# Presentation: 093141

## 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

**Data Coordinating Center**
**James Rochon PhD  **
**Duke University**

**NIDDK:**
**Jose Serrano MD; PhD (Project Scientist). **
**Jay Hoofnagle, MD, Leonard Seeff MD, Jay Everhart, MD, M.P.H.**
**(Scientific Advisors)**

**Five Clinical Research Centers**

## Drug Induced Liver Injury Network - DILIN

**U Michigan**
**Robert Fontana MD**

**1 academic, 1 VA, 4 community**
**(3,400 otal beds)**

**Indiana U**
**Naga Chalasani MD**

**1 academic (adult and pediatric), 1 VA, **
**5 community, CAM pain center, state poison center**

**NE Consortium  12 academic,  5 community, **
**	****	****3 pediatric, 1 VA**

**U Connecticut**
**Herbert Bonkovsky MD**

## Drug Induced Liver Injury Network - DILIN

**Drug Induced Liver Injury Network - DILIN**

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**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

**DILIN: Sphere of Influence**

**12.8 million lives**

## Drug Induced Liver Injury Network Objectives

- 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 Objectives**

##  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.

**Drug Induced Liver Injury Network**
**Goals**

## 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**

- <date/time>

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**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

- <date/time>

**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**

- <date/time>

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**	****Study #2: Prospective (Odyssey?)**
** ****Specific Aims**
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**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.**
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- <date/time>

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**	**** ****Prospective study**
** ****Specific Aims, cont.**
**3).  To identify genetic risk factors that may help explain variability in susceptibility and outcome of drug- and CAM-induced  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.**
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**3.****     **

- <date/time>

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***   ******    ******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.
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- <date/time>

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**Evaluations Performed at entry and six-month follow-up**
**        **_**Interval medical history:**_
**        **_**Physical exam**_
**	**_**Symptom score (visual analogue):**_**  Self-****	****	****	****administered**
**       **_**Quality of life form**_**: The SF-36  will be self-****	****administered 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**_**  **
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- <date/time>

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**Evaluations at the 6 + 12-Month Follow-ups**
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_**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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- <date/time>

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**Causation committee –   Leonard Seeff**
**Ancillary Studies Committee – Herb Bonkovsky**
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