Clinical trial NCT03503773
Conditions: Hypertension Hypertension,Essential
Keywords: Renal Denervation Neurolysis
Sponsor: Ablative Solutions, Inc.
Start date: 2018-09-24; Completion date: 2024-01-10
Enrollment: 350 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To obtain an assessment of the efficacy and safety of renal denervation by alcohol-mediated neurolysis using the Peregrine Kit in hypertensive subjects in the absence of antihypertensive medications.

Detailed description:

Arms: arm 1: Renal denervation (using the Peregrine Kit) performed with alcohol infused through the Peregrine Catheter arm 2: Only renal angiography performed
Interventions: intervention 1: Alcohol intervention 2: Sham control
Intervention descriptions: intervention 1: Alcohol is directly infused/delivered to the adventitial and periadventitial space of the renal arteries intervention 2: endovascular, renal angiography

Protocol documents:
Prot_000.pdf: 
 
 
 
 
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PROTOCOL SYNOPSIS 
INVESTIGATIONAL PRODUCT 
Name of Investigational 
Product (IP) 
Combination Product: Peregrine System™ Kit (also referred to as 
Peregrine Kit) 
Drug Part: Dehydrated Alcohol Injection, USP (also referred to as 
alcohol, dehydrated alcohol, ethanol, absolute ethanol, ethyl alcohol, or 
absolute alcohol) 
Device Part: Peregrine System™ Infusion Catheter (also referred to as 
Peregrine Catheter) 
Name(s) of Active 
Ingredient(s) 
Dehydrated Alcohol Injection, USP 
CLINICAL CONDITION(S)/INDICATION(S) 
Hypertension 
Protocol ID 
CR0014 
Protocol Version and Date 
7.0 14 DEC 2021 
EudraCT Number 
2018-000036-96 
Protocol Title 
A Phase 2, Multicenter, Blinded, Sham Procedure-Controlled Trial of 
Renal Denervation by the Peregrine System Kit, in Subjects with 
Hypertension, in the Absence of Antihypertensive Medications 
Short Title 
The TARGET BP OFF-MED Trial 
Study Phase 
Phase 2 (Proof-of-Concept) 
PLANNED STUDY PERIOD 
Initiation 
MAY 2018 
Primary Endpoint 
Completion 
JUN 2021 
Study Completion 
MAR 2023 
Duration 
Approximately 5.0 years 
STUDY OBJECTIVES AND PURPOSE 
Study Purpose 
To obtain an assessment of the efficacy and safety of renal denervation by alcohol-mediated neurolysis 
using the Peregrine Kit in hypertensive subjects in the absence of antihypertensive medications. 
Primary Objective  
• 
To evaluate the efficacy of renal denervation by alcohol-mediated neurolysis using the Peregrine 
Kit in hypertensive subjects, when used in the absence of antihypertensive medications, as 
evaluated by change in mean 24-hour ambulatory systolic blood pressure (SBP) from baseline 
to 8 weeks post-treatment. 


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Secondary Objectives 
• 
To evaluate the acute and chronic safety of renal denervation by alcohol-mediated neurolysis 
using the Peregrine Kit in hypertensive subjects, up to 2 years post-treatment. 
• 
To evaluate the efficacy of renal denervation by alcohol-mediated neurolysis using the Peregrine 
Kit on blood pressure in hypertensive subjects, up to 1 year post-treatment.  
STUDY DESIGN 
Study Type/ Classification/ 
Discipline 
Proof-of-Concept for efficacy (ambulatory blood pressure monitoring 
[ABPM], office blood pressure) 
Control Type 
Sham Treatment 
Study Indication Type 
Treatment 
Intervention Model 
Parallel 
Blinding/Masking 
Blinded (The subject, sponsor, and hypertensionist/nephrologist 
performing the screening and follow-up assessments are blinded. The 
interventionalist and cath lab staff are unblinded.) 
Study Design 
This is a Phase 2, prospective, randomized, blinded, sham procedure-
controlled, multicenter trial to assess the efficacy and safety of renal 
denervation by alcohol-mediated neurolysis using the Peregrine Kit. 
Subjects with a documented history of uncontrolled hypertension who 
are taking 0, 1, or 2 antihypertensive medications at enrollment will be 
recruited. Following screening, eligible subjects will enter a 4-week 
run-in period during which they will take no antihypertensive 
medications. 
Subjects who continue to be eligible at the end of the run-in period will 
attend the study site for the day of procedure. All subjects will receive 
sedation and analgesia and undergo a diagnostic renal angiogram per 
standard procedures. Note: the type of sedation and analgesia will take 
into account the subject’s preference, the interventionalist’s and 
anesthesiologist’s standard of practice, and institutional policy for this 
type of procedure. Subjects will then be randomized in a 1:1 ratio to one 
of the following 2 groups via central randomization (stratified by study 
site): 
• 
Treatment Arm: renal denervation (using the Peregrine Kit) 
performed with alcohol (0.6 mL per treated renal artery) 
infused through the Peregrine Catheter (minimum treatment: 
the 2 main renal arteries [1 per side]; physician is also 
permitted to treat up to 1 additional accessory artery on each 
side. Thus, the planned maximum total dose is 4 x 0.6 mL = 
2.4 mL.) 
• 
Sham Control Arm: only renal angiography performed. No 
renal denervation and no alcohol infusion will be performed. 
Subjects will be discharged from the study site the day after the 
procedure if there are no safety concerns, per the physician’s judgment. 
Subjects with an estimated glomerular filtration rate (eGFR) of >45 and 
<60 mL/min/1.73 m2 will return to provide a blood sample for 
measurement of serum creatinine 48 to 96 hours after the procedure. 
Subjects will continue to take no antihypertensive medications during 
the first 8 weeks after the procedure (except for emergencies, as defined 


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in the protocol). After 8 weeks, antihypertensive medications are 
permitted according to the protocol-defined criteria and proposed 
titration scheme. 
Follow-up visits will be performed at 4 weeks, 8 weeks, 3 months, 
6 months, 1 year, and 2 years. 
The study will be unblinded after the last subject has completed the 
1-year follow-up visit. 
Crossover from the Sham Control Arm to the Treatment Arm may be 
allowed, at the discretion of the treating investigator, after the Data 
Safety Monitoring Board (DSMB) has reviewed the 1-year data from 
all subjects and the study has been unblinded. 
Study Geography/ Number 
of Planned Investigational 
Sites 
United States (US) and Europe 
Multicenter trial with approximately 25 investigational sites (in the US 
and Europe) 
Number of Groups/ 
Arms/Cohorts 
2 groups (Treatment Arm, Sham Control Arm; randomized 1:1) 
Number of Targeted 
Subject Treatment, Total 
and in Each Arm 
Approximately 90 subjects randomized: 
• 
45 subjects in the Treatment Arm 
• 
45 subjects in the Sham Control Arm 
Planned Duration of 
Subject Participation 
Approximately 26 months* (for each subject) 
• 
Screening period: approximately 4 to 8 weeks 
• 
Run-in period: 4 weeks 
• 
In-hospital period: 2 days 
• 
Follow-up period: 2 years 
*May be different for subjects in Sham Control Arm in the case of 
crossover: subjects will have a final 1-year follow-up visit after 
crossover treatment. 
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION 
Active Product 
Combination Product: Peregrine System Kit 
Drug Constituent Part: Dehydrated Alcohol Injection, USP 
Device Constituent Part: Peregrine System Infusion Catheter 
Dose: 0.6 mL alcohol per treated renal artery. Maximum total dose per 
subject = 2.4 mL at one treatment session (i.e. during the same 
procedure). 
Dosage form: Solution for injection 
Dosage frequency: Once during the study procedure 
Mode of administration: Direct infusion to the perivascular space, 
during an endovascular procedure using the device constituent part 
Placebo/Control/ 
Comparator 
In the Sham Control Arm, only renal angiography will be performed. 
No alcohol infusion (i.e. no renal denervation) will be performed.  
Dosage form: Not applicable 
Dosage frequency: Once during the study procedure 
Mode of administration: Endovascular 


