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出境医 / 临床实验 / Alternate Day Fasting Combined and NAFLD for the Treatment of Non-alcoholic Fatty Liver Disease (NAFLD)
Alternate Day Fasting Combined and NAFLD for the Treatment of Non-alcoholic Fatty Liver Disease (NAFLD)
Study Description
Brief Summary:
Approximately 65% of obese individuals have non-alcoholic fatty liver disease (NAFLD), and this condition is strongly related to the development of insulin resistance and diabetes. Innovative lifestyle strategies to treat NAFLD are critically needed. The proposed research will demonstrate that alternate day fasting (ADF) combined with exercise is an effective non-pharmacological therapy to help obese prediabetic individuals with NAFLD reduce fatty liver and prevent progression of prediabetes to diabetes.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Non-Alcoholic Fatty Liver Disease Obesity Pre-diabetes | Other: Alternate day fasting Other: Exercise | Not Applicable |
Detailed Description:
Background: Approximately 65% of obese individuals have non-alcoholic fatty liver disease (NAFLD), and this condition is strongly related to the development of insulin resistance and diabetes. Innovative lifestyle strategies to treat NAFLD are critically needed. Alternate day fasting (ADF) has been shown in animals to reduce hepatic steatosis and improve hepatic insulin sensitivity, but these findings have yet to be confirmed in human subjects. ADF consists of a "feast day" where individuals are permitted to consume food ad libitum, alternated with a "fast day" where individuals consume 25% of their usual intake (~500 kcal). We performed a pilot study to evaluate the effects of ADF combined with exercise, versus ADF or exercise alone, on hepatic parameters in prediabetic patients. Our results show that the combination of ADF plus exercise produced greater reductions in alanine aminotransferase (ALT; an indirect marker of hepatic steatosis), compared to ADF alone, or exercise alone, after 12 weeks. Greater decreases in insulin resistance, HbA1c, LDL cholesterol, and more pronounced increases in HDL cholesterol, were observed in the combination group versus individual interventions. Data from our pilot trial also suggest that these decreases in insulin resistance may be mediated in part by changes in hepatocyte-derived hormones (hepatokines) that occur with liver fat reduction. Although these pilot findings are very promising, these data still require confirmation by a well powered longer-term (24 week) clinical trial. Hypotheses: The present proposal will test the following hypotheses: (1) The combination group (ADF plus exercise) will experience greater reductions in hepatic steatosis (measured by magnetic resonance spectroscopy; MRS) when compared to ADF or exercise alone; (2) The combination group will experience greater improvements in hepatokine profile (fetuin-A, fetuin B, FGF-21, RBP4, selenoprotein P, SHBG, adropin) when compared to ADF or exercise alone; (3) The combination group will experience greater improvements in hepatic insulin sensitivity, insulin resistance and HbA1c and other metabolic disease risk variables (fasting glucose, fasting insulin, triglycerides, LDL cholesterol, blood pressure, inflammatory parameters) when compared to ADF or exercise alone. Methods: To test these objectives, a 24-week randomized, controlled, parallel-arm feeding trial will be implemented. Obese prediabetic individuals with NAFLD (n = 360) will be randomized to 1 of 4 groups: (1) ADF (fast day: 25% energy intake, feed day: ad libitum fed, no exercise), (2) exercise (ad libitum fed, training 5 days/week supervised), (3) combination (ADF plus exercise), and (4) control (ad libitum fed, no exercise). Significance: If the aims of this application are achieved, this study will be the first to show that the combination of alternate day fasting plus aerobic exercise is an effective non-pharmacological therapy to reduce hepatic steatosis, improve hepatic insulin sensitivity and prevent the progression of prediabetes to type 2 diabetes in NAFLD patients.
Study Design
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 180 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Single (Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | Alternate Day Fasting Combined With Exercise for the Treatment of Non-alcoholic Fatty Liver Disease (NAFLD) |
| Actual Study Start Date : | September 1, 2019 |
| Estimated Primary Completion Date : | September 1, 2023 |
| Estimated Study Completion Date : | September 1, 2023 |
Arms and Interventions
| Arm | Intervention/treatment |
|---|---|
|
Experimental: Alternate day fasting
These participants will consume 25% of their baseline energy needs on the "fast day" and eat ad libitum at home on alternating "feed days".
|
Other: Alternate day fasting
The diet involves consuming 25% of their baseline energy needs on the "fast day" and eat ad libitum at home on alternating "feed days".
|
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Experimental: Exercise
These participants will participate in a supervised aerobic exercise program 5 times per week, 40-60 min per session.
