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

Sponsor

Boehringer Ingelheim (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05741385

Collaborator

(none)

Enrollment

Arms

13.3

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The main trial objective is to ascertain whether the metabolism activity of selected cytochrome (CYP) isozymes caffeine (CYP1A2 probe drug), warfarin (CYP2C9 probe drug), omeprazole (CYP2C19 probe drug), metopolol (CYP2D6 probe drug), and midazolam (CYP3A probe drug) are similar or different in F4 liver cirrhosis patients on standard therapy compared to healthy subjects.

Condition or Disease	Intervention/Treatment	Phase
Liver Cirrhosis	Drug: Caffeine Drug: Warfarin sodium Drug: Omeprazole Drug: Metoprolol Drug: Midazolam	N/A

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

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

Anticipated Study Start Date :

Mar 6, 2023

Anticipated Primary Completion Date :

Apr 14, 2024

Anticipated Study Completion Date :

Apr 14, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1: Healthy participants Every participant receives a cocktail of Caffeine, Warfarin sodium, Omeprazole, Metoprolol, Midazolam.	Drug: Caffeine Caffeine Drug: Warfarin sodium Warfarin sodium Drug: Omeprazole Omeprazole Drug: Metoprolol Metoprolol Drug: Midazolam Midazolam
Experimental: Group 2: F4 Child-Turcotte-Pugh class A (Child-Pugh A) subjects (compensated) Every participant receives a cocktail of Caffeine, Warfarin sodium, Omeprazole, Metoprolol, Midazolam. Compensated=without any disease symptoms	Drug: Caffeine Caffeine Drug: Warfarin sodium Warfarin sodium Drug: Omeprazole Omeprazole Drug: Metoprolol Metoprolol Drug: Midazolam Midazolam
Experimental: Group 3: F4 Child-Turcotte-Pugh class B (Child-Pugh B) subjects (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: Caffeine Caffeine Drug: Warfarin sodium Warfarin sodium Drug: Omeprazole Omeprazole Drug: Metoprolol Metoprolol Drug: Midazolam Midazolam

Arm

Intervention/Treatment

Experimental: Group 1: Healthy participants

Every participant receives a cocktail of Caffeine, Warfarin sodium, Omeprazole, Metoprolol, Midazolam.

Drug: Caffeine

Caffeine

Drug: Warfarin sodium

Warfarin sodium

Drug: Omeprazole

Omeprazole

Drug: Metoprolol

Metoprolol

Drug: Midazolam

Midazolam

Experimental: Group 2: F4 Child-Turcotte-Pugh class A (Child-Pugh A) subjects (compensated)

Every participant receives a cocktail of Caffeine, Warfarin sodium, Omeprazole, Metoprolol, Midazolam. Compensated=without any disease symptoms

Drug: Caffeine

Caffeine

Drug: Warfarin sodium

Warfarin sodium

Drug: Omeprazole

Omeprazole

Drug: Metoprolol

Metoprolol

Drug: Midazolam

Midazolam

Experimental: Group 3: F4 Child-Turcotte-Pugh class B (Child-Pugh B) subjects (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: Caffeine

Caffeine

Drug: Warfarin sodium

Warfarin sodium

Drug: Omeprazole

Omeprazole

Drug: Metoprolol

Metoprolol

Drug: Midazolam

Midazolam

Outcome Measures

Primary Outcome Measures

Area under the concentration time curve of the analyte in plasma over the time interval from 0 to 24 hours (AUC0-24) for caffeine, omeprazole, metoprolol, and midazolam [Up to 108 hours]
Area under the concentration time curve of warfarin, R-warfarin and S-warfarin in plasma over the time interval from 0 to 96 hours (AUC0-96) [Up to 108 hours]
Maximum measured concentration of the analyte in plasma (Cmax) for each component of the CYP-cocktail: caffeine, warfarin, omeprazole, metoprolol, and midazolam [Up to 108 hours]
Ratio of AUC0-24 or AUC0-96 for metabolite to parent (RAUCM/P) for caffeine (paraxanthine), omeprazole (5'-hydroxyomeprazole), metoprolol, α-hydroxymetoprolol, midazolam (1'hydroxymidazolam) [Up to 108 hours]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts 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
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