Hypertension
Conditions
Keywords
Treatment-resistant hypertension, Renal denervation, Sympathetic nervous system
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.
Interventions
PROCEDURERenal denervation
Renal denervation in the intervention group
Sponsors
KU Leuven
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Parallel group trial
Eligibility
Sex/Gender
ALL
Age
20 Years to 69 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Systolic Blood Pressure From Baseline to 6 Months on 24-h Ambulatory Measurement (Follow-up Minus Baseline Measurement) | The primary endpoint has been assessed 6 months after randomization. | 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. |
| Change in Glomerular Filtration Rate | This endpoint has been assessed 6 months after randomization. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Intensity of Medical Treatment | This endpoint will be assessed 6 months after randomization. | The number and doses of blood-pressure lowering drugs in the 2 arms of the trial. |
Countries
Belgium
Participant flow
Recruitment details
From 28 March 2014 until 11 May 2016, 3 Belgian centers screened 29 patients, of whom 4 did not meet the criteria to enter the run-in period. Of 25 remaining patients, 8 were not eligible for randomization. Of 17 eligible patients, 9 were randomized to control and 8 to RDN. Of the 8 patients randomized to intervention, two did not undergo RDN.
Participants by arm
| Arm | Count |
|---|---|
| Control Group Standard antihypertensive drug treatment
Renal denervation: Renal denervation in the intervention group | 9 |
| Intervention Group Renal denervation plus standard antihypertensive drug treatment
Renal denervation: Renal denervation in the intervention group | 6 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Intervention Group | Total | Control Group |
|---|---|---|---|
| Age, Continuous | 48.4 years STANDARD_DEVIATION 10.8 | 48.1 years STANDARD_DEVIATION 9.3 | 47.9 years STANDARD_DEVIATION 8.8 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Belgium | 6 participants | 15 participants | 9 participants |
| Sex: Female, Male Female | 3 Participants | 8 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 6 |
| other Total, other adverse events | 0 / 9 | 0 / 6 |
| serious Total, serious adverse events | 0 / 9 | 0 / 6 |
Outcome results
Primary
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.
Time frame: This endpoint has been assessed 6 months after randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control Group | Change in Glomerular Filtration Rate | 81.6 ml/min/1.73 m2 | Standard Deviation 24.1 |
| Intervention Group | Change in Glomerular Filtration Rate | 92.4 ml/min/1.73 m2 | Standard Deviation 15.9 |
Comparison: Difference between control and intervention group at 6 monthsp-value: 0.86t-test, 2 sided
Primary
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.
Time frame: The primary endpoint has been assessed 6 months after randomization.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Control Group | Change in Systolic Blood Pressure From Baseline to 6 Months on 24-h Ambulatory Measurement (Follow-up Minus Baseline Measurement) | 0.7 mmHg |
| Intervention Group | Change in Systolic Blood Pressure From Baseline to 6 Months on 24-h Ambulatory Measurement (Follow-up Minus Baseline Measurement) | -21.7 mmHg |
Comparison: We used mixed models to compare blood pressure changes between randomized groups at 6 months, while adjusting for the baseline blood pressure; statistical significance was a P-value less than 0.05 on two-sided tests.p-value: 0.018Mixed Models Analysis
Secondary
The Intensity of Medical Treatment
The number and doses of blood-pressure lowering drugs in the 2 arms of the trial.
Time frame: This endpoint will be assessed 6 months after randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control Group | The Intensity of Medical Treatment | 4 number of drugs taken per day |
| Intervention Group | The Intensity of Medical Treatment | 3 number of drugs taken per day |
Comparison: Wilcocon rank sum testp-value: 0.032Wilcoxon (Mann-Whitney)
p-value: 0.032Wilcoxon (Mann-Whitney)