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Other: Exercise
The exercise intervention involves supervised aerobic exercise program 5 times per week, 40-60 min per session.
|
|
Experimental: Combination alternate day fasting plus exercise
These participants will consume 25% of their baseline energy needs on the "fast day" and eat ad libitum at home on alternating "feed days". They will also participate in a supervised aerobic exercise program 5 times per week, 40-60 min per session.
|
Other: Alternate day fasting
The diet involves consuming 25% of their baseline energy needs on the "fast day" and eat ad libitum at home on alternating "feed days".
Other: Exercise The exercise intervention involves supervised aerobic exercise program 5 times per week, 40-60 min per session.
|
|
No Intervention: Control
Controls will be instructed to maintain their weight throughout the trial, and not to change eating or physical activity habits.
|
Outcome Measures
Primary Outcome Measures :
- Change in hepatic steatosis [ Time Frame: Change from week 1 to week 24 ]Hepatic steatosis will be measured by magnetic resonance spectroscopy
- Change in body weight [ Time Frame: Change from week 1 to week 24 ]Body weight will be measured by a digital scale
Secondary Outcome Measures :
- Change in hepatic insulin sensitivity [ Time Frame: Change from week 1 to week 24 ]Hepatic insulin sensitivity will be assessed by the oral glucose tolerance test (OGTT).
- Change in triglyceride levels [ Time Frame: Change from week 1 to week 24 ]Triglycerides will be measured by an enzymatic kit
- Change in HbA1c [ Time Frame: Change from week 1 to week 24 ]HbA1c will be measured by an enzymatic kit
Eligibility Criteria
| Ages Eligible for Study: | 18 Years to 65 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
Criteria
Inclusion Criteria:
- Age between 18 to 65 years old
- BMI between 30.0 and 49.9 kg/m2
- NAFLD (hepatic steatosis ≥ 5%)
- Prediabetic
- Sedentary (<20 min, 2x/week of light activity for 3 mo prior to study)
Exclusion Criteria:
- Have chronic liver disease other than NAFLD (hepatitis B or C, primary biliary cirrhosis, sclerosing cholangitis, autoimmune hepatitis, hemochromatosis, Wilson's disease, a1-antitrypsin deficiency)
- Consume excessive amounts of alcohol (Michigan Alcohol Screening Test score > 4)
- Have a history of known cardiovascular, pulmonary or renal disease
- Diagnosed T1DM or T2DM (fasting glucose: >126 mg/dl, 2-h glucose OGTT ≥ 200 mg/dl, HbA1c: >6.5%))
- Have contraindications for participation in an exercise program based on ACSM recommendations
- Are not weight stable for 3 months prior to the beginning of study (weight gain or loss > 4 kg)
- Are claustrophobic or have implanted metallic/electrical devices (e.g. cardiac pacemaker, neuro-stimulator)
- Are not able to keep a food diary or activity log for 7 consecutive days during screening
- Are taking drugs that induce steatosis (e.g. corticosteroids, estrogens, methotrexate, Ca channel blockers)
- Are taking drugs that benefit NAFLD (e.g. betaine, pioglitazone, rosiglitazone, metformin, or gemifibrozil)
- Are taking drugs that influence study outcomes (weight loss, lipid-lowering, glucose-lowering medications)
- Are perimenopausal or have an irregular menstrual cycle (menses that does not appear every 27-32 days)
- Are pregnant, or trying to become pregnant
- Are smokers
Contacts and Locations
Locations
| United States, Illinois | |
| University of Illinois Chicago | |
| Chicago, Illinois, United States, 60612 | |
Sponsors and Collaborators
University of Illinois at Chicago
Investigators
| Principal Investigator: | Krista Varady, PhD | University of Illinois Chicago |
| Tracking Information | |||||
|---|---|---|---|---|---|
| First Submitted Date ICMJE | June 28, 2019 | ||||
| First Posted Date ICMJE | July 2, 2019 | ||||
| Last Update Posted Date | April 5, 2021 | ||||
| Actual Study Start Date ICMJE | September 1, 2019 | ||||
| Estimated Primary Completion Date | September 1, 2023 (Final data collection date for primary outcome measure) | ||||
| Current Primary Outcome Measures ICMJE |
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| Original Primary Outcome Measures ICMJE | Same as current | ||||
| Change History | |||||
| Current Secondary Outcome Measures ICMJE |
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| Original Secondary Outcome Measures ICMJE | Same as current | ||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||
| Descriptive Information | |||||
| Brief Title ICMJE | Alternate Day Fasting Combined and NAFLD for the Treatment of Non-alcoholic Fatty Liver Disease (NAFLD) | ||||
| Official Title ICMJE | Alternate Day Fasting Combined With Exercise for the Treatment of Non-alcoholic Fatty Liver Disease (NAFLD) | ||||
| Brief Summary | Approximately 65% of obese individuals have non-alcoholic fatty liver disease (NAFLD), and this condition is strongly related to the development of insulin resistance and diabetes. Innovative lifestyle strategies to treat NAFLD are critically needed. The proposed research will demonstrate that alternate day fasting (ADF) combined with exercise is an effective non-pharmacological therapy to help obese prediabetic individuals with NAFLD reduce fatty liver and prevent progression of prediabetes to diabetes. | ||||
