Can Aspirin Reduce the Risk of HCC in Cirrhosis: The AspiRe HCC Trial

The AspiRe HCC trial is a large clinical study designed to find out whether daily low-dose aspirin (100 mg) can help prevent hepatocellular carcinoma (HCC)-the most common form of liver cancer-in people who already have liver cirrhosis.

HCC rates are rising in Australia and worldwide and more than 90% of HCC cases occur in people with cirrhosis. Less than 20% of people with cirrhosis have HCC diagnosed early enough for it to be curable. Diagnosis of HCC at an early stage increases the chances of being able to cure it or stop it from growing or spreading. Previous research suggests aspirin may reduce the risk of developing HCC by 50-70%, with stronger benefits in people who already have cirrhosis.

Ideally, we need to prevent HCC developing in the first place. However, there is no current treatment to preventing HCC in people with cirrhosis.

Experimental studies in animals and humans have shown that that aspirin treatment is safe and may prevent HCC, reducing the risk by at least 50% in people with cirrhosis. Studies from around the world have shown that people taking low-dose aspirin (100 mg daily or sometimes called "mini-aspirin") for other reasons (such as for heart disease or stroke prevention) have a much lower risk of developing HCC. Importantly, people who use aspirin in these settings do not seem to have any increase in the rates of side effects compared to people who do not take aspirin.

If proven effective, aspirin could become a simple and affordable preventative treatment, potentially saving hundreds of lives each year and reducing healthcare costs.

People with lived experience of cirrhosis and liver cancer have been involved in designing and reviewing the study to ensure it is relevant, ethical and meaningful. They will continue contributing as members of the Trial Steering Committee.

This trial is a multi-centre, prospective, pragmatic 4-year RCT of aspirin versus placebo therapy in 890 stable, well-compensated cirrhotic participants attending hospital outpatient clinics and otherwise receiving standard of care treatment at up to seven sites across Australian.

Participants will be randomly assigned in a 1:1 ratio to either a 100 mg tablet of enteric-coated aspirin daily or placebo therapy, according to a block-randomisation procedure and their date of enrolment in the study.

Participants will continue their usual care. At each 6 monthly standard of care visit, during their 4 years on study, the site team will enter data into a REDCap database:

• Routine blood test results
• Routine liver imaging for monitoring of occurrence of HCC (ultrasound, CT, or MRI)
• Routine liver elastography once a year
• Any hospital admissions or new symptoms
• QOL information via two surveys' (Ed-5q-5L and CLDQ)

Western Australian participants may consent to optional additional blood sample collection, at baseline and end of trial, for a biological specimen repository to support future research.

All participants will be invited to consent to provision of their MBS/PBS data during the trial, to analyse the cost of treatment and life years saved.

Any participant who is diagnosed with HCC during their time on trial has reached the primary endpoint and will cease their participation

Inclusion criteria

• Provide written informed consent to participate in the trial according to ICH GCP (R3) and national/local regulations.
• Diagnosed with liver cirrhosis for at least 6 months
• Has a current Child-Pugh score ≤6 (Child A - clinically and biochemically compensated cirrhosis)
• Has been participating in ultrasound or non-ultrasound (computed tomography (CT) or magnetic resonance imaging (MRI)) based surveillance for at least 6 months prior to entry.
• Has not had any focal lesions, other than haemangiomas, detected during the past 6 months.

Exclusion criteria

• Any of the following:

• autoimmune liver disease.
• primary biliary cholangitis.
• primary sclerosing cholangitis.
• prior HCC
• alcohol consumption >3 standard drinks per day in men and 2 standard drinks per day in women.
• currently taking a nonsteroidal anti-inflammatory drug, anticoagulant drugs, non-vitamin K anticoagulant frugs, or other antiplatelet drugs, including aspirin, within the last 6 months.
• a known bleeding disorder
• a platelet count <50 x 109/L.
• known history or endoscopic evidence of high risk oesophageal (grade 2 or higher) or gastric varices or, a history of bleeding varices.
• chronic iron deficiency anaemia.
• a prior history of liver decompensation or liver transplantation.
• known peptic ulcer disease.
• chronic kidney disease with eGFR <50ml/min; a contraindication to aspirin.
• Any participant considered by the PI to be deemed unlikely to complete the study due to other comorbid conditions or poor compliance will also be excluded.

Pregnancy:

• Whilst low dose aspirin is considered safe in pregnancy, male and female participants of child-bearing potential are recommended use effective contraception during this trial.
• Any female participants who fall pregnant during the trial will be withdrawn if their treating obstetric doctor advises that you should do so.