Drug-induced Disorder of LiverNCT02353455
Cells of Monocytic Origin as Surrogate Markers for Individual Drug Effects and Hepatotoxicity
An observational study of Drug-induced Disorder of Liver and Adverse Reaction to Drug, run by Andreas Benesic, MD at 5 sites in 5 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 years and olderHealthy volunteers can take part
- Conditions the study is for
- Drug-induced Disorder of Liver, Adverse Reaction to Drug
- What is being tested?
- Blood sampling
- Type of treatment
- Surgery or procedure
- How many people
- 300 participants
- Where
- 5 sitesin 5 countries
- Study dates
- Mar 2013to Aug 2022
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 years and older
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
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.
Who may be able to join
- 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
Who cannot join
- Anemia requiring blood transfusion
- acute or chronic hepatitis B, C or human immunodeficiency virus infection
- lack of informed consent
Trial locations and contacts
5 sites in 5 countries.
5 sites in 5 countries
Australia1 site, 1 recruiting
- Recruiting
Gastroenterology, Alfred Health
Melbourne, Victoria
Joanne Mitchell, CTC, (03) 9076 2583, J.Mitchell@alfred.org.au
Germany1 site, 1 recruiting
- Recruiting
Liver Center Munich®, Department of Internal Medicine II, LMU University Hospital, Campus Grosshadern
Munich, Bavaria, 81377
Andreas Benesic, MD, +49 89 44007 ext. 3130, andreas.benesic@med.uni-muenchen.de
Hong Kong1 site, 1 recruiting
- Recruiting
Chinese University of Hong Kong
Hong Kong
Peter Tse, petse@cuhk.edu.hk
Henry LY Chan, Professor
Japan1 site, 1 recruiting
- Recruiting
Department of Gastroenterology and Hepatology Nagoya University School of Medicine
Nagoya
Masatoshi Ishigami, MD, +81-52-744-2190, masaishi@med.nagoya-u.ac.jp
South Korea1 site, 1 recruiting
- Recruiting
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine
Seoul
Han Ah Lee, Ass Prof, amelia86@naver.com
About this study
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.
Read the 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.
- Being tested
- Blood sampling
- Medical subject headings
- Chemical and Drug Induced Liver Injury, Drug-Related Side Effects and Adverse Reactions
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Blood samplingProcedure or surgery
In each group a blood sample of approximately 50 mL will be obtained upon study inclusion.
| Study group | Role | What they receive |
|---|---|---|
| healthy | donors/patients without liver disease, with and without ongoing drug therapy including buffy coat samples of healthy blood / thrombocyte donors.
After pseudonymisation a detailed history and clinical data are obtained and blood sampling will be performed . Buffy coats are obtained anonymously. Receives: Procedure: Blood sampling | |
| prior to therapy | History will be obtained and blood sampling will be performed in patients in whom a drug therapy with a drug with DILI potential is planned. Receives: Procedure: Blood sampling | |
| iDILI | Patients with clinical suspicion of idiosyncratic drug-induced liver injury. After pseudonymisation a detailed history and clinical data are obtained and blood sampling will be performed. Receives: Procedure: Blood sampling | |
| non DILI | Patients with other forms of liver injury. After pseudonymisation a detailed history and clinical data are obtained and blood sampling will be performed. Receives: Procedure: Blood sampling |
What is being measured
The primary outcome is the main question the study is designed to answer.
Reflection of individual drug hepatotoxicity in monocyte derived cells
After blood sampling, monocyte derived cells will be generated and tested in vitro for the respective compounds in short term and up to 4 weeks. If possible, the patient will have a clinical follow up during routine care to assess liver injury , course and outcome of the disease when applicable.
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Feb 2015 (estimated)
- Study startMar 2013
- Primary completionMar 2020 (estimated)
- Study completionAug 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (15)Papers the sponsor has linked to this study.
- Other trials for Drug-induced Disorder of LiverStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 300 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Andreas Benesic, MD
- Sponsor type
- University, hospital or other
- Collaborators
- MetaHeps GmbH
- Responsible party
- Sponsor-investigator, Andreas Benesic, MD, Ludwig-Maximilians - University of Munich
- Investigators
- Alexander L Gerbes, Prof. MD, Principal investigator, Liver Center Munich®, Internal Medicine II, Ludwig-Maximilians University Hospital, Campus Grosshadern, Munich; Marchioninistr. 15; D81377 Munich, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02353455
- Sponsor's protocol ID
- 055-13
- Status last verified
- Nov 2019
- First submitted
- 28 Jan 2015
- Last updated
- 26 Nov 2019
- Results posted
- No
- Data monitoring committee
- No
Publications
Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl. 2004 Aug;10(8):1018-23. doi: 10.1002/lt.20204.
PubMed 15390328Chalasani 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.
PubMed 18955056Watkins 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.
PubMed 16496329Chalasani 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.
PubMed 20394749Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003 Jul 31;349(5):474-85. doi: 10.1056/NEJMra021844. No abstract available.
PubMed 12890847Bell 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.
PubMed 19826967Zimmerman HJ. Drug-induced liver disease. Drugs. 1978 Jul;16(1):25-45. doi: 10.2165/00003495-197816010-00002.
PubMed 352664Lee WM, Senior JR. Recognizing drug-induced liver injury: current problems, possible solutions. Toxicol Pathol. 2005;33(1):155-64. doi: 10.1080/01926230590522356.
