Clinical trial NCT06559891: THRIVE- THerapeutic IntravasculaR Ultrasound (TIVUS™) REnal Denervation System Versus Sham for the Adjunctive Treatment of Hypertension
Official title: A Pivotal, Prospective, Multicenter, 2:1 Randomized, Double Blind, Controlled, Study Comparing the THerapeutic IntravasculaR Ultrasound (TIVUS™) REnal Denervation System Versus Sham for the Adjunctive Treatment of Hypertension (The THRIVE Study)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Hypertension
Lead sponsor: SoniVie Inc.
Sponsor class: INDUSTRY
Collaborators: name: NAMSA
name: European Cardiovascular Research Center
First posted: 2024-08-19
Enrollment: 261
Sex: ALL
Minimum age (years): 22
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 2:1 randomization will be used to assign subjects to treatment (RDN) or control (sham). Randomization will occur immediately after the renal angiogram.
Primary purpose: TREATMENT

Brief summary: The primary objective of the THRIVE Pivotal study is to demonstrate the adjunctive effectiveness and the safety of the TIVUS system in:

1. subjects with hypertension (HTN) receiving up to 2 anti-hypertensive drugs of different classes in whom the anti-hypertensive medications will be stopped for a 4-week wash-out period before RDN/Sham procedure and during 2 months after procedure.
2. subjects with controlled hypertension receiving up to 2 anti-hypertensive drugs of different classes and who accept to be off-medications for a 4-week wash-out period before RDN/Sham procedure and 2 months after the procedure

Detailed description: THRIVE is an international, multicenter, randomized, double blind, sham-controlled study, designed to demonstrate the adjunctive effectiveness and safety of the TIVUS System in hypertensive subjects while subjects are maintained off-antihypertensive medications for a 4-week wash-out period before RDN/Sham procedure and 2 months after procedure. At two months after procedure, subjects with uncontrolled hypertension are put back on antihypertensive medication according to a medication escalation protocol. Unblinding will be performed at 6 months. Uncontrolled sham subjects can cross-over to RDN procedure at 6-months. The sham procedure will be minimally invasive to reduce risk to subjects. All subjects treated with TIVUS will be followed for a maximum of 36 months post procedure.

Eligibility criteria: Inclusion Criteria:

1. Appropriately signed and dated informed consent
2. Male and female adults with age between ≥22 and ≤75 years at time of consent
3. Documented history of hypertension
4. Previously or currently prescribed antihypertensive therapy
5. Subject has an office BP (average of 3 seated measurements) of:

   1. Uncontrolled BP: ≥ 140/90 mmHg \<180/110 mmHg at Screening Visit (V0) while stable for at least 4 weeks on 0-2 anti-hypertensive medications of different classes\* and willing to stop anti-hypertensive medication(s) for 4 weeks wash-out and 2-months post-procedure, (subjects with a history of treatment with anti-hypertensive medications but are not currently taking any at screening will undergo a 4-week run-in period) or,
   2. Controlled BP: \< 140/90 mmHg while stable for at least 4 weeks on 1-2 antihypertensive medications of different classes and willing to stop anti-hypertensive medication(s) for 4 weeks wash-out and 2-months post-procedure
6. Able and willing to comply with all study procedures
7. Subject is willing to have and is a good candidate for conscious sedation

Subjects who meet the following criteria will be considered eligible for randomization:

* Documented daytime systolic ABP ≥ 135 mmHg and \< 180 mmHg after 4-week washout/run-in period.\*\*
* Suitable renal anatomy compatible with the renal denervation procedure, documented by renal CTA or MRA of good quality performed within one year prior to consent (a CTA or MRA will be obtained in subjects without a recent (≤1 year) cross-sectional renal imaging). The renal angiogram procedure done in the cath lab prior to randomization will serve as the final anatomy compatibility check.

  * Potassium-sparing diuretics such as Amiloride hydrochloride and Triamterene may be prescribed in combination with another diuretic (e.g. a thiazide or loop diuretic) for their potassium conservation properties. In this situation, the diuretic combination is considered as a single class of anti-hypertensive.

