Clinical trial NCT02353455: Cells of Monocytic Origin as Surrogate Markers for Individual Drug Effects and Hepatotoxicity
Official title: Cells of Monocytic Origin as Surrogate Markers for Individual Drug Effects and Hepatotoxicity
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Drug-induced Disorder of Liver
Adverse Reaction to Drug
Lead sponsor: Ludwig-Maximilians - University of Munich
Sponsor class: OTHER
Collaborators: name: MetaHeps GmbH
First posted: 2015-02-02
Enrollment: 300
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The groups or cohorts will be selected from patients treated at the LMU University Hospital.

Sampling Method is non-probability sample: patients are invited to volunteer to participate.

Brief summary: Drug metabolism in the liver is subject to large fluctuations (differences between women and men, people of different ethnic backgrounds, children and adults). These large differences are responsible for very different drug effects and side-effects (and especially liver damage caused by drugs) between individuals. Recent scientific findings suggest that blood derived cells can be used to model individual effects of drugs on the liver reflect inter-individual differences. Since liver damage caused by drugs is a diagnosis of exclusion, the aforementioned cells can be used to identify patients that show higher sensitivity to hepatotoxic side-effects and - in case several drugs are involved - identify the causal agent or possible interactions.

Detailed description: Drug-induced liver injury (DILI), especially its idiosyncratic for is often an unpredictable complication of drug therapy. Until now it is very challenging to predict occurrence, severity and outcome of DILI. Previous data provide evidence that cells from peripheral blood may reflect hepatocellular damage (Fannin RD, Hepatology. 2010). Own research could show that peripheral monocytes are capable to obtain several hepatocyte-like functions while maintaining individual characteristics of the donor, especially cytochrome P450 metabolism (Benesic, Gerbes, et al, Lab Invest 2012). This study investigates the effects of potentially hepatotoxic drugs on cells generated from patient blood in comparison to the clinical presentation. Its aim is the evaluation of in vitro tests using monocyte derived cells for diagnosis and exclusion of DILI and the potential to use the patient derived-cells for mechanistic investigations of DILI. 4 groups are investigated: 1) donors without liver disease 2) patients who will start a therapy with DILI-potential; 3) DILI patients; 4) patients with liver injuries other than DILI.

Patient history and clinical data are obtained and a single blood sample will be collected after informed consent.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 2 years
* Informed consent given by the patient or in case of inability to give informed consent informed consent of the legally nominated consultee

Exclusion Criteria:

* Anemia requiring blood transfusion
* acute or chronic hepatitis B, C or human immunodeficiency virus infection
* lack of informed consent

Primary outcomes:
measure: Reflection of individual drug hepatotoxicity in monocyte derived cells
timeFrame: 12 months
Secondary outcomes:
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Gastroenterology, Alfred Health
state: Victoria
city: Munich
country: Germany
facility: Liver Center Munich®, Department of Internal Medicine II, LMU University Hospital, Campus Grosshadern
state: Bavaria
city: Hong Kong
country: Hong Kong
facility: Chinese University of Hong Kong
city: Nagoya
country: Japan
facility: Department of Gastroenterology and Hepatology Nagoya University School of Medicine
city: Seoul
country: Korea, Republic of
facility: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine
Study officials:
affiliation: Liver Center Munich®, Internal Medicine II, Ludwig-Maximilians University Hospital, Campus Grosshadern, Munich; Marchioninistr. 15; D81377 Munich, Germany
name: Alexander L Gerbes, Prof. MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008 Dec;135(6):1924-34, 1934.e1-4. doi: 10.1053/j.gastro.2008.09.011. Epub 2008 Sep 17.
citation: Watkins PB, Seeff LB. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology. 2006 Mar;43(3):618-31. doi: 10.1002/hep.21095.
citation: Chalasani N, Bjornsson E. Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology. 2010 Jun;138(7):2246-59. doi: 10.1053/j.gastro.2010.04.001. Epub 2010 Apr 12.
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citation: Bell LN, Chalasani N. Epidemiology of idiosyncratic drug-induced liver injury. Semin Liver Dis. 2009 Nov;29(4):337-47. doi: 10.1055/s-0029-1240002. Epub 2009 Oct 13.
citation: Zimmerman HJ. Drug-induced liver disease. Drugs. 1978 Jul;16(1):25-45. doi: 10.2165/00003495-197816010-00002.
citation: Lee WM, Senior JR. Recognizing drug-induced liver injury: current problems, possible solutions. Toxicol Pathol. 2005;33(1):155-64. doi: 10.1080/01926230590522356.
citation: Fannin RD, Russo M, O'Connell TM, Gerrish K, Winnike JH, Macdonald J, Newton J, Malik S, Sieber SO, Parker J, Shah R, Zhou T, Watkins PB, Paules RS. Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation. Hepatology. 2010 Jan;51(1):227-36. doi: 10.1002/hep.23330.
citation: Benesic A, Rahm NL, Ernst S, Gerbes AL. Human monocyte-derived cells with individual hepatocyte characteristics: a novel tool for personalized in vitro studies. Lab Invest. 2012 Jun;92(6):926-36. doi: 10.1038/labinvest.2012.64. Epub 2012 Apr 2.
citation: Weber S, Benesic A, Neumann J, Gerbes AL. Liver Injury Associated with Metamizole Exposure: Features of an Underestimated Adverse Event. Drug Saf. 2021 Jun;44(6):669-680. doi: 10.1007/s40264-021-01049-z. Epub 2021 Feb 27.
citation: Benesic A, Rotter I, Dragoi D, Weber S, Leitl A, Buchholtz ML, Gerbes AL. Development and Validation of a Test to Identify Drugs That Cause Idiosyncratic Drug-Induced Liver Injury. Clin Gastroenterol Hepatol. 2018 Sep;16(9):1488-1494.e5. doi: 10.1016/j.cgh.2018.04.049. Epub 2018 Apr 30.
citation: Benesic A, Leitl A, Gerbes AL. Monocyte-derived hepatocyte-like cells for causality assessment of idiosyncratic drug-induced liver injury. Gut. 2016 Sep;65(9):1555-63. doi: 10.1136/gutjnl-2015-309528. Epub 2015 Jun 4.