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| General |
| Study Status |
Ongoing |
Application Number /
Requirement Number |
P220026 / PAS001 |
| Date Original Protocol Accepted |
11/17/2023
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| Date Current Protocol Accepted |
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| Study Name |
SPYRAL HTN-OFF MED and HTN-ON MED Cont f/u studies
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| Device Name |
Symplicity Spyral™ Renal Denervation System
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| Clinical Trial Number(s) |
NCT02439749 NCT02439775 NCT04311086 NCT05198674
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| General Study Protocol Parameters |
| Study Design |
Randomized Clinical Trial
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| Data Source |
Sponsor Registry
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| Comparison Group |
Concurrent Control
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| Analysis Type |
Analytical
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| Study Population |
Adult: At least 22 yrs
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| Detailed Study Protocol Parameters |
| Study Population |
Device only
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| Sample Size |
up to 200
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| Key Study Endpoints |
• Office and ambulatory blood pressure
• Renal imaging
• Adverse events
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| Follow-up Visits and Length of Follow-up |
5 years post procedure
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| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
337 randomized subjects (206 to Denervation group and 131 to Sham Control group)
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| Actual Number of Sites Enrolled |
56
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| Patient Follow-up Rate |
In the RDN group through 36 months, there were 9 withdrawals and 2 deaths. Of the 195 RDN subjects eligible at 36 months, 79% (155/195) completed 24-hour BP measurement and 90% (175/195) completed Office BP measurement.
In the Sham Control group, through 36 months there was a total of 85 subject crossovers, 6 withdrawals and 1 death. Of the remaining 39 subjects eligible at 36 months, 77% (30/39) completed 24-hour BP measurement and 82% (32/39) completed Office BP measurement.
Twelve (12) additional subjects from the Sham Control arm crossed over after 36 months for a total 97 crossover subjects.
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| Final Safety Findings |
Composite Safety Endpoint is defined as a composite of the following events at 3, 6, 12, 24 and 36 months post -procedure:
-All-cause mortality
-End-stage renal disease (ESRD)
-Significant embolic event resulting in end-organ damage
-Renal artery perforation requiring intervention
-Renal artery dissection requiring intervention
-Vascular complications
-Hospitalization for hypertensive crisis/emergency
-New renal artery stenosis > 70%
The study met the composite primary safety endpoint at 1 month with a composite event rate of 1.0% (2/206) in the Denervation group 1-sided Upper 95 CI of 3.0% compared to the performance goal of 7.1%, p<0.001. There were 2 vascular complications requiring surgical repair, intervention, thrombin of injection or blood transfusion.
At 36 months, the composite safety endpoint rate was 3.3% (6/184) and 2.7% (3/113) (p=1.000) in the Denervation and Control groups, respectively.
The CEC adjudicated five events as procedure related but not catheter, generator or therapy related all of which were associated with vascular access site complications.
There were 3 reported deaths in the SPYRAL HTN-ON MED study. All deaths were adjudicated by the CEC as cardiovascular deaths and not related to the study catheter, generator or procedure.
Follow-up imaging determined that 10 of 15 cases (67%) were false positives, resulting in RAS >50% in 5 of 557 patients (0.9%) based on noninvasive imaging. However, the RAS was determined to be <60% in 4 of these 5 patients. A potential stenosis >70% was identified in the left renal artery in one patient via MRA at 3 years post-procedure.
Renal Function
The mean change in serum creatinine at 36 months was 0.04 +/-0.14 mg/dL (p= <0.001 for change from baseline in the RDN group and 0.05 +/-0.15 mg/dL (p= 0.060 for change from baseline) in the Control group. The mean change in eGFR at 36 months was -2.86 +/-12.01 mL/min/1.73 m2 (p= 0.002 for change from baseline) in the RDN group and -3.71 +/-12.06 mL/min/1.73 m2 (p= 0.091 for change from baseline) in the Control group.
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| Final Effect Findings |
Primary Efficacy Endpoint Analysis (ITT Population)
The primary effectiveness endpoint was the baseline-adjusted change (using Analysis of Covariance) in 24- hour systolic blood pressure from baseline to 6-months. This analysis used a Bayesian design incorporating the Pilot data as an informative prior which was then discounted independently for each group in the ITT population.
The treatment difference between the Denervation and Control groups was -0.030 mmHg (Bayesian 95% credible interval: -2.82 to 2.77) in 24-hour systolic blood pressure. The primary effectiveness endpoint was not met in the ITT population at 6 months.
At 6 months, the change from baseline for office systolic BP for the RDN group was -9.9 mmHg compared to Control group change of -5.1 mmHg (ANCOVA difference -4.9 mmHg; p=0.001). Thus, the study met the secondary endpoint of office systolic BP reduction compared to control at 6 months.
24-hour Systolic Blood Pressure
At 24 months the average 24-hour systolic blood pressure between the RDN (137.3 +/- 14.9 mmHg) and control groups (143.5 +/- 13.2 mmHg) showed statistically significant differences in favor of the RDN group, p=0.028.
At 24 months, the average 24-hour SBP difference between the RDN and Control groups (-12.1 vs -7.0 mmHg) was a statistically significant (adjusted for baseline and change in medication burden) difference of -5.4 mmHg (p=0.042).
At the 36 months, the RDN group had an average 24-hour systolic blood pressure of 135.4 +/- 13.2 mmHg, versus 139.2 +/- 12.2 mmHg in the Control group (p=0.150). There was an average change of -14.0 +/- 14.0 mmHg in the RDN group compared to -10.7 +/- 14.1 mmHg in the control group.
At 36 months, the average 24-hour SBP difference between the RDN and Control groups (-14.0 vs -10.7 mmHg) was a statistically significant (adjusted for baseline and change in medication burden) difference of -5.8 mmHg (p=0.02).
Office Systolic Blood Pressure (office SBP)
At the 24-months, the RDN group had an average office SBP of 145.5 +/- 15.9 mmHg, compared to 154.3 +/- 17.0 mmHg in the Control group (p=0.003). The changes from baseline were statistically significant, with the RDN group showing a change of -17.4 +/- 16.1 mmHg compared to the Control group's change of -9.0 +/- 19.4 mmHg (p=0.007)
At the 36-months, the RDN group had an average office SBP of 144.2 +/- 17.1 mmHg, compared to 143.9 +/- 14.6 mmHg (p=0.905) in the Control group. The RDN group showed a change of -18.5 +/- 17.8 mmHg compared to the Control group's change of -18.7 +/- 16.7 mmHg (p=0.948).
Target Blood Pressure
At 24 months, the percentage that achieved target office systolic BP<140 mmHg in the RDN group was 35.3% compared to Control 17.1% (p=0.048).
At the 12-month, 29.1% of RDN patients achieved target office BP <140 mmHg compared to 19.7% in the Control group (p=0.159), and at 36 months, this was 46.9% vs 43.8% in the Control group (p=0.848).
Prescribed Anti-Hypertensive Medication to 36 months
At 12 months, the mean medication burden score, as measured by Index 2A, was higher in the Control group compared to the RDN group with mean scores of 5.34 vs. 4.06, respectively, p = 0.035.
At the 36- months, the mean medication burden scores (measured by Index 2A) were 5.73 for the RDN group and 9.70 for the Control group (p=0.122).
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| Study Strengths & Weaknesses |
This was a randomized, multicenter, international study. The study did not meet the primary effectiveness endpoint of baseline-adjusted change in 24- hour systolic blood pressure from baseline to 6-months.
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| Recommendations for Labeling Changes |
Labeling update is recommended
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