The objective of this study is to evaluate safety and blood pressure response after renal denervation in patients with uncontrolled hypertension compared to a sham-controlled population, in the absence of antihypertensive medications. These data,…
ID
Source
Brief title
Condition
- Vascular hypertensive disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The following safety endpoints will be evaluated:
* Acute safety (up to 30 days post-procedure) and chronic safety at 3, 6, 12,
24 and 36 months post-procedure
* Incidence of Major Adverse Events (MAE), defined as a composite of the
following events, compared between groups through 4 weeks post procedure:
o All-cause mortality
o End-stage Renal Disease (ESRD)
o Significant embolic event resulting in end-organ damage
o Renal artery perforation requiring intervention
o Renal artery dissection requiring intervention
o Vascular complications
o Hospitalization for hypertensive crisis not related to confirmed
non-adherence with medications or the protocol.
o New renal artery stenosis > 70%, confirmed by angiography
o New Myocardial Infarction
o New Stroke
o Renal artery re-intervention
o Major bleeding according to TIMI definition (i.e. intracranial hemorrhage;
*5g/dl decrease in hemoglobin concentration, a*15% absolute decrease in
hematocrit, or death due to bleeding within 7 days of the procedure)
o Increase in serum creatinine > 50% from Screening Visit 2
The following efficacy endpoints will be evaluated:
* Change in systolic blood pressure (SBP) from baseline (Screening Visit 2) as
measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM) at 3, 6, 12, 24
and 36 months post-procedure.
* Change in office systolic blood pressure from baseline (Screening Visit 2) at
1, 3, 6, 12, 24 and 36 months post-procedure.
* Incidence of achieving target office systolic blood pressure (SBP <140 mmHg
or <130 mmHg for patients with diabetes or renal disease) at 1, 3, 6, 12, 24
and 36 months post-procedure.
* Change in office diastolic blood pressure from baseline (Screening Visit 2)
at 1, 3, 6, 12, 24 and 36 months post-procedure.
* Change in diastolic blood pressure from baseline (Screening Visit 2) as
measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM) at 3, 6, 12, 24
and 36 months post-procedure.
Secondary outcome
The following additional analyses will be conducted:
* Antihypertensive medication usage through 36 months.
* Additional procedural characteristics e.g. treatment duration, frequency of
distal renal artery treatment, ablations per vessel, location of ablations,
number of ablations per patient and other characteristics will be analyzed to
assess their impact on blood pressure.
Background summary
The kidneys are an important regulator of blood pressure and it is thought that
in patients whose blood pressure cannot be
controlled, there is increased activity in the nervous system between the brain
and kidney which results in the kidneys releasing an
excessive amount (more than normal) of hormones that raises blood pressure.
Medications alone may not be effective in
controlling blood pressure. Previous research has shown that disrupting certain
nerves may decrease blood pressure in some
cases. In the past, one technique that was used to treat severe high blood
pressure was a surgical procedure to cut nerves.
However, this surgery is no longer commonly performed, because it was a complex
invasive procedure.
This clinical research study will provide additional information about the
safety and effect of renal denervation on blood pressure, without the
confounding presence of antihypertensive medications, using the Symplicity
Spyral* catheter and G3* generator, compaired to a placebocontrolled group.
These data, obtained without the confounding presence of antihypertensive
medications, in conjunction with the data generated in the companion on
medications study (SPYRAL HTN-ON MED), will help determine whether commonly
used antihypertensive medications synergize, antagonize, or have no impact on
the effect of renal denervation on elevated blood pressure. These data,
combined with the data from the SPYRAL HTN-ON MED study, are important for
determining the design of a pivotal renal denervation study.
Study objective
The objective of this study is to evaluate safety and blood pressure response
after renal denervation in patients with uncontrolled hypertension compared to
a sham-controlled population, in the absence of antihypertensive medications.
