Liver Cirrhosis
Conditions
Keywords
Liver Cirrhosis, Alcohol Related Liver Disease (ARLD), Metabolic dysfunction-associated steatotic liver disease, Apixaban, MetALD
Brief summary
Liver disease is the only common cause of death that is increasing in numbers. Once people develop severe scarring (cirrhosis), there are no medications proven to help them live longer, healthier lives. Apixaban is already commonly used to prevent or treat blood clots and is known to be safe for those with cirrhosis. In the early stages of cirrhosis, most people have no symptoms and lead normal lives; this is called "compensated" cirrhosis. However, when the liver stops working properly, they develop "decompensated" cirrhosis, which causes yellow skin, confusion, vomiting of blood and painful fluid build-up. This is serious, and people are extremely unwell with a poor quality of life, often need to go to the hospital and on average only live for 2 more years. The APEACH trial will investigate whether giving compensated cirrhosis patients Apixaban will help stop them from developing decompensated cirrhosis and stay in good health for longer. Previous research studies suggest that taking blood-thinning drugs is safe and helpful for cirrhosis. However, these did not have enough participants to be confident enough in the results to recommend use in everyday clinical care. The APEACH trial will include enough participants to make it clear whether Apixaban is helpful or not.
Interventions
Participants randomised to this arm will receive Apixaban 2.5mg twice daily
DRUGPlacebo
Placebo will be given as oral tablet and taken twice daily
Sponsors
University College, London
Royal Free Hospital NHS Foundation Trust
NHS Greater Glasgow and Clyde
University Hospital of Wales
University of Nottingham
Liverpool University Hospitals NHS Foundation Trust
University Hospital Southampton NHS Foundation Trust
King's College Hospital NHS Trust
King's College London
Hull University Teaching Hospitals NHS Trust
Imperial College London
The Leeds Teaching Hospitals NHS Trust
The Royal London Hospital, UK
BRITISH LIVER TRUST
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
A randomised, double blind, parallel group, placebo controlled, Phase 3 trial of Apixaban 2.5mg twice daily to prevent liver decompensation in patients with liver cirrhosis
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Liver cirrhosis secondary to alcohol, with or without associated metabolic risk factors, i.e. Alcohol related liver disease (ARLD) or metabolic dysfunction-associated steatotic liver disease, where there has been a significant history of alcohol consumption (MetALD) 2. Cirrhosis will be based on histology, or clear radiological evidence, e.g. nodular or heterogeneous liver or non-invasive testing (e.g. Fibroscan®, or Enhanced Liver Fibrosis (ELF) test 3. Childs A Cirrhosis (Participants with a previous episode of decompensated cirrhosis who have now recompensated can be included) 4. Participants with no hepatic encephalopathy or low-grade hepatic encephalopathy (Grade 0 or 1) taking lactulose and/or rifaximin 5. Aged ≥18 years 6. Clinical evidence of portal hypertension, defined as any 1 of: * Evidence of abdominal collateral circulation, recanalised umbilical vein or varices on imaging * Asymptomatic ascites (trace only) seen around the liver on imaging in patients who are not taking diuretics * Liver stiffness measurement \>20kPa on FibroScan®/ Vibration- Controlled Transient Elastography (VCTE) (where BMI \<35) * Presence of Gastro-oesophageal varices at endoscopy * Hepatic venous pressure gradient ≥ 10mmHg Or Platelet count \< 150,000 μL AND any 1 of: * Spleen size \>13 cm in length * Liver stiffness measurement \>20kPa on FibroScan®/VCTE (where BMI \>35) * Presence of portal hypertensive gastropathy at endoscopy
Exclusion criteria
1. Evidence of decompensation (e.g. ascites requiring treatment other than a thin rim around liver on imaging, as above) (Evidence of decompensation as follows: Grade 2 or 3 Ascites, Grade 2 - 4 Hepatic Encephalopathy, Variceal Haemorrhage) 2. Causes for cirrhosis other than alcohol, including those with MASLD who have never drunk alcohol above government recommended levels (14 units/week) 3. Pre-existing splanchnic vein thrombosis (portal, splenic, mesenteric, and hepatic veins) 4. Use of (and need for) anticoagulation or dual antiplatelet therapy or clopidogrel 5. Platelets \<50x109/L at screening 6. Moderate-severe renal impairment defined as eGFR \<30ml/min at screening 7. Recent variceal bleed or untreated large varices 8. Malignancy in last 2 years if unlikely to survive trial because of comorbidity in the location PI's opinion 9. Hepatocellular carcinoma 10. Severe cardiac failure1 or Chronic Obstructive Pulmonary Disease (COPD) 11. Pregnancy 12. INR \>1.7 (After vitamin K correction) at screening 13. Previous hypersensitivity reaction to Apixaban
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time from randomisation to first decompensation event, assessed up to 49 months | Time from randomisation to first decompensation event, assessed up to 49 months | First decompensation event is defined as at least one of the following: Grade 2 or 3 ascites according to the International Club of Ascites (ICA), or spontaneous bacterial peritonitis; Grade 2-4 hepatic encephalopathy; variceal haemorrhage (gastrointestinal bleeding secondary to rupture of varices); and liver-related death measured using METHOD at 6-monthly trial follow-up visits and throughout the trial, when location study teams become aware of these events, as decompensation normally involves hospitalisation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time from randomisation to first decompensation event, assessed up to 49 months | Time from randomisation to first decompensation event, assessed up to 49 months | Time to event for individual decompensation events measured at 6-monthly follow-up visits, assessed up to 49 months |
| Time to development of grade 1 (small volume) ascites | Time from randomisation assessed up to 49 months | Small volume ascites |
| Assessment of safety of anticoagulation in Childs A cirrhosis patients | Time from randomisation assessed up to 49 months | Assessment of safety of anticoagulation in Childs A cirrhosis patients, including incidence of clinically relevant combined major bleeding and non-major bleeding during trial treatment period |
| Time to all-cause mortality | Time from randomisation assessed up to 49 months | — |
| Time to portal vein thrombosis or other thromboembolic events | Time from randomisation assessed up to 49 months | — |
| Incidence of cardiac events | Time from randomisation assessed up to 49 months | — |
| Alcohol use | Time from baseline assessed up to 49 months | Alcohol use will be determined by patient reporting on AUDIT-C questionnaire |
| Health-related quality of life assessed using EQ-5D-5L questionnaire | Time from randomisation assessed up to 49 months | — |
Contacts
CONTACTAPEACH Trial Team
CONTACTLee Webber
PRINCIPAL_INVESTIGATORAlastair O'Brien
Queen Mary University of London
Outcome results
None listed