| Detailed Description | Background: Approximately 65% of obese individuals have non-alcoholic fatty liver disease (NAFLD), and this condition is strongly related to the development of insulin resistance and diabetes. Innovative lifestyle strategies to treat NAFLD are critically needed. Alternate day fasting (ADF) has been shown in animals to reduce hepatic steatosis and improve hepatic insulin sensitivity, but these findings have yet to be confirmed in human subjects. ADF consists of a "feast day" where individuals are permitted to consume food ad libitum, alternated with a "fast day" where individuals consume 25% of their usual intake (~500 kcal). We performed a pilot study to evaluate the effects of ADF combined with exercise, versus ADF or exercise alone, on hepatic parameters in prediabetic patients. Our results show that the combination of ADF plus exercise produced greater reductions in alanine aminotransferase (ALT; an indirect marker of hepatic steatosis), compared to ADF alone, or exercise alone, after 12 weeks. Greater decreases in insulin resistance, HbA1c, LDL cholesterol, and more pronounced increases in HDL cholesterol, were observed in the combination group versus individual interventions. Data from our pilot trial also suggest that these decreases in insulin resistance may be mediated in part by changes in hepatocyte-derived hormones (hepatokines) that occur with liver fat reduction. Although these pilot findings are very promising, these data still require confirmation by a well powered longer-term (24 week) clinical trial. Hypotheses: The present proposal will test the following hypotheses: (1) The combination group (ADF plus exercise) will experience greater reductions in hepatic steatosis (measured by magnetic resonance spectroscopy; MRS) when compared to ADF or exercise alone; (2) The combination group will experience greater improvements in hepatokine profile (fetuin-A, fetuin B, FGF-21, RBP4, selenoprotein P, SHBG, adropin) when compared to ADF or exercise alone; (3) The combination group will experience greater improvements in hepatic insulin sensitivity, insulin resistance and HbA1c and other metabolic disease risk variables (fasting glucose, fasting insulin, triglycerides, LDL cholesterol, blood pressure, inflammatory parameters) when compared to ADF or exercise alone. Methods: To test these objectives, a 24-week randomized, controlled, parallel-arm feeding trial will be implemented. Obese prediabetic individuals with NAFLD (n = 360) will be randomized to 1 of 4 groups: (1) ADF (fast day: 25% energy intake, feed day: ad libitum fed, no exercise), (2) exercise (ad libitum fed, training 5 days/week supervised), (3) combination (ADF plus exercise), and (4) control (ad libitum fed, no exercise). Significance: If the aims of this application are achieved, this study will be the first to show that the combination of alternate day fasting plus aerobic exercise is an effective non-pharmacological therapy to reduce hepatic steatosis, improve hepatic insulin sensitivity and prevent the progression of prediabetes to type 2 diabetes in NAFLD patients. | ||||
| Study Type ICMJE | Interventional | ||||
| Study Phase ICMJE | Not Applicable | ||||
| Study Design ICMJE | Allocation: Randomized Intervention Model: Parallel Assignment Masking: Single (Outcomes Assessor) Primary Purpose: Treatment |
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| Condition ICMJE |
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| Intervention ICMJE |
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| Study Arms ICMJE |
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| Publications * | Not Provided | ||||
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||
| Recruitment Status ICMJE | Enrolling by invitation | ||||
| Estimated Enrollment ICMJE |
180 | ||||
| Original Estimated Enrollment ICMJE | Same as current | ||||
| Estimated Study Completion Date ICMJE | September 1, 2023 | ||||
| Estimated Primary Completion Date | September 1, 2023 (Final data collection date for primary outcome measure) | ||||
| Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
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| Sex/Gender ICMJE |
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| Ages ICMJE | 18 Years to 65 Years (Adult, Older Adult) | ||||
| Accepts Healthy Volunteers ICMJE | Yes | ||||
| Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||
| Listed Location Countries ICMJE | United States | ||||
| Removed Location Countries | |||||
| Administrative Information | |||||
| NCT Number ICMJE | NCT04004403 | ||||
| Other Study ID Numbers ICMJE | 2019-0300 | ||||
| Has Data Monitoring Committee | No | ||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement ICMJE |
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| Responsible Party | Krista Varady, University of Illinois at Chicago | ||||
| Study Sponsor ICMJE | University of Illinois at Chicago | ||||
| Collaborators ICMJE | Not Provided | ||||
| Investigators ICMJE |
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| PRS Account | University of Illinois at Chicago | ||||
| Verification Date | April 2021 | ||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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