Low-energy total diet replacement in the treatment of compensated cirrhosis
| ISRCTN | ISRCTN13053035 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN13053035 |
| IRAS number | 307043 |
| Secondary identifying numbers | IRAS 307043 |
- Submission date
- 21/01/2022
- Registration date
- 26/01/2022
- Last edited
- 28/04/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Digestive System
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English summary of protocol
Background and study aims
The build-up of fat in the liver can cause inflammation and a lot of scarring in the liver. This condition is called compensated cirrhosis due to non-alcoholic fatty liver disease (CC-NAFLD). It is a serious disease that may require liver transplant and increases the risk of early death. It affects about 200,000 UK adults, most of whom are also living with obesity.
Currently, there is no drug available to treat CC-NAFLD. Weight loss programmes might improve it, but only if they lead to large weight loss. One programme that could achieve this on a large scale is a low-energy diet with professional support. In this programme, people eat only soups and shakes for 16 weeks (about 860 calories per day). Then, slowly over the next 8 weeks, they swap some soups and shakes for regular food. The support helps people stick to the programme and develop healthier eating habits. We know people lose weight rapidly and lower their risk of heart disease. This may also be a good treatment for CC-NAFLD, but there is a concern that rapid weight loss may worsen scarring in the liver. Here we will test the programme in a small group of people with detailed monitoring of the health of their liver to see if this concern is a reality.
This information will tell us if we can confidently plan a full trial to test whether this programme can delay progression of this liver disease.
Who can participate?
Adults with CC-NAFLD and excess weight
What does the study involve?
A computer will decide at random if patients continue with their care as usual or are offered the programme. We will see whether enough patients are willing to take part in the trial, stick to the programme, and return for follow up visits. We will examine whether the treatment appears to be safe at 2, 4, 16, and 24 weeks with blood tests. If there are signs of worsening of the disease, we will stop the treatment. At the start of the programme and at 24 weeks, we will do a liver scan to make a more detailed assessment of liver scarring. We will also monitor changes in weight, body composition, risk of heart disease, and physical function.
What are the possible benefits and risks of participating?
There are no risks or benefits in the care as usual group. If there are signs of worsening of the disease in the intervention group, we will stop the treatment. Weight loss can also reduce the risk of heart disease and type 2 diabetes.
Where is the study run from?
University of Oxford (UK)
When is the study starting and how long is it expected to run for?
November 2021 to March 2024
Who is funding the study?
NIHR Oxford Biomedical Research Centre (UK)
Who is the main contact?
Dr Dimitrios Koutoukidis, dimitrios.koutoukidis@phc.ox.ac.uk
Contact information
Dr Dimitrios Koutoukidis
Principal Investigator
Principal Investigator
Radcliffe Observatory Quarter
Woodstock Road
Oxford
OX2 6GG
United Kingdom
 ORCID ID |
0000-0002-1955-7234 |
|---|---|
| Phone | +44 1865617767 |
| dimitrios.koutoukidis@phc.ox.ac.uk |
Study information
| Study design | Interventional randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | 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 |
| Study acronym | LiFT 2 |
| Study objectives | This randomised controlled trial aims to examine whether people with compensated cirrhosis due to non-alcoholic fatty liver disease can be recruited, stick to the treatment, and present for follow-up, whether the treatment appears to be safe, and to look for early signs of attenuation of the progression of this liver disease. |
| Ethics approval(s) | Approved 23/12/2021, South Central - Oxford B Research Ethics Committee (Ground Floor, Temple Quay House, 2 The Square, Bristol, BS1 6PN, UK; +44 207 104 8360; oxfordb.rec@hra.nhs.uk), ref: 21/SC/0408 |
