Focused Power Ultrasound Mediated Inferior Perirenal Adipose Tissue Modification Therapy for Non-Alcoholic Fatty Liver Disease (PARADISE-NAFLD)

Focused Power Ultrasound Mediated Inferior Perirenal Adipose Tissue Modification Therapy for Non-Alcoholic Fatty Liver Disease: a Randomized Controlled Trial (PARADISE-NAFLD)

This randomized, blinded, sham-control trial aims to evaluate the efficacy and safety of a novel focused power ultrasound mediated inferior perirenal adipose tissue modification therapy for non-alcoholic fatty liver disease.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-alcoholic Fatty Liver Disease
• Intervention / Treatment: Device: focused power ultrasound mediated inferior perirenal adipose tissue modification; Device: sham-control group

Detailed Description

Visceral adiposity is closely related to the incidence of non-alcoholic fatty liver disease (NAFLD), and it is also directly associated with liver inflammation and fibrosis. Visceral adiposity, via its unique location and enhanced lipolytic activity, releases toxic free fatty acids, which are delivered in high concentrations directly to the liver and lead to the accumulation and storage of hepatic fat. Furthermore, it has been recognized as an important endocrine organ, and a variety of factors secreted by visceral adiposity may lead to an increased risk of NAFLD.

Peri-renal fat is a special type of visceral adiposity which is different from other type of visceral fat in histology, physiology, and functions. The position of peri-renal fat is more stable than other visceral fat. The investigators found that prophylactic perirenal adipose tissue ablation can prevent the development of NAFLD in mice induced by high fat diets, and also this novel focused power ultrasound can rapidly and efficiently promote the peri-renal adipose tissue fibrosis in the model of swine. Moreover, the investigators performed a single arm, small sample study to investigate the feasibility of the novel focused power ultrasound to modify the inferior peri-renal adipose tissue in NAFLD participants, showing that this kind of method was feasible and safe.

In this study, the investigators aim to further evaluate the efficacy and safety of a novel focused power ultrasound mediated inferior perirenal adipose tissue modification therapy for NAFLD.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Xiangqing Kong; Phone Number: +8613951610265; Email: kongxq@njmu.edu.cn
• Study Contact Backup: Name: Jing Shi; Phone Number: +8615051872305; Email: shijing5499@jsph.org.cn

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • JiangSu Province Hospital / The First Affiliated Hospital of Nanjing Medical University
    • Nanjing, Jiangsu, China, 210000
      • The Affiliated Jiangning Hospital of Nanjing Medical University
    • Suzhou, Jiangsu, China, 215000
      • Suzhou Municipal Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18 years or older at the time of screening.
• Total liver fat content ≥10% measured by MRI-PDFF.
• Body mass index (BMI) ≥ 25 kg/m^2.
• The anteroposterior, transverse and axial diameters of inferior perirenal fat pad measured by ultrasound should be at least 20mm.
• Participants should be willing to sign the informed consent form of the study.

Exclusion Criteria:

• History of significant alcohol consumption (significant alcohol consumption was defined as more than 140 g/week in females and more than 210 g/week in males in the last 12months before screening, on average).
• Secondary factors causing hepatic steatosis, including viral hepatitis C, autoimmune hepatitis, total parenteral nutrition, celiac disease, Wilson's disease, hypothyroidism, hereditary hemochromatosis, drug factors (amiodarone, glucocorticoids, methotrexate, tamoxifen), etc.
• Complicating other chronic liver diseases, mainly including viral hepatitis, cholestatic liver disease, drug-induced liver injury, etc.
• Weight change >10% in the past 3 months.
• Clinical or pathological diagnosis of cirrhosis.
• NAFLD treatment drugs (such as vitamin E, obecholic acid, thiazolidinediones, etc.) were used within 6 months before enrollment.
• History of bariatric surgery.
• History of kidney and/or surrounding tissue surgery.
• Waist skin infection.
• Urinary stones and/or hematuria (positive for gross hematuria or occult blood).
• Unstable cardiovascular diseases: (1) Myocardial infarction, unstable angina pectoris or cerebrovascular accident occurred in the last 6 months. (2) Persistent atrial fibrillation without anticoagulation. (3) Severe structural heart disease (including valvular heart disease, cardiomyopathy). (4) second degree and above atrioventricular block and/or sick sinus syndrome. (5) Uncontrolled hypertension.
• Type 1 diabetes or uncontrolled hyperglycemia (HBA1c ≥ 9.5%).
• Participants with untreated tumors.
• Laboratory screening results include one or more of the following: (1) Neutrophil absolute value <1.0x10^9/L. (2) Platelet count <100x10^9/L. (3) Hemoglobin <100g/L. (4) Albumin <35g/L. (5) International standard value >1.5. (6) Total bilirubin >1.5 times the upper limit of normal value. (7) The estimated glomerular filtration rate was <60ml/ (minx1.73m^2).
• Participants who are pregnant, breastfeeding or trying to conceive.
• Any contraindication or inability to obtain an MRI.
• Participants who were unable to follow up.
• Any other situation that the investigator considers to be detrimental to the patient's health, hindering the completion of the study, or interfering with the results of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: intervention group; In intervention group, participants will receive the whole peri-renal fat modification therapy (including peri-renal fat ultrasonic measurement and localization, focused ultrasound treatment parameters setting and initiating)	Device: focused power ultrasound mediated inferior perirenal adipose tissue modification; This novel focused power ultrasound is an externally delivered, completely noninvasive focused therapeutic ultrasound device. It is capable of focusing the resulting ultrasound beam to a small "cigar"-shaped volume and monitoring the temperature of the target area, which leads to the rapid elevation of the peri-renal adipose tissue temperature and the destruction of target tissue eventually.
Sham Comparator: sham-control group; In sham control group, participants will receive the sham control therapy (including peri-renal fat ultrasonic measurement and localization, focused ultrasound treatment parameters setting), however, without initiating the focused ultrasound equipment.	Device: sham-control group; Participants will receive the sham control therapy (including peri-renal fat ultrasonic measurement and localization, focused ultrasound treatment parameters setting), however, without initiating the focused ultrasound equipment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change in Liver Fat Content	Absolute change in liver fat content assessed by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) at 3-month compared with baseline	From baseline to 3 months post-procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative Change in Liver Fat Content	Relative change in liver fat content assessed by MRI-PDFF at 3-month compared with baseline	From baseline to 3 months post-procedure
Proportion of MRI-PDFF Responders	Proportion of MRI-PDFF responders in two groups at 3-month of treatment. MRI-PDFF responder is defined as a ≥30% relative reduction in MRI-PDFF between baseline and end of treatment	From baseline to 3 months post-procedure
Change in Alanine Aminotransferase (ALT)	ALT is increased with liver damage. The blood levels of ALT are used to detect liver injury.	From baseline to 3 months post-procedure
Change in Concentration of Cytokeratin-18	Change in concentration of cytokeratin-18 in two groups at 3-month of treatment	From baseline to 3 months post-procedure
Change in Liver Stiffness Measurement and Controlled Attenuation Parameter	Change in liver stiffness measurement and controlled attenuation parameter measured by transient elastography at 3-month of treatment	From baseline to 3 months post-procedure
Change in Enhanced Liver Fibrosis Test	The markers of fibrosis assessed in this test comprised hyaluronic acid, tissue inhibitor of metalloproteinase 1 and procollagen III N-terminal peptide; these are elevated during fibrogenesis as a result of activation of the hepatic stellate cell.	From baseline to 3 months post-procedure

