Predicting Response and Exposure Changes in Cirrhosis for Effectiveness (PRECISE)

August 7, 2026 updated by: Marten A Lantinga, MD PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

The goal of this clinical trial is to learn how liver cirrhosis affects the way the body processes drugs in adults with different stages of liver cirrhosis. This information may help improve drug dosing for people with liver cirrhosis in the future. The main question it aims to answer is:

• How does the severity of liver cirrhosis affect the way the body processes a combination of five drugs, each used to measure the activity of a different liver enzyme?

Researchers will compare participants with mild, moderate, and severe liver cirrhosis to see whether the processing of drugs differs between these groups.

Participants will:

  • Fast overnight for 8 hours before receiving the drugs
  • Have a scan to measure the stiffness of their liver and spleen
  • Receive a single low dose of five drugs: caffeine, warfarin, esomeprazole, metoprolol, and midazolam
  • Have blood samples taken before and at several times up to 72 hours after receiving the drugs, including samples for genetic testing and blood clotting checks
  • Avoid caffeine-containing food and drinks from 48 hours before receiving the drugs until the final blood sample

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Objective: to identify and quantify the effect of changes in liver-metabolism that occur in different grades of cirrhosis disease severity on the PK of five probe drugs that are each selectively metabolised by one CYP isoform using a probe drug cocktail as proxy.

Study design: Single-dose interventional PK study

Study population: 45 patients with (decompensated) cirrhosis, 18 years or older.

Intervention: This study consists of a single intervention where patients receive a single oral administration of a drug probe cocktail. The oral probe drug cocktail consists of 100 mg caffeine, 5 mg warfarin, 20 mg esomeprazole, 50 mg metoprolol and 0.03 mg/kg midazolam.

Main study parameters/endpoints: The primary endpoint is the unbound clearance (CL) of each parent of the probe drugs with the total and unbound area under the plasma concentration versus time curve (AUC) of each drug. Secondary endpoints include pharmacokinetic (PK) parameters such as volume of distribution of the central (V1) and peripheral compartment (V2) and intercompartment clearance (Q) of each probe drug.

Secondary study parameters are:

• To identify covariates that may influence PK changes in cirrhosis in the development of a population PK model:

  • Effect of different disease severity scores on PK (Model for End-stage Liver Disease (MELD) MELD, MELD-Na, MELD 3.0, reMELD-Na).
  • Effect of presence of portal hypertension (ascites, hepatic encefalopathie (HE), spontaneous bacterial peritonitis (SBP), variceal bleeding)
  • Effect of severity of portal hypertension on PK (spleen stiffness measurement; spleen stiffness measurement (SSM))
  • Effect of inflammation on PK
  • Effect of acute-on-chronic liver failure (ACLF) on PK
  • Effect of concurrent acute kidney injury (AKI) on PK
  • Effect of plasma albumin and bilirubin on PK
  • Effect of CYP-polymorphisms on PK (metaboliser status and/or activity score of each CYP enzyme)

Study Type

Interventional

Enrollment (Estimated)

45

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age ≥ 18 years
  • Clinical, radiological and/or histological diagnosis of cirrhosis
  • Informed consent signed prior to participation in the study

Exclusion Criteria:

  • Original MELD score > 30
  • Estimated creatinine clearance < 30 mL/min, calculated by using the Cockcroft-Gault equation
  • Known poor metaboliser status for one of the CYP enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A) described in the medical record
  • Previous clinically relevant adverse reaction or intolerance to one of the drugs in the probe drug cocktail

  • Recent exposure to one of the drugs in the drug probe cocktail within five elimination half-lives prior to drug administration (corresponding to approximately 1-10 days depending on the probe drug)36-40:

    • caffeine: 5h x 5 = 25 hours
    • warfarin: 50h x 5 = 250 hours
    • esomeprazole: 1.3h x 5 = 6.5 hours
    • metoprolol: 3.5h x 5 = 17.5 hours
    • midazolam: 2.5h x 5 = 12.5 hours

