MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease)
Conditions
Keywords
Time-restricted eating, Obesity, MASLD, circadian rhythms
Brief summary
The objective of this study is to demonstrate that an \< or equal to 8-hour time-restricted eating (i.e., fasting for at least 16 hours every day), not focusing on reducing caloric intake, reduces intra-hepatic fat in patients with obesity and Metabolic dysfunction-Associated Steatotic liver Disease (MASLD).
Detailed description
Obesity is a growing health problem. The increase in obesity is driving the growing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly called non-alcoholic fatty liver disease or NAFLD). Chronobiology has revealed new risk factors for metabolic disease including MASLD. Proof-of-concept studies showed that time-restricted eating (TRE), a dietary intervention that involves longer fasting periods (typically \> 12 h per day) without caloric restriction, reprograms metabolism favorably. The state of the art now justifies clinical trials on clinical populations. The aim of this randomized, parallel group, controlled study is to test the efficacy of Time Restricted Eating (TRE) implemented with dietary coaching and a dedicated mobile application compared to usual care. The primary endpoint is the evolution of liver fat content quantified by Magnetic Resonance Imaging (MRI). Patients presenting all inclusion criteria without non-inclusion ciriteria will be included and a Magnetic Resonnance Imaging of the liver will be programmed. Randomization will be performed within 3 months post inclusion after MRI results are obtained. Only patients showing Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) \> or equal to 8% will be randomized. Other patients will be withdrawn from study before randomization. After randomization, both groups will benefit from the standard of care for obesity management and metabolic assessment. Both groups will benefit from dietary counselling to achieve a balanced diet (no calorie restriction) and increase physical activity as recommended. This counselling will be performed by weekly phone calls of a centralized dietetician during a period of 12 weeks. Both groups of patients will use a mobile application to daily register time of first food intake and of time of last food intake (through time-stamped photos of first and last feedings). This will allow to know length of the patient's eating period per 24 hours. Difference between the 2 groups of patients is only that, in the experimental arm (TRE), patients will additionnaly be instructed to reduce time of daily food intake to a window of 8 hours per day or less and thus increase daily fasting to at least 16 hours. This coaching will be performed during the weekly phone calls of a centralized dietetician.
Interventions
BEHAVIORALTime Restricted Eating
Coaching of the patient by a dietetician for reduction of time of daily food intake to a window of 8 hours per day or less and thus increase of daily fasting to at least 16 hours, in addition to usual dietary counselling to achieve a balanced diet (no calorie restriction) and increase physicial activity as recommended (current guidelines).
BEHAVIORALUsual care only
Usual care: dietary counselling to achieve a balanced diet (no calorie restriction) and increase physicial activity as recommended (current guidelines).
Sponsors
Nantes University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Body mass index (BMI) between 30.0 and 49.9 kg/m2 * Age between 18 and 65 years (limits included) * Sedentary (light-intensity physical activity less than 1 hour per week) or moderately active (moderate exercise 1 to 2 hours per week). Self-declared criteria. * Weight stable for at least 3 months prior to the beginning of the study (gain or loss \<4 kg). Self-declared criteria. * Able to give written informed consent * Self-reported eating interval \> 12 hours per day * Subject who owns a smartphone with access to the internet, and agrees to use it in the study * Affiliation with French social security system or beneficiary from such system * Fibroscan® Controlled Attenuation Parameter (CAP) \> 300 dB/ms * Hepatitis B and C serologies negative (or showing past-infection or protective immunization)
Exclusion criteria
* Alcohol intake \> 20 g/day * Night-shift workers or rotating shift workers * Smoking * Patient with diabetes if HbA1c not at target (\<7%) and/or using a non-authorized medication) * Chronic liver disease other than MASLD * Severe hepatic disease (cirrhosis, hepatocellular carcinoma) * Severe cardiac disease (Chronic heart failure classified as being in New York Heart Association (NYHA) Class III or IV) * Severe Kidney disease with CKD-EPI\<30 mL/min/1,73m2 * Initiation of hormonal treatment during the study period * Medications affecting weight or energy balance * Magnetic Resonance Imaging (MRI) not possible due to patient's anthropometric characteristics. Any of the following: * abdominal and/or thoracic circumference with arms greater than 200 cm * Sagittal diameter (or abdominal height, i.e. the distance between