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

University of Bologna42 enrolled

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).

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Interventions

Very-low-calorie ketogenic diet (VLCKD) with meal replacementsDIETARY_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).

Mediterranean low-calorie diet (LCD)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).

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Change of at least one grade of liver fibrosis

Histological change of liver fibrosis without worsening of NASH

Time frame: 12 months

Change of histological features of NASH

NASH parameters variation. Improvement in disease activity is defined as decrease in NAFLD Activity Score (NAS) ≥1 points. The worsening of fibrosis is defined as any numerical increase in the stage.

Time frame: 12 months

Secondary Outcomes

Histological NIH NASH CRN Score

Assessment of individual histological components that make up the NIH NASH CRN (NASH Clinical Research Network) Score. NAS (NAFLD Activity Score) is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. NAS of ≥5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as not NASH.

Time frame: 12 months

Histological FLIP/SAF changes

Assessment of individual histological components that make up the FLIP (fatty liver inhibition of progression) SAF (steatosis activity fibrosis) score (based on steatosis, ballooning, lobular inflammation, fibrosis, etc.). The score ranges from 0 (not NAFLD) to 3 (NASH).

Time frame: 12 months

Biochemical test changes 1

Evaluation of variation of the biochemical tests panel based on normal ranges provided by the local laboratory. Multiple parameters are included in biochemical panel: aspartate transaminase (AST). Normal range: \<50 U/L

Time frame: 12 months

Biochemical test changes 2

Evaluation of variation of the biochemical tests panel based on normal ranges provided by the local laboratory. Multiple parameters are included in biochemical panel: alanine aminotransferase (ALT). Normal range: \<45 U/L

Time frame: 12 months

Biochemical test changes 3

Evaluation of variation of the biochemical tests panel based on normal ranges provided by the local laboratory. Multiple parameters are included in biochemical panel: Alkaline Phosphatase (range variable according to age and sex) Normal range: Females: 30 - 120 U/L Males: 30 - 120 U/L

Time frame: 12 months

Biochemical test changes 4

Evaluation of variation of the biochemical tests panel based on normal ranges provided by the local laboratory. Multiple parameters are included in biochemical panel: Gamma-glutamyltransferase Normal range: Females: \< 38 U/L Males: \< 55 U/L

Time frame: 12 months

Biochemical test changes 5

Evaluation of variation of the biochemical tests panel based on normal ranges provided by the local laboratory. Multiple parameters are included in biochemical panel: bilirubin Normal range: \< 1.60 mg/dL

Time frame: 12 months

Biochemical test changes 6

Evaluation of variation of the biochemical tests panel based on normal ranges provided by the local laboratory. Multiple parameters are included in biochemical panel: glycemia (glucose) Normal range: 70 - 105 mg/dL

Time frame: 12 months

Biochemical test changes 7

Evaluation of variation of the biochemical tests panel based on normal ranges provided by the local laboratory. Multiple parameters are included in biochemical panel: HDL cholesterol Normal range: Females \> 45 mg/dL Males \> 35 mg/dL

Time frame: 12 months

Biochemical test changes 8

Evaluation of variation of the biochemical tests panel based on normal ranges provided by the local laboratory. Multiple parameters are included in biochemical panel: LDL cholesterol Normal range: Very high risk: objective \< 55 high risk: \< 70 moderate risk: \< 100 low risk: \< 116

Time frame: 12 months

Biochemical test changes 9

Evaluation of variation of the biochemical tests panel based on normal ranges provided by the local laboratory. Multiple parameters are included in biochemical panel: albumin Normal range: 35.0 - 50.0 g/L

Time frame: 12 months

Biochemical test changes 10

Evaluation of variation of the biochemical tests panel based on normal ranges provided by the local laboratory. Multiple parameters are included in biochemical panel: total proteins Normal range: 6.6 - 8.3 g/dL

Time frame: 12 months

Biochemical test changes 11

Evaluation of variation of the biochemical tests panel based on normal ranges provided by the local laboratory. Multiple parameters are included in biochemical panel: glicate hemoglobin Normal range: 20 - 42 mmol/mol

Time frame: 12 months

Biochemical test changes 12

Evaluation of variation of the biochemical tests panel based on normal ranges provided by the local laboratory. Multiple parameters are included in biochemical panel: Vitamin D Normal range: 15.2 - 90.1 pg/mL

Time frame: 12 months

Biochemical test changes 13

Evaluation of variation of the biochemical tests panel based on normal ranges provided by the local laboratory. Multiple parameters are included in biochemical panel: uric acid Normal range: Females 2.4 - 5.7 Males 3.4 - 7.0 mg/dL

Time frame: 12 months

Fibrosis-4 test (FIB-4 ) variation

Liver biochemical biomarker (FIB4) variation

Time frame: 12 months

NAFLD Fibrosis Score (NFS) change

Liver biochemical biomarker (NAFLD Fibrosis Score, NFS) change

Time frame: 12 months

FAST (FibroScan-AST) score variation

Liver biochemical biomarker (FibroScan-AST) variation

Time frame: 12 months

Fatty Liver Index (FLI) modification

Liver biochemical biomarker (Fatty Liver Index (FLI) modification

Time frame: 12 months

Changes in LSM

Changes in physical liver biomarkers of fibrosis with Transient Elastometry (Fibroscan, Echosens, France) by reducing the kPa after treatment.

Time frame: 12 months

Variation of steatosis by CAP

Changes in biomarker of fatty liver disease evaluated with the controlled attenuation parameter (CAP, Echosens, France) by the reduction of decibel/sec (dB/sec) after treatment

Time frame: 12 months

Body Mass Index (BMI) improvement

Anthropometric parameters (BMI) improvement

Time frame: 12 months

Side effects evaluation for VLCKD therapy by VAS (Visual Analogue Scale)

The tolerability measured by a VAS (Visual Analogue Scale) that assesses the occurrence of side effects in patients undergoing diet therapy with VLCKD. The lowest value (0) indicates the best result, while the highest value (10) indicates absence of tolerability.

Time frame: 3 months

Compliance to VLCKD evaluated by VAS (Visual Analogue Scale)

The tolerability measured by a VAS (Visual Analogue Scale) that assesses the compliance of patients undergoing diet therapy with VLCKD. The lowest value (0) indicates the best result, while the highest value (10) indicates absence of tolerability.

Time frame: 3 months

Variation of steatosis by ultrasound assessment

Physical biomarkers of hepatic steatosis evaluated by qualitative method (mild, moderate, severe) hepatic ultrasound.

Time frame: 12 months

Questionnaires 1

Questionnaires on quality of life (Health-related quality of life, HRQoL). The answers follow this scheme: 1 \["best outcome"\] to 3 \["worst outcome"\].

Time frame: 12 months

Questionnaires 2

Questionnaires on lifestyle (physical exercise/sedentary habits). A score is not provided.

Time frame: 12 months

Questionnaires 3

Questionnaires on liver disease-related events (NASH-CHECK). 0=no pain, 10=worst pain.

Time frame: 12 months

Questionnaires 4

Questionnaires on liver disease-related events (CLDQ). 1=always, 7=never.

Time frame: 12 months

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts