Screening of Susceptibility Genes for APAP Induced Drug Induced LIver Injury in ChiNese Population: a Case-control Study

NCT04964310 | Recruiting FDA Drug

• 1 other identifier: FirstNanjingMUED
• Study Type: observational
• Target: 339
• Locations: 1 country
• Sites: 1

Brief Summary

Acetaminophen (APAP) is the most commonly used NSAIDS in clinic, and it is also a common cause of drug-induced liver injury (DILI). In 2012, the proportion of DILI caused by APAP in the United States was 51%, while in Asia, it was only 7.10%. Previously, a small cohort study in the United States screened for some of the susceptibility genes for DILI due to APAP by the Genome wide association study (GWAS) method. However, the genetic susceptibility loci based on the US cohort were not applicable to the Chinese population. Therefore, we make a study design include Chinese population who ingested APAP and divided them into case group and control group according to the occurrence of DILI. We hope to be able to find the root of differences at the genetic level and explore new pathogenic mechanisms.

Conditions

Acetaminophen; Drug-Induced Liver Injury; Pharmacogenetics; China

Keywords

Acetaminophen; Drug-Induced Liver Injury; Pharmacogenetics; China; Case-Control Studies; candidate gene

Outcome Measures

Primary Outcomes (1)

• genetic polymorphism

  the genetic polymorphism（HLA、SNPs ）frequency difference between case and control groups

  2 year

Study Arms (2)

APAP_DILI

（①/②）+③+④： ① history of acetaminophen exposure ② abnormal acetaminophen concentration in blood or urine：≥150µg/mL after 4 hour ，≥4.5µg/mL at anytime，measurable ≥24 hours③ liver impairment：Alanine aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≥ 1000 IU/L ④ liver impairment is caused by acetaminophen：Russel U-Calf Causality Assessment Method(RUCAM) causality score\>6

Genetic: genetic polymorphism

APAP_NO-DILI（NDILI）

（①/②）not（③/④）： ① history of acetaminophen exposure ② abnormal acetaminophen concentration in blood or urine：≥150µg/mL after 4 hour ，≥4.5µg/mL at anytime，measurable ≥24 hours③ liver impairment：ALT or AST ≥ 1000 IU/L④ liver impairment is caused by acetaminophen：RUCAM causality score\>6

Interventions

genetic polymorphism GENETIC

Observe the genetic polymorphism frequency difference between case and control groups

APAP_DILI

Eligibility Criteria

• Age: 14 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

history of acetaminophen exposure

You may qualify if:

• A clear history of acetaminophen (or acetaminophen-containing drugs) ingestion.
• Plasma and/or urine testing for acetaminophen components if history of ingestion is unclear.
• Monitoring of Alanine aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≥ 1000 IU/L at any time after APAP administration and Roussel Uclaf Causality Assessment Method(RUCAM) score \> 6
• Age ≥ 14 years old
• The subject or guardian agrees to participate in this project and signs an informed consent form.

You may not qualify if:

• The use of drugs for which frequency of adverse reactions to liver damage is defined as "common or very common" (≥1%) in the instructions.
• Concurrent use of herbs that are clearly susceptible to liver damage (see list of definitions in the Annex).
• Have a known definite cause of liver damage: active viral hepatitis; alcoholic liver disease; autoimmune liver disease; primary or secondary liver tumors; and other underlying liver disease that has affected liver function.
• Those who fail to provide complete general information and clinical information.
• Subjects or guardians who do not agree to see this project do not sign the informed consent form.

Sponsors & Collaborators

• The First Affiliated Hospital with Nanjing Medical University: lead
• University of Colorado, Denver: collaborator
• Beijing Genomics Institute: collaborator
• Nanjing Medical University: collaborator

Study Sites (1)

The First Affiliated Hospital with Nanjing Medical University

Nanjing, Jiangsu, China

RECRUITING

Related Publications (8)

• Danan G, Teschke R. RUCAM in Drug and Herb Induced Liver Injury: The Update. Int J Mol Sci. 2015 Dec 24;17(1):14. doi: 10.3390/ijms17010014.

  PMID: 26712744 BACKGROUND

• Major JM, Zhou EH, Wong HL, Trinidad JP, Pham TM, Mehta H, Ding Y, Staffa JA, Iyasu S, Wang C, Willy ME. Trends in rates of acetaminophen-related adverse events in the United States. Pharmacoepidemiol Drug Saf. 2016 May;25(5):590-8. doi: 10.1002/pds.3906. Epub 2015 Nov 3.

  PMID: 26530380 BACKGROUND

• Bower WA, Johns M, Margolis HS, Williams IT, Bell BP. Population-based surveillance for acute liver failure. Am J Gastroenterol. 2007 Nov;102(11):2459-63. doi: 10.1111/j.1572-0241.2007.01388.x. Epub 2007 Jun 29.

  PMID: 17608778 BACKGROUND

• Chiew AL, Reith D, Pomerleau A, Wong A, Isoardi KZ, Soderstrom J, Buckley NA. Updated guidelines for the management of paracetamol poisoning in Australia and New Zealand. Med J Aust. 2020 Mar;212(4):175-183. doi: 10.5694/mja2.50428. Epub 2019 Dec 1.

  PMID: 31786822 BACKGROUND

• Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988 Dec 15;319(24):1557-62. doi: 10.1056/NEJM198812153192401.

  PMID: 3059186 BACKGROUND

• Leventhal TM, Gottfried M, Olson JC, Subramanian RM, Hameed B, Lee WM; Acute Liver Failure Study Group. Acetaminophen is Undetectable in Plasma From More Than Half of Patients Believed to Have Acute Liver Failure Due to Overdose. Clin Gastroenterol Hepatol. 2019 Sep;17(10):2110-2116. doi: 10.1016/j.cgh.2019.01.040. Epub 2019 Feb 5.

  PMID: 30731196 BACKGROUND

• Lammers LA, Achterbergh R, Pistorius MC, Romijn JA, Mathot RA. Quantitative Method for Simultaneous Analysis of Acetaminophen and 6 Metabolites. Ther Drug Monit. 2017 Apr;39(2):172-179. doi: 10.1097/FTD.0000000000000373.

  PMID: 28045783 BACKGROUND

• Monte AA, Sonn B, Saben J, Rumack BH, Reynolds KM, Dart RC, Heard KJ. The Genomics of Elevated ALT and Adducts in Therapeutic Acetaminophen Treatment: a Pilot Study. J Med Toxicol. 2021 Apr;17(2):160-167. doi: 10.1007/s13181-020-00815-2. Epub 2020 Oct 13.

  PMID: 33051802 BACKGROUND

Related Links

• FDA. Prescription Drug Products Containing Acetaminophen: Actions to Reduce Liver Injury from Unintentional Overdose. 2011

Biospecimen

Retention: SAMPLES WITH DNA

whole blood for DNA extraction

MeSH Terms

Conditions

Chemical and Drug Induced Liver Injury

Interventions

Polymorphism, Genetic

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Poisoning

Intervention Hierarchy (Ancestors)

Genetic Variation; Genetic Phenomena

Study Officials

• Jingsong Zhang, professor

  The First Affiliated Hospital with Nanjing Medical University

  STUDY CHAIR

Central Study Contacts

Hao Sun, professor

CONTACT

13584017821; haosun@njmu.edu.cn

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: associate professor

Study Record Dates

• First Submitted: July 7, 2021
• First Posted: July 16, 2021
• Study Start: August 31, 2020
• Primary Completion: December 31, 2025
• Study Completion (Estimated): December 31, 2026
• Last Updated: February 26, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)