Study Setting
This trial is initiated by the Cardiology Department, The First Affiliated Hospital of Nanjing Medical University. Eligible participants with uncontrolled BP will be recruited at three implementation sites, including the First Affiliated Hospital of Nanjing Medical University (Jiangsu Province), Nanjing Jiangning Hospital (Jiangsu Province), and Suzhou Municipal Hospital (Jiangsu Province).
Eligibility Criteria
The inclusive criteria are as follows:
Individuals aged 18–65 years old;
Individuals have uncontrolled BP when receiving a medication regimen of one, two, or three antihypertensive medication classes for at least 4 weeks; and uncontrolled BP is defined as office systolic blood pressure (SBP) ≥ 140mmHg and < 180mmHg, and 24-hour ambulatory BP monitoring (ABPM) average SBP ≥ 135mmHg, regardless of diastolic BP.
Individuals have at least 20mm in the anteroposterior, transverse, and axial diameters of inferior perirenal fat measured by ultrasound
Individuals are willing to sign the informed consent of the study.
The exclusive criteria are as follows:
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Individuals are diagnosed with secondary hypertension (e.g. renal parenchymal hypertension, renal artery stenosis, primary aldosteronism, pheochromocytoma, Cushing's syndrome, aortic coarctation, severe obstructive sleep apnea-hypopnea syndrome);
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Individuals have a history of kidney and or kidney surrounding tissue surgery;
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Individuals have impairment of liver or kidney function (ALT, AST, or creatinine is greater than 3 times the upper limit of normal reference);
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Individuals have a myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack within 6 months before enrollment;
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Individuals have type 1 diabetes or poorly-controlled type 2 diabetes;
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Individuals have uncontrolled thyroid dysfunction;
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Individuals have urinary calculi and/or hematuria;
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Individuals have atrial fibrillation;
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Individuals have severe structural heart disease (e.g. heart valve disease, cardiomyopathy, congenital heart disease);
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Individuals have second-degree and above atrioventricular block;
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Individuals have abnormal coagulation function;
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Individuals have infected waist skin;
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Individuals have a malignant tumor;
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Individuals are pregnant, nursing, or planning to be pregnant;
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Individuals are unwilling to sign informed consent;
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Individuals fail to complete the screening period.
Intervention
Eligible patients will undergo either PFM with focused ultrasound or sham procedure. It is expected that their prescribed antihypertensive medications should be unchanged in the three months follow-up period after the intervention.
Pfm Procedure
For patients who are assigned to the PFM group, they will be placed in a lateral position on the treatment bed. Firstly, an ultrasonic probe is used to locate the rough position of inferior perirenal fat and the location needs being marked on the waist skin. Secondly, a focused power ultrasonic probe is applied to determine the precise target area of perirenal fat. Sequentially, automatic physique measurement starts to calculate the optimal output power for individuals. Lastly, treatment initiates. Bilateral inferior perirenal fat share the same procedure. The training sessions including recognition of inferior perirenal fat from ultrasonic image and operation of the equipment have been conducted at each study site by only one designated operator.
Sham Procedure
For patients who are assigned to the sham control group, they share the same procedure as PFM does except that the focused ultrasound will not transmit energy.
Criteria For Discontinuing
Participants may discontinue this trial for any of the following reasons:
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They may choose to withdraw for any reason.
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They have severe side effects that require unmarking to get cured.
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Their blood pressure is within “escape criteria”, defined as office SBP ≥ 180mmHg, or ༜90mmHg.
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They have a significant deviation from the study algorithm, e.g. changing the established antihypertensive drugs scheme.
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Any other rational reasons to withdraw from the study.
Strategies To Improve Adherence
Before enrollment, we repeatedly confirm the participants’ willingness and compliance with the study’s requirements, especially drug numbers and doses, and being able to follow-up within the next three months. We make efforts to monitor the adherence to drug use which is prescribed before allocation for at least 4 weeks. Blood and urine samples will be collected to measure the concentration of the antihypertensive drugs (diuretic, calcium channel blocker (CCB), angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blocker (ARB), beta-blocker, and alpha-blocker) at baseline, one-month and three-month.
Relevant Concomitant Care And Interventions
Though lifestyle modification should be recommended for all hypertensive patients according to the hypertension guidelines. we asked recruited participants to maintain their current lifestyle, including physical activities, diet, and regular rest habits. In order to assess the changes in lifestyle, weight, waist circumference, or hip circumference will be recorded at each follow-up time.
Outcomes
We speculate that PFM will have significant blood-pressure lowering effects compared with the sham-control group. The endpoints in the present study include primary endpoints, secondary endpoints, and safety endpoints.
