Clinical Trials

Clinical Trials

Registry

The Acute Liver Failure Study Group (ALFSG) has maintained, since 1998, a clinical registry now numbering more than 3,400 patients who have been enrolled over this period of time at 32 sites over the 22-year period. The study is now closed, and the database locked. 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.  In the next year, the searchable database will be updated with data through the end of the study. All the patient information is thoroughly de-identified in strict accordance with HIPAA regulations.

Enrollment criteria for the study were 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

Much earlier, ALFSG performed the NAC trial between 2001 and 2006, 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). Several other publications highlight the apparent benefit of NAC; however, use of NAC for non-acetaminophen ALF is not an FDA-approved indication. 

STOP-ALF

Between 2012 and 2016, we conducted a study in partnership with Ocera Therapeutics, Inc., 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. Study results are available in the following article: Stravitz RT, et al. Hepatology 2018; 67:1003-13. In brief, OPA appeared to be safe and to effectively lower ammonia levels in patients with ALF at the highest dose studied, 20 gm/day. Preliminary results were presented in November 2016 at the AASLD meeting in Boston; the manuscript with full study results in currently submitted and under review.

Recent Trials

ALFSG has concluded two interesting studies as outlined below: MBT and ROTEM. The group evaluated 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. Several precautions were in place to assure that there is no acetaminophen toxicity related to the methacetin ingestion since it is metabolized briefly to acetaminophen.

MBT

The 13C-Methacetin breath test (MBT) is a non-invasive, quantitative test of hepatic metabolic function. The aim of this prospective, multicenter study was to determine the utility of initial and serial 13C- MBT results for predicting 21 day outcomes in adults with acute liver failure (ALF) and non-acetaminophen acute liver injury (ALI).
Methods: The 13C-MBT Breath ID device (Exalenz Biosciences) provided the percent dose recovery (PDR) throughout 60 minutes after administration of 13C methacetin solution as the change in exhaled 13CO2/ 12CO2 compared to pre-ingestion ratio on study days 1, 2, 3, 5, and 7 after enrollment. Results were correlated with 21-day transplant-free survival and other prognostic indices.
Results: 280 subjects were screened for enrollment between May 2016 and August 2019. Mean age of the 62 enrolled patients with adequate data was 43 years, 79% were Caucasian and 76% had ALF with the remaining 24% having ALI. The mean PDR peak on Day 1 or 2 was significantly lower in non-survivors compared to transplant-free survivors (9.1 vs 2.3, p < 0.0001). In addition, serial peak PDR’s were consistently lower in non-survivors vs survivors (p < 0.0001). The AUROC of the 13C-MBT in the combined cohort was 0.88 (95% CI: 0.79-0.97) and higher than that provided by King’s College (AUROC= 0.70) and MELD scores (AUROC=0.83). The 13C-MBT was well tolerated with only 2 gastrointestinal adverse events reported.
Conclusions: The 13C-MBT provides a promising estimate of the likelihood of hepatic recovery in ALF and ALI patients. Use of the PDR peak data from the 13C-MBT point of care test may assist with medical decision making and help avoid unnecessary transplantation in critically ill ALF and ALI patients.

Full Results of the MBT study were published: Fontana RJ, et al. Prognostic Value of the C-Methacetin Breath Test in Adults with Acute Liver Failure and Non-Acetaminophen Acute Liver Injury. Hepatology. 2021 Mar 3. doi: 10.1002/hep.31783. Epub ahead of print. PMID: 33660316.

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.

Abstract

Background & Aims. Despite an abnormal hemostatic profile, patients with acute liver injury and failure (ALI/ALF) experience bleeding complications uncommonly. Rotational thromboelastometry (ROTEM), which assesses clot formation in whole blood, was explored to determine whether abnormal hemostasis contributes to bleeding events, illness severity, or outcome. Approach & Results. 200 patients were recruited from sites of the ALF Study Group. Blood collected daily for up to 5 days was analyzed using ROTEM delta® devices. Consistent with standard laboratory evidence of hypocoagulability (median INR 2.9 and platelet count 144x109/L), patients frequently exhibited ROTEM parameters outside of the normal range (73% and 62% had abnormalities in clot formation from extrinsic and intrinsic clotting cascades, respectively); however, measures of clot stability were generally normal. Eighteen patients (9%) experienced bleeding events, in whom clot initiation, assembly, and firmness were more severely deranged than patients without bleeding. Abnormal ROTEM parameters were more frequently observed in patients with non-acetaminophen (APAP) ALI/ALF than those with APAP ALI/ALF (clot initiation (P<0.001), assembly (P=0.02), firmness at 10 min (P=0.05), and maximal firmness (P=0.06)). Patients with more severe systemic complications (high-grade hepatic encephalopathy and the need for renal replacement therapy) also had a higher incidence of abnormal ROTEM parameters. Finally, more hypocoagulable ROTEM parameters were observed in patients who died or underwent liver transplantation than those who survived with their native liver (clot initiation (P=0.005), stiffness at 10 min (P=0.05), and maximal stiffness by fibrin assembly (P=0.004)). Conclusions. In patients with ALI/ALF, abnormal hemostasis by ROTEM is frequent and proportional to disease severity. Whether the increased bleeding risk associated with abnormal ROTEM indicates hemostatic failure or is a proxy for disease severity requires additional study.

Full Results of the ROTEM study were published: Stravitz RT, et al. Coagulopathy, Bleeding Events and Outcome According to Rotational Thromboelastometry in Patients with Acute Liver Injury/Failure. Hepatology. 2021 Feb 26. doi:10.1002/hep.31767. Epub ahead of print. PMID: 33636020.

Future Trials

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