Role of the Very Low Calorie Ketogenic Diet (VLCKD) in Patients With Non-Alcoholic Steatohepatitis (NASH) With Fibrosis

Official title

The Role of Very Low Calorie Ketogenic Diet (VLCKD) in Patients Affected by Non-Alcoholic Steatohepatitis (NASH) With Significant Fibrosis (KETONASH)

Overview

The purpose of the KETONASH study is to evaluate, in patients with metabolic-associated fatty liver disease (MAFLD) with non-alcoholic steatohepatitis (NASH) and significant liver fibrosis, the effect of a very low-calorie ketogenic diet (VLCKD) compared to that of a standard low-calorie diet (standard Mediterranean LCD - in accordance with the European Association for the Study of the Liver/European Society for Clinical Nutrition and Metabolism guidelines on MAFLD/NAFLD).

Detailed description

The KETONASH study is a multicenter, open-label, randomised, controlled clinical trial that will be consecutively proposed to all patients with histological diagnosis of non-alcoholic steatohepatitis (NASH) and significant hepatic fibrosis in the context of chronic metabolic liver disease (MAFLD/NAFLD).

Once the inclusion criteria are confirmed and the exclusion criteria are ruled out, patients will be subsequently randomly assigned (randomisation) with a 2:1 ratio to one of the two study arms:

* VLCKD Study Arm → will receive experimental diet therapy with very low-calorie ketogenic meals (VLCKD) consisting of 5 successive phases (600 - 1500 kcal/day). * LCD Control Arm → will receive standard low-calorie diet therapy, a Mediterranean-type diet in accordance with the most recent guidelines on MAFLD/NAFLD (1200-1500 kcal/day).

The KETONASH study consists of an initial 4-month diet intervention phase (Visits 1-8), followed by a second 8-month weight maintenance phase (Visits 9-15). In both study arms, the intervention will be conducted through a standardised multidisciplinary approach (Physician/Dietitian/Nurse/Psychologist) aimed at weight loss through changes in dietary regimen, exercise program, and emotional support techniques.

The two study arms differ in nutritional composition, types of foods, and caloric intake.

Interventions

• Dietary supplement Very-low-calorie ketogenic diet (VLCKD) with meal replacements
  The VLCKD study arm will receive an experimental diet therapy with very-low-calorie ketogenic meal replacements (VLCKD) consisting of 5 successive phases (600 - 1500 kcal/day).
• Dietary supplement Mediterranean low-calorie diet (LCD)
  The Control arm LCD will receive standard Mediterranean type low-calorie diet (LCD) therapy by the most recent guidelines on MAFLD/NAFLD (1200-1500 kcal/day).

Primary outcome measures

• Change of at least one grade of liver fibrosis [Time frame: 12 months]
• Change of histological features of NASH [Time frame: 12 months]

Secondary outcome measures (12)

• Histological NIH NASH CRN Score [Time frame: 12 months]
• Histological FLIP/SAF changes [Time frame: 12 months]
• Biochemical test changes 1 [Time frame: 12 months]
• Biochemical test changes 2 [Time frame: 12 months]
• Biochemical test changes 3 [Time frame: 12 months]
• Biochemical test changes 4 [Time frame: 12 months]
• Biochemical test changes 5 [Time frame: 12 months]
• Biochemical test changes 6 [Time frame: 12 months]
• Biochemical test changes 7 [Time frame: 12 months]
• Biochemical test changes 8 [Time frame: 12 months]
• Biochemical test changes 9 [Time frame: 12 months]
• Biochemical test changes 10 [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

• Patients aged ≥18 years with histological diagnosis of NASH with evidence of fibrosis (defined according to NASH CRN) obtained no more than 6 months before enrollment;
• Stable weight for more than 6 months with BMI between 30-40 kg/m2;
• Patients in whom it is safe and feasible to proceed with liver biopsy and who consent to undergo liver biopsy after 12 months of enrollment to assess the effect of dietary treatment;
• Obtained informed consent.

Exclusion criteria

• BMI <30 or BMI >40
• Presence of evolved chronic liver disease into cirrhosis (histological F4 or elastometric LSM >14 kPa)
• Type 1 diabetes mellitus
• Model for End-stage Liver Disease (MELD) score >12, AST or ALT ≥5× ULN, HbA1c >9.5%, INR ≥1.4, creatinine >1.5 mg/dl, platelets <100,000/mm3, and total bilirubin >1.5 mg/dl.
• Concurrent presence of any other known chronic liver disease beyond MAFLD/NAFLD, such as alcoholic liver disease, viral (HCV/HBV), cholestatic-autoimmune (PBC/PSC/AIH), Wilson's disease, hemochromatosis, drug-induced liver injury (DILI), or the presence or suspicion of hepatocellular carcinoma (HCC);
• Average alcohol consumption exceeding 4/2 units/day (males/females) in the preceding 6 months and a history of excessive alcohol consumption in the last 5 years;
• Previous or planned liver transplant, bariatric surgery, ileal resection, or biliary diversion;
• History of acute cholecystitis and biliary obstructions (cholangitis);
• Recent (in the last 12 months) or concurrent use of agents known to cause hepatic steatosis (long-term systemic corticosteroids \[>10 days\], amiodarone, methotrexate, tamoxifen, tetracyclines, high-dose estrogens, valproic acid);
• Recent (in the last 3 months) change in the dose/regimen or introduction of Vitamin E (at doses ≥400 IU/day), ursodeoxycholic acid (UDCA), betaine, S-adenosyl methionine, silymarin, or pentoxifylline;
• Presence of psychiatric disorders and/or diagnosis of any eating disorder;
• Life expectancy <6 months.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Italy · 1 center

• IRCCS Azienda Ospedaliero-Universitaria di Bologna — Bologna

Identifiers

NCT: NCT06308757 · 495/2021/Sper/AOUBo

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