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

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05741385

Enrollment

Registered

2023-02-23

Start date

2023-10-10

Completion date

2024-08-23

Last updated

2025-09-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Liver Cirrhosis

Brief summary

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.

Interventions

DRUGCaffeine

Caffeine

DRUGWarfarin sodium

Warfarin sodium

DRUGOmeprazole

Omeprazole

DRUGMetoprolol

Metoprolol

DRUGMidazolam

Midazolam

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Area Under the Concentration Time Curve of Caffeine, Omeprazole and Metoprolol in Plasma Over the Time Interval From 0 to 24 Hours (AUC0-24)	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 caffeine, omeprazole and metoprolol in plasma over the time interval from 0 to 24 hours (AUC0-24) is reported.
Area Under the Concentration Time Curve of Midazolam in Plasma Over the Time Interval From 0 to 24 Hours (AUC0-24)	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) is reported.
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)	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) is reported.
Maximum Measured Concentration of Caffeine, Omeprazole, Metoprolol, R-warfarin and S-warfarin in Plasma (Cmax)	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) is reported.
Maximum Measured Concentration of Midazolam in Plasma (Cmax)	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) is reported.

Countries

Germany

Participant flow

Recruitment details

The study aimed to investigate whether the metabolic activity of selected CYP isozymes differs between F4 liver cirrhosis patients receiving standard therapy and healthy subjects. It was planned that 12 healthy subjects, 12 compensated F4 Child-Pugh A patients and a minimum of 6 decompensated Child-Pugh B patients following clinical confirmation enter the study. Due to insufficient enrollment only 4 patients, all from Child-Pugh A cohort, were entered into the trial.

Pre-assignment details

All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated

Participants by arm

Arm	Count
Child-Pugh A Patients with compensated liver cirrhosis and advanced fibrosis grade F4 and hepatic impairment that met the criteria for Child-Pugh A received a drug cocktail of caffeine, warfarin, omeprazole, metoprolol and midazolam. The drug cocktail was given as single oral dose of 100 mg caffeine (2 tablets), 5 mg warfarin sodium (1 tablet), 20 mg omeprazole (1 tablet), 50 mg metoprolol (1 tablet) and 2 mg/mL oral solution midazolam, with 240 mL of water after a standardized breakfast on Day 1.	4
Total	4

Arm

Count

Child-Pugh A

Patients with compensated liver cirrhosis and advanced fibrosis grade F4 and hepatic impairment that met the criteria for Child-Pugh A received a drug cocktail of caffeine, warfarin, omeprazole, metoprolol and midazolam. The drug cocktail was given as single oral dose of 100 mg caffeine (2 tablets), 5 mg warfarin sodium (1 tablet), 20 mg omeprazole (1 tablet), 50 mg metoprolol (1 tablet) and 2 mg/mL oral solution midazolam, with 240 mL of water after a standardized breakfast on Day 1.

Total

Baseline characteristics

Characteristic	Child-Pugh A
Age, Continuous	66.8 Years STANDARD_DEVIATION 7.1
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	4 Participants
Sex: Female, Male Female	3 Participants
Sex: Female, Male Male	1 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 4
other Total, other adverse events	2 / 4
serious Total, serious adverse events	0 / 4

Outcome results

Primary

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.