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SUBJECT SELECTION 
Subjects will be enrolled in the study at the time they sign the informed consent form. No study-specific 
procedures will be performed until after the subject has provided written informed consent. 
Subject Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible and undergo the procedure: 
Prior to run-in period 
1. 
Subject has provided written informed consent. 
2. 
Male or female subject, aged ≥18 and ≤80 years at time of enrollment. 
3. 
If subject has a documented history of uncontrolled hypertension (see definition in Definition of 
Terms section of protocol) and is currently taking no (0) antihypertensive medications, he/she must: 
• 
Have 3 office blood pressure measurements with a mean office systolic blood pressure (SBP) of 
≥140 mmHg and ≤180 mmHg AND mean office diastolic blood pressure (DBP) ≥90 mmHg, 
and 
• 
Be willing to adhere to the no-medication regimen for at least 12 weeks (4-week run-in period 
and 8-week post-treatment period). 
4. 
If subject has a documented history of uncontrolled hypertension (see definition in Definition of 
Terms section of protocol) and is currently taking 1 or 2 antihypertensive medications, he/she must: 
• 
Have 3 office blood pressure measurements with a mean office SBP of ≥120 mmHg and 
≤180 mmHg and 
• 
Be willing to discontinue his/her antihypertensive medication(s), and to adhere to the 
no-medication regimen for at least 12 weeks (4-week run-in period and 8-week post-treatment 
period). 
5. 
Investigator judges that the subject can be discontinued safely from all current antihypertensive 
medication (where applicable) and managed safely for at least 12 weeks (4-week run-in period and 
8-week post-treatment period) without antihypertensive medication intake. 
6. 
Female subjects of childbearing potential must agree to use acceptable methods of contraception (as 
defined in the protocol), from the time of informed consent through to the last follow-up visit. 
7. 
Subject agrees to have all study procedures performed and is able and willing to comply with all 
study follow-up visits and protocol requirements. 
End of run-in period 
8. 
Subject has 3 office blood pressure measurements with a mean office SBP of ≥140 mmHg and 
≤180 mmHg AND mean office DBP ≥90 mmHg. 
9. 
Subject has a mean 24-hour ambulatory SBP of ≥135 mmHg and ≤170 mmHg with ≥70% valid 
readings (as determined by ABPM measurement device). 
Exclusion Criteria 
If ANY of the following exclusion criteria are met, the subject must be excluded from the trial and cannot 
be randomized or undergo the procedure: 
1. 
Subject has a contraindication known for conventional percutaneous interventional procedures such 
as: 
• 
Intolerance for antiplatelet/anticoagulant therapy 
• 
Known allergy to contrast media that cannot be adequately pre-medicated 
• 
Bleeding/coagulation disorders (such as bleeding diathesis, thrombocytopenia, and severe 
anemia) 
• 
Occlusive peripheral vascular disease that would preclude percutaneous femoral access for the 
procedure. 


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2. 
Subject has an acute or sub-acute infection that the investigator judges would pose unacceptable 
procedural risks to the subject. 
3. 
Subject has imaging-assessed renal artery anatomy abnormalities or variations based on 
investigator’s evaluation of the screening images (i.e. magnetic resonance angiography 
[MRA]/computed tomography angiography [CTA] examination and/or renal angiography) meeting 
one of the following criteria: 
• 
Main renal artery that has a diameter of <4 mm or >7 mm and length of <5 mm 
• 
Accessory renal arteries with diameter >2 mm or <4 mm, which supply >20% of the whole 
kidney parenchyma on that side, per the investigator’s judgment. NOTE: subjects with more than 
one eligible accessory renal artery per side will be excluded. 
• 
Renal artery stenosis >50% of the normal diameter segment (diameter stenosis, compared to the 
angiographically normal proximal or distal segment) 
• 
Any renal artery abnormality or disease that, per the physician assessment, precludes the safe 
insertion of the guiding catheter (including, but not limited to, severe renal artery aneurysm, 
excessive tortuosity, severe renal artery calcification) 
• 
Previous renal angioplasty associated with stenting or other implants, that, per the physician’s 
assessment, precludes the safe deployment of the Peregrine Catheter components in the target 
treatment segment of the renal artery 
• 
Previous renal denervation 
• 
Fibromuscular dysplasia of the renal arteries. 
4. 
Subject has documented severe untreated obstructive sleep apnea (apnea hypopnea index [AHI] 
≥30 per hour). 
5. 
Subject has documented diagnosis of the following causes of hypertension: Cushing’s disease or 
Cushing’s Syndrome, hyperaldosteronism, pheochromocytoma, thyroid and parathyroid 
abnormalities, or onset of hypertension prior to the age of 18. 
6. 
Subject has a history of pre-eclampsia. 
7. 
Subject has orthostatic hypotension at screening, or documented history of orthostatic hypotension 
within 12 months prior to the planned procedure, defined as a drop in blood pressure that is 
>20 mmHg in SBP and/or >10 mmHg in DBP within 3 minutes upon standing from sitting or from 
a lying down face-up (supine) position. 
8. 
Subject has Type 1 diabetes mellitus, or uncontrolled Type 2 diabetes mellitus (defined as 
hemoglobin A1c [HbA1c] ≥9.0%). 
9. 
Subject has an eGFR of ≤45 mL/min/1.73 m2, based on the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation; or is on chronic renal replacement therapy. 
10. Subject has nephrotic syndrome. 
11. Subject has a history of recurrent (>1 episode) kidney stones, or history of kidney stones within 
12 months prior to the planned procedure. 
12. Subject has a history of nephrectomy, a single kidney or kidney tumor, or urinary tract obstruction 
(with potential for hydronephrosis). NOTE: Simple renal cysts are not an exclusion. 
13. Subject has a renal transplant, or is known to have a non-functioning kidney or unequal renal size 
(>2 cm difference in renal length between kidneys associated with a chronic kidney disease or a 
deterioration of the kidney function).  
14. Subject has a history of myocardial infarction, unstable angina pectoris, or stroke/transient ischemic 
attack (TIA) within 6 months prior to the planned procedure. 
15. Subject has any of the following conditions: severe cardiac valve stenosis, heart failure (New York 
Heart Association [NYHA] Class III or IV), chronic atrial fibrillation, and known primary 
pulmonary hypertension (>60 mmHg pulmonary artery or right ventricular systolic pressure). 