These data, obtained without the confounding presence of antihypertensive
medications, in conjunction with the data generated in the companion on
medications study (SPYRAL HTN-ON MED), will help determine whether commonly
used antihypertensive medications synergize, antagonize, or have no impact on
the effect of renal denervation on elevated blood pressure. These data,
combined with the data from the SPYRAL HTN-ON MED study, are important for
determining the design of a pivotal renal denervation study.
Study design
Multi-center, international, prospective, single blinded, 1:1 randomized,
interventional, sham-controlled study.
Intervention
Following Screening Visit 1 (SV1), eligible subjects will undergo a minimum of
three and a maximum of four weeks antihypertensive medication washout period.
If at any time the SBP is *180 mmHg, the subject will return within 72 hours
for a repeat BP assessment. If the SBP remains *180 mmHg, the subject will be
exited from the study and antihypertensive medication restarted at the
investigators discretion. Subjects who continue to meet eligibility criteria
will return for Screening Visit 2 (SV2). Subjects who were not previously
treated with antihypertensive medications will also return for Screening Visit
2 within three to four weeks. Subjects who continue to meet eligibility
criteria after completion of Screening Visit 2 and who have received
randomization approval by the Sponsor will be randomized. The renal denervation
or control procedure will occur within a maximum of two weeks following
Screening Visit 2. All efforts should be undertaken to schedule the procedure
within one week of Screening Visit 2.
Following the renal denervation or control procedure, subjects will be followed
at 2, 4, 6, 8, 10 and 12 weeks post-procedure. Subjects with an office SBP *180
mmHg at any time from randomization up to the 3 month visit will be seen within
72 hours for a repeat office BP. If the subject*s office SBP remains *180 mmHg,
the subject will be put back on an antihypertensive medication regimen per the
investigator*s discretion. The subject will be exited from the off medications
portion of the study and will be followed according to instructions listed in
Table 3 of the protocol. At the three months follow-up, after office and
ambulatory blood pressure measurements are obtained, subjects will be titrated
back onto standard medical therapy according to Section F.9. All subjects will
return for follow-up at 6 months and 12 months. Subjects and blinded study
personnel will be unblinded to the randomization assignment at 12 months.
Subjects randomized to renal denervation will continue to be followed annually
through 36 months post-procedure (Table 1 of the protocol). Subjects randomized
to the control group will not be required to return annually for office visits,
but will be contacted by phone at 24 and 36 months to obtain vital status only.
After the study blinded period (i.e., 12-Month subject follow-up visits are
completed), the study sponsor will review preliminary study data. If the
outcomes in the Denervation Group are considered to be positive as determined
by the study sponsor in consultation with the study Executive Steering
Committee and Site Investigator, control subjects may be offered renal
denervation therapy (crossover) after meeting key inclusion criteria and no key
exclusion criteria. In this case, crossover subjects will return for office
visits at 1, 6, 12 and 24 months post-renal denervation procedure (Table 2 of
the protocol).
Study burden and risks
Standard treatment in The Netherlands is prescribing antihypertensive
medication for these hypertensive patients. There is no alternative treatment
for patients with uncontrolled hypertension that is reimbursed by the health
insurance. Renal denervation is an alternative which is not yet reimbursed in
The Netherlands. For this study, patients are not allowed to take
antihypertensive medications up to the 3 months follow up visit, after which
they will be titrated back on hypertensive medication. As described in E9, the
risks for the OFF med period will not be different than the risks associated to
the 6 months of uncontrolled hypertension. The possible positive effect of the
renal denervation on the bloodpressure will outweigh the risks.
This study follows the guidelines that have been recommended for the follow up
visits/care for the renal denervation. This study adds aditional contact
moments up to the 3 months visit, to carefully monitor the bloodpressure and
patients' safety and adverse events, while the patient isn't taking any
antihypertensive medication.
Additionally, patients will undergo drug adherence tests to see if they are
compliant to the medication regimen (not taking antihypertension meds up to 3
months visit and taking the meds as of 3 months visit). In a previous trial the
medication intake incompliance of the patients was one of the problems that may
have let to insignificant data.
