Focused Power Ultrasound Mediated Inferior Perirenal Adipose Tissue Modification Therapy for Essential Hypertension (PARADISE HTN-III)

Focused Power Ultrasound Mediated Inferior Perirenal Adipose Tissue Modification Therapy for Essential Hypertension: a Multicenter, Randomized, Controlled Phase II/III Clinical Trial (PARADISE HTN-III)

This seamless two-stage phase II/III clinical trial aims to evaluate the efficacy and safety of a novel focused power ultrasound mediated inferior perirenal adipose tissue modification therapy for essential hypertension. Stage 1 is a phase II, multicenter, open-label, randomized trial to determine the optimal treatment strategy. Stage 2 is a phase III, multicenter, randomized, double-blind trial investigating the efficacy and safety of optimal treatment strategy compared to sham control.

Study Overview

• Status: Not yet recruiting
• Conditions: Cardiovascular Diseases; Hypertension; Blood Pressure
• Intervention / Treatment: Device: focused power ultrasound mediate inferior perirenal adipose tissue modification; Device: Sham-control group

Detailed Description

The increase of visceral fat is closely related to the occurrence of hypertension, and it is one of the main independent risk factors of hypertension. Visceral fat has been recognized as an important endocrine organ, and a variety of factors secreted by visceral fat lead to an increased risk of cardiovascular disease. Peri-renal fat is a special type of visceral fat which is different from other type of visceral fat in histology, physiology, and functions. The positon of peri-renal fat is more stable than other visceral fat, which might be influenced by breath or body position changes. Studies have found that perirenal fat is an early predictor of ASCVD, and its accumulation is closely related to the occurrence and development of ASCVD. Therefore, the reduction or modification of visceral fat, especially peri-renal fat, has a sufficient scientific basis for the treatment of hypertension.

In the investigators' previous experiments, this novel focused power ultrasound can rapidly and efficiently promote the perirenal adipose tissue fibrosis and control the blood pressure 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 perirenal adipose tissue in human volunteers, showing that this kind of method was feasible and safe.

This seamless two-stage phase II/III clinical trial aims to evaluate the efficacy and safety of a novel focused power ultrasound mediated inferior perirenal adipose tissue modification therapy for essential hypertension. In Stage 1, 30 participants will be 1:1:1 randomly allocated to 3 intervention groups (single treatment group, consecutive treatment group A, and consecutive treatment group B). The optimal treatment strategy will be selected based on the decrease of blood pressure and safety evaluation and proceed to Stage 2. In Stage 2, participants will be randomly assigned to intervention group (optimal treatment strategy selected formerly in Stage 1) and sham control group.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yanhui Sheng; Phone Number: 13851647530; Email: yhsheng@njmu.edu.cn
• Study Contact Backup: Name: Yang Hua; Phone Number: 13851624359; Email: 759150674@qq.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • The First Affiliated Hospital of Nanjing medical University
      • Contact: Wei Sun; Phone Number: 13815860536; Email: shunwee@126.com
      • Contact: Fang Zhou; Phone Number: 13815401066; Email: zhoufang7408@163.com
      • Principal Investigator: Fang Zhou
    • Nanjing, Jiangsu, China, 210000
      • The Affiliated Jiangning Hospital of Nanjing Medical University
      • Contact: Yuqing Zhang; Phone Number: 13851672168
      • Contact: Qin Tao; Phone Number: 1585062208
      • Principal Investigator: Yuqing Zhang
    • Nantong, Jiangsu, China, 210000
      • Affiliated Hospital of Nantong University
      • Contact: Hongzhuan Sheng; Phone Number: 13515203348
      • Contact: Jian Zhuo; Phone Number: 18206297131
      • Principal Investigator: Hongzhuan Sheng
    • Suzhou, Jiangsu, China, 210000
      • Suzhou Municipal Hospital
      • Contact: Yang Hua; Phone Number: 13851624359; Email: 759150674@qq.com
      • Contact: Yanhui Sheng; Phone Number: 13851647530; Email: yhshengnjmu@163.com
      • Principal Investigator: Yanhui Sheng

