9 will receive single oral dose of M2951 (BTK inhibitor).	Drug: M2951 (BTK inhibitor); Participants will receive a single oral dose of M2951 (BTK inhibitor).; Other Names: Evobrutinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC 0-inf) of M2951 (BTK inhibitor)	Pre-dose up to 32 hours post-dose
Maximum Observed Plasma Concentration (Cmax) of M2951 (BTK inhibitor)	Pre-dose up to 32 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)		Day 1 up to Day 6
Number of Participants With Clinically Significant Change From Baseline in Vital Signs, Laboratory Parameters and Electrocardiogram Findings	Number of participants with clinically significant change from baseline in vital signs, laboratory parameters and electrocardiogram findings will be reported.	Day 1 up to Day 6
Time to Reach Maximum Plasma Concentration (Tmax) of M2951 (BTK inhibitor)		Pre-dose up to 32 hours post-dose
Apparent Elimination Half Life (t1/2) of M2951 (BTK inhibitor)		Pre-dose up to 32 hours post-dose
Area Under The Plasma Concentration-Time Curve From Time Zero to Time 12 Hours After M2951 (BTK inhibitor) Administration (AUC0-12)		Pre-dose up to 12 hours
Area Under the Plasma Concentration-Time Curve From Time Zero to Time 24 Hours After M2951(BTK inhibitor) Administration (AUC0-24)		Pre-dose up to 24 hours post-dose
Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M2951 (BTK inhibitor)		Pre-dose up to 32 hours post-dose
Apparent Total Body Clearance (CL/f) of M2951 (BTK inhibitor)		Pre-dose up to 32 hours post-dose
Apparent Volume of Distribution During Terminal Phase (VZ/f) of M2951 (BTK inhibitor)		Pre-dose up to 32 hours post-dose
Fraction of Unbound Drug (M2951 [BTK inhibitor]) in the Plasma (fu)		Pre-dose up to 32 hours post-dose
Area Under Plasma Concentration for Unbound Drug (M2951 [BTK inhibitor]) From Time Zero to Infinity (AUC0-inf-u)		Pre-dose up to 32 hours post-dose
Maximum Observed Plasma Concentration of Unbound M2951 (BTK inhibitor) (Cmax, u)		Pre-dose up to 32 hours post-dose
Apparent Oral Clearance (CL,u/F) of Unbound M2951 (BTK inhibitor)		Pre-dose up to 32 hours post-dose

Collaborators and Investigators

• Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Publications and helpful links

Helpful Links

• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2020
• Primary Completion (Actual): May 16, 2021
• Study Completion (Actual): May 16, 2021

Study Registration Dates

• First Submitted: September 10, 2020
• First Submitted That Met QC Criteria: September 10, 2020
• First Posted (Actual): September 14, 2020

Study Record Updates

• Last Update Posted (Actual): July 12, 2021
• Last Update Submitted That Met QC Criteria: July 9, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Hepatic Impairment
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases
• Other Study ID Numbers: MS200527_0059; 2020-001920-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany, will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.merckgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No