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16. Subject is allergic or intolerant to the neurolytic agent (i.e. dehydrated alcohol). 
17. Subject is being treated chronically (e.g. daily use) with non-steroidal anti-inflammatory drugs 
(NSAIDs), immunosuppressive medications, or immunosuppressive doses of steroids. Aspirin 
therapy and nasal pulmonary inhalants are allowed. 
18. Any contraindication to the imaging as required per the protocol. 
19. Subject for whom an ABPM device cannot be used due to arm size (>42 cm arm circumference) or 
other reasons as identified by the investigator. 
20. Subject has any other acute or chronic condition that the investigator believes will adversely affect 
the ability to interpret the data or will prevent the subject from completing the trial procedures, or 
has a life expectancy of <12 months. 
21. Subject has a known history of drug use or alcohol dependency, or lacks the ability to comprehend 
or follow instructions, or for any reason, in the opinion of the investigator, would be unlikely or 
unable to comply with study protocol requirements. 
22. If female, subject is pregnant or lactating at the time of enrollment or planning to become pregnant 
during the trial time period. 
23. Subject has participated in another clinical study involving an investigational drug or investigational 
device within 30 days prior to enrollment or is scheduled to participate in another clinical study 
involving an investigational drug or investigational device during the course of this study. Subjects 
enrolled in observational registries not involving renal denervation may still be eligible. 
24. Subject is in custody or an institution. 
25. Subject has close affiliation with the study site or sponsor (e.g. employee, close relative of an 
employee). 
26. Subject has a history of hypertensive emergency in the previous 3 months (see definition of 
hypertensive emergencies in Definition of Terms section of protocol). 
ENDPOINTS AND STATISTICAL ANALYSIS 
Sample Size Calculation 
The primary efficacy endpoint of the change in mean 24-hour ambulatory SBP at 8 weeks post-treatment 
will be compared between the 2 treatment groups. 
This study is designed as a proof-of-concept study. It is not formally powered for the primary endpoint. 
The purpose of the trial is to determine if there is an adequate treatment effect to proceed to a pivotal 
study. It is planned to randomize approximately 90 subjects (45 per group) to achieve 80 evaluable 
subjects (for primary efficacy endpoint analysis). 
The following table provides examples of observed treatment effects and standard deviations (SDs) that 
would be considered statistically significant at alpha = 0.05, for the change in mean 24-hour ambulatory 
SBP at 8 weeks post-treatment with 80 evaluable subjects: 
Treatment Difference 
Standard Deviation 
3.5 mmHg 
8 mmHg 
4.4 mmHg 
10 mmHg 
5.3 mmHg 
12 mmHg 
 
A study of the planned size would be powered at 80% to detect a difference between intervention and 
control of 5.1 mmHg assuming a SD of 8 mmHg in each group and two-sided alpha of 0.05 using the 
independent two sample t-test. A difference between treatment and control of 5 mmHg is considered 


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clinically meaningful and consistent with previous trials of renal denervation in a similar population1. 
An observed difference between groups of 5 mmHg with an observed SD as high as 11.2 mmHg per 
group would be considered statistically significant at a two-sided alpha level of 0.05. 
Endpoints and Planned Statistical Analysis 
The following populations are defined for analysis: 
The Intent-to-Treat (ITT) Analysis Set will include all subjects who were randomized regardless of 
whether treatment was received. Subjects will be analyzed according to their randomized treatment 
group, irrespective of treatment received. 
The Safety Analysis Set will include all subjects who received treatment. Subjects will be analyzed 
according to the actual treatment received, irrespective of treatment assignment. 
The Per-Protocol (PP) Analysis Set will include subjects with no important protocol deviations. Subjects 
will be analyzed according to the actual treatment received. 
Primary efficacy endpoint 
The primary efficacy endpoint is defined as the change in mean 24-hour ambulatory SBP from baseline 
to 8 weeks post-treatment. This will be summarized and compared between the 2 treatment groups using 
the independent two-sample t-test. 
Secondary efficacy endpoints: 
• 
Change in mean 24-hour, daytime, (07:00 to 21:59), and nighttime (22:00 to 06:59) ambulatory 
SBP and DBP from baseline to time points post-treatment. 
• 
Change in mean office SBP and DBP from baseline to time points post-treatment. 
• 
Percentage of subjects controlled to target blood pressure values. 
• 
Use of antihypertensive medication(s) from time of procedure to 8 weeks post-treatment 
(emergency use medication). 
• 
Use of antihypertensive medication(s) (including increases/decreases) from 8 weeks to 6 months 
and 1-year post-treatment (titrated according to standardized formula to maintain a target SBP 
of <140 mmHg and ≥90 mmHg). 
• 
Compliance with not taking antihypertensive medications through 8 weeks post-treatment. 
Changes from baseline will be computed as the paired mean difference and will be summarized with 
descriptive statistics (n, mean, SD, range, median). The 95% confidence interval (CI) of the difference 
between treatment groups at each time point will be computed. Categorical data will be summarized as 
frequencies and percentages. Relative risks and 95% CIs will be computed. Secondary efficacy endpoints 
are considered supportive and thus there is no adjustment to alpha for multiplicity with a single primary 
efficacy endpoint. Analysis of efficacy endpoints will be conducted in the ITT and PP Analysis Sets. For 
the primary efficacy endpoint analysis, the main population is considered the ITT, and the PP is 
considered supportive. 
For all continuous primary and secondary blood pressure endpoints, changes over time will be 
additionally explored in mixed effects repeated measures analyses, including the values at all time points. 
It is planned to conduct an 8-week blinded interim analysis, a 6-month blinded interim analysis, and an 
unblinded 1-year interim analysis after all subjects have completed the 1-year follow-up visit and the 
study has been unblinded. 
Secondary safety endpoints: 
• 
Major adverse events (MAEs) through 30 days post-treatment, as adjudicated by the Clinical Events 
Committee (CEC). An MAE is defined as any of the following: 
 
1 Townsend RR, Mahfoud F, Kandzari DE, et al. Catheter-based renal denervation in patients with uncontrolled hypertension in 
the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial. 
Lancet 2017;390(10108):2160-70. 


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o 
All-cause death 
o 
End-stage renal disease (ESRD) (eGFR <15 mL/min/1.73 m2 or need for renal replacement 
therapy) 
o 
Significant embolic event resulting in end-organ damage or requiring intervention to prevent it 
o 
Major vascular complications, including major renal artery dissection, renal artery aneurysm or 
pseudoaneurysm that required intervention or led to renal artery stenosis (>60% diameter 
stenosis) 
o 
Major bleeding related to renal denervation within the renal arteries, or related to the Peregrine 
Catheter when in the body (per protocol bleeding definition) 
o 
Significant acute (post-procedural) renal artery stenosis (>60% diameter stenosis) as indicated 
by the renal angiogram post renal denervation, and confirmed by the angiography core 
laboratory, which led to one of the following: (i) acute kidney injury per modified Risk, Injury, 
Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) definition, as 
confirmed by renal function blood test, or (ii) percutaneous intervention. 
o 
Hypertensive crisis (hypertensive emergency only) 
o 
Hypotensive crisis 
o 
Symptomatic hypotension that required a change in antihypertensive medications, or 
medications to increase blood pressure (e.g. persistent syncope, lightheadedness) 
• 
Changes in eGFR from baseline to 8 weeks, 6 months, and 1-year post-treatment. 
• 
Decreases in eGFR >25% from baseline to 8 weeks, 6 months, and 1-year post-treatment. 
• 
Rate of adverse events (serious and non-serious), peri-procedurally, at discharge, and at each of the 
follow-up time points. 
• 
Device success (defined as the ability to insert the Peregrine Catheter into the lumen of the renal 
artery [target vessel], deploy the guide tubes inside the renal artery, deploy the needles through the 
arterial wall, deliver the intended dose of alcohol, retract the needles and the guide tubes back in the 
catheter, and remove the catheter from the access site without any related complications or events) 
• 
Procedure success (defined as device success with freedom from peri-procedural MAEs). 
The percentage of subjects with any MAE through 30 days post-treatment will be displayed by treatment 
group. The relative risk will be displayed with 95% CIs. The 2 groups will be compared using Fisher’s 
exact test. 
Other safety endpoints will be summarized as frequencies and percentages. Relative risks and 95% CIs 
will be computed. Analysis of all safety endpoints will be conducted using the Safety Analysis Set. 
 