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Individual with office systolic blood pressure (SBP) ≥ 140 mmHg and <160 mmHg, and office diastolic blood pressure (DBP)<100mmHg after standardized antihypertensive drug treatment for 1 month;
2. Individual with 24-hour Ambulatory Blood Pressure Monitoring (ABPM) average systolic blood pressure (ASBP) ≥130 mmHg；
3. The anteroposterior, transverse and axial diameters of inferior perirenal fat pad measured by ultrasound should be at least 20mm；
4. Individual is willing to sign the informed consent of the study.

Exclusion Criteria:

1. Individual diagnosed as secondary hypertension (e.g. renal parenchymal hypertension, renal artery stenosis, primary aldosteronism, pheochromocytoma, Cushing's syndrome, aortic coarctation, obstructive sleep apnea hypopnea syndrome)；
2. Individuals with ≥ 3 cardiovascular risk factors (male>55 years old, female>65 years old; smoking or passive smoking; 2-hour postprandial blood glucose 7.8-11mmol/L and/or impaired fasting glucose (6.1-6.9mmol/L); LDL-C ≥ 3.4mmol/L (130mg/dl), HDL-C<1.0mmol/L (40mg/dl) or TC ≥ 5.2mmol/L (200mg/dl); Family history of early onset of cardiovascular disease, age of onset of first degree relatives<50 years old; Abdominal obesity, waist circumference: male>90cm, female>85cm or BMI>28kg/m2) or hypertensive target organ damage;
3. riser hypertension (defined as night blood pressure higher than daytime blood pressure by ABPM)
4. Regular night shift workers
5. Individuals taking other medications that may affect blood pressure (such as glucocorticoids);
6. Individual with history of kidney or kidney surrounding tissue surgery;
7. Individuals with impairment of liver or kidney function (ALT, AST or creatinine greater than 2 times of the upper limit of normal reference);
8. Individual with myocardial infarction, unstable angina pectoris, cerebrovascular accident or transient ischemic attack within 6 months of enrollment;
9. Individual with type 1 diabetes or uncontrolled type 2 diabetes；
10. Individual with uncontrolled thyroid dysfunction;
11. Individual with urinary calculi or hematuria；
12. Individual with atrial fibrillation;
13. Individual with severe structural heart disease (e.g. valvular heart disease, cardiomyopathy, congenital heart disease);
14. Individual with second degree and above atrioventricular block and/or sick sinus syndrome;
15. Individual with abnormal coagulation function;
16. Individual with infected waist skin;
17. Individual with claustrophobia；
18. Individual with malignant tumor;
19. History of allergy to amlodipine, olmesartan, and hydrochlorothiazide
20. Individual is pregnant, nursing or planning to be pregnant;
21. Individual is unwilling to sign informed consent;
22. Individual fails to complete the screening period.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Stage 2: Intervention group; Participants will receive optimal treatment strategy selected formerly in Stage 1	Device: focused power ultrasound mediate 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: Stage 2: 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.
Experimental: Stage 1: Intervention group; This arm is combined with 3 groups and a total of 30 participants will be 1:1:1 allocated (each group with 10 participants). Single treatment group: receive treatment once after enrollment; Consecutive treatment group A: receive 3 consecutive treatments, each with an interval of 3 days; Consecutive treatment group B: receive 3 consecutive treatments, each with an interval of 7 days. In Stage 1, the investigators will select optimal treatment strategy and proceed to Stage 2.	Device: focused power ultrasound mediate 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ambulatory Blood Pressure	Changes of mean systolic blood pressure measured by 24-hour ambulatory blood pressure monitoring at 1-month compared with baseline	From baseline to 1 month post-procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Office Systolic Blood Pressure	Changes of office systolic blood pressure at 1-month compared with baseline	From baseline to 1 month post-procedure
Ambulatory Blood Pressure	Changes of mean systolic blood pressure measured by 24-hour ambulatory blood pressure monitoring at 3-month compared with baseline	From baseline to 3 month post-procedure
Office Systolic Blood Pressure	Changes of office systolic blood pressure at 3-month compared with baseline	From baseline to 3 month post-procedure
Ambulatory Blood Pressure	Changes of mean diastolic blood pressure measured by 24-hour ambulatory blood pressure monitoring at 1-month compared with baseline	From baseline to 1 month post-procedure
Ambulatory Blood Pressure	Changes of mean diastolic blood pressure measured by 24-hour ambulatory blood pressure monitoring at 3-month compared with baseline	From baseline to 3 month post-procedure
Home Blood Pressure	Changes of home blood pressure at 1-month compared with baseline	From baseline to 1 month post-procedure
Home Blood Pressure	Changes of home blood pressure at 3-month compared with baseline	From baseline to 3 month post-procedure
Blood pressure control rate	The control rate of blood pressure (defined as office systolic blood pressure<140/90mmHg) at 3-month	From baseline to 3 month post-procedure
Antihypertensive drug load index	Changes of antihypertensive drug load index at 1-month and 3-month compared with baseline	From baseline to 1 month and 3 month post-procedure

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Any adverse events (AE) or severe adverse events (SAE) related to intervention. The SAE were defined as acute renal failure, acute intestinal perforation, and thromboembolic events, et al.	From baseline to 3 month post-procedure

Collaborators and Investigators

• Sponsor: Suzhou Municipal Hospital
• Collaborators: The First Affiliated Hospital with Nanjing Medical University; Affiliated Hospital of Nantong University; The Affiliated Jiangning Hospital of Nanjing Medical University

Publications and helpful links

General Publications

• Chandra A, Neeland IJ, Berry JD, Ayers CR, Rohatgi A, Das SR, Khera A, McGuire DK, de Lemos JA, Turer AT. The relationship of body mass and fat distribution with incident hypertension: observations from the Dallas Heart Study. J Am Coll Cardiol. 2014 Sep 9;64(10):997-1002. doi: 10.1016/j.jacc.2014.05.057.
• Hayashi T, Boyko EJ, Leonetti DL, McNeely MJ, Newell-Morris L, Kahn SE, Fujimoto WY. Visceral adiposity is an independent predictor of incident hypertension in Japanese Americans. Ann Intern Med. 2004 Jun 15;140(12):992-1000. doi: 10.7326/0003-4819-140-12-200406150-00008.
• Hutley L, Prins JB. Fat as an endocrine organ: relationship to the metabolic syndrome. Am J Med Sci. 2005 Dec;330(6):280-9. doi: 10.1097/00000441-200512000-00005.
• Li P, Liu B, Wu X, Lu Y, Qiu M, Shen Y, Tian Y, Liu C, Chen X, Yang C, Deng M, Wang Y, Gu J, Su Z, Chen X, Zhao K, Sheng Y, Zhang S, Sun W, Kong X. Perirenal adipose afferent nerves sustain pathological high blood pressure in rats. Nat Commun. 2022 Jun 6;13(1):3130. doi: 10.1038/s41467-022-30868-6.

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: February 21, 2024
• First Submitted That Met QC Criteria: February 21, 2024
• First Posted (Actual): February 28, 2024

Study Record Updates

• Last Update Posted (Estimated): March 4, 2024
• Last Update Submitted That Met QC Criteria: March 1, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Hypertension; Cardiovascular diseases; Focused ultrasound; Novel method
• Additional Relevant MeSH Terms: Vascular Diseases; Hypertension; Cardiovascular Diseases; Essential Hypertension
• Other Study ID Numbers: PARADISE HTN-III

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