Renal Denervation for Management of Drug-Resistant Hypertension

Study Overview
=================
Brief Summary
-----------------
INSPiRED is a multicenter parallel-group trial comparing usual medical treatment (control group) or usual medical treatment plus renal denervation (intervention). In both groups adherence will be monitored both before randomization and during 36 months of follow-up.

Detailed Description
-----------------
Objectives: To compare the blood pressure lowering efficacy and safety of renal denervation vs. usual medical therapy. The primary endpoints for efficacy and safety are the baseline-adjusted between-group differences in 24-h systolic blood pressure and in glomerular filtration rate as estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Secondary endpoints for efficacy and safety include other indexes of blood pressure control and renal function, metabolic variables and morbidity and mortality. These endpoints will be assessed 6 months after randomization. Trial design: Randomized controlled trial with blinded assessment of the primary and secondary endpoints. The study consists of 6 stages. Supervised and nonsupervised follow-up refer to assessment of outcome at or outside the participating center, respectively. Screening involves checking eligibility and ruling out secondary hypertension. Run-in period of 3 months to optimize medical treatment and to assess adherence to treatment. Stratification and randomization Eligible patients will be stratified by center and age group (adults vs. elderly, 20-49 vs. 50-69 years) and randomized centrally in a one-to-one proportion to control or intervention. Renal sympathetic denervation in the intervention group, patients of the control group will be offered renal denervation after 6 months. Supervised follow-up at 1, 3 and 6 months after randomization. Long-term supervised or non-supervised follow-up of morbidity and mortality beyond 6 months and up to 3 years. Sample size: To detect a 10-mm Hg difference (SD 20 mm Hg) in systolic blood pressure between the randomized groups with a 2-sided P-value of 0.01 and 90% power in total 240 patients need to be randomized. Allowing 50% screening failures, 480 patients would have to be screened. Assessment of adherence: Adherence to treatment will be assessed by measurement of drugs or drug metabolites in biological fluids. Jung and coworkers developed a liquid chromatography-mass spectrometric method that allows detecting all antihypertensive drugs or their metabolites in a single urine sample. This obligatory approach will be implemented. Assessment of quality of life Assessment of quality of life is compulsory at baseline and at each visit during the supervised follow-up, using the EuroQol 5D. Assessment of sympathetic modulation: heart rate variability (HRV) will be assessed at baseline and at the 6-month follow-up visit, based on 15 minutes ECG recordings. A software program, developed in LabVIEW by the group of Aubert et al. will be used. Relevance: INSPiRED differs from previous and ongoing studies in several aspects: (1) a stringent selection of patients; (2) drug optimization with assessment of adherence throughout the study; (3) out-of-the-office blood pressure for patient selection and follow-up; (4) state-of-the-art renal artery imaging by computerized tomographic angiography; (5) validation of urinary proteomic biomarkers to predict blood pressure responses and changes in renal function; (6) follow-up will be beyond 6 months up to 3 years; (7) use of heart rate variability and renal nerve stimulation to assess the completeness of renal denervation.

Official Title
-----------------
Investigator-Steered Project on Intravascular Renal Denervation for Management of Drug-Resistant Hypertension

Conditions
-----------------
Hypertension

Intervention / Treatment
-----------------
* Procedure: Renal denervation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Women and men are eligible. Women of reproductive age should apply effective contraception. Age ranges from 20 years (inclusive) to less than 70 years. Patients should have essential hypertension. Treatment-resistant hypertension in patients taking a stable drug regimen for at least 4 weeks consisting of 3 or more antihypertensive medications from different classes, including a diuretic. Under maximal therapy, office blood pressure should be ≥140/90 mmHg and the 24-h ambulatory blood pressure should be 130 mm Hg systolic or 80 mm Hg diastolic or higher. eGFR must be ≥ 60 mL/min/1.73 m2. The patients should accept to have adherence checked before randomisation and during supervised follow-up, but both patients and doctors will remain blinded to the results; Informed written consent. Exclusion criteria: Suboptimal clinical context, because of recent history or concurrent disease. Isolated systolic and diastolic hypertension. Body-mass index ≥ 40kg/m2. The anatomy of the renal arteries is suboptimal for renal denervation. Pregnancy. Alcohol or substance abuse or psychiatric illnesses. Participation in other study. The clinical context is suboptimal for renal denervation.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 69 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel group trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Control group<br>Standard antihypertensive drug treatment | Procedure: Renal denervation<br>* Renal denervation in the intervention group<br>* Other names: Renal denervation, using an intravascular catheter system;|
| Experimental: Intervention group<br>Renal denervation plus standard antihypertensive drug treatment | Procedure: Renal denervation<br>* Renal denervation in the intervention group<br>* Other names: Renal denervation, using an intravascular catheter system;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Systolic Blood Pressure From Baseline to 6 Months on 24-h Ambulatory Measurement (Follow-up Minus Baseline Measurement) | The primary endpoint deals with efficacy of renal denervation with regard to controlling blood pressure on ambulatory measurement. It consists of the baseline-adjusted between-group difference in the changes in 24-h systolic blood pressure. Because automated blood pressure monitors will be used, the assessment of the primary endpoint is blind. | The primary endpoint has been assessed 6 months after randomization. | 
| Change in Glomerular Filtration Rate | The primary endpoint for safety of renal denervation is the baseline-adjusted between group difference in the change of glomerular filtration rate estimated by using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. | This endpoint has been assessed 6 months after randomization. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Intensity of Medical Treatment | The number and doses of blood-pressure lowering drugs in the 2 arms of the trial. | This endpoint will be assessed 6 months after randomization. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Treatment-resistant hypertension, Renal denervation, Sympathetic nervous system