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Table 1 
Schedule of Study Assessments (Main Study) 
Period 
Scrn 
Period 
Run-In Period1 
In-Hospital 
Period 
Follow-Up Period 
ET2 
Visit Time Point 
Up to 
Wk -8 
Wk -4 
Wk -2 
Wk -1 
(Baseline) 
D 03 
D 1 
D 2 to D 4 
(48-96 h)4 
Wk 4 
Wk 8 
Mth 3 
Mth 6 
Yr 1  
and 2 
 
Visit Window 
 
 
+/-4 D 
+/-2 D 
 
 
 
+/-7 D 
+/-7 D 
+/-2 
Wk 
+/-4 
Wk 
+/-8 Wk 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Office BP 
pressure5 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
24-hour ABPM6 
 
 
 
X7 
 
 
 
 
X 
 
X 
X8 
 
MRA/CTA9 
X10 
 
 
 
 
 
 
 
 
 
X11 
 
 
Post-contrast 
serum creatinine12 
X4 
 
 
 
 
 
X4 
 
 
 
X4 
 
 
Blood sample13 
X14 
 
 
X 
X*15 
 
 
X16 
X 
 
X 
X 
X 
Urine sample13 
 
 
 
X 
 
 
 
X16 
X 
 
X 
X 
X 
Pregnancy test 
(serum) 
X 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
No 
antihypertensive 
meds permitted17 
 
X→ 
→ 
→ 
→ 
→ 
→ 
→ 
→X 
 
 
 
 
Antihypertensive 
meds, if 
required18 
 
 
 
 
 
 
 
 
X→ 
→ 
→ 
→ 
 
Physical 
examination, vital 
signs19 
X 
 
X 
X 
X* 
X 
 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
 


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Period 
Scrn 
Period 
Run-In Period1 
In-Hospital 
Period 
Follow-Up Period 
ET2 
Visit Time Point 
Up to 
Wk -8 
Wk -4 
Wk -2 
Wk -1 
(Baseline) 
D 03 
D 1 
D 2 to D 4 
(48-96 h)4 
Wk 4 
Wk 8 
Mth 3 
Mth 6 
Yr 1  
and 2 
 
Visit Window 
 
 
+/-4 D 
+/-2 D 
 
 
 
+/-7 D 
+/-7 D 
+/-2 
Wk 
+/-4 
Wk 
+/-8 Wk 
 
Nephrologist/ 
hypertension 
specialist review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Renal duplex 
ultrasound 
 
 
 
 
 
 
 
 
 
 
X11 
 
 
Dispense/review 
subject diary 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
Subject completes 
diary20 
 
X→ 
→ 
→ 
→ 
→ 
→ 
→ 
→X 
 
 
 
 
Renal 
angiography 
 
 
 
 
X* 
 
 
 
 
 
X11 
 
 
Randomization 
 
 
 
 
X*21 
 
 
 
 
 
 
 
 
Renal 
denervation (if 
randomized to 
this arm) 
 
 
 
 
X* 
 
 
 
 
 
 
 
 
Treatment 
perception 
assignment 
questionnaire 
 
 
 
 
X22 
 
 
 
X 
 
 
 
 
Product 
performance and 
procedural safety 
 
 
 
 
X* 
 
 
 
 
 
 
 
 
Product 
accountability  
 
 
 
 
X* 
 
 
 
 
 
 
 
 
AE collection23 
X→ 
→ 
→ 
→ 
→* 
→ 
→ 
→ 
→ 
→ 
→ 
→X 
X 
Prior/concomitant 
medications24 
X→ 
→ 
→ 
→ 
→* 
→ 
→ 
→ 
→ 
→ 
→ 
→X 
X 


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Period 
Scrn 
Period 
Run-In Period1 
In-Hospital 
Period 
Follow-Up Period 
ET2 
Visit Time Point 
Up to 
Wk -8 
Wk -4 
Wk -2 
Wk -1 
(Baseline) 
D 03 
D 1 
D 2 to D 4 
(48-96 h)4 
Wk 4 
Wk 8 
Mth 3 
Mth 6 
Yr 1  
and 2 
 
Visit Window 
 
 
+/-4 D 
+/-2 D 
 
 
 
+/-7 D 
+/-7 D 
+/-2 
Wk 
+/-4 
Wk 
+/-8 Wk 
 
Discharge from 
study site 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Possible 
crossover from 
Sham Control 
Arm25 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: ABPM = ambulatory blood pressure monitoring; AE = adverse event; BP = blood pressure; CTA = computed tomography angiography; D = day; 
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; ET = early termination; HR = heart rate; MAE = major adverse event; 
MRA = magnetic resonance angiography; Mth = month; SAE = serious adverse event; Scrn = screening; Wk = week; Yr = year 
*Peri-procedural AE and concomitant medication recording, as well as all assessments performed in the cath lab/special procedure lab and/or in relation to the 
procedure, will be performed by unblinded personnel. 
1 The run-in period starts approximately 4 weeks prior to the planned date of the procedure. The subject must start the run-in period on 0 antihypertensive 
medications. In the case of subjects taking 1 or 2 antihypertensive medications that require down-titration, these subjects must down-titrate their medications 
prior to the start of the run-in period. If a subject takes antihypertensive medication during the run-in period but still wishes to enter the study, one re-start of 
the run-in period is possible if this is acceptable to the physician as well as the subject, and if the physician believes that the subject will be compliant. 
2 Where possible, subjects who discontinue early from the study will undergo these procedures. 
3 Subjects may be admitted on Day -1 for logistical reasons. For the day of the procedure (Day 0), flexibility in scheduling is permitted (up to 1 week), e.g. due 
to cath lab availability, based on physician discretion and with careful consideration of subject safety. 
4 For applicable subjects only (see footnote 12). 
5 One set of 3 measurements using the same cuff and same arm as used at screening. See office blood pressure manual. 
6 ABPM measurements must be collected at the same time as office BP measurements, where applicable. Office BP measurements are collected before ABPM 
set-up. 
7 24-Hour ABPM at this time point is only performed if office BP measurements meet the inclusion criteria. 
8 At 1 year only. 
9 An MRA will be performed for assessment of renal vasculature. For sites that would prefer to use CTA instead, agreement may be reached with the sponsor 
on a case-by-case basis (depending upon local regulatory approvals and site capacity).  
10 Scheduled at the initial screening visit, then performed and assessed prior to the start of the run-in period to check renal artery anatomy. If either of the 
imaging tests has been performed within 12 months prior to the time of enrolment, review of the images by the core lab may be performed, with consultation 
by the sponsor and principal investigator, to determine if a repeat of the protocol imaging test is needed to assess anatomical eligibility. Must be performed 
after screening serum creatinine sampling and only to be performed if eGFR based on this sample is >45 mL/min/1.73 m2. 