Furthermore, pregnancy tests will be performed to exclude patients that are
pregnant prior to the procedure, as it is unclear what the consequences are for
the unborn child. Also a quality of life questionnaire needs to be completed,
which will not be a big burden for the patient.
There is an extended risk-benefit analysis report available, in which all risks
and benefits have been described. See the SPYRAL HTN-OFF MED Study Risk Benefit
Analysis version 2, 23 April 2015. To summarize:
The risks associated with participation in this study are devided in
1) Anticipated Risks for the Symplicity Spyral Renal Denervation System
2) Procedural risk
3) Study Specific risks
The primary risks of the renal denervation procedure are similar to the risks
of all diagnostic procedures requiring catheterization of the arteries of the
body. Catheterization risks are considered low with most occurring in less than
1% of patients. Complication rates associated with medications and the catheter
insertion site are expected to be higher than 1%, but less than 10%, based on
historical precedence.
There are additional risks that could possibly be associated with the
denervation procedure/therapy. Procedural risks are low with rates similar to
catheterization referenced above.
Renal denervation involves exposure to a small amount of radiation. As part of
everyday living, people are exposed to naturally occurring background radiation
and receive a dose of about 3 mSv each year. The effective dose from the
denervation procedure is about 8 mSv. The dose from this procedure is
comparable to that received from many diagnostic medical x-ray and nuclear
medicine procedures.
The study may involve unknown or unforeseen side effects or complications other
than those mentioned above. If the above complications occur, they may lead to
repeat or prolonged hospitalization, repeat procedures, emergency surgery,
other emergency procedures, or, in rare
cases, death.
There are additional risks that could possibly be associated with the tests and
procedures performed for the clinical study, like risks related to the blood
tests required for the study, renal imaging (MRA/CT when no DUS can be made or
inconclusive DUS) and risks related to the unborn child.
The data presented in the answers to BfArM questions support that the risks
associated with not having a controlled blood pressure during the first 6
months of the study and the risks associated with being off antihypertensive
medications for approximately 4 months are no different from the subject*s risk
of these events had they not participated in this study.
The detrimental effects of uncontrolled hypertension and the issues of drug
adherence to prescribed medications are well established and an alternative
treatment is worth of continued study. Renal denervation using the Symplicity
SpyralTM catheter and Symplicity G3TM generator is one such alternative.
Although there are several theoretical risks that could be associated with the
device and procedure, the likelihood of those risks is expected to be low and
will be carefully monitored in the study. The potential benefits, including
blood pressure reduction in these uncontrolled hypertension patients and the
associated beneficial effects of lowered blood pressure in these patients
outweigh the risks and justify the investigation of renal denervation in this
study.
Endepolsdomein 5
Maastricht 6229 GW
NL
Endepolsdomein 5
Maastricht 6229 GW
NL
Listed location countries
Age
Inclusion criteria
1. Individual is * 20 and * 80 years old at time of randomization.
2. Individual has an office systolic blood pressure (SBP) * 150 mmHg and <180 mmHg and an office DBP *90 mmHg measured at Screening Visit 2, according to the guidelines in Appendix L.7 of the protocol.
3. Individual has a 24-hour Ambulatory Blood Pressure Monitoring (ABPM) average SBP *140 mmHg and <170 mmHg measured at Screening Visit 2 according to guidelines in Appendix L.7 of the protocol.
4. Individual agrees to have all study procedures performed, and is competent and willing to provide written, informed consent to participate in this clinical study.
5. Individual is willing to discontinue current antihypertensive medications at Screening Visit 1 through the three month post-procedure visit.