| Health condition(s) or problem(s) studied | Compensated cirrhosis due to non-alcoholic fatty liver disease |
| Intervention | 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). |
| Intervention type | Behavioural |
| Primary outcome measure | 1. Biochemistry (ALT, AST, total bilirubin) by blood test - at 0, 2, 4, 16, & 24 weeks 2. Iron-corrected T1 relaxation time (cT1) values by magnetic resonance imaging (MRI) - at 0 & 24 weeks 3. Liver stiffness by magnetic resonance elastography (MRE) - at 0 & 24 weeks |
| Secondary outcome measures | 1. Liver stiffness by transient elastography - at 0, 16, & 24 weeks 2. Proton density fat fraction (PDFF) on MRI - at 0 & 24 weeks 3. Controlled attenuation parameter by transient elastography - at 0, 16, & 24 weeks 4. Enhanced liver fibrosis (ELF) score - at 0 & 24 weeks 5. UK Model for end-stage liver disease (UKELD) score - at 0, 4, 16, & 24 weeks 6. Mortality predicted by Child-Pugh score - at 0, 4, 16, & 24 weeks 7. Physical performance test - at 0 & 24 weeks 8. Adverse events (patien records) - at 0, 2, 4, 16, & 24 weeks 9. Body weight (kg) - at 0, 4, 16, & 24 weeks 10. Total fat-free mass on bioelectrical impedance - at 0, 4, 16, & 24 weeks 11. Visceral fat on MRI - at 0 & 24 weeks 12. Muscle mass on MRI - at 0 & 24 weeks 13. Adjustment in the number and dose of medication - at 0, 4, 16, & 24 weeks 14. Blood pressure (mmHg, sphygmomanometer) - at 0, 4, 16, & 24 weeks 15. HbA1c (blood test) - at 0, 16, & 24 weeks 16. Lipid profile (blood test) - at 0 & 24 weeks Process outcome measures (measured using patient records and case report forms unless noted): 1. Number of potentially eligible participants - pre-baseline 2. Proportion of eligible participants randomised - pre-baseline 3. Reasons for non-enrolment - pre-baseline 4. Proportion of intervention sessions attended - at 0, 4, 16, & 24 weeks 5. Reasons for non-engagement- at 0, 4, 16, & 24 weeks 6. Proportion of randomised participants completing a 24-week follow-up visit - at 24 weeks 7. Reasons for dropout - at 2, 4, 16, & 24 weeks 8. Feedback questionnaire - at 24 weeks 9. Alcohol intake questions - at 0, 4, 16, & 24 weeks |
| Overall study start date | 11/11/2021 |
| Completion date | 20/03/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 24 |
| Total final enrolment | 17 |
| Key inclusion criteria | 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. |
| Key exclusion criteria | 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 biliary diversion. 18. Acute cholecystitis or acute biliary obstruction. 19. Contraindication to MRI. 20. Documented arrhythmia, except atrial fibrillation, or prolonged QT syndrome. 21. Taking warfarin. 22. Chronic renal failure of stage 4 or 5. 23. Scheduled for elective surgery under general anaesthesia. 24. Female participant who is pregnant, lactating, or planning pregnancy during the course of the trial. 25. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial. 26. Currently taking part in other interventional clinical trials unless approved by the CI. 27. Insulin use for more than 10 years for type 2 diabetes management AND C-peptide <600pmol/L. 28. Type 1 diabetes. 29. Evidence of proliferative retinopathy. _____ Previous exclusion criteria as of 20/10/2022: 1. Evidence for any of the following alternative or co-existing aetiologies: alcohol [alcohol screening tool (AUDIT-C) score ≥ 8], 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. Evidence of medium or large oesophageal or gastric varices based on: Presence of moderate (grade II) or large (grade III) varices OR the presence of varices with red signs at endoscopy within 1 year of screening [OR, IF NO ENDOSCOPY WITHIN 1 YEAR: exceeding the expanded Baveno VI criteria (platelet < 110x10^9 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 biliary diversion. 18. Acute cholecystitis or acute biliary obstruction. 19. Contraindication to MRI. 20. Documented arrhythmia, except atrial fibrillation, or prolonged QT syndrome. 21. Taking warfarin. 22. Chronic renal failure of stage 4 or 5. 23. Scheduled for elective surgery under general anaesthesia. 24. Female participant who is pregnant, lactating, or planning pregnancy during the course of the trial. 25. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial. 26. Currently taking part in other interventional clinical trials unless approved by the CI. 27. Insulin use for more than 10 years for type 2 diabetes management AND C-peptide <600pmol/L. 28. Type 1 diabetes. 29. Evidence of proliferative retinopathy. _____ Previous exclusion criteria: 1. Evidence for any of the following alternative or co-existing aetiologies: alcohol [alcohol screening tool (AUDIT-C) score ≥ 8], 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. Evidence of medium or large oesophageal or gastric varices based on: Presence of moderate (grade II) or large (grade III) varices OR the presence of varices with red signs at endoscopy within 1 year of screening [OR, IF NO ENDOSCOPY WITHIN 1 YEAR: exceeding the expanded Baveno VI criteria (platelet < 110x10^9 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. Current insulin use. 13. Listed for liver transplantation. 14. History of hepatocellular carcinoma or history of hepatocellular carcinoma treatment. 15. HIV infection. 16. Weight loss of 10% or more since diagnostic biopsy or, if biopsy not present, within the last 6 months. 17. Previous bariatric surgery or ileal resection. 18. History of biliary diversion. 19. Acute cholecystitis or acute biliary obstruction. 20. Contraindication to MRI. 21. Documented arrhythmia, except atrial fibrillation, or prolonged QT syndrome. 22. Taking warfarin. 23. Chronic renal failure of stage 4 or 5. 24. Scheduled for elective surgery under general anaesthesia. 25. Female participant who is pregnant, lactating, or planning pregnancy during the course of the trial. 26. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial. 27. Currently taking part in other interventional clinical trials unless approved by the CI. |
| Date of first enrolment | 11/03/2022 |
| Date of final enrolment | 12/10/2023 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Oxford University Hospitals NHS Foundation Trust
John Radcliffe Hospital
Headley Way
Headington
Oxford
OX3 9DU
United Kingdom
Headley Way
Headington
Oxford
OX3 9DU
United Kingdom
Sponsor information
University of Oxford
University/education
University/education
Research Governance
Ethics & Assurance Team
Joint Research Office
Churchill Drive
Headington
Oxford
OX3 7GB
England
United Kingdom
| ctrg@admin.ox.ac.uk | |
| Website | https://researchsupport.admin.ox.ac.uk/contacts/rgea |
"ROR" |
https://ror.org/052gg0110 |
Funders
Funder type
Government
NIHR Oxford Biomedical Research Centre
Private sector organisation / Research institutes and centers
Private sector organisation / Research institutes and centers
- Alternative name(s)
- NIHR Biomedical Research Centre, Oxford, OxBRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/01/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Publication in a high-impact journal at the end of the study. We will send a lay summary of the trial results to participants at the end of the study. |
| IPD sharing plan | The current data sharing plans for this study are unknown and will be available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Statistical Analysis Plan | version 2.0 | 08/03/2022 | 10/03/2022 | No | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Results article | 01/06/2025 | 28/04/2025 | Yes | No |
Additional files
Editorial Notes
28/04/2025: Publication reference added.
28/06/2024: The following changes were made:
1. The recruitment end date was changed from 30/06/2024 to 12/10/2023.
2. The overall study end date was changed from 01/01/2025 to 20/03/2024.
3. The total final enrolment number was added.
01/08/2023: The participant exclusion criteria have been changed.
06/01/2023: The recruitment end date was changed from 30/09/2023 to 30/06/2024.
20/10/2022: The exclusion criteria were changed.
17/10/2022: The recruitment end date was changed from 30/09/2022 to 30/09/2023.
14/03/2022: The recruitment start date was changed from 01/03/2022 to 11/03/2022.
10/03/2022: The statistical analysis plan has been uploaded as an additional file.
26/01/2022: Trial's existence confirmed by South Central - Oxford B Research Ethics Committee.