Primary Endpoint Measure:
Secondary Outcome Measures:
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Changes of office blood pressure at 3-month compared with baseline
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Changes of mean systolic blood pressure measured by 24-hour ambulatory blood pressure monitoring at 1-month compared with baseline
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Changes of mean systolic blood pressure measured by 24-hour ambulatory blood pressure monitoring at 3-month compared with baseline
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Changes of the heart rate at 1-month compared with baseline
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Changes of the mean heart rate measured by 24-hour ambulatory blood pressure monitoring at 1-month compared with baseline
Safety Endpoint Measures:
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Any severe adverse events (SAE) related to the intervention. The SAE was defined as acute renal failure, acute intestinal perforation, and thromboembolic events, et al.
Participant Timeline
The participant timeline is shown in Table 1. Briefly, all participants will undergo either PFM of sham-control therapy during 14 days screening period. They will be asked to follow up at 1-day, 14-day, 30-day, and 90-day after randomization.
Sample Size
PASS software (version 2011) was used to calculate the sample size. This study is a parallel group design, whose primary endpoint is the difference in office BP at 1-month compared with baseline. Based on the outcome of our previous study, the mean change of office SBP from baseline to 1-month was expected to 10mmHg with a deviation of 13mmHg in the PFM group. Meanwhile, we assumed that a mean difference of office SBP was 5mmHg[15, 16] with a deviation of 13mmHg in the sham control group. The sample size was calculated as 100 in each group with a power of 80%, a two-sided significance level of 5%, and a drop-out rate of 15%.
Recruitment
Potential eligible participants will be screened at outpatient clinics of each study center. Advertisements of the trail introduction will be posted via onsite the hospital and social media platform.
Assignment Of Interventions: Allocation
Sequence generation
Randomized allocation sequence was generated at a 1:1 ratio in a complete random design among 200 participants by a statistician via the SAS 9.4 software (SAS Institute, Cary NC, USA) and integrated with a central computerized randomization system (Biomed information Technology Co., Ltd. Beijing).
Concealment Mechanism
The randomization codes were generated by a statistician and embedded in the computerized randomization system. The main investigators will not have permissions to view the allocation except for principal investigator of each study cite and operators who are responsible for PFM operation. The principal investigators are only authorized for urgent unblinding when a serious complication related to PFM procedure occurs.
Implementation
An independent randomization system account is created for investigators at each study site for the randomization implementation. Each investigator will log in to the system via website to enter the randomization page, input the information of the participants, check the name and code of study site, and confirm the randomization information. Then, the randomization code and allocated arm of the participant will be generated in the system background which is blinded for the investigators. Additionally, the operator at each study site will log in to the system using an independent account with an authority to view the allocated arms. At this time, the participants are successfully enrolled in this study.
Blinding
Study participants and all staff, including investigators, clinical care providers, statisticians and personnels who recruit, follow-up participants and collect data are blinded to the randomizations. The operators will be unblinded to implement the PFM procedure, and required to keep blinded to all other staff. Once the severe adverse events (SAE) that might be related to the PFM procedure occur, the principal investigators will be able to disclose the arm allocation. The disclosure reason, date, location will be recorded detailly.
Methods: Data Collection, Management, And Analysis
Data collection
The outcomes will be assessed at baseline, 1 day, 14 days, 30 days, and 90 days after intervention. All staff involved in the collection of data were trained in accordance with a standard operating procedure of the study. The data will be recorded utilizing electronic CRFs and EDC system.
Baseline Data Collection
The following measures will be completed at baseline.
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Written informed consent
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Clinical questionnaire
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Office BP and 24-hour ambulatory BP
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Anthropometric information including height, weight, waist circumference, and hip circumference
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Electrocardiography and cardiac ultrasound
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Arteries stiffness assessments (PWV)
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Imaging examinations including ultrasonic examinations of renal and perirenal fat, carotid ultrasound, and magnetic resonance imaging for perirenal fat and hypothalamic function
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Blood tests including routine blood tests, blood biochemical tests, and C-reactive protein.
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Urine tests including routine urine tests, urine biomarkers of acute renal injury (Ngal, TIMP2, IGFBP7)
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Hypertensive drugs concentration detection (serum and urine).
Data Collection At 1 Day After Intervention
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Office BP and 24-hour ambulatory BP
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Electrocardiography
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Arteries stiffness assessments (PWV)
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Imaging examinations including ultrasonic examinations of renal and perirenal fat, carotid ultrasound
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Blood tests including routine blood tests, blood biochemical tests, and C-reactive protein.
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Urine tests including routine urine tests, urine biomarkers of acute renal injury (Ngal, TIMP2, IGFBP7)
Data Collection At 14 Days After Intervention
Data Collection At 30 Days After Intervention
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Office BP and 24-hour ambulatory BP
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Anthropometric information including height, weight, waist circumference, and hip circumference
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Electrocardiography
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Arteries stiffness assessments (PWV)
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Imaging examinations including ultrasonic examinations of renal and perirenal fat, carotid ultrasound, and magnetic resonance imaging for perirenal fat and hypothalamic function
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Blood tests including routine blood tests, blood biochemical tests.