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Page 12 of 24 
11 If the renal duplex ultrasound assessment at 6 months cannot be performed, or if the results are non-diagnostic, CTA/MRA/renal angiography may be 
performed if agreed with the sponsor (depending upon local regulatory approvals and site capacity). If renal artery stenosis of >60% or any other significant 
abnormality is suspected or confirmed by renal duplex ultrasound, as evaluated by the core laboratory, or as the result of other clinical assessments, those 
findings should be confirmed using the imaging modality used at screening (CTA/MRA/renal angiography). The choice of imaging may be changed at the 
discretion of the investigator and should be discussed with the sponsor. 
12 Subjects with an eGFR of >45 and <60 mL/min/1.73 m2 based on the screening serum creatinine sample will undergo blood sampling for post-contrast serum 
creatinine measurement 48-96 hours after imaging at screening. Subjects with an eGFR of >45 and <60 mL/min/1.73 m2 based on the Week -1 (baseline) 
serum creatinine sample will undergo blood sampling for post-contrast serum creatinine measurement 48-96 hours after imaging during the procedure and 
any subsequent procedure where imaging contrast is used. 
13 See Table 3 for details of blood and urine parameters. Tests to be done in the case of ET will be as for the Month 6 visit, but excluding compliance tests. 
14 For measurement of serum creatinine only (all subjects). This sample must be taken prior to imaging at screening, because the eGFR value based on this 
measurement will be used to assess whether the subject is excluded or may proceed to have the screening imaging assessment. 
15 Activated coagulation time (ACT) only is performed on Day 0, per the hospital’s standard of care. 
16 For compliance testing only. 
17 No antihypertensive medications are permitted from the start of the run-in period until the subject has completed the visit at 8 weeks post-treatment (except in 
the case of emergencies). 
18 Antihypertensive medications may be given after the 8-week visit if necessary (according to pre-defined criteria and proposed titration schedule). 
19 Screening visit: full physical examination, height, weight, temperature, and HR. Week -2: abbreviated physical examination, weight, temperature, and HR; 
Week -1: temperature and HR; Day 0: single measurement of cuff BP and HR before and after study procedure (while in cath lab/special procedure lab); 
Day 1: abbreviated physical examination, single measurement of cuff BP, HR, and temperature; Weeks 4 and 8, and Month 3: weight, HR, and temperature; 
Month 6: full physical examination, weight, HR, and temperature; Years 1 and 2: weight, HR, and temperature; ET visit: abbreviated physical examination, 
weight, temperature, and HR. 
20 Subjects will record BP twice daily, any antihypertensive medication(s) taken, and other notes (e.g. symptoms, illnesses). Subjects do not have to complete 
the subject diary during the in-hospital period. 
21 Randomization will be performed in the cath lab/special procedure lab after the subject has been sedated and after renal angiography. 
22 Questionnaire to be conducted post-treatment (>4 hours and <24 hours). 
23 All AEs must be recorded from the time of signing the informed consent form through the end of study participation. 
24 All medications (prescribed or over-the-counter, including supplements) must be recorded from the time of signing the informed consent form through the 
6-month follow-up visit (or time of early termination from the study, if prior to 6 months). All antihypertensive medications must be recorded starting from 
the time of signing the informed consent form through the 2-year follow-up visit (or time of early termination from the study). In addition, all medications 
(prescribed or over-the-counter, including supplements) taken within 14 days prior to the onset of a serious AE (SAE) or major AE (MAE), as well as during 
the SAE or MAE timeframe, must be recorded starting from the time of signing the informed consent form through the 2-year follow-up visit (or time of early 
termination from the study). 
25 Crossover from the Sham Control Arm to the Treatment Arm may be allowed, at the discretion of the treating investigator, after the Data Safety Monitoring 
Board (DSMB) has reviewed the 1-year data from all subjects and the study has been unblinded.  
 


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Page 13 of 24 
Table 2 
Schedule of Study Assessments (Crossover Phase)  
Period 
Re-Screening 
Period 
In-Hospital Period 
Follow-Up Period 
ET1 
Visit Time Point 
Up to Wk -4 
D 02 
D 1 
D 2 to D 4 
(48-96 h)3 
Wk 4 
Mth 6 
 
Visit Window 
 
 
 
 
+/-7 D 
+/-4 Wk 
 
Informed consent 
X 
 
 
 
 
 
 
Eligibility check4 
X 
 
 
 
 
 
 
Office BP pressure5 
X 
 
 
 
X 
X 
X 
MRA/CTA 
X6 
 
 
 
 
X7 
 
Renal angiography 
 
X 
 
 
 
X7 
 
Post-contrast serum creatinine8 
X3 
 
 
X3 
 
X3 
 
Blood sample9 
X 
X10 
 
 
X 
X 
X 
Urine sample9 
X 
 
 
 
X 
X 
X 
Pregnancy test (serum) 
X 
 
 
 
X 
X 
X 
Physical examination, vital signs11 
X 
X 
X 
 
X 
X 
X 
12-lead ECG 
 
 
 
 
 
X 
 
Renal duplex ultrasound 
 
 
 
 
 
X7 
 
Renal denervation 
 
X 
 
 
 
 
 
Product performance and 
procedural safety 
 
X 
 
 
 
 
 
Product accountability  
 
X 
 
 
 
 
 
AE collection12 
→ 
→ 
→ 
→ 
→ 
→ 
X 
Prior/concomitant medications13 
→ 
→ 
→ 
→ 
→ 
→ 
X 
Discharge from study site 
 
 
X 
 
 
 
 
Abbreviations: AE = adverse event; BP = blood pressure; CTA = computed tomography angiography; D = day; ECG = electrocardiogram; eGFR = estimated 
glomerular filtration rate; ET = early termination; HR = heart rate; MAE = major adverse event; MRA = magnetic resonance angiography; Mth = month; 
SAE = serious adverse event; Scrn = screening; Wk = week; Yr = year 


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Clinical Study Protocol No. CR0014 
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Page 14 of 24 
1 Where possible, subjects who discontinue early from the crossover phase will undergo these procedures. 
2 Subjects may be admitted on Day -1 for logistical reasons. 
3 For applicable subjects only (see footnote 8). 
4 Eligibility criteria for the crossover phase. 
5 One set of 3 measurements using the same cuff and same arm as used at screening. See office blood pressure manual. 
6 At the discretion of the investigator, an MRA will be performed again for assessment of renal vasculature to assess eligibility. For sites that would prefer to 
use CTA instead, agreement may be reached with the sponsor on a case-by-case basis (depending upon local regulatory approvals and site capacity).  
7 If the renal duplex ultrasound assessment at 6 months cannot be performed, or if the results are non-diagnostic, CTA/MRA/renal angiography may be 
performed if agreed with the sponsor (depending upon local regulatory approvals and site capacity). If renal artery stenosis of >60% or any other significant 
abnormality is suspected or confirmed by renal duplex ultrasound, as evaluated by the core laboratory, or as the result of other clinical assessments, those 
findings should be confirmed using the imaging modality used at screening (CTA/MRA/renal angiography). The choice of imaging may be changed at the 
discretion of the investigator and should be discussed with the sponsor. 
8 Blood sampling for post-contrast serum creatinine measurement is dependent on when imaging procedure is performed and the subject’s eGFR measurement: 
blood is to be drawn and measured 48-96 hours after any procedure where imaging contrast is used and ONLY on subjects with an eGFR of >45 and 
<60 mL/min/1.73 m2 (as measured at the study re-screening visit). 
9 See Table 4 for details of blood and urine parameters. Tests to be done in the case of ET will be as for the Month 6 visit.  
10 Activated coagulation time (ACT) is performed on Day 0, per the hospital’s standard of care. 
11 Re-screening visit: full physical examination, height, weight, temperature, and HR; Day 0: single measurement of cuff BP and HR before and after study 
procedure (while in cath lab/special procedure lab); Day 1: abbreviated physical examination, single measurement of cuff BP, HR, and temperature; Week 4: 
weight, HR, and temperature; Month 6: full physical examination, weight, HR, and temperature. ET visit: abbreviated physical examination, weight, 
temperature, and HR. 
12 All AEs must be recorded from the time of signing the informed consent form (in the main study) through the end of the study (including crossover phase). 
13 All antihypertensive medications must be recorded starting from the time of signing the informed consent form (in the main study) through the end of the 
study (including crossover phase) (or time of early termination, if applicable). In addition, all medications (prescribed or over-the-counter, including 
supplements) taken within 14 days prior to the onset of a serious AE (SAE) or major AE (MAE), as well as during the SAE or MAE timeframe, must be 
recorded starting from the time of signing the informed consent form (in the main study) through the end of the study (including crossover phase) (or time of 
early termination, if applicable). 
 