Exclusion Criteria:

1. Subject has been previously diagnosed with abnormal renal artery anatomy and/or renal anatomy such as a single kidney, ectopic or horseshoe kidney, polycystic kidney disease, kidney tumors or other findings precluding renal denervation therapy as detailed in the angiographic exclusion criteria
2. Uncorrected causes of secondary hypertension other than sleep apnea (including, but not limited to): aldosteronism, renal parenchymal disease, renovascular disease, excess catecholamines, Cushing's syndrome, erythropoietin use, pheochromocytoma, hypo/hyperthyroidism, hyperparathyroidism, acromegaly)
3. Type I diabetes mellitus or uncontrolled Type II diabetes (defined as a plasma HbA1c ≥ 9.0%)
4. eGFR of \<40 mL/min/1.73 m2 CKD-EPI as calculated using the CKD-EPI 2021 equation
5. Cerebrovascular event (e.g. stroke, transient ischemic event, cerebrovascular accident) within 6 months prior to consent
6. History of severe cardiovascular event (e.g. myocardial infarction, unstable angina, CABG, acute heart failure requiring hospitalization (NYHA III-IV) within 12 months prior to consent
7. Subject has severe valvular stenosis or insufficiency
8. Documented repeat (\>1) hospitalization for hypertensive crisis within the prior 12 months and/or any hospitalization for hypertensive crisis within three (3) months prior to consent
9. Prescribed to any standard antihypertensive cardiovascular medication (e.g. beta blockers) for other chronic conditions (e.g. ischemic heart disease) such that discontinuation might pose serious risk to health in the opinion of the investigator
10. Subject with rapid, uncontrolled, symptomatic atrial fibrillation
11. Active implantable medical device (e.g. ICD or CRT-D; neuromodulator/spinal stimulator; baroreflex stimulator)
12. Chronic oxygen support or mechanical ventilation other than nocturnal respiratory support for sleep apnea.
13. Subject has a planned major surgery (any procedure requiring general anesthesia) in the next 12 months.
14. Subject on anticoagulant therapy that cannot be temporarily withheld for study procedure.
15. Primary pulmonary hypertension
16. Documented contraindication or allergy to contrast medium not amenable to treatment
17. Limited life expectancy of \< 1 year at the discretion of the Investigator
18. Night shift worker
19. Subject has frequent intermittent or chronic pain that results in treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) for two or more days per week over the month prior to enrollment.
20. Subject is taking immunosuppressive therapy for diseases featuring vasculitis
21. Any known, unresolved history of drug use or alcohol dependency, lacks the ability to comprehend or follow instructions, or for any reason in the opinion of the investigator, would be unlikely or unable to comply with study protocol requirements or whose participation may result in data analysis confounders
22. Pregnant, nursing or planning to become pregnant within 12 months post procedure.

    Negative pregnancy test required, documented within a maximum of 7 days prior to procedure for all women of childbearing potential. Documentation of effective contraception is also required for women of childbearing potential
23. Subject has a planned major surgery or cardiovascular intervention in the next 6 months
24. Subject with history of renal transplantation
25. Evidence of active infection within 7 days of procedure (based on positive lab test and requiring therapy).
26. Subject has hypertrophic cardiomyopathy or amyloidosis.
27. Prior renal denervation procedure
28. Concurrent enrollment in any other investigational drug or device trial (participation in non-interventional studies/registries is acceptable)
29. Subject on a beta blocker for a condition other than antihypertension

Angiographic Exclusion Criteria:

The following characteristics identified either on the renal artery CT scan or MRI or on the Eligibility II Renal artery Angiogram will prevent the subject from being included:

1. Main renal arteries lumen diameter \< 4 mm.
2. Main renal treatable artery length \<20mm (may include proximal branching).
3. Accessory renal arteries that supplies ≥ 25% of the parenchyma, and \< 4 mm in lumen diameter.
4. Aorto-renal angle that prevents a safe cannulation of the renal artery.
5. Severe common femoral artery, common and/or external iliac artery, renal, iliac or aortic calcification or tortuosity that may compromise the safe performance and completion of the TIVUS™ procedure.
6. Hemodynamically or anatomically significant renal artery abnormality or stenosis in either renal artery which, would interfere with safe cannulation of the renal artery or meets local standards for surgical repair or interventional dilation (NOTE: vessel areas with calcification and fibromuscular dysplasia (FMD) should be avoided as intended treatment areas).
7. Any renal artery stenosis \> 30% by visual assessment.
8. Any renal artery aneurysm (\>50% of the main renal artery reference vessel diameter by visual estimate).
9. Presence of fibromuscular dysplasia of the renal arteries
10. Significant renal artery atheroma, aneurysm, calcification in the target vessel identified on CT Angiogram

