Executive Summary

Updated as of 16 September 2011

Background and Rationale

Drug-induced liver injury (DILI) is the single most common reason for regulatory actions concerning drugs, including failure to gain approval for marketing, removal from the marketplace, and restriction of prescribing indications. DILI is also a significant cause of morbidity and mortality in many patient populations. Establishing a diagnosis of DILI is difficult due to the presence of other potential causes of liver injury, and the injury itself can range from mild and transient to severe and protracted, and even lead to acute liver failure. To stimulate and facilitate research into DILI, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has recently established the Drug-Induced Liver Injury Network (DILIN). One of the initial projects to be conducted by the network is to retrospectively establish a nationwide registry of patients who have suffered severe idiosyncratic liver injury associated with drugs (ILIAD), and to collect, immortalize, and store serum, DNA, and lymphocytes from these patients (hereafter referred to as the “ILIAD protocol”). This ILIAD protocol will serve as a resource for subsequent mechanistic investigations of the basis for susceptibility to severe idiosyncratic DILI.

Specific Aims and Objectives

The primary goal of the ILIAD protocol is to create: (a) a clinical database consisting of individuals who have experienced severe DILI caused by drugs or Herbal and Dietary Supplements known as HDS, and the relevant clinical data concerning the episode of DILI; and (b) to create a bank of biological specimens obtained from these individuals and a similar number of appropriate controls. Corresponding information from control subjects will also be collected. These biological specimens will be DNA, plasma, and immortalized lymphocytes. Immortalized lymphocytes will provide unlimited amounts of genomic DNA for study as well as living immune cells for phenotyping studies. A secondary goal of the ILIAD protocol is to maintain a registry of cases in the ILIAD database so that they may be recontacted in the future. It is expected that this will facilitate additional studies exploring the mechanisms of DILI.

Targeted Drugs

The initial drugs to be targeted in the ILIAD protocol are isoniazid, phenytoin, clavulanic acid / amoxicillin, and valproic acid (Depakote), Nitrofurantoin, Trimethoprim-sulfamethoxazole, Minocycline, and Quinolone antibiotics. The target drugs were chosen because they cause severe DILI at a high rate compared with other drugs, making our target enrollment for each drug (n = 50-100) attainable. In addition, these drugs are frequently administered to reasonably healthy patients not concurrently receiving other drugs more likely to be hepatotoxic, facilitating causation assessment.

Study Population

Cases are individuals who suffered drug-induced liver injury due to one of the targeted drugs. For INH, phenytoin, or clavulanic acid / amoxicillin, severe liver injury is defined as a documented serum total bilirubin > 2.5 mg/dl; for valproic acid, the criteria are compatible symptomatic clinical presentation that is severe enough to prompt hospitalization and evidence of liver dysfunction (INR > 1.5 or ALT > 3 X ULN, and/or characteristic liver biopsy). Subjects must be living and may have undergone liver transplantation, but the DILI episode must have occurred since January 1, 1994. Subjects will be excluded if they are not willing to have medical information and blood samples taken, or if they are unable to adequately give informed consent to participate in the study. Individuals less than 2 years old at the time of study enrollment are excluded due to blood volume requirements.

Data Collection Protocol

Several phases of data collection are envisaged for this study. Basic demographic information, family information, and prior history of liver disease and other medical conditions will be gathered using a telephone or personal interview format. Detailed clinical information concerning the DILI episode will be abstracted from patient charts and medication records. This includes concomitant medical conditions and illnesses, laboratory and liver function tests, as well as serological and other assays. Finally, detailed information from the NIDDK Genetics Repository will be forwarded to the DCC and merged with the clinical information. These data will be forwarded to the DILIN Causality Committee, which will weigh the evidence and determine whether the liver injury was indeed caused by the medication.

Statistical Considerations

An important goal of this study is to generate hypotheses for consideration in future studies. Type-II error, i.e., failing to find an interesting association when there is one, is an important consideration. Thus, as a compromise between type-I and type-II error, α = 0.01 will be applied to declare any effect statistically significant. Because the suspected DILI mechanism is thought to be different for each drug, statistical analysis will be performed separately for each medication. The conditional logistic regression model will be the primary analytic model. The adjusted odds ratio, together with its confidence interval, will be estimated from the associated regression parameters.

Power Calculations and Analyses for Genetic/Genomic Studies

The primary goals of this study are to create a clinical database consisting of individuals who have experienced a drug-induced liver injury caused by one of the identified drugs, and to create a bank of biological specimens obtained from these individuals so that genomic DNA as well as living im-mune cells for phenotyping studies is available for genetic studies. (Plasma will also be stored since it is automatically obtained during isolation of the lymphocytes and because it may be useful in future studies). It is also expected that ILIAD patients will be recontacted for future studies exploring a variety of biomedical mechanisms of drug-induced liver injury. ILIAD is designed as a multi-center, retrospective, registry study. DILI cases will be identified and enrolled in the study. Detailed exposure information will be recorded using a telephone interview with the participants as well as from patient charts and medical records.

Although we would like to include thousands of DILI cases in the registry, this study is limited by the network’s capacity to find and enroll DILI cases over the timeframe of this study. After careful consideration, it is considered feasible to enroll 50-100 DILI cases for each of implicated drugs. Genetic studies are one of the main focuses in DILIN. For genetics analyses, drug matched controls may not be necessary. This is because DILI is extremely rare (ranging from 1:500 to fewer than 1:10,000 prescriptions, depending on the precipitant drug) so there is a very low probability of misclassification, i.e., DILI cases contaminating the control series. Without drug-matched controls, we plan to use population controls to carry out genetic analyses to determine DILI-associated genetic risk factors. Sample size and power calculations are carried out based on the proposed genetic analyses using existing population control subjects. Because the cases enrolled in the retrospective study will be combined with cases from the prospective study for genetic/genomic studies, the power calculations and analyses for genetic/genomic studies are the same as ones in the prospective study protocol.

Statistical Considerations

An important goal of this study is to generate hypotheses for consideration in future studies. Type-II error, i.e., failing to find an interesting association when there is one, is an important consideration. Thus, as a compromise between type-I and type-II error, α = 0.01 will be applied to declare any effect statistically significant. Because the suspected DILI mechanism is thought to be different for each drug, statistical analysis will be performed separately for each medication. The conditional logistic regression model will be the primary analytic model. The adjusted odds ratio, together with its confidence interval, will be estimated from the associated regression parameters.

Study Administration

The administrative and funding mechanism used to undertake this project is an NIH “Cooperative Agreement” (U01). The Steering Committee is the main governing body of the project. It is composed of the principal investigators of the field centers, the principal investigator of the data coordinating center, and the NIDDK project scientist. All decisions are determined by majority vote. In addition, a number of subcommittees have been established and report to the main Steering Committee. A policy concerning ancillary studies has been established, and detailed procedures for proposing and conducting these studies have been established.