Introduction
Methods
Program overview
Trial design
Inclusion criteria |
Age 20–80 years at enrolment |
Office SBP < 180 mm Hga,b |
Office SBP ≥ 150 mm Hga,c |
Office DBP ≥ 90 mm Hga,c |
24 h ABPM average SBP ≥ 140 mm Hg and < 170 mm Hgd−f |
SPYRAL HTN-OFF MED Pivotal only: willing to discontinue current antihypertensive medications at Screening Visit 1 through the 3-month post-procedure visit |
Agrees to have all study procedures performed, is competent and willing to provide written informed consent |
Exclusion criteria |
Undergone prior renal denervation |
Renal anatomy that is ineligible for treatment |
Main renal artery for each kidney is < 3 mm or > 8 mm |
Lack of main renal arterial vessel that does not allow four simultaneous quadratic ablations in main renal artery or equivalent |
Presence of fibromuscular dysplasia |
> 50% stenosis in any treatable vessel |
Renal artery stent placed < 3 months prior to denervation procedure |
Presence of aneurysm defined as any localized increase in vessel diameter |
Treatment area within 5 mm segment in the renal artery contains an atheroma, calcification, or renal artery stent |
eGFR < 45 mL/min/1.73 m2, using the 4-variable MDRD calculationg |
Taking SGLT2 inhibitors or GLP-1 agonists that have been prescribed < 90 days prior to Screening Visit 1 or without plan to remain on those medications for duration of trial |
≥ 1 episode of orthostatic hypotension not related to medication changes within the past year or a reduction in SBP ≥ 20 mm Hg or DBP ≥ 10 mm Hg within 3 min of standing coupled with symptoms during the screening process |
Requires chronic oxygen support or mechanical ventilation (other than nocturnal respiratory support for sleep apnea) |
Documented primary pulmonary hypertension |
Untreated secondary cause of hypertension (known or suspected) or taking medications that increase sympathetic tone that could contribute to hypertension |
Frequent intermittent or chronic pain that results in treatment with NSAIDs for ≥ 2 days per week over the month prior to enrollment (aspirin and clopidogrel permitted for cardiovascular risk reduction) |
HIV on anti-retroviral drug therapy but without documentation that hypertension preceded initiation of anti-retroviral drug therapy |
SPYRAL HTN-OFF MED Pivotal: history of myocardial infarction, stable or unstable angina, transient ischemic attack, cerebrovascular accident, heart failure, or atrial fibrillation within 3 months of enrolment |
SPYRAL HTN-ON MED Expansion: History of myocardial infarction, unstable angina pectoris, syncope, transient ischemic attack, or a cerebrovascular accident within 3 months of the screening period, or widespread atherosclerosis with documented intravascular thrombosis or unstable plaques |
Peptic ulcer or gastrointestinal bleeding within 6 months before consent |
History of bleeding diathesis or coagulopathy or refuses blood transfusions |
Polycystic kidney disease, unilateral kidney, or history of renal transplant |
Scheduled or planned surgery that may affect study endpoints, in opinion of Investigator |
Documented condition that would prohibit or interfere with ability to obtain an accurate blood pressure measurement (e.g., upper arm circumference outside cuff size ranges available by geography or arrhythmia that interferes with automatic monitor’s pulse sensing) |
Severe cardiac valve stenosis for which a significant reduction of blood pressure is contraindicated, in opinion of investigator |
Documented confounding medical condition that may adversely affect the safety of the subject, in opinion of investigator (e.g., clinically significant peripheral vascular disease or aortic aneurysm) |
