Clinical Trials

Clinical Trials

Registry

The Acute Liver Failure Study Group (ALFSG) has maintained, since 1998, a clinical registry now numbering nearly 3,000 patients who have been enrolled over this period of time at 24 sites, with 12 sites still currently enrolling in the study. This study has provided critical information on all forms of ALF with detailed clinical histories and laboratory and outcome data available. A searchable public use website is accessible via NIDDK for data prior to 2010.

Current enrollment criteria are divided into two categories, as follows:

Acute Liver Injury (no hepatic encephalopathy)

Inclusion Criteria

  1. If presumed acetaminophen etiology: acute hepatic illness < 2 weeks, with INR ≥ 2.0, alanine aminotransferase (ALT) of ≥ 10X ULN.
  2. If presumed non-acetaminophen etiology: acute hepatic illness of < 26 weeks, with INR ≥ 2.0, ALT of ≥ 10X ULN, total bilirubin of ≥ 3.0 mg/dL.
  3. Hospitalized patient
  4. Written informed consent from the patient

Exclusion Criteria

  1. Altered mentation of any degree (=ALF)

Acute Liver Failure (must have hepatic encephalopathy of some degree)

Inclusion Criteria 

  1. Acute liver failure (fulminant or sub-fulminant; liver-related illness).
  2. Altered mentation of any degree (presumed not due to sedation alone).
  3. Evidence of moderately severe coagulopathy (INR ≥ 1.5) and
  4. Presumed acute illness onset of less than 26 weeks.
  5. Written informed consent from the patient’s LAR or family member if patient is considered encephalopathic.

Exclusion Criteria

  1. Known cirrhosis
  2. Illness longer than 28 weeks

NAC Trial

In addition, ALFSG has performed between 2001 and 2006, the NAC trial testing whether N-acetylcysteine, the antidote for acetaminophen overdoses is of use in the management of other forms of acute liver failure. That study was analyzed and the results published in 2009. See publications list (Lee WM et al Gastroenterology 2009;137:856-864). 

STOP-ALF

Since that time, we have conducted in partnership with Ocera Therapeutics, Inc., a study of the Safety and Tolerability of Ornithine Phenylacetate for management of hepatic encephalopathy in the setting of ALF. This was not an efficacy study but meant to determine safety and tolerability. These results are currently under analysis but there were no safety signals identified. Preliminary results were presented at the recent AASLD meeting in Boston.

Current Trials

ALFSG is currently undertaking two interesting studies: one evaluating the Methacetin Breath Test (MBT), a method to determine hepatic functional mass (how much functioning liver is remaining) in order to help predict need for transplantation. 13C-methacetin is a medication containing a non-radioactive isotope, that is taken in a small dose (75 mg) and converted by the liver into 13CO2, which is then excreted via the lungs and its percent excretion compared to normal standards to reflect the amount of liver impairment present. It can be performed daily to aid in determining risk of death and the need for liver transplantation. This is not a therapy trial, but involves giving the test substance so does involve this small dose of medication that is converted to acetaminophen. Several precautions are in place to assure that there is no acetaminophen toxicity related to its ingestion.

This is an open label, non-randomized study to determine the value of the 13C-Methacetin Breath Test System in predicting the 21-day outcome of patients diagnosed with acute liver failure.

Inclusion Criteria (Abbreviated)

  • Men & women, ages 18-70 (have not reached their 71th birthday).
  • Severe Acute Liver Injury with INR ≥ 1.5
  • Presence of any degree of hepatic encephalopathy
  • Duration of illness < 26 weeks
  • Enrolled into the ALFSG Registry
  • Written informed consent from the patient or patient’s legally authorized representative or family member

Exclusion Criteria (Abbreviated)

  • History of chronic liver disease or evidence of cirrhosis (unless clinically acute Wilson disease or autoimmune ALF)
  • ALF due to Budd-Chiari Syndrome, caused by malignancy or by known or suspected herpes simplex virus requiring acyclovir therapy
  • Liver transplantation prior to enrollment (Note: Listing for LT does not preclude participation in the trial.)
  • Pre-existing New York Heart Association stage III/IV heart failure
  • Severe obstructive lung disease or shock or severe ARDS
  • History of chronic renal failure requiring hemodialysis or chronic hemodialysis prior to hospital admission for ALF
  • Previous extensive bowel resection or upper GI bleeding at enrollment
  • Allergic to acetaminophen
  • Contra-indicated enteral drugs or fluids, no appropriately placed naso/orogastric tube in situ, or cannot tolerate taking substrate orally
  • Received amiodarone or an HMG-CoA reductase inhibitors (Statins) 30 days prior to enrollment
  • Consumption of: any of the drugs that may interfere with the metabolism of 13C-Methacetin in the 48 hours; alcohol in the last 24 hours; and smoking cigarettes in the 8 hours prior to study enrollment
  • Pregnant or breastfeeding women

ROTEM

ALFSG is performing a separate study simultaneously that again is not a therapeutic intervention trial, but is to determine the nature of clotting in the setting of acute liver failure. Classically, it has been thought that patients with ALF were at great risk of bleeding because of markedly altered coagulation parameters such as the prothrombin time/INR test. Although PT/INR is abnormal there are other compensatory changes in clotting in the ALF setting that likely counteract the loss of clotting factors due to the damaged liver, setting up a re-balanced coagulation system that may not be all that abnormal overall. Thromboelastography is a dynamic method for testing the adequacy of an individual’s clotting mechanism, that requires only a small blood sample to perform. There is little data to date in the setting of ALF and the present study should help answer whether coagulation is abnormal in ALF and, if so, in what settings and how much.

Each ALFSG patient enrolled into the registry will be eligible for the ROTEM test that will be performed daily on days 1,2,3 5 and 7 of the study period.

Future Trials

No additional therapy trials are contemplated at present. Future possibilities include use of liver assist devices or transplantation of hepatocytes. Stay tuned.