 


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Clinical Study Protocol No. CR0014 
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Page 15 of 24 
Table 3 
Schedule of Blood and Urine Sample Collection (Main Study) 
Period 
 
Scrn 
Period 
Run-In Period 
Treat-
ment 
Follow-Up Period 
Visit Time 
Point 
 
Up to 
Wk -8 
Wk -4 
Wk -2 
Wk -1 
(Base) 
D 0 
D 2 to D 4 
(48-96 h)1 
Wk 4 
Wk 8 
Mth 3 
Mth 6 
Yr 1  
and 2 
Visit Window 
 
 
 
+/-4 D 
+/-2 D 
 
 
+/-7 D 
+/-7 D 
+/-2 Wk 
+/-4 
Wk 
+/-8 Wk 
Serum 
chemistry 
Sodium 
 
 
 
X 
 
 
 
X 
 
X 
X 
Potassium 
 
 
 
X 
 
 
 
X 
 
X 
X 
Serum chloride 
 
 
 
X 
 
 
 
X 
 
X 
X 
BUN/urea 
 
 
 
X 
 
 
 
X 
 
X 
X 
Uric acid 
 
 
 
X 
 
 
 
X 
 
X 
X 
Cystatin C 
 
 
 
X 
 
 
 
X 
 
X 
X 
Glucose 
 
 
 
X 
 
 
 
X 
 
X 
X 
Serum creatinine 
X2 
 
 
X 
 
X3 
 
X 
 
X 
X 
eGFR4 
X 
 
 
X 
 
X5 
 
X 
 
X 
X 
Liver panel 
AST (SGOT) 
 
 
 
X 
 
 
 
X 
 
X 
 
ALT (SGPT) 
 
 
 
X 
 
 
 
X 
 
X 
 
Alk phos 
 
 
 
X 
 
 
 
X 
 
X 
 
Bilirubin (conj) 
 
 
 
X 
 
 
 
X 
 
X 
 
Bilirubin (total) 
 
 
 
X 
 
 
 
X 
 
X 
 
LDH 
 
 
 
X 
 
 
 
X 
 
X 
 
Albumin 
 
 
 
X 
 
 
 
X 
 
X 
 
Total protein 
 
 
 
X 
 
 
 
X 
 
X 
 
Hematology 
RBC 
 
 
 
X 
 
 
 
X 
 
X 
 
WBC (total and 
differential) 
 
 
 
X 
 
 
 
X 
 
X 
 
HGB 
 
 
 
X 
 
 
 
X 
 
X 
 
HCT 
 
 
 
X 
 
 
 
X 
 
X 
 
Platelets 
 
 
 
X 
 
 
 
X 
 
X 
 
Coagulation 
aPTT 
 
 
 
X 
 
 
 
 
 
 
 
PT 
 
 
 
X 
 
 
 
 
 
 
 
INR 
 
 
 
X 
 
 
 
 
 
 
 
ACT6 
 
 
 
 
X 
 
 
 
 
 
 


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Clinical Study Protocol No. CR0014 
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Page 16 of 24 
Period 
 
Scrn 
Period 
Run-In Period 
Treat-
ment 
Follow-Up Period 
Visit Time 
Point 
 
Up to 
Wk -8 
Wk -4 
Wk -2 
Wk -1 
(Base) 
D 0 
D 2 to D 4 
(48-96 h)1 
Wk 4 
Wk 8 
Mth 3 
Mth 6 
Yr 1  
and 2 
Visit Window 
 
 
 
+/-4 D 
+/-2 D 
 
 
+/-7 D 
+/-7 D 
+/-2 Wk 
+/-4 
Wk 
+/-8 Wk 
Urinalysis 
Specific gravity 
 
 
 
X 
 
 
 
X 
 
X 
X 
pH 
 
 
 
X 
 
 
 
X 
 
X 
X 
Glucose 
 
 
 
X 
 
 
 
X 
 
X 
X 
Ketones 
 
 
 
X 
 
 
 
X 
 
X 
X 
Protein (total) 
 
 
 
X 
 
 
 
X 
 
X 
X 
Bilirubin 
 
 
 
X 
 
 
 
X 
 
X 
X 
Hemoglobin 
 
 
 
X 
 
 
 
X 
 
X 
X 
Nitrite 
 
 
 
X 
 
 
 
X 
 
X 
X 
WBC 
 
 
 
X 
 
 
 
X 
 
X 
X 
RBC 
 
 
 
X 
 
 
 
X 
 
X 
X 
Bacteria 
 
 
 
X 
 
 
 
X 
 
X 
X 
Crystals 
 
 
 
X 
 
 
 
X 
 
X 
X 
Casts 
 
 
 
X 
 
 
 
X 
 
X 
X 
Spot 
microalbumin 
 
 
 
X 
 
 
 
X 
 
X 
X 
Spot creatinine 
 
 
 
X 
 
 
 
X 
 
X 
X 
Compliance7 
Urine test 
 
 
 
X 
 
 
X 
X 
 
X 
 
Blood test 
 
 
 
X 
 
 
X 
X 
 
X 
 
Other 
Pregnancy test 
(serum) 
X 
 
 
X 
 
 
 
X 
 
X 
X 
HbA1c 
 
 
 
X 
 
 
 
X 
 
X 
X 
Renin 
 
 
 
X 
 
 
 
X 
 
X 
 
Aldosterone 
 
 
 
X 
 
 
 
X 
 
X 
 
TSH 
 
 
 
X 
 
 
 
 
 
 
 
Abbreviations: ACT = activated clotting time; Alk phos = alkaline phosphatase; ALT (SGPT) = alanine aminotransferase (serum glutamate pyruvate 
transaminase); aPTT = activated partial thromboplastin time; AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
Base = baseline; BUN = blood urea nitrogen; D = day; eGFR = estimated glomerular filtration rate; h = hour; HbA1c = hemoglobin A1c; HCT = hematocrit: 
HGB = hemoglobin; INR = international normalized ratio; LDH = lactate dehydrogenase; Mth = month; PT = prothrombin time; RBC = red blood cell(s); 
Scrn = screening; TSH = thyroid-stimulating hormone; WBC = white blood cell(s); Wk = week; Yr = year 
 