the dorsum and the apex of the abdomen, which was measured in the supine position at the midpoint between the iliac crest and the last rib) over 70 cm * body weight over 160 kg * MRI not possible due to the following (an MRI safety screening form will have to be filled for inclusion): presence of a pacemaker or cardiac defibrillator or cardiovascular catheter or neurostimulator or an implantable electronic pump for automated drug injection or an electronically-controlled implantable chamber. Ocular metallic foreign bodies * History of severe eating disorders: Binge Eating Disorder, Bulimia Nervosa; Night eating syndrome * Minors * Adults under guardianship, trusteeship or under safeguard of justice * Other clinical trial participation that could interfere with the study * Pregnant women or women trying to be pregnant * Nursing mothers * Any treatment triggering hepatic steatosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Liver fat content quantified by Magnetic Resonance Imaging Proton Density Fat Fraction | 12 weeks post randomization | Liver fat content quantified Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) before randomization and then at 12 weeks post randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average lenght of the eating period per 24 hours | 12 weeks post randomization | Average lenght of the eating period per 24 hours as assessed byt he self-declared times of first and last food intake every day of the 12 weeks intervention. (Daily registration of time of first food intake and of time of last food intake will be performed by all patients on the dedicated mobile application through time-stamped photos of first and last feedings) |
| Liver steatosis and Stiffness as assessed by the Fibroscan | 12 weeks post randomization | Liver steatosis ans stiffness evaluated by Fibroscan Controlled Attenuation Parameter before randomization and then at 12 weeks post randomization |
| Hepatic outcomes evaluated through aspartates aminotransferases (ASAT) blood level before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of aspartate aminotransferases (ASAT) in blood before randomization and at 12 weeks post randomization. |
| Physical activity level measured by accelerometry with a watch accelerometer | 12 weeks post randomization | Physical activity measured by accelerometry with a watch accelerometer during 7 days before randomization, then during 7 days of the sixth and twelfth weeks after randomization. |
| Anthropometric outcomes assessed by body weight. | 12 weeks post randomization | Patient weight assessed before randomization, then at 6 and 12 weeks post randomization |
| Anthropometric outcomes assessed by impedancemetry | 12 weeks pour randomization | Anthropometric oucome : body fat assessed by impedancemetry before randomization, then at 6 and 12 weeks post randomization |
| Anthropometric outcomes assessed by Magnetic Resonance Imaging of the liver | 12 weeks post randomization | Percentage of visceral and sub-cutaneaous fat, percentage of muscle fat and muscular surface assessed by Magnetic Resonance Imaging before randomization and at 12 weeks post randomization. |
| Blood pressure | 12 weeks post randomization | Blood pressure measured before randomization, then at 6 and 12 weeks post randomization |
| Metabolic outcomes related to energy balance evaluated through glycated hemoglobin (HbA1c) blood level before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of HbA1c in blood before randomization and at 12 weeks post randomization. |
| Metabolic outcomes related to energy balance or insulin signaling/resistance assessed through indirect calorimetry | 12 weeks post randomization | Metabolic outcome : resting energy expenditure as assessed by indirect calorimetry at assessed by indirect calorimetry before randomization then at 12 weeks post randomization. |
| Depression assessed using the PHQ-9 questionnaire | 12 weeks post randomization | Depression assessed using the PHQ-9 (Patient Health Questionnaire-9) before randomization , then at 12 weeks post randomization |
| Anxiety assessed using the GAD-7 questionnaire | 12 weeks post randomization | Anxiety assessed using the Generalized Anxiety Disorder questionnaire (GAD-7) before randomization, then at 12 weeks post randomization |
| Quality of sleep using Pittsburgh sleep quality index | 12 weeks post randomization | Quality of sleep using Pittsburgh sleep quality index before randomization, then at 12 weeks post randomization |
| Quality of life assessed by EQ-5D questionnaire | 12 weeks post randomization | Quality of life assessed by the Euro Quality of Life-5 Dimensions (EQ-5D) questionnaire before randomization, then at 12 weeks post randomization. |
| Chronotype as assessed by Micro Munich ChronoType Questionnaire | 12 weeks post randomization | Chronotype as assessed by Micro Munich ChronoType Questionnaire before randomization, then at 12 weeks post randomization |
| Appetite as assessed by FCQ-T-r questionnaire | 12 weeks post randomization | Appetite as assessed by Food Craving Questionnaire-Trait-reduced (FCQ-T-r) before randomization, then at 12 weeks post randomization |
