A Study to Compare How Different Substances (Caffeine, Warfarin, Omeprazole, Metoprolol, and Midazolam) Are Handled by the Body of Healthy People and People With Liver Cirrhosis

Profiling Study for the Hepatic Cytochrome P450 (CYP) Isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A in Healthy Subjects and in Patients With Stage 4 (F4) Liver Fibrosis / Cirrhosis by the Combined Administration of the Probe Substrates (the Cocktail) Caffeine, Warfarin, Omeprazole, Metoprolol, and Midazolam

This study is open to healthy adults and adults with liver cirrhosis. The purpose of this study is to compare how different medicines are handled by the body in people with and without liver cirrhosis. The study measures if the approved medicines caffeine, warfarin,omeprazole, metoprolol, and midazolam are processed differently in people with liver cirrhosis than in people without liver cirrhosis. This study will help to understand how new medicines being developed are handled by the body in people with liver cirrhosis.

There are 3 groups in this study: people without liver cirrhosis, people with mild liver cirrhosis, and people with moderate liver cirrhosis. All participants get 1 dose each of caffeine, warfarin, omeprazole, metoprolol, and midazolam by mouth. The participants with liver cirrhosis continue their regular treatment for the condition during the study.

Participants are in the study for about 1 month. During this time, they visit the study site 5 times. For 1 of the visits, participants stay overnight for 2 nights at the study site. To assess the main study endpoint, the doctors take frequent blood samples from the participants. The doctors also regularly check participants' health and take note of any unwanted effects.

Study Overview

• Status: Completed
• Conditions: Liver Cirrhosis
• Intervention / Treatment: Drug: Midazolam; Drug: Caffeine; Drug: Warfarin sodium; Drug: Omeprazole; Drug: Metoprolol

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Mannheim, Germany, 68167
    • CRS Clinical Research Services Mannheim GmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

Healthy subjects and F4 liver cirrhosis patients:

• Signed and dated written informed consent in accordance with the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial

• Either male subject, or female subject who meets any of the following criteria for a highly effective contraception from at least 30 days before the first administration of trial medication until 30 days after trial completion:

  • Use of combined (estrogen and progestogen containing) hormonal contraception that prevents ovulation (oral, intravaginal, or transdermal), plus condom
  • Use of progestogen-only hormonal contraception that inhibits ovulation (only injectables or implants), plus condom
  • Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
  • Sexually abstinent
  • A vasectomised sexual partner who received medical assessment of the surgical success (documented absence of sperm) and provided that the partner is the sole sexual partner of the trial participant
  • Surgically sterilised (including hysterectomy)
  • Postmenopausal, defined as no menses for 1 year without an alternative medical cause (in questionable cases a blood sample with levels of follicle-stimulating hormone (FSH) above 40 units per liter (U/L) and estradiol below 30 nanograms per liter (ng/L) is confirmatory)
• Not taking any components in the cocktail within 4 weeks of enrolment (except from caffeine: methylxanthine-containing drinks or foods such as coffee, tea, cola, energy drinks, or chocolate are not allowed within 48 hours (h) before and during the inhouse confinement at the trial site)

Healthy subjects only:

• Healthy male or female subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), and clinical laboratory tests
• Age of 18 to 75 years (inclusive)
• Body mass index (BMI) of 18.5 to 35 kilograms per meter squared (kg/m2) (inclusive). A BMI of ≥ 30 is no exclusion criterion when the subject can be considered healthy apart from the elevated BMI
• further inclusion criteria apply

F4 liver cirrhosis patients only

• Male and female subjects, 18 to 75 years
• BMI of 18.5 to 40.0 kg/m2 (inclusive)
• Stable treatment for at least 4 weeks prior to taking the cocktail. Furthermore, patients can only be included into the trial a) if they are in constant specialist care at the timepoint of enrollment into the study and b) if they are willing to continue to be in specialist care after participation in the 0352.2190 study
• further inclusion criteria apply

Exclusion criteria

Healthy subjects and F4 liver cirrhosis patients:

• Subjects already taking any components in the cocktail within 4 weeks before cocktail administration (except from caffeine: methylxanthine-containing drinks or foods such as coffee, tea, cola, energy drinks, or chocolate are not allowed within 48 h before and during the in-house confinement at the trial site)
• Subjects with any other condition that would preclude administration of caffeine, warfarin, omeprazole, metoprolol, and midazolam (i.e., contraindicated as per Summary of Product Characteristics (SmPC)), such as hypersensitivity to active ingredient or any of the excipients or to any beta receptor blockers
• Repeated measurement of systolic blood pressure outside the range of 90 to 150 millimeter of mercury (mmHg), diastolic blood pressure outside the range of 50 to 95 mmHg, or pulse rate outside the range of 50 to 90 beats per minute (bpm)
• Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
• Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders
• History of relevant orthostatic hypotension, fainting spells, or blackouts
• Relevant (other than Hepatitis B virus (HBV) or Hepatitis C virus (HCV)) chronic or acute infections (including an ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection)
• Patients receiving antiviral therapy at the time of inclusion into the trial
• further exclusion criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• 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: Healthy participants; Every participant receives a cocktail of Caffeine, Warfarin sodium, Omeprazole, Metoprolol, Midazolam.	Drug: Midazolam; Midazolam; Drug: Caffeine; Caffeine; Drug: Warfarin sodium; Warfarin sodium; Drug: Omeprazole; Omeprazole; Drug: Metoprolol; Metoprolol
Experimental: Group 2: F4 Child-Turcotte-Pugh class A (Child-Pugh A) participants (compensated); Every participant receives a cocktail of Caffeine, Warfarin sodium, Omeprazole, Metoprolol, Midazolam. Compensated=without any disease symptoms	Drug: Midazolam; Midazolam; Drug: Caffeine; Caffeine; Drug: Warfarin sodium; Warfarin sodium; Drug: Omeprazole; Omeprazole; Drug: Metoprolol; Metoprolol
Experimental: Group 3: F4 Child-Turcotte-Pugh class B (Child-Pugh B) participants (decompensated); Every participant receives a cocktail of Caffeine, Warfarin sodium, Omeprazole, Metoprolol, Midazolam. Decompensated= with disease symptoms like aszites, variceal bleeding, hepatic encephalopathy, hepato-renal syndrome	Drug: Midazolam; Midazolam; Drug: Caffeine; Caffeine; Drug: Warfarin sodium; Warfarin sodium; Drug: Omeprazole; Omeprazole; Drug: Metoprolol; Metoprolol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration Time Curve of Caffeine, Omeprazole and Metoprolol in Plasma Over the Time Interval From 0 to 24 Hours (AUC0-24)	Area under the concentration time curve of caffeine, omeprazole and metoprolol in plasma over the time interval from 0 to 24 hours (AUC0-24) is reported.	2 hours before drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48-72 and 96 (+/-12) hours after drug administration.
Area Under the Concentration Time Curve of Midazolam in Plasma Over the Time Interval From 0 to 24 Hours (AUC0-24)	Area under the concentration time curve of midazolam in plasma over the time interval from 0 to 24 hours (AUC0-24) is reported.	2 hours before drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48-72 and 96 (+/-12) hours after drug administration.
Area Under the Concentration Time Curve of R-warfarin and S-warfarin in Plasma Over the Time Interval From 0 to 96 Hours (AUC0-96)	Area under the concentration time curve of R-warfarin and S-warfarin in plasma over the time interval from 0 to 96 hours (AUC0-96) is reported.	2 hours before drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48-72 and 96 (+/-12) hours after drug administration.
Maximum Measured Concentration of Caffeine, Omeprazole, Metoprolol, R-warfarin and S-warfarin in Plasma (Cmax)	Maximum measured concentration of caffeine, omeprazole, metoprolol, R-warfarin and S-warfarin in plasma (Cmax) is reported.	2 hours before drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48-72 and 96 (+/-12) hours after drug administration.
Maximum Measured Concentration of Midazolam in Plasma (Cmax)	Maximum measured concentration of midazolam in plasma (Cmax) is reported.	2 hours before drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48-72 and 96 (+/-12) hours after drug administration.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2023
• Primary Completion (Actual): August 9, 2024
• Study Completion (Actual): August 23, 2024

Study Registration Dates

• First Submitted: February 14, 2023
• First Submitted That Met QC Criteria: February 14, 2023
• First Posted (Actual): February 23, 2023

Study Record Updates

• Last Update Posted (Estimated): September 10, 2025
• Last Update Submitted That Met QC Criteria: August 22, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Digestive System Diseases; Liver Diseases; Fibrosis; Pathological Conditions, Signs and Symptoms; Liver Cirrhosis; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pyrans; Alkaloids; Amines; Purinones; Purines; Alcohols; Benzazepines; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Propanols; Coumarins; Benzopyrans; Benzodiazepines; Xanthines; 4-Hydroxycoumarins; Midazolam; Metoprolol; Warfarin; Caffeine; Omeprazole
• Other Study ID Numbers: 0352-2190

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents. Exceptions might apply, e.g., studies in products where Boehringer Ingelheim is not the license holder; studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials; studies conducted in a single center or targeting rare diseases (in case of low number of patients and therefore limitations with anonymization). For more details refer to: https:// www.mystudywindow.com/msw/datatransparency

Drug and device information, study documents

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