  • Absolute contraindication for one of the drugs in the probe drug cocktail36-40:

    • caffeine: drug hypersensitivity
    • warfarin: drug hypersensitivity and active bleeding
    • esomeprazole: drug hypersensitivity, congenital long QT syndrome and suspected gastrointestinal malignancy
    • metoprolol: drug hypersensitivity, cardiogenic shock, second- and third degree AV block, bradycardia (< 50 beats per minute), sick sinus syndrome including SA block, symptomatic hypotension (mean arterial pressure < 65 mmHg), metabolic acidosis and untreated pheochromocytoma
    • midazolam: drug hypersensitivity, severe chronic obstructive pulmonary disease, myasthenia gravis, sleep apnoea syndrome requiring CPAP, Parkinson's disease, severe respiratory insufficiency or acute respiratory depression
  • Interactions with strong to moderate CYP inhibitors and inducers of the following P450 enzymes: CYP1A2 (inhibitors: ciprofloxacin, fluvoxamine), CYP2C9, CYP2C19, CYP2D6 (inhibitors: bupropion, cinacalcet, fluoxetine, quinidine, paroxetine, terbinafine) and CYP3A (inducers: apalutamide, carbamazepine, efavirenz, enzalutamide, phenobarbital, phenytoin, hypericum, lumacaftor, mitotane, nevirapine, primidone, rifabutin, rifampicin; inhibitors: clarithromycin, cobicistat, erythromycin, itraconazole, ketoconazole, posaconazole, ritonavir, voriconazole)41,42
  • Use of concomitant medication with a clinically relevant PK or PD interaction with one or more components of the probe drug cocktail, if the interaction is expected to affect PK endpoint interpretation or compromise participant safety and cannot be appropriately managed
  • Refusing or unable to give informed consent (e.g. hepatic encephalopathy)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Single-Dose Five-Drug CYP Probe Cocktail
Participants with Child-Pugh class A, B, or C liver cirrhosis will receive the same single-dose combination of five CYP probe medicines. Pharmacokinetic outcomes will be compared between the three Child-Pugh classes.
Drug: Five-Drug CYP Probe Cocktail
A single dose of a five-drug CYP probe cocktail consisting of caffeine 100 mg, warfarin 5 mg, esomeprazole 20 mg, metoprolol 50 mg, and midazolam 0.03 mg/kg.
Other Names:
  • Warfarin
  • Metoprolol
  • Midazolam
  • Esomeprazole
  • Caffeine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Unbound clearance (CL) of each parent drug
Time Frame: 24 months
Unbound clearance (CL) of each parent drug
24 months
Total and unbound area under the plasma concentration versus time curve (AUC) of each parent drug
Time Frame: 24 months
Total and unbound area under the plasma concentration versus time curve (AUC) of each parent drug
24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Volume of distribution of the central compartment (V1) of each parent drug
Time Frame: 24 months
Volume of distribution of the central compartment (V1) of each parent drug
24 months
Volume of distribution of the peripheral compartment (V2) of each parent drug
Time Frame: 24 months
Volume of distribution of the peripheral compartment (V2) of each parent drug
24 months
Intercompartment clearance (Q) of each parent drug
Time Frame: 24 months
Intercompartment clearance (Q) of each parent drug
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

November 1, 2026

Primary Completion (Estimated)

November 1, 2028

Study Completion (Estimated)

December 1, 2028

Study Registration Dates

First Submitted

August 3, 2026

First Submitted That Met QC Criteria

August 3, 2026

First Posted (Actual)

August 6, 2026

Study Record Updates

Last Update Posted (Actual)

August 11, 2026

Last Update Submitted That Met QC Criteria

August 7, 2026

Last Verified

August 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL-011165
  • NL-OMON61340 (Registry Identifier: Research with human participants (OMON))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Individual participant data is available upon reasonable request

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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