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Clinical Study Protocol No. CR0014 
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Page 17 of 24 
Note: Tests to be done in the case of ET will be as for the Month 6 visit, but excluding compliance tests. 
1 For applicable subjects only (see footnote 3). 
2 Subjects with an eGFR of >45 and <60 mL/min/1.73 m2 based on the screening serum creatinine sample will also undergo blood sampling for post-contrast 
serum creatinine measurement 48-96 hours after imaging at screening. 
3 Subjects with an eGFR of >45 and <60 mL/min/1.73 m2 based on the Week -1 (baseline) serum creatinine sample will undergo blood sampling for post-
contrast serum creatinine measurement 48-96 hours after imaging during the procedure and any subsequent procedure where imaging contrast is used. 
4 eGFR will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. For all subjects, if the calculated eGFR is 
reduced >25% from baseline (Week -1), the investigator should repeat the serum creatinine test as soon as possible, but no later than 1 week after the first 
test. If the repeated calculated eGFR remains >25% from baseline, the investigator should refer the subject for further renal functions evaluations, including 
review by a nephrologist. Similarly, if a subject’s eGFR drops to ≤45 mL/min/1.73 m2, then he/she will have renal function monitored and managed by a 
nephrologist as an additional safety measure following this event and until the event is resolved. In either case, the decrease in eGFR will be reported as an 
AE. 
5 Only calculated for those subjects who have serum creatinine measured at this time point. 
6 Performed per the hospital’s standard of care and analyzed at site. 
7 Compliance testing in relation to antihypertensive medications. 
 
 


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Clinical Study Protocol No. CR0014 
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CONFIDENTIAL 
 
Page 18 of 24 
Table 4 
Schedule of Blood and Urine Sample Collection (Crossover Phase)  
Period 
 
Re-Screening Period 
Treatment 
Follow-Up Period 
Visit Time Point 
 
Up to Wk -4 
D 0 
D 2 to D 4 
(48-96 h)1 
Wk 4 
Mth 6 
Visit Window 
 
 
 
 
+/-7 D 
+/-4 Wk 
Serum chemistry 
Sodium 
X 
 
 
X 
X 
Potassium 
X 
 
 
X 
X 
Serum chloride 
X 
 
 
X 
X 
BUN/urea 
X 
 
 
X 
X 
Uric acid 
X 
 
 
X 
X 
Cystatin C 
X 
 
 
X 
X 
Glucose 
X 
 
 
X 
X 
Serum creatinine 
X 
 
X2 
X 
X 
eGFR3 
X 
 
X4 
X 
X 
Liver panel 
AST (SGOT) 
X 
 
 
X 
X 
ALT (SGPT) 
X 
 
 
X 
X 
Alk phos 
X 
 
 
X 
X 
Bilirubin (conj) 
X 
 
 
X 
X 
Bilirubin (total) 
X 
 
 
X 
X 
LDH 
X 
 
 
X 
X 
Albumin 
X 
 
 
X 
X 
Total protein 
X 
 
 
X 
X 
Hematology 
RBC 
X 
 
 
X 
X 
WBC (total and 
differential) 
X 
 
 
X 
X 
HGB 
X 
 
 
X 
X 
HCT 
X 
 
 
X 
X 
Platelets 
X 
 
 
X 
X 


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Clinical Study Protocol No. CR0014 
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CONFIDENTIAL 
 
Page 19 of 24 
Period 
 
Re-Screening Period 
Treatment 
Follow-Up Period 
Visit Time Point 
 
Up to Wk -4 
D 0 
D 2 to D 4 
(48-96 h)1 
Wk 4 
Mth 6 
Visit Window 
 
 
 
 
+/-7 D 
+/-4 Wk 
Coagulation 
aPTT 
X 
 
 
 
 
PT 
X 
 
 
 
 
INR 
X 
 
 
 
 
ACT5 
 
X 
 
 
 
Urinalysis 
Specific gravity 
X 
 
 
X 
X 
pH 
X 
 
 
X 
X 
Glucose 
X 
 
 
X 
X 
Ketones 
X 
 
 
X 
X 
Protein (total) 
X 
 
 
X 
X 
Bilirubin 
X 
 
 
X 
X 
Hemoglobin 
X 
 
 
X 
X 
Nitrite 
X 
 
 
X 
X 
WBC 
X 
 
 
X 
X 
RBC 
X 
 
 
X 
X 
Bacteria 
X 
 
 
X 
X 
Crystals 
X 
 
 
X 
X 
Casts 
X 
 
 
X 
X 
Spot microalbumin 
X 
 
 
X 
X 
Spot creatinine 
X 
 
 
X 
X 
Other 
Pregnancy test 
(serum) 
X 
 
 
X 
X 
Abbreviations: ACT = activated clotting time; Alk phos = alkaline phosphatase; ALT (SGPT) = alanine aminotransferase (serum glutamate pyruvate 
transaminase); aPTT = activated partial thromboplastin time; AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
BUN = blood urea nitrogen; D = day; eGFR = estimated glomerular filtration rate; h = hour; HCT = hematocrit: HGB = hemoglobin; INR = international 
normalized ratio; LDH = lactate dehydrogenase; Mth = month; PT = prothrombin time; RBC = red blood cell(s); Scrn = screening; WBC = white blood 
cell(s); Wk = week; Yr = year 


Ablative Solutions, Inc. 
Clinical Study Protocol No. CR0014 
Version 7.0: 14 DEC 2021
 
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Page 20 of 24 
1 For applicable subjects only (see footnote 2). 
2 Blood sampling for post-contrast serum creatinine measurement is dependent on when imaging procedure is performed and the subject’s eGFR measurement: 
blood is to be drawn and measured 48-96 hours after any procedure where imaging contrast is used and ONLY on subjects with an eGFR of >45 and 
<60 mL/min/1.73 m2 (as measured at the study re-screening visit). 
3 eGFR will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. For all subjects, if the calculated eGFR is 
reduced >25% from baseline (as measured at re-screening visit), the investigator should repeat the serum creatinine test as soon as possible, but no later than 
1 week after the first test. If the repeated calculated eGFR remains >25% from baseline, the investigator should refer the subject for further renal functions 
evaluations, including review by a nephrologist. Similarly, if a subject’s eGFR drops to ≤45 mL/min/1.73 m2, then he/she will have renal function monitored 
and managed by a nephrologist as an additional safety measure following this event and until the event is resolved. In either case, the decrease in eGFR will 
be reported as an AE. 
4 Only calculated for those subjects who have serum creatinine measured at this time point. 
5 Performed per the hospital’s standard of care and analyzed at site. 
 