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chang in Fasting Lipid Profile	These include triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol	From baseline to 3 months post-procedure
Change in Concentration of Fasting Plasma Glucose (FPG)	Change in concentration of FPG at 3-month compared with baseline	From baseline to 3 months post-procedure
Change in Concentration of Fasting serum insulin (FINS)	Change in concentration of FINS at 3-month compared with baseline	From baseline to 3 months post-procedure
Change in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Index	From the results of FPG and FINS, insulin resistance will be estimated using the HOMA-IR algorithm: HOMA-IR = FPG (mmol/L) × FINS (μU/mL) / 22.5	From baseline to 3 months post-procedure
Change in Percentage of Glycosylated Hemoglobin (Hba1c)	The structure of Hba1c is relatively stable. Its concentration can effectively reflect the average blood glucose level in the past 8-12 weeks. It should be expressed as a percentage of adult hemoglobin	From baseline to 3 months post-procedure
Change in Body Weight	Body weight will be measured on a calibrated scale (to the nearest 0.1 kilogram). The measurement will be performed with the study subject in underwear and without shoes; or while wearing minimal indoor clothing	From baseline to 3 months post-procedure
Change in Waist Circumference	Change in waist circumference at 3-month compared with baseline	From baseline to 3 months post-procedure
Change in Waist to Hip (WTH) Ratio	The WTH ratio is calculated as the ratio of waist to hip circumference	From baseline to 3 months post-procedure
Change in Office Systolic Blood Pressure	Change in office systolic blood pressure at 3-month compared with baseline	From baseline to 3 months post-procedure
Change in Office Diastolic Blood Pressure	Change in office diastolic blood pressure at 3-month compared with baseline	From baseline to 3 months post-procedure
Incidence of Adverse Events (AEs)	The Incidence AEs will be reported for each arm	From baseline to 3 months post-procedure
Incidence of Severe Adverse Events (SAEs)	The Incidence SAEs will be reported for each arm	From baseline to 3 months post-procedure

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University
• Collaborators: Suzhou Municipal Hospital; The Affiliated Jiangning Hospital of Nanjing Medical University
• Investigators: Principal Investigator: shijing5499@jsph.org.cn Kong, The First Affiliated Hospital with Nanjing Medical University

Publications and helpful links

General Publications

• Xu C, Ma Z, Wang Y, Liu X, Tao L, Zheng D, Guo X, Yang X. Visceral adiposity index as a predictor of NAFLD: A prospective study with 4-year follow-up. Liver Int. 2018 Dec;38(12):2294-2300. doi: 10.1111/liv.13941. Epub 2018 Sep 6.
• Petta S, Amato MC, Di Marco V, Camma C, Pizzolanti G, Barcellona MR, Cabibi D, Galluzzo A, Sinagra D, Giordano C, Craxi A. Visceral adiposity index is associated with significant fibrosis in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2012 Jan;35(2):238-47. doi: 10.1111/j.1365-2036.2011.04929.x. Epub 2011 Nov 24.
• van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, London R, Peduto T, Chisholm DJ, George J. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology. 2008 Aug;48(2):449-57. doi: 10.1002/hep.22350.

Study record dates

Study Major Dates

• Study Start (Estimated): February 20, 2024
• Primary Completion (Estimated): October 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: January 4, 2024
• First Submitted That Met QC Criteria: January 25, 2024
• First Posted (Actual): January 26, 2024

Study Record Updates

• Last Update Posted (Actual): February 22, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Focused ultrasound; Non-alcoholic Fatty Liver Disease; Novel method
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: PARADISE-NAFLD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No