| Caloric intake | 12 weeks post randomization | Total caloric intake and macronutrient repartition as assessed by registration on the dedicated mobile application of photos of patient's intakes during 3 days before randomization, then during 3 days of the sixth and twelfth weeks after randomization |
| Occurrence of the following adverse events: headache, nausea, diarrhea, constipation, dizziness, fatigue and irritability | 12 weeks post randomization | Occurrence of the following adverse events: headache, nausea, diarrhea, constipation, dizziness, fatigue and irritability up to 12 weeks post randomization |
| Hepatic outcomes evaluated through alanine aminotransferase (ALAT) blood level before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of alanine aminotransferase (ALAT) in blood before randomization and at 12 weeks post randomization. |
| Hepatic outcomes evaluated through gamma glutamyl-transpeptidase (gamma-GT) blood level before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of gamma glutamyl-transpeptidase (gamma-GT) in blood before randomization and at 12 weeks post randomization. |
| Hepatic outcomes evaluated through alcaline phosphatases (ALP) blood level before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of alcaline phosphatases (ALP) in blood before randomization and at 12 weeks post randomization. |
| Hepatic outcomes evaluated through bilirubin blood level before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of bilirubin in blood before randomization and at 12 weeks post randomization. |
| Hepatic outcomes evaluated through blood parameter transferrin saturation coefficient before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of transferrin saturation coefficient before randomization and at 12 weeks post randomization. |
| Hepatic outcomes evaluated through ferritin blood level before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of ferritin in blood before randomization and at 12 weeks post randomization. |
| Hepatic outcomes evaluated through blood parameter prothrombin ratio before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of prothrombin ratio before randomization and at 12 weeks post randomization. |
| Hepatic outcomes evaluated through iron blood level before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of iron in blood before randomization and at 12 weeks post randomization. |
| Hepatic outcomes evaluated through protein C-reactive (CRP) blood level before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of protein C-reactive (CRP) in blood before randomization and at 12 weeks post randomization. |
| Anthropometric outcomes assessed by waist circumference. | 12 weeks post randomization | Patient waist circumference assessed before randomization, then at 6 and 12 weeks post randomization. |
| Anthropometric outcomes assessed by hip circumference. | 12 weeks post randomization | Patient hip circumference assessed before randomization, then at 6 and 12 weeks post randomization. |
| Metabolic outcomes related to energy balance evaluated through total cholesterol blood level before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of total cholesterol in blood before randomization and at 12 weeks post randomization. |
| Metabolic outcomes related to energy balance evaluated through LDL-cholesterol blood level before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of LDL-cholesterol in blood before randomization and at 12 weeks post randomization. |
| Metabolic outcomes related to energy balance evaluated through HDL-cholesterol blood level before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of HDL-cholesterol in blood lbefore randomization and at 12 weeks post randomization. |
| Metabolic outcomes related to energy balance evaluated through triglycerids blood level before randomization and at 12 weeks post randomization. | 12 weeks post randomization | Level of triglycerids in blood before randomization and at 12 weeks post randomization. |
| Metabolic outcomes related to energy balance or insulin signaling/resistance assessed through glucose continuous monitoring | 12 weeks post randomization | Continous monitroing of glucose in blood during 7 days before randomization and during 7 days of the sixth and of the twelfth weeks after randomization |
| Metabolic outcomes related to energy balance or insulin signaling/resistance assessed through determination of HOMA-IR | 12 weeks post randomization | Homesotasis Model Assessment of Insulin Resistance (HOMA-IR) calculated from basal (fasting) glucose and insulin before randomization then at 12 weeks post randomization |
| Metabolic outcomes related to energy balance or insulin signaling/resistance assessed through determination of HOMA-beta | 12 weeks post randomization | Homesotasis Model Assessment for Beta-cell function (HOMA-beta) calculated from basal (fasting) glucose and insulin before randomization then at 12 weeks post randomization |
Countries
France
Contacts
CONTACTDavid JACOBI, MD
Outcome results
None listed