PubMed 15805067Fannin 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.
PubMed 19918972Benesic 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.
PubMed 22469698Weber S, Erhardt F, Allgeier J, Saka D, Donga N, Neumann J, Lange CM, Gerbes AL. Drug-Induced Liver Injury Caused by Metamizole: Identification of a Characteristic Injury Pattern. Liver Int. 2025 Mar;45(3):e70012. doi: 10.1111/liv.70012.
PubMed 39912769Weber 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.
PubMed 33638811Benesic A, Jalal K, Gerbes AL. Drug-Drug Combinations Can Enhance Toxicity as Shown by Monocyte-Derived Hepatocyte-like Cells From Patients With Idiosyncratic Drug-Induced Liver Injury. Toxicol Sci. 2019 Oct 1;171(2):296-302. doi: 10.1093/toxsci/kfz156.
PubMed 31407002Benesic 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.
PubMed 29723689Benesic 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.
PubMed 26045135
Study at a glance
From the registry record, last updated by the sponsor on 26 Nov 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cells of Monocytic Origin as Surrogate Markers for Individual Drug Effects and Hepatotoxicity
- ClinicalTrials.gov ID
- NCT02353455
- Acronym / sponsor ID
- 055-13
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 300 participants (estimated)
- Lead sponsor
- Andreas Benesic, MDUniversity, hospital or other
- Collaborators
- MetaHeps GmbH
- Study start
- Mar 2013
- Primary completion
- Mar 2020 (estimated)
- Study completion
- Aug 2022 (estimated)
- First posted
- 2 Feb 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| healthy | – | Procedure: Blood samplingdonors/patients without liver disease, with and without ongoing drug therapy including buffy coat samples of healthy blood / thrombocyte donors. After pseudonymisation a detailed history and clinical data are obtained and blood sampling will be performed . Buffy coats are obtained anonymously. |
| prior to therapy | – | Procedure: Blood samplingHistory will be obtained and blood sampling will be performed in patients in whom a drug therapy with a drug with DILI potential is planned. |
| iDILI | – | Procedure: Blood samplingPatients with clinical suspicion of idiosyncratic drug-induced liver injury. After pseudonymisation a detailed history and clinical data are obtained and blood sampling will be performed. |
| non DILI | – | Procedure: Blood samplingPatients with other forms of liver injury. After pseudonymisation a detailed history and clinical data are obtained and blood sampling will be performed. |
Who may qualify
- Ages
- 2 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- 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.
Key inclusion criteria (2 listed)
- 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
Key exclusion criteria (3 listed)
- Anemia requiring blood transfusion
- acute or chronic hepatitis B, C or human immunodeficiency virus infection
- lack of informed consent
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Blood samplingIn each group a blood sample of approximately 50 mL will be obtained upon study inclusion. | Procedure or surgery | healthy, iDILI, non DILI, prior to therapy |
Primary outcome
Reflection of individual drug hepatotoxicity in monocyte derived cells
Time frame: 12 months
After blood sampling, monocyte derived cells will be generated and tested in vitro for the respective compounds in short term and up to 4 weeks. If possible, the patient will have a clinical follow up during routine care to assess liver injury , course and outcome of the disease when applicable.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Nov 2019.
- Background: PubMed 15390328Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl. 2004 Aug;10(8):1018-23. doi: 10.1002/lt.20204.
- Background: PubMed 18955056Chalasani 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.
- Background: PubMed 16496329Watkins 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.
- Background: PubMed 20394749Chalasani 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.
- Background: PubMed 12890847Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003 Jul 31;349(5):474-85. doi: 10.1056/NEJMra021844. No abstract available.
- Background: PubMed 19826967Bell 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.
- Background: PubMed 352664Zimmerman HJ. Drug-induced liver disease. Drugs. 1978 Jul;16(1):25-45. doi: 10.2165/00003495-197816010-00002.
- Background: PubMed 15805067Lee WM, Senior JR. Recognizing drug-induced liver injury: current problems, possible solutions. Toxicol Pathol. 2005;33(1):155-64. doi: 10.1080/01926230590522356.
- Background: PubMed 19918972Fannin 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.
- Background: PubMed 22469698Benesic 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.
- Derived from this study: PubMed 39912769Weber S, Erhardt F, Allgeier J, Saka D, Donga N, Neumann J, Lange CM, Gerbes AL. Drug-Induced Liver Injury Caused by Metamizole: Identification of a Characteristic Injury Pattern. Liver Int. 2025 Mar;45(3):e70012. doi: 10.1111/liv.70012.
- Derived from this study: PubMed 33638811Weber 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.
- Homepage Liver Center MunichLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alexander L Gerbes, Prof. MD principal investigator
Liver Center Munich®, Internal Medicine II, Ludwig-Maximilians University Hospital, Campus Grosshadern, Munich; Marchioninistr. 15; D81377 Munich, Germany
5 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Drug-induced Disorder of Liver and Adverse Reaction to Drug, run by Andreas Benesic, MD at 5 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 26 Nov 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Australia, Germany, Hong Kong, Japan, South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Andreas Benesic, MD (+49 89 44007 ext. 3130, andreas.benesic@med.uni-muenchen.de), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Reflection of individual drug hepatotoxicity in monocyte derived cells (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02353455, which also lists 15 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Nov 2019.