Currently prescribed narcotic drugs or methadone |
Currently taking anti-mineralocorticoid medications, unless weaned off by ≥ 8 weeks prior to Screening Visit 1 |
Known unresolved history of drug use or alcohol dependency, lacks ability to comprehend or follow instructions, or would be unlikely or unable to comply with study follow-up requirements |
Currently enrolled in a concurrent investigational drug or device study, unless approved by study sponsor |
Pregnant, nursing or planning to become pregnant during course of the study or follow-up |
Works night shifts |
Screening, randomization, and blinding
Symplicity Spyral catheter
Procedure
Endpoints
Endpoint | Time after index procedure | |
---|---|---|
SPYRAL HTN-OFF MED Pivotal | SPYRAL HTN-ON MED Expansion | |
Powered primary safety endpoint | 1 monthb | 1 monthb |
Incidence of major adverse eventsa | ||
Powered primary efficacy endpoint | 3 months | 6 months |
Baseline-adjusted change from baseline in SBP, measured by 24 h ABPMc | ||
Powered secondary efficacy endpoint | 3 months | NAd |
Baseline-adjusted change from baseline in office SBP | ||
Secondary safety endpoints | 1, 3, 6, 12, 24, and 36 months | 1, 3, 6, 12, 24, and 36 months |
Significant embolic event resulting in end-organ damagee | ||
Renal artery perforation requiring interventione | ||
Renal artery dissection requiring interventione | ||
Vascular complicationse | ||
All-cause mortalityf | ||
End-stage renal disease | ||
≥ 40% decline in eGFR | ||
New myocardial infarction | ||
New stroke | ||
Renal artery reintervention | ||
Major bleeding according to TIMI definitiong | ||
Increase in serum creatinine > 50% from Screening Visit 2 | ||
New renal artery stenosis > 70%h | ||
Hospitalization for hypertensive crisis not related to confirmed non-adherence or the protocol | ||
Composite safety secondary endpointi | 3, 6, 12, 24, and 36 months | 3, 6, 12, 24, and 36 months |
Secondary efficacy endpoints | 1, 3, 6, 12, 24, and 36 months | 1, 3, 6, 12, 24, and 36 months |
Change from baseline in SBP, by 24 h ABPMc,j | ||
Change from baseline in office SBPc | ||
Change from baseline in DBP, by 24 h ABPMc,j | ||
Change from baseline office in DBPc | ||
Incidence of achieving target office SBP (< 140 mm Hg) | ||
Quality-of-life measures | ||
EuroQol-5D | ||
SF-36k |
Safety and quality control
Statistics
Bayesian design and prespecified interim analyses
Determination of sample size and prespecified interim looks
Simulation parameter | SPYRAL HTN-OFF MED Pivotal | SPYRAL HTN-ON MED Expansion | |
---|---|---|---|
Primary efficacy endpoint | Secondary efficacy endpoint | Primary efficacy endpoint | |
Pilot studies | |||
Pilot study treatment arm baseline-adjusted mean/SE | − 5.30/1.65 mm Hg | − 9.69/2.20 mm Hg | − 8.8/1.8 mm Hg |
Pilot study treatment arm N | 35 | 37 | 36 |
Pilot study control arm baseline-adjusted mean/SE | − 0.74/1.62 mm Hg | − 2.54/2.09 mm Hg | − 1.8/1.8 mm Hg |
Pilot study control arm N | 36 | 41 | 36 |
Maximum pilot study subjects | 35 + 36 = 71 | 37 + 41 = 78 | 36 + 36 = 72 |
Pivotal study | |||
Pivotal/prospective study expected treatment difference | 4.0 mm Hg | 6.5 mm Hg | 5.0 mm Hg |
Pivotal/prospective study treatment arm mean/SD | − 4.74/12 mm Hg | − 9.04/16 mm Hg | − 6.8/12 mm Hg |
Pivotal/prospective study control arm mean/SD | − 0.74/12 mm Hg | −2.54/16 mm Hg | − 1.8/12 mm Hg |
Weibull discount function parameters | Shape: k = 3, scale: λ = 0.5 | Shape: k = 3, scale: λ = 0.5 | Shape: k = 3, scale: λ = 0.25 |