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Clinical Trial Summary

Non-alcoholic fatty liver disease (NAFLD) is a common complication of obesity which can progress to deadly complications like end-stage liver disease and hepatocellular carcinoma. In the wake of the obesity epidemic, NAFLD is becoming the main etiology of liver transplantation in the United States. Currently, there are no Federal Drug Administration (FDA) approved pharmacological treatments for NAFLD. Weight loss through lifestyle modifications, pharmacotherapy and bariatric surgery can be effective strategies for the management of NAFLD. Even though substantial weight loss and improvement in NAFLD can be achieved with bariatric surgery, only a small proportion of patients with obesity undergo surgery. Very-low calorie diets (VLCD) are replacement meals manufactured to substitute natural foods and limited total intake of 800-960 kcal in divided meals. Very low-calorie diets can produce substantial weight loss of 10% over 2 to 3 months. It is hypothesized that VLCD reduce liver steatosis and fibrosis measured non-invasively with transient elastography. The main aim is #1 to assess the effect of VLCD on liver fatty infiltration and fibrosis. There are also two exploratory aims exploring novel pathogenic factors that mediate the improvement of NAFLD by VLCD: #2 assess the effect of VLCD on micro RNAs (miRs) associated with pathophysiology of NAFLD and #3 assess the effect of VLCD on changes of salivary and fecal microbiome in the setting of NAFLD. This pilot project will produce preliminary data for the development of a larger grant application to study the efficacy of VLCD and a physical activity intervention in the management of NAFLD. Furthermore, it will potentially identify factors that mediate improvement of NAFLD after VLCD. Twenty to 25 subjects with obesity and NAFLD will be treated for 8 weeks with a physical activity intervention and VLCD and obtain transient elastography before and after the interventions along with other measurements of interest. Of note, there will not be a control parallel group because of funding limitation. This project may have significant impact by establishing VLCD as a clinically effective option for the improvement of liver steatosis and fibrosis in patients with obesity and NAFLD ineligible or without access to bariatric surgery.


