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NCT Number: NCT06308757

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

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).

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Key information

Conditions

NASH Body Weight Digestive System Diseases Fatty Liver Fibrosis Liver Cirrhosis Liver Diseases Liver Fibrosis NAFLD Non-alcoholic Fatty Liver Disease Nutrition Disorders Nutritional and Metabolic Diseases Obesity Overnutrition Overweight Pathologic Processes Pathological Conditions, Signs and Symptoms Signs and Symptoms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

IRCCS Azienda Ospedaliero-Universitaria di Bologna

Bologna, 40138, Italy

Location status: Recruiting

Location contact

Fabio Piscaglia, Professor

PRINCIPAL_INVESTIGATOR

Federico Ravaioli

CONTACT

[email protected]

+393333176759

Federico Ravaioli, MD, PhD

SUB_INVESTIGATOR

Maria Letizia Petroni, Professor

SUB_INVESTIGATOR

Silvia Ferri, MD

SUB_INVESTIGATOR

Simona Leoni, MD

SUB_INVESTIGATOR

Sofia Penazza

CONTACT

[email protected]

0512142477

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

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

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).

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).

Primary outcomes

  1. Change of at least one grade of liver fibrosis

    Time frame: 12 months

    Histological change of liver fibrosis without worsening of NASH

  2. Change of histological features of NASH

    Time frame: 12 months

    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.

Secondary outcomes

  1. Histological NIH NASH CRN Score

    Time frame: 12 months

    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.

  2. Histological FLIP/SAF changes

    Time frame: 12 months

    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).

  3. Biochemical test changes 1

    Time frame: 12 months

    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

  4. Biochemical test changes 2

    Time frame: 12 months

    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

  5. Biochemical test changes 3

    Time frame: 12 months

    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

  6. Biochemical test changes 4

    Time frame: 12 months

    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

  7. Biochemical test changes 5

    Time frame: 12 months

    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

  8. Biochemical test changes 6

    Time frame: 12 months

    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

  9. Biochemical test changes 7

    Time frame: 12 months

    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

  10. Biochemical test changes 8

    Time frame: 12 months

    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

  11. Biochemical test changes 9

    Time frame: 12 months

    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

  12. Biochemical test changes 10

    Time frame: 12 months

    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

  13. Biochemical test changes 11

    Time frame: 12 months

    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

  14. Biochemical test changes 12

    Time frame: 12 months

    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

  15. Biochemical test changes 13

    Time frame: 12 months

    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

  16. Fibrosis-4 test (FIB-4 ) variation

    Time frame: 12 months

    Liver biochemical biomarker (FIB4) variation

  17. NAFLD Fibrosis Score (NFS) change

    Time frame: 12 months

    Liver biochemical biomarker (NAFLD Fibrosis Score, NFS) change

  18. FAST (FibroScan-AST) score variation

    Time frame: 12 months

    Liver biochemical biomarker (FibroScan-AST) variation

  19. Fatty Liver Index (FLI) modification

    Time frame: 12 months

    Liver biochemical biomarker (Fatty Liver Index (FLI) modification

  20. Changes in LSM

    Time frame: 12 months

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

  21. Variation of steatosis by CAP

    Time frame: 12 months

    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

  22. Body Mass Index (BMI) improvement

    Time frame: 12 months

    Anthropometric parameters (BMI) improvement

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

    Time frame: 3 months

    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.

  24. Compliance to VLCKD evaluated by VAS (Visual Analogue Scale)

    Time frame: 3 months

    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.

  25. Variation of steatosis by ultrasound assessment

    Time frame: 12 months

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

  26. Questionnaires 1

    Time frame: 12 months

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

  27. Questionnaires 2

    Time frame: 12 months

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

  28. Questionnaires 3

    Time frame: 12 months

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

  29. Questionnaires 4

    Time frame: 12 months

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

Study contacts

Contact information is provided by the study sponsor or research team.

Fabio Piscaglia, MD, PhD, Professor

CONTACT

[email protected]

0512142214

Federico Ravaioli, MD, PhD

CONTACT

[email protected]

+393333176759

Sponsors and collaborators

Lead sponsor

University of Bologna

Other

Registry information

Official study title

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

Acronym: KETONASH

Important dates

Study start
2021
Primary completion
2024
Study completion
2026
First posted
Mar 13, 2024
Registry last updated
Mar 15, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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