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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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| VLCKD arm | Experimental | The VLCKD dietary intervention consists of five phases: Ketogenic Low-Calorie Period (2 months):
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). |
|
| Control LCD arm | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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). |
| Measure | Description | Time Frame |
|---|---|---|
| Change of at least one grade of liver fibrosis | Histological change of liver fibrosis without worsening of NASH | 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. | 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 12 months |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Fabio Piscaglia, MD, PhD, Professor | Contact | 0512142214 | fabio.piscaglia@unibo.it | |
| Federico Ravaioli, MD, PhD | Contact | +393333176759 | f.ravaioli@unibo.it |
| Name | Affiliation | Role |
|---|---|---|
| Fabio Piscaglia | University of Bologna | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| IRCCS Azienda Ospedaliero-Universitaria di Bologna | Recruiting | Bologna | 40138 | Italy |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 23, 2023 |
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Multicentric, Prospective, Open, Randomized, Controlled, and Interventional, with no medicinal use
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Two-arms, 2: 1 randomization stratified by type 2 diabetes mellitus and gender
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| 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). |
|
| 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). | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 12 months |
| Fibrosis-4 test (FIB-4 ) variation | Liver biochemical biomarker (FIB4) variation | 12 months |
| NAFLD Fibrosis Score (NFS) change | Liver biochemical biomarker (NAFLD Fibrosis Score, NFS) change | 12 months |
| FAST (FibroScan-AST) score variation | Liver biochemical biomarker (FibroScan-AST) variation | 12 months |
| Fatty Liver Index (FLI) modification | Liver biochemical biomarker (Fatty Liver Index (FLI) modification | 12 months |
| Changes in LSM | Changes in physical liver biomarkers of fibrosis with Transient Elastometry (Fibroscan, Echosens, France) by reducing the kPa after treatment. | 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 | 12 months |
| Body Mass Index (BMI) improvement | Anthropometric parameters (BMI) improvement | 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. | 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. | 3 months |
| Variation of steatosis by ultrasound assessment | Physical biomarkers of hepatic steatosis evaluated by qualitative method (mild, moderate, severe) hepatic ultrasound. | 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"]. | 12 months |
| Questionnaires 2 | Questionnaires on lifestyle (physical exercise/sedentary habits). A score is not provided. | 12 months |
| Questionnaires 3 | Questionnaires on liver disease-related events (NASH-CHECK). 0=no pain, 10=worst pain. | 12 months |
| Questionnaires 4 | Questionnaires on liver disease-related events (CLDQ). 1=always, 7=never. | 12 months |
| Feb 19, 2024 |
| Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Feb 14, 2024 | Feb 19, 2024 | ICF_001.pdf |
| ID | Term |
|---|---|
| D065626 | Non-alcoholic Fatty Liver Disease |
| D009765 | Obesity |
| D008103 | Liver Cirrhosis |
| ID | Term |
|---|---|
| D005234 | Fatty Liver |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D005355 | Fibrosis |
| D010335 | Pathologic Processes |
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