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Urine tests including routine urine tests.
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Hypertensive drugs concentration detection (serum and urine).
Data Collection At Final Visit
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Office BP and 24-hour ambulatory BP
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Anthropometric information including height, weight, waist circumference, and hip circumference
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Electrocardiography
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Arteries stiffness assessments (PWV)
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Imaging examinations including ultrasonic examinations of renal and perirenal fat, carotid ultrasound, and magnetic resonance imaging for perirenal fat and hypothalamic function
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Blood tests including routine blood tests, blood biochemical tests.
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Urine tests including routine urine tests.
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Hypertensive drugs concentration detection (serum and urine).
All the eligible participants will have comprehensive health examinations, and receive PFM therapy or sham-procedure for free. They will have close relationship with physicians who can provide professional consultations, medication guidance for their health problems. Traffic and accommodation subsidies will provide for all participants to promote participants retention and complete follow-up. If participants discontinue from follow-up, the reasons will be detailly recorded, their clinical treatment and other rights shall not be affected.
Data Management
Study data will be recorded via the Electronic Data Capture (EDC) system (Nanjing Yike Valtai Information Technology Co., Ltd). Well trained practitioners will log into the website () and input data. The EDC system has the function of automatically checking data format, rules, and range so as to ensure the accuracy of data. Moreover, manually reconfirmation by a third staff is also required. Any change in data recording is permitted and tracked with reasons and date in the EDC system. Additionally, data quality will be under the supervision of a third party. All documents and data will be stored at the institutional office of each study site.
Statistical Method
For primary endpoint, mixed-effect model for repeated measures (MMRM) adjusted with baseline office SBP will be used to compare the group difference of the office SBP changes from baseline to one month. For secondary endpoint, we will also use MMRM method adjusted with mean SBP or heart rate to assess the changes of the mean SBP or heart rate from baseline to each visit point. And LS-means method adjusted with baseline SBP or heart rate will be used to estimate the changes of SBP or heart rate and 95% confident intervals. Imputation for missing values of the main indicator will be conducted using Markov Chain Monte Carlo (MCMC) model which will be performed as the results of sensitive analysis. We predefine an adverse event of laboratory index that is significantly abnormal at follow-up compared with baseline. Detailed presentation of adverse events will be described and explore the relationship with PFM product. The efficacy analyses will be carried out based on the full analysis set and the pre-protocol set. All baseline characteristics analysis will be conducted on the basis of the full analysis set. The safety evaluation will be analyzed from the safety-analysis set. A two-sided P < 0.05 will indicate significance in all statistical analysis used by SAS software V.9.4 (SAS Institute, Cary, NC).
An interim analysis is planned when 50 subjects (100 subjects in total) are enrolled in each group and completed 1 month follow-up, which will be conducted by independent data monitoring committee (IDMC). The purposes of the interim analysis are as follows: 1) to evaluate the safety. A necessary disruption of the study is considered when there are serious or expected adverse events. 2) to assess the efficacy. This trial will be expected to terminate in advance if the hypothesis test P value is less than the boundary value of the interim analyzed α for the primary endpoint. And If the P value is greater than interim analyzed α with statistical power less than 60%, re-estimating the sample size is needed to make the final statistical power greater than 80%. In accordance with O’Brien- Fleming method, the interim analyzed α = 0.005, and final α = 0.048.
Methods: Monitoring
Data monitoring
In order to monitor the trial process and participants safety, an independent data monitoring committee (IDMC) was established. The members from IDMC are the experts from different professional fields, including hypertension management, cardiovascular disease, biostatistics and other fields. IDMC will be served as the role of monitoring the participants safety, efficacy from interim analysis, and quality of the trial. IDMC of this trial is absolutely independent from and has no competing interests with the funder and sponsor. Data and safety monitoring committee meeting will be hold regularly at each study site.
Harms And Auditing
In this study, potential risks of PFM therapy are the thermal damages of local skin, subcutaneous tissue and organs adjacent to perirenal fat. Any discomforts or abnormal indicators changes through energy emission path including skin, muscles, renal area, and intestine, will be identified as adverse events (AEs), and will be recorded in eCRF and EDC system with details of onset time, severity, and duration. The severity of AEs and their correlations with PFM therapy will be carefully evaluated in accordance with the Common Terminology Criteria for Adverse Events[17]. Severe adverse events (SAEs) included deaths, life-threatening disease or injury, permanent damage to body structure or function, and diseases requiring hospitalization treatment that are determined by investigator according to the principles of GCP. Investigators are responsible for dealing with the SAEs to protect the participants as much as possible, and reporting the SAEs to the local ethics committee within 24 hours. AEs will be reported within three days after each visit. All adverse events will be revealed in the trial publication. And the trial will be audited onsite periodically.