The Role of Very Low Calorie Ketogenic Diet (VLCKD) in Patients Affected by Non-Alcoholic Steatohepatitis (NASH) With Significant Fibrosis (KETONASH)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 42
- 试验地点
- 2
- 主要终点
- Change of at least one grade of liver fibrosis
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Two-arms, 2: 1 randomization stratified by type 2 diabetes mellitus and gender
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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).
干预措施: Very-low-calorie ketogenic diet (VLCKD) with meal replacements (Dietary Supplement)
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.
干预措施: Mediterranean low-calorie diet (LCD) (Dietary Supplement)
结局指标
主要结局
Change of at least one grade of liver fibrosis
时间窗: 12 months
Histological change of liver fibrosis without worsening of NASH
Change of histological features of NASH
时间窗: 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.
次要结局
- Histological NIH NASH CRN Score(12 months)
- Biochemical test changes 3(12 months)
- Biochemical test changes 2(12 months)
- Biochemical test changes 6(12 months)
- FAST (FibroScan-AST) score variation(12 months)
- Compliance to VLCKD evaluated by VAS (Visual Analogue Scale)(3 months)
- Questionnaires 1(12 months)
- Questionnaires 3(12 months)
- Histological FLIP/SAF changes(12 months)
- Biochemical test changes 10(12 months)
- Biochemical test changes 7(12 months)
- Biochemical test changes 8(12 months)
- Biochemical test changes 11(12 months)
- Questionnaires 2(12 months)
- Questionnaires 4(12 months)
- Variation of steatosis by ultrasound assessment(12 months)
- Biochemical test changes 1(12 months)
- Biochemical test changes 4(12 months)
- Biochemical test changes 5(12 months)
- Biochemical test changes 12(12 months)
- Changes in LSM(12 months)
- Body Mass Index (BMI) improvement(12 months)
- Side effects evaluation for VLCKD therapy by VAS (Visual Analogue Scale)(3 months)
- Biochemical test changes 9(12 months)
- Fatty Liver Index (FLI) modification(12 months)
- Biochemical test changes 13(12 months)
- Fibrosis-4 test (FIB-4 ) variation(12 months)
- NAFLD Fibrosis Score (NFS) change(12 months)
- Variation of steatosis by CAP(12 months)
研究者
Fabio Piscaglia
Professor
University of Bologna