Clinical Trial Description

Study design: The investigators plan to perform a non-controlled, non-randomized, open-label, pilot clinical trial to evaluate the effect of an 8-week VLCD intervention on NAFLD. The main variable of this study is the magnitude of liver steatosis and fibrosis assessed non-invasively by elastography. The investigators will compare these variables before and after the VLCD intervention. The investigators do not plan to include a parallel control group because the main objective of this budget-limited pilot clinical trial is to collect preliminary data for a larger grant proposal. Data prior to VLCD intervention will serve as control for each subject. Hereby, it is hypothesized that VLCD reduces liver steatosis and fibrosis. Study Subjects: Potential adult participants with obesity [age ≥ 21 years old; body mass index (BMI) ≥ 30 kg/m2 and ≤ 50 kg/m2] will be recruited at the Weight Management Clinic, at the Diabetes Center and at the Digestive Health Center, all at University of Iowa Health Care (UIHC). The investigators will invite potential participants with sex-specific abnormal alanine aminotransferase (ALT) (female ≥ 32 U/L; male ≥ 41 U/L), but less than 100 U/L, with negative tests for viral hepatitis C and autoimmune hepatitis, and elastography results positive for fibrosis grade F2 through F4 [that is, liver stiffness measurement (LSM) between 6 and 124 kPa] and/or steatosis grade S1 through S3 [that is, controlled attenuation parameter (CAP) ≥ 248 dB/m] within the last 6 months. The above tests, along with complete blood count (CBC), basic metabolic profile (BMP), thyroid stimulating hormone (TSH) with reflex free thyroxine (free T4) and hemoglobin A1c are routinely obtained as part of the standard of care at the recruitment clinics. Oral health status of these patients will be obtained from the available dental charts, if not, a dental examination will be performed. With Institutional Board Review (IRB) authorization, the investigators will interrogate the charts to verify whether subjects meet criteria for participation. Case managers will contact potential participants by telephone, electronic mail or letter. Detailed sessions: Visit #1 (enrolment visit): Subjects who meet the above criteria will be invited for visit #1 at UIHC Clinical Research Unit. Subjects will fast for 12 hours for visit #1. After signing informed consent, the inclusion/exclusion criteria will be reviewed again. Clinical history and physical exam will be charted from the last clinical note. Subjects will fill the AUDIT C, a screening questionnaire for alcohol consumption. Vitals signs (that is, seated and standing blood pressure and heart rate, ambient air pulse saturation of oxygen, weight, height, and neck and waist circumferences). Blood samples for sodium, potassium, creatinine, cell blood count (CBC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides, glucose, insulin, hemoglobin A1c (table 1) and micro ribonucleic acid (micro RNA) will also be drawn during visit #1. Female participants at reproductive age will be asked to provide urine sample for pregnancy test. Unstimulated saliva will be collected from the participants by asking them to spit into a collection tube. Supplies for stool collection with instructions for sample return will be provided for assessment of baseline fecal microbiome testing. Stools samples should be returned to the research center before VLCD initiation. The participant will also meet the research manager for education about the VLCD and physical activity interventions during visit #1. The research manager will dispense 2-week worth of Optifast® replacement meals, a Fitbit® device and a wireless scale. Visit #2: At the end of week #3, the participant will return to the UIHC Clinical Research Unit, when vital signs will be assessed and blood samples for laboratory tests will be drawn (table 1). On visit #2, sodium, potassium and creatinine will be assessed. Participants will complete of an adverse event questionnaire. Very low-calorie diets will be dispensed at visit #2. Visit #3: At the end of week #5, the participant will return to the UIHC Clinical Research Unit, when vital signs will be assessed and blood samples for laboratory tests will be drawn (table 1). On visit #3, sodium, potassium, creatinine, ALT, AST, and uric acid will be assessed. Participants will complete of an adverse event questionnaire. Very low-calorie diets will be dispensed at visit #3. Visit #4 (closing visit): At the end of week #9, the participant will return to the UIHC Clinical Research Unit for visit #4. Subjects will fast 12 hours for visit #4 when saliva and blood samples for sodium, potassium, creatinine, CBC, ALT, AST, triglycerides, glucose, insulin, A1c (table 1) and miR will be collected. The participant will be instructed to bring a stool sample for microbiome analysis using collection supplies dispensed beforehand. The post-VLCD elastography will be performed during the final visit. Participants will complete of an adverse event questionnaire. The participant will also meet the research manager and receive education about transitioning from VLCD to a low calorie, low fat diet during the closure visit. The participants will be instructed to weight themselves weekly after the VLCD intervention. The research manager will contact the participant by telephone or video-call to assess adherence to low calorie, low fat diet and to review the weight trajectory 1 and 2 months after termination of the study. Telephone and/or video-call contacts: Between visits #1 and #4, the research manager will contact the participant by telephone or video-call on a weekly basis for diet and physical activity compliance, and assessment of adherence, response and adverse events of VLCD for 8 weeks. Very low-calorie diet treatment: The VLCD program will last 8 weeks and then will be followed by a gradual re-introduction of food through the next 2 months. The only sources of nutrition during this phase are the Optifast® products providing up to 800 kcal per day. Two liters (67.63 fl oz) of water should also be consumed each day. Participants will receive Optifast® replacement meals at no cost. The replacement meals will be dispensed at the UIHC Clinical Research Unit on weeks #1, #2, and #4. Participants will be instructed to use 5 replacement meals per day (800 kcal total) with 40% of calories as protein, 40% as carbohydrate, and 20% as fat (Ard, Lewis et al. 2019). Exercise intervention: Participants will be provided a Fitbit® activity monitor (Inspire 2®) to wear on the wrist each day throughout the 8-week VLCD intervention. Participants will also receive access to the Fitbit® mobile app. Participants will be encouraged to wear their Fitbit® 24 hours/day for a 7-day period (baseline). Participants will then connect with a health coach via Zoom®. During this conversation, participants will: 1) establish a daily walking goal with the intent of meeting the physical activity guidelines (150 minutes/week of moderate intensity physical activity); 2) identify and problem solve barriers that are preventing them from being active; 3) establish an action plan for meeting their walking goal. Participants will be encouraged to self-monitor their progress towards their daily goals by accessing the dashboard on the Fitbit® app each day. Participants will also be invited to a private social network through the Fitbit® app. In the social group, participants will receive educational/motivational on the benefits of physical activity and tips for becoming more active. Finally, participants will be invited to participate in regular walking games and challenges through the Fitbit® app to help them meet their walking goal. The investigators will objectively measure physical activity (steps, time spent engaged in sedentary, light-intensity, moderate-intensity, and vigorous-intensity activity) on a daily frequency. The Fitbit® Inspire 2® is a small tri-axial accelerometer-based activity monitor. Fitbits® have been demonstrated as an accurate measure of daily steps (overall mean error = -9%), time spent sedentary (overall mean error = <10%), energy expenditure (overall mean error = +4%) in free living conditions when compared to accelerometers which are considered gold standard field measures of physical activity. The investigators will track user's daily physical activity throughout the 8 weeks through the Fitbit® website. Participants will be encouraged to wear the Fitbit® monitor 24 hours/day throughout the 8-week intervention including sleep time. Participants should remove the monitor only to charge it and during swimming/bathing when the monitor will be submerged in water. Participants will need to create a Fitbit® profile and share their user name and password with the research team so that the investigators can download their physical activity data through the Fitbit® website. Compliance with the intervention (days met walking goal) will also be measured with the Fitbit® activity monitor. ;


Study Design


Related Conditions & MeSH terms


NCT number NCT04861571
Study type Interventional
Source University of Iowa
Contact Marcelo L Correia, MD PhD
Phone 1-319-541-4513
Email [email protected]
Status Not yet recruiting
Phase Phase 1
Start date June 1, 2021
Completion date April 2024

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