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

NCT ID: NCT06308757

Last Updated: 2024-03-15

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-09-29
• Study Completion Date: 2026-12-12

Brief Summary

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.

Conditions

NASH; NAFLD; Obesity; Liver Fibrosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

VLCKD arm

The VLCKD dietary intervention consists of five phases:

Ketogenic Low-Calorie Period (2 months):

• Phase 1 (30 days - Visits 1-3): Ketogenic diet with low-fat content, 600 kcal/day.
• Phase 2 (15 days - Visit 5): 660 kcal/day.
• Phase 3 (15 days - Visit 5): 730 kcal/day

Low-Calorie Period (2 months):

Phase 4 (30 days - Visits 6-7): Hypocaloric diet with the reintroduction of different foods, 1,050 kcal/day.

• Phase 5 (30 days - Visits 7-8): 1,400 kcal/day.

During these phases, the patient will receive nutritional supplementation with vitamins, trace elements, and omega-3 fatty acids. Throughout the very low-calorie ketogenic period, the patient will have three interim dietetic consultations (Visits 2-4) and a medical visit (Visit 5). During the low-calorie period, the patient will receive alternating two dietetic consultations (Visits 6 and 7) and one medical visit every 30 days (Visit 8).

Group Type: EXPERIMENTAL

Very-low-calorie ketogenic diet (VLCKD) with meal replacements

Intervention Type: DIETARY_SUPPLEMENT

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).

Control LCD arm

The control LCD arm consists of a diet with natural low-calorie foods (1200-1500 kcal/day or a reduction of 500-1000 kcal/day compared to baseline) and a low glycemic index based on the "Mediterranean Diet" model, following the most recent guidelines on MAFLD/NAFLD. Similar to the VLCKD arm, for the entire duration of the dietetic treatment, the patient will alternately receive dietetic consultations and medical visits.

At the end of the dietary intervention, patients from both study arms will continue with a controlled, low glycemic index diet tailored to the patient's basal metabolic rate (BMR) (estimated with bioimpedance assessment) for an additional six months.

Both study arms will follow a physical activity schedule and will have psychological-motivational support.

Group Type: ACTIVE_COMPARATOR

Mediterranean low-calorie diet (LCD)

Intervention Type: DIETARY_SUPPLEMENT

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).

Interventions

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).

Intervention Type: 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).

Intervention Type: DIETARY_SUPPLEMENT

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Bologna

OTHER

Sponsor Role: lead

Responsible Party

Fabio Piscaglia

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Fabio Piscaglia

Role: PRINCIPAL_INVESTIGATOR

University of Bologna

Locations

IRCCS Azienda Ospedaliero-Universitaria di Bologna

Bologna, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Fabio Piscaglia, MD, PhD, Professor

Role: CONTACT

fabio.piscaglia@unibo.it

0512142214

Federico Ravaioli, MD, PhD

Role: CONTACT

f.ravaioli@unibo.it

+393333176759

Facility Contacts

Federico Ravaioli

Role: primary

f.ravaioli@unibo.it

+393333176759

Sofia Penazza

Role: backup

sofia.penazza2@unibo.it

0512142477

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

495/2021/Sper/AOUBo

Identifier Type: -

Identifier Source: org_study_id