Exclusion criteria
1. Individual has undergone prior renal denervation.
2. Individual has renal artery anatomy that is ineligible for treatment including:
a. Lacks at least one renal arterial vessel for each kidney greater than 3 mm and less than 8 mm in diameter (including accessory, branch, and main renal arteries)
b. Main renal artery which contains renal artery stenosis (>50%), renal artery aneurysm, fibromuscular dysplasia (FMD), presence of a renal artery stent or calcification which does not allow at least four radio frequency ablations to be delivered in areas free of these abnormalities. FMD is defined as visible beading of the artery on angiography.
c. Unilateral kidney.
3. Individual has an estimated glomerular filtration rate (eGFR) of <45 mL/min/1.73m2, using the MDRD calculation. (Note: an eGFR calculation specific to Japanese patients will be used for subjects enrolled in Japan)
4. Individual has documented type 1 diabetes mellitus or poorly-controlled type 2 diabetes mellitus with glycosylated hemoglobin greater than 8.0%.
5. Individual has had *1 episode(s) of orthostatic hypotension not related to medication changes within the past year or has a reduction of SBP of *20 mmHg or DBP of *10 mmHg within 3 minutes of standing coupled with symptoms during the screening process.
6. Individual requires chronic oxygen support or mechanical ventilation other than nocturnal respiratory support for sleep apnea (e.g. CPAP, BiPAP).
7. Individual is being treated chronically (e.g. daily use) with non-steroidal anti-inflammatory drugs (NSAIDs). Aspirin therapy is allowed.
8. Individual has documented primary pulmonary hypertension.
9. Individual has known pheochromocytoma, Cushing*s Disease (adrenal insufficiency), coarctation of the aorta, untreated hyper- or hypothyroidism, or primary hyperparathyroidism. (Note: treated hyperthyroidism and treated hypothyroidism are permissible).
10. Individual has experienced a myocardial infarction, unstable angina pectoris, syncope, or a cerebrovascular accident within three months of the screening period, or has widespread atherosclerosis, with documented intravascular thrombosis or unstable plaques.
11. Individual has a scheduled or planned surgery that, in the opinion of the Investigator, may affect study endpoints.
12. Individual has a documented condition that would prohibit or interfere with ability to obtain an accurate blood pressure measurement using the protocol-specified automatic blood pressure monitor (e.g., upper arm circumference outside cuff size ranges available by geography or arrhythmia that interferes with automatic monitor*s pulse sensing and prohibits an accurate measurement).
13. Individual works night shifts.
14. Individual has severe cardiac valve stenosis for which, in the opinion of the investigator, a significant reduction of blood pressure is contraindicated.
15. Individual has a documented confounding medical condition, which in the opinion of the investigator, may adversely affect the safety of the participant (e.g., patients with clinically significant peripheral vascular disease, aortic aneurysm, bleeding disorders such as thrombocytopenia, hemophilia, or significant anemia).
16. Individual is pregnant, nursing or planning to become pregnant during the course of the study follow-up. (Note: Pre-menopausal female participants must have a negative serum or urine human chorionic gonadotropin (hCG) pregnancy test prior to angiography).
17. Individual has a known unresolved history of drug use or alcohol dependency, lacks the ability to comprehend or follow instructions, or would be unlikely or unable, in the opinion of the investigator, to comply with study follow-up requirements.
18. Individual is currently enrolled in a concurrent investigational drug or device study, unless approved by the study sponsor. (Note: For the purpose of this protocol, participants involved in extended follow-up studies for products that were investigational but are currently commercially available are not considered enrolled in an investigational study).
19. Individual is currently taking mineralocorticoid drugs.
20. Individual has an active peptic ulcer or upper gastrointestinal (GI) bleeding within the prior six months.
21. Individual has a history of bleeding diathesis or coagulopathy or will refuse blood transfusions.
22. Individual has polycystic kidney disease or history of renal transplant.
23. Individual is taking medications that impact blood pressure for one or more of the following conditions: coronary artery disease, myocardial infarction, heart failure, unstable angina, cerebrovascular accident or transient ischemic attack, or atrial fibrillation.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT02439749 |
| CCMO | NL53372.041.15 |