Clinical trial NCT00345930: DILIN - Prospective Study
Official title: A Multi-Center, Longitudinal Study of Drug-and CAM-Induced Liver Injury
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Liver Diseases
Keywords: Complementary and alternative medicine
Complementary therapies
Alternative therapies
Prescription Drugs
Non prescription Drugs
Liver Disease
Chemical Ind
Phenotype
Proteomics
Metabolomics
Cholestatic Liver Injury
Hepatocellular Liver Injury
Mixed Liver Injury
Matched Case Control Studies
Genotype
Liver Dis
Chem Ind
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2006-06-29
Enrollment: 4000
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients who have suffered a drug induced liver injury and meet inclusion and exclusion criteria

Brief summary: The purpose of this study is to identify individuals who have suffered a liver injury arising as an idiosyncratic reaction to a prescription drug or a complementary and alternative medicine. Recently added acute cases enrollment that meets criteria to the protocol. Also added Fibroscans to the protocol that will be completed at baseline and follow-up on chronic subjects.

Detailed description: Liver injury due to prescription and non-prescription medication use is a medical, scientific and public health problem of increasing frequency and importance in the United States. Indeed, drug-induced liver injury (DILI) is the most important reason for non-approval, withdrawal, limitation in use and clinical monitoring by the Food and Drug Administration (FDA). However, detection of signals for liver injury frequently relies upon the reporting of cases by practitioners to health authorities in post-marketing surveillance. Under-reporting of cases, lack of mandatory reporting systems, and difficulties in establishing a diagnosis make the current system sub-optimal. Moreover, with the growing use of complementary and alternative medications (CAM), there have also been increasing reports of liver toxicity due to various non-prescription herbal, dietary and food additive supplements. Because the manufacturing, dispensing and testing of these products is not regulated, the hepatotoxic potential of these formulations is poorly characterized or completely unknown.

The DILIN Prospective Study is a multi-centered epidemiological study designed to gather clinical information and biological specimens on cases of suspected liver injury due to drugs and CAM. The goals of this study are to develop a database of recent DILI cases, identify the clinical, environmental and genetic risk factors that predict DILI, develop standardized instruments and terminology and perform careful longitudinal follow-up of DILI subjects. Biological samples collected will be used in future studies of the mechanisms and genetics of DILI.

Patients who are referred to one of the DILIN clinical sites and who, in the opinion of gastroenterologist/hepatologist, experienced a drug-induced liver injury are enrolled. Detailed clinical data and biological specimens are collected. Clinical data will be reviewed by the DILIN Causality Committee and the final determination on whether the subject qualifies as a bona fide DILI case is made by consensus opinion. DILI cases (only) are followed for at least 6 months to derive the longitudinal profile of drug-and CAM-induced liver injury. Detailed clinical data including liver elastography (FibroScans) and biological specimens are collected. Patients who satisfy the definition of chronic DILI will be evaluated with additional FibroScans at 12, 24, 36 and 48 months thereafter.

Eligibility criteria: Inclusion Criteria:

* Age \> 2 years at enrollment into the study.
* Evidence of liver injury that is known or suspected to be related to consumption of a drug or CAM product in the 6-month period prior to enrollment.
* Written Informed consent from the patient or the patient's legal guardian.
* Documented clinically important DILI, defined as any of the following:

  1. ALT or AST \>5 x ULN or A P'ase \>2 x ULN confirmed on at least 2 consecutive blood draws in patients with previously normal values.
  2. If baseline (BL) ALT, AST or A P'ase are known to be elevated, then ALT or AST \>5 x BL or A P'ase \>2 x BL on at least 2 consecutive blood draws. "Baseline" is defined as the average of at least 2 measurements performed during the 12-month period prior to starting the DILI medication.
  3. Any elevation of ALT, A P'ase, or AST, associated with (a) increased total bilirubin \[ ≥ 2.5 mg/dL\], in absence of prior diagnosis of liver disease, Gilbert's syndrome, or evidence of hemolysis or (b) coagulopathy with INR \> 1.5 in absence of coumadin therapy or known vitamin K deficiency.

Exclusion Criteria:

Patients with any of the following will not be eligible for participation:

* Competing cause of acute liver injury such as hepatic ischemia that is felt by the investigator to be the primary reason for observed liver injury and supported by laboratory tests, serologies, liver biopsy, or radiology.
* Known, pre-existing autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or other chronic biliary tract disease which may confound the ability to make a diagnosis of DILI.
* Acetaminophen hepatotoxicity.
* Liver/bone marrow transplant prior to the development of drug- or CAM-induced liver injury.

Primary outcomes:
measure: Develop a database of recent DILI cases
timeFrame: July 2028
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Bethesda
country: United States
facility: NIH Clinical Site
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Chapel Hill
country: United States
facility: Univeristy of North Carolina at Chapel Hill
state: North Carolina
city: Philadelphia
country: United States
facility: Thomas Jefferson
state: Pennsylvania
Study officials:
affiliation: Duke University
name: Huiman X. Barnhart, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Univ. of Michiganl
name: Robert Fontana, MD
role: STUDY_CHAIR
References:
citation: Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, Rochon J; DILIN Study Group. Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct. Drug Saf. 2009;32(1):55-68. doi: 10.2165/00002018-200932010-00005.
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: Devarbhavi H, Ghabril M, Barnhart H, Patil M, Raj S, Gu J, Chalasani N, Bonkovsky HL. Leflunomide-induced liver injury: Differences in characteristics and outcomes in Indian and US registries. Liver Int. 2022 Jun;42(6):1323-1329. doi: 10.1111/liv.15189. Epub 2022 Feb 15.
citation: Vuppalanchi R, Bonkovsky HL, Ahmad J, Barnhart H, Durazo F, Fontana RJ, Gu J, Khan I, Kleiner DE, Koh C, Rockey DC, Phillips EJ, Li YJ, Serrano J, Stolz A, Tillmann HL, Seeff LB, Hoofnagle JH, Navarro VJ; Drug-Induced Liver Injury Network. Garcinia cambogia, Either Alone or in Combination With Green Tea, Causes Moderate to Severe Liver Injury. Clin Gastroenterol Hepatol. 2022 Jun;20(6):e1416-e1425. doi: 10.1016/j.cgh.2021.08.015. Epub 2021 Aug 14.
citation: Martinez MA, Vuppalanchi R, Fontana RJ, Stolz A, Kleiner DE, Hayashi PH, Gu J, Hoofnagle JH, Chalasani N. Clinical and histologic features of azithromycin-induced liver injury. Clin Gastroenterol Hepatol. 2015 Feb;13(2):369-376.e3. doi: 10.1016/j.cgh.2014.07.054. Epub 2014 Aug 9.
citation: Navarro VJ, Barnhart H, Bonkovsky HL, Davern T, Fontana RJ, Grant L, Reddy KR, Seeff LB, Serrano J, Sherker AH, Stolz A, Talwalkar J, Vega M, Vuppalanchi R. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network. Hepatology. 2014 Oct;60(4):1399-408. doi: 10.1002/hep.27317. Epub 2014 Aug 25.
citation: Ghabril M, Bonkovsky HL, Kum C, Davern T, Hayashi PH, Kleiner DE, Serrano J, Rochon J, Fontana RJ, Bonacini M; US Drug-Induced Liver Injury Network. Liver injury from tumor necrosis factor-alpha antagonists: analysis of thirty-four cases. Clin Gastroenterol Hepatol. 2013 May;11(5):558-564.e3. doi: 10.1016/j.cgh.2012.12.025. Epub 2013 Jan 17.