Safety signals and potential efficacy of a low-energy total diet replacement programme with behavioural support to delay disease progression in compensated cirrhosis due to non-alcoholic fatty liver disease: a feasibility randomised controlled trial
Compensated cirrhosis due to non-alcoholic fatty liver disease
The intervention is a low-energy total diet replacement programme with behavioural support (TDR) and has three phases. In phase 1 (sole source TDR, weeks 0-16), participants will consume a nutritionally complete package of 4 formula products per day [soups, shakes, and bars (860 kcal/day)]. In phase 2 (food-re-introduction, weeks 17-22), products will be gradually reduced and replaced with food-based meals. During this phase, participants will consume 3 products per day for weeks 17-18, 2 products per day for weeks 19-20, and 1 product per day for weeks 21-22 together with food-based meals. In phase 3 (weight maintenance, weeks 23-24), participants will consume food-based meals. Participants will have contact with the dietitian for around 15 minutes each week (or 30 minutes fortnightly) over the 24 weeks for behavioural support. This will be over the phone or the app depending on participant preference. Care as usual group: Participants in the comparator control group will receive care as usual which includes, but not limited to, advice for healthy eating and weight loss by their doctor. This will allow for a comparison of the study intervention to the existing standard of care. Randomisation: Participants will be individually randomised with a 2:1 allocation to receive either the intervention or care as usual through minimisation with a 20% random element. The two stratified variables will be BMI (≥/< 35 kg/m2) and type 2 diabetes (yes/no).
1. Participant is able to communicate in English and is willing and able to give informed consent for participation in the trial. 2. Aged ≥18 years. 3. BMI ≥30 kg/m² (or BMI ≥27.5 kg/m² for people of Black, Asian, or minority ethnic origin as per the NICE guidance for obesity screening) 4. Diagnosed with compensated cirrhosis due to non-alcoholic fatty liver disease based on one of the following: 4a. Biopsy with histological evidence of fibrosis score of 4 [with or without NASH (NASH defined as score of ≥1 for each of steatosis, inflammation, and ballooning] based on the NASH Clinical Research Network criteria 4b. Previous biopsy with evidence of NASH but with current non-histological diagnosis of cirrhosis* 4c. Previous biopsy or imaging with evidence of hepatic steatosis but with current nonhistological diagnosis of cirrhosis* [*Definition of non-histological diagnosis of cirrhosis: Liver stiffness by transient elastography ≥15 kPA AND ANY of: - imaging evidence of nodular OR irregular liver AND/OR - presence of porto-systemic collateral vessels AND/OR - splenomegaly (without alternative cause) AND/OR - thrombocytopaenia in absence of primary haematological disease.] 5. Stable dose of medication(s) for type 2 diabetes for at least 3 months prior to screening visit. 6. Willing to allow his or her General Practitioner and consultant to be notified of participation in the trial.
Current exclusion criteria as of 01/08/2023: 1. Evidence for any of the following alternative or co-existing aetiologies: alcohol [alcohol screening tool (AUDIT-C) score ≥8, and for patients for whom alcohol may have been a contributing factor to their diagnosis of cirrhosis, they will be excluded if they have any history of sustained harmful alcohol intake defined as ≥35 units for females and ≥50 units for males per week], active viral hepatitis (subjects cured for hepatitis C virus infection less than 2 years prior to screening are not eligible), haemochromatosis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, severe alpha-1-antitrypsin deficiency (ZZ phenotype), and autoimmune hepatitis . 2. Alcohol intake of ≥18 units for females and ≥26 units for males over the last 7 days, as per the NAFLD diagnostic criteria. 3. Platelet count <100 x 10(9) cells/l AND either medium (grade II) oesophageal or gastric varices with endoscopic high-risk stigmata (e.g., red signs), or large (grade III) varices on endoscopy within 1 year of screening [OR, IF NO ENDOSCOPY WITHIN 1 YEAR: exceeding the expanded Baveno VI criteria (platelet < 110 × 10(9) cells/L AND/OR stiffness >25 kPa)]. 4. History or presence of hepatic decompensation (jaundice, ascites, hepatic encephalopathy, or variceal haemorrhage). 5. Model for end-stage liver disease (MELD) score ≥ 13. 6. Child-Pugh score ≥8. 7. Total bilirubin >25.5 μmol/L (Note: Patients with documented Gilbert’s syndrome but conjugated bilirubin within normal range are eligible). 8. ALT ≥5x upper limit of normal. 9. AST ≥5x upper limit of normal. 10. INR >1.3. 11. HbA1c >11.3% (>100mmol/mol). 12. Listed for liver transplantation. 13. History of hepatocellular carcinoma or history of hepatocellular carcinoma treatment. 14. HIV infection. 15. Weight loss of 10% or more since diagnostic biopsy or, if biopsy not present, within the last 6 months. 16. Previous bariatric surgery or ileal resection. 17. History of bil