Primary outcomes:
measure: Reduction in average daytime ambulatory systolic BP
timeFrame: From baseline to 2 months post-procedure
measure: Subject level composite of the incidence of Major Adverse Events (MAE)
timeFrame: From Baseline to 30 day and 6 months post procedure
Secondary outcomes:
measure: Reduction in average 24-hr ambulatory systolic BP
timeFrame: From baseline to 2 Months post procedure
measure: Reduction in average home systolic BP
timeFrame: From baseline to 2 Months post procedure
measure: Reduction in average office systolic BP
timeFrame: From baseline to 2 Months post procedure
measure: Reduction in average daytime ambulatory diastolic BP
timeFrame: From baseline to 2 Months post procedure
measure: Reduction in average 24-hr ambulatory diastolic BP
timeFrame: From baseline to 2 Months post procedure
measure: Reduction in average home diastolic BP
timeFrame: From baseline to 2 Months post procedure
measure: Reduction in average office diastolic BP
timeFrame: From baseline to 2 Months post procedure
measure: Percentage of subjects with Systolic Blood Pressure (SBP) at target (daytime SBP <135 mmHg; office SBP <140
timeFrame: From baseline to 2 and 6 Months post procedure
measure: Percentage of subjects with SBP at target (daytime SBP <135 mmHg; office SBP <140 mmHg) in the absence of. changes in hypertensive medication in each arm
timeFrame: From baseline to 2 and 6 Months post procedure
measure: Incidence of ambulatory systolic BP (daytime/24-hr/night-time) reductions of ≥5 mmHg, ≥10 mmHg, and ≥15 mm Hg
timeFrame: From baseline to 2, 6, and 12 Months post procedure
Other outcomes:
measure: Reduction in average night-time ambulatory systolic/diastolic BP
timeFrame: From baseline to 2, 6 and 12, Months post procedure
measure: Reduction in average daytime & 24-hr ambulatory systolic BP at 6- and 12-months post procedure.
timeFrame: From baseline to 6 and 12 Months post procedure
measure: Reduction in average daytime & 24-hr ambulatory diastolic BP
timeFrame: From baseline to 6 and 12 Months post procedure
measure: Reduction in average office systolic BP
timeFrame: From baseline to 6 and 12 Months post procedure
measure: Reduction in average home systolic/diastolic BP
timeFrame: From baseline to 1, 3, 4, 5, 6, and 12-Months post procedure
measure: Reduction in office and ambulatory pulse pressure
timeFrame: From baseline to 2, 6 and 12 Months post procedure
measure: Reduction in office and ambulatory heart rate
timeFrame: From baseline to 2, 6, and 12 Months post procedure
measure: Antihypertensive medication burden (number of antihypertensive drugs, doses, classes)
timeFrame: From baseline to 2, 6 and 12 Months post procedure
measure: Percentage of subjects meeting escape criteria
timeFrame: From baseline to 2 Months post procedure
measure: Percentage of subjects requiring initiation of antihypertensive drug therapy
timeFrame: From baseline to 2 and 6 Months post procedure
measure: Percentage of subjects without any antihypertensive treatment
timeFrame: From baseline to 6 and 12 Months post procedure
measure: Percentage of subjects requiring initiation of anti-hypertensive drug therapy at any available time points post procedure
timeFrame: From baseline through completion of study
measure: Change in adherence to medications assessed by urine chemical adherence testing using liquid chromatography with tandem mass spectrometry (LCMSMS)
timeFrame: From baseline to 2, 6, 12, 24 and 36 Months.
Locations:
city: Birmingham
country: United States
facility: Cardiology, PC
state: Alabama
city: Scottsdale
country: United States
facility: Honor Health Research Institue
state: Arizona
city: Jonesboro
country: United States
facility: Cardiology Associates Research Group
state: Arkansas
city: Little Rock
country: United States
facility: Arkansas Heart Hospital
state: Arkansas
city: Los Angeles
country: United States
facility: Cedar-Sinai Medical Center
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Springfield
country: United States
facility: Southern Illinois University, School of Medicine
state: Illinois
city: Houma
country: United States
facility: Cardiovascular Institute of the South
state: Louisiana
city: Reno
country: United States
facility: Renown Regional Medical Center
state: Nevada
city: New York
country: United States
facility: Nyph/Cumc
state: New York
city: Raleigh
country: United States
facility: NC Heart and Vascular
state: North Carolina
city: Fort Worth
country: United States
facility: Medical City
state: Texas
city: Houston
country: United States
facility: Houston Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: St Marks Hospital
state: Utah
city: Richmond
country: United States
facility: Chippenham Hospital
state: Virginia
Study officials:
affiliation: Columbia University
name: Ajay Kirtane, MD
role: STUDY_CHAIR
affiliation: George Pompidou Hospital
name: Michel Azizi, MD
role: STUDY_CHAIR
affiliation: University of Basel
name: Felix Mahfoud, MD
role: STUDY_CHAIR
References: