Drug Induced Liver Injury Network DILIN
A cooperative Agreement funded by the Division of Digestive Diseases and Nutrition,
National Institute of Diabetes and Digestive and Kidney Diseases
Drug Induced Liver Injury Network DILIN Cooperative Agreement
NIDDK:
Jose Serrano MD; PhD (Project Scientist). Jay Hoofnagle, MD, Leonard Seeff MD, Jay Everhart, MD, M.P.H. (Scientific Advisors)
Data Coordinating Center
James Rochon PhD Duke University
Five Clinical Research Centers
Drug Induced Liver Injury Network - DILIN
U Connecticut
Herbert Bonkovsky MD
NE Consortium 12 academic, 5 community, 3 pediatric, 1 VA
Indiana U
Naga Chalasani MD
1 academic (adult and pediatric), 1 VA, 5 community, CAM pain center, state poison center
U Michigan
Robert Fontana MD
1 academic, 1 VA, 4 community (3,400 otal beds)
Drug Induced Liver Injury Network - DILIN
U North Carolina
Paul Watkins MD
3 academic, 4 community, 2 pediatric, 1 VA
UC San Francisco
Tim Davern MD
3 academic centers, 2 community, Script II TB network, SFGH, 1 pediatric, 1 large HMO, CAM Trial
DILIN: Sphere of Influence
12.8 million lives
Drug Induced Liver Injury Network Objectives
• To develop standardized instruments to identify drug, CAM and toxin- induced liver injury
• Study the epidemiology and clinical spectrum of hepatotoxicity and
• Collection of biological samples for study of the pathogenesis of hepatotoxicity using biochemical, serological and genetic techniques
Drug Induced Liver Injury Network Goals • To elucidate the genetics and the mechanisms of hepatotoxicity. • To provide the foundation for the development of molecular screening tools to prevent drug-induced liver toxicities and
• Focus of learning in hepatotoxicity. Regional and national clinical resource for advice on hepatotoxicity.
DILIN
• First Phase
– – – – – working definitions for drug-induced liver toxicity, diagnostic algorithms, causality assessment protocol or instrument, study design to identify cases, manual of operations for clinical data & specimen collection, and patient consent form.
• Second Phase
– implement operating procedures, – enroll patients and control subjects, – capture data and samples (serum, tissue, DNA).
Source: RFA-DK-02-033
Drug Induced Liver Injury Network Proposed Studies 1). limited retrospective study Idiosyncratic Liver Injury Associated with Drugs (ILIAD): 2). Prospective study Drug Induced Liver Injury Network (DILIN) study
Protocol #1: ILIAD specific aims
1. To establish and maintain a clinical database on patients who have suffered severe idiosyncratic DILI. 2. Establish a bank of biological specimens (serum, DNA, and immortalized lymphocytes) prepared from cases and suitable controls.
ILIAD specific aims, con’t
3). Maintain a registry, including yearly updated contact information of the subjects enrolled in the clinical database so that it is possible to recontact these individuals at a later date to offer participation in phenotype/genotype studies.
Considerations for target drugs for ILIAD
1). Must have “signature” presentations 2). Must be given to relatively healthy people 3). Must be able to collect 50-100 cases 4). Clues to mechanisms 5). Diverse mechanisms
Drugs Targeted
(target n= 50-100 / drug)
1). INH 2). valproate 3). phenytoin 4). amoxacillin/clavulanic acid
Study #2: Prospective (Odyssey?)
Specific Aims
1). To prospectively evaluate bona fide cases of liver injury due to drugs and complementary and alternative medications within six months of presentation and to collect clinical data, blood, DNA, urine, and liver samples from affected patients and controls for future mechanistic and genetic studies. 2) To identify clinical, immunological, and environmental risk factors for drug-mediated hepatotoxicity by comparing patients to controls with a similar drug exposure history and no evidence of liver injury.
Prospective study Specific Aims, cont.
3). To identify genetic risk factors that may help explain variability in susceptibility and outcome of drug- and CAMinduced liver injury. 4). To determine the natural history of drug- and CAM-induced DILI for at least 6 months following enrollment. For those in whom there is evidence of on-going liver injury at 6 months, to determine the natural history of their disease at 12 and 24 months from the time of initial presentation. 5). To develop and test causality assessment instruments for drug- and CAM-induced liver injury that are sensitive, specific, and reproducible.
Inclusion Criteria 1). Evidence of liver injury known or suspected to be related to consumption of a drug or CAM product in the past 6 months defined as: Serum ALT or AST >5 x ULN or A P’ase >2 x ULN confirmed on at least 2 consecutive blood draws. If baseline (BL) ALT, AST or A P’ase are known and elevated, then ALT or AST >5 x BL or A P’ase >2 x BL on at least 2 consecutive blood draws. or Any elevation of serum ALT, A P’ase, or AST, associated with (a) increased serum total bilirubin [ ≥ 2.5 mg/dL], in absence of prior diagnosis of liver disease, Gilbert’s syndrome, or evidence of hemolysis.
Evaluations Performed at entry and six-month follow-up Interval medical history: Physical exam Symptom score (visual analogue): Selfadministered Quality of life form: The SF-36 will be selfadministered by all study subjects Alcohol use questionnaire: Interval medication history: Standard blood studies: CBC with diff and plts, INR, BUN, creatinine, total protein, albumin, AST, ALT, alk phos, total and fractionated bili, urinalysis. Research blood and urine samples
Evaluations at the 6 + 12-Month Follow-ups
Chronic DILI assessment: Review all available laboratory, radiological, and clinical information. PI will make a determination if the patient meets criteria for chronic DILI (i.e. liver injury persisting for more than 6 months from onset).
Liver radiology: A liver ultrasound will be obtained at 6 months if chronic DILI present.
12 month follow up – chronic cases only. Liver biopsy recommended if there remains evidence of liver disease.
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Committees and Chairs
Causation committee – Leonard Seeff
Ancillary Studies Committee – Herb Bonkovsky
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