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Clinical Study Protocol No. CR0014 
Version 7.0: 14 DEC 2021 
 
CONFIDENTIAL 
 
Page 21 of 24 
Figure 1 
Overall Study Design 
 
The subject, sponsor, hypertensionist/nephrologist, and research team performing the screening and follow-up assessments will 
be blinded to the subject’s randomized treatment assignment (Treatment Arm or Sham Control Arm). The interventionalist 
and catheterization laboratory (cath lab) staff will be unblinded. 
2 
At a screening visit, after written informed consent has been provided, initial screening assessments will be made. Subjects 
will then attend for magnetic resonance angiography (MRA) to assess renal vasculature before the start of the run-in period. 
For sites that would prefer to use computed tomography angiography (CTA) instead, agreement may be reached with the 
sponsor on a case-by-case basis (depending upon local regulatory approvals and site capacity). Subjects must have an 
estimated glomerular filtration rate (eGFR) of >45 mL/min/1.73 m2 confirmed before imaging at screening. Subjects who are 
currently taking antihypertensive medications will down-titrate their medications, if necessary, so that they are taking 
0 antihypertensive medications at the start of the run-in period. 
3 
Subjects will take 0 antihypertensive medications from the start of the run-in period (Week -4). During the run-in period, a 
safety visit will take place approximately 2 weeks before the procedure (Week -2). Further study assessments and a final 
check of eligibility criteria will be performed approximately 1 week before the procedure (Week -1), including office blood 
pressure and ambulatory blood pressure monitoring (ABPM) measurements. 
4 
Subjects may be admitted on Day -1 for logistical reasons. For the day of the procedure (Day 0), flexibility in scheduling is 
permitted (up to 1 week), e.g. due to cath lab availability, based on physician discretion and with careful consideration of 
subject safety. Randomization 1:1 (Treatment Arm : Sham Control Arm) will be performed in the cath lab/special procedure 
lab on the day of the procedure (Day 0), after the subject has been sedated and undergone diagnostic renal angiography. 
5 
Subjects will continue to use 0 antihypertensive medications during the first 8 weeks after the procedure (except for 
emergencies). After 8 weeks, antihypertensive medications are permitted, if necessary (see Appendix I)). 
6 
Study unblinding will be performed after the last subject has completed the 1-year follow-up visit. 
7 
Crossover from the Sham Control Arm to the Treatment Arm may be allowed, at the discretion of the treating investigator, 
after the Data Safety Monitoring Board (DSMB) has reviewed the 1-year data from all subjects and the study has been unblinded. 
 
 


Ablative Solutions, Inc. 
Clinical Study Protocol No. CR0014 
Version 7.0: 14 DEC 2021 
 
CONFIDENTIAL 
 
Page 22 of 24 
Figure 2 
Study Flow Diagram: Subject Screening, Run-in, and Treatment 
 
 
BP = blood pressure; DBP = diastolic blood pressure; N = number of subjects; SBP = systolic blood pressure 
 
 
 
In-hospital period
Renal angiography
Randomization 1:1
 Prior to run-in period:
Subject has a mean of 3 office BP measurements: 
SBP ≥140 to ≤180 mmHg AND office DBP ≥90 mmHg
 AND 
Subject is willing not to take any antihypertensive meds for 
12 weeks (4 weeks run-in + 8 weeks post-treatment)   
Treatment Arm:
Renal denervation performed 
with dehydrated alcohol, using 
the Peregrine Catheter
N = 45
Sham Control Arm:
Renal angiography only 
(No renal denervation, no alcohol 
infusion)
N = 45
 At end of run-in period:
Subject has a mean of 3 office BP measurements:
SBP ≥140 to ≤180 mmHg AND office DBP ≥90 mmHg
 AND 
Mean 24-hour ambulatory SBP ≥135 and ≤170 mmHg 
with ≥70% valid readings  
(Baseline BP measurements)
Blinded Treatment
Identify and screen subjects
Approx. N = 400
 
Informed consent signed
before any study-specific 
procedure
Prior to run-in period:
Subject has a mean of 3 office BP measurements: 
SBP of ≥120 mmHg and ≤180 mmHg 
AND 
Subject is willing to discontinue antihypertensive meds, and 
not to take any antihypertensive meds for at least 12 weeks 
(4 weeks run-in + 8 weeks post-treatment) 
Note: All meds must be stopped before run-in.
Subject has documented history of uncontrolled 
hypertension and is on 0 antihypertensive medications
Subject has documented history of uncontrolled 
hypertension and is on 1 or 2 antihypertensive medications
4-week run-in period


Ablative Solutions, Inc. 
Clinical Study Protocol No. CR0014 
Version 7.0: 14 DEC 2021 
 
CONFIDENTIAL 
 
Page 23 of 24 
Figure 3 
Study Flow Diagram: Post-Treatment Milestones and Endpoints 
 
AE = adverse event; BP = blood pressure; DBP = diastolic blood pressure; DSMB = Data Safety Monitoring Board; 
eGFR = estimated glomerular filtration rate; N = number of subjects; SBP = systolic blood pressure. 
 
 


Ablative Solutions, Inc. 
Clinical Study Protocol No. CR0014 
Version 7.0: 14 DEC 2021 
 
CONFIDENTIAL 
 
Page 24 of 24 
Appendix I 
Proposed Structured Drug Titration 
 
After 8 weeks post-treatment, subjects may take antihypertensive medications to maintain a target office 
SBP of <140 mmHg and ≥90 mmHg (based on a mean of 3 measurements). The titration regimen provided 
in the following table should be followed if possible. 
 
Step (Target SBP 
<140 mmHg and ≥90 mmHg)1 
Drug 
Treatment Score 
0 (not needed) 
None 
0 
1 (if needed) 
CCB: mid-dose 
1 
2 (if needed) 
ACE inhibitor or ARB: full dose 
2 
3 (if needed) 
Hydrochlorothiazide 12.5 mg 
3 
4 (if needed) 
Hydrochlorothiazide 25 mg 
4 
5 (if needed) 
CCB: increase to full dose 
5 
6 (if needed) 
Spironolactone or beta-blocker or clonidine 
6 
7 (if needed) 
Spironolactone or beta-blocker or clonidine 
7 
8 (if needed) 
Spironolactone or beta-blocker or clonidine 
8 
Abbreviations: ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BP = blood pressure; CCB = calcium 
channel blocker; SBP = systolic blood pressure. 
 
1 
There will usually be 2 to 3 weeks between steps. If the target is reached, there are no further steps even if BP fluctuates above 
the target. For Steps 6, 7, and 8, the choice of drug and dose is at the investigator’s discretion. If initial systolic BP is 
≥160 mmHg, Steps 1 and 2 can be combined. Fixed-combination drug products can be used to decrease pill burden. 
 
Source: Weber MA, Kirtane A, Mauri L, et al. Renal denervation for the treatment of hypertension: making a new start, getting it 
right. J Clin Hypertens 2015;17(10):743-50. 
 
 

SAP_001.pdf: 
CPL0001, Statistical Analysis Plan 
 
Page 1 
CR0014 
 
 
 
CONFIDENTIAL. The data and information contained herein may not be reproduced, used, or disclosed without 
prior written permission from Ablative Solutions, Inc. 
STATISTICAL ANALYSIS PLAN 
The TARGET BP OFF-MED Trial 
 
A Phase 2, Multicenter, Blinded, Sham Procedure-Controlled Trial of Renal Denervation by the 
Peregrine System Kit, in Subjects with Hypertension, in the Absence of Antihypertensive 
Medications 
 
Sponsor: 
Ablative Solutions, Inc. 
301 Edgewater Place 
Suite 100 
Wakefield, MA 01880 
 
Indication: 
Hypertension 
 
Protocol ID: 
CR0014 v6.0 01 July 2020 
 
Document Date: 
19 November 2021 
Document Version: 
4.0 
 
 


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CONFIDENTIAL. The data and information contained herein may not be reproduced, used, or disclosed without 
prior written permission from Ablative Solutions, Inc. 
TABLE OF CONTENTS 
Section 
Page 
1. 
List of Abbreviations and Definitions of Terms .................................................................................. 4 
2. 
Introduction ............................................................................................................................................ 5 
3. 
Investigational Plan ................................................................................................................................ 6 
3.1. 
Study Objective ........................................................................................................................ 6 
3.2. 
Overall Study Design and Plan ............................................................................................... 6 
3.2.1. 
Blinding ....................................................................................................................... 7 
3.3. 
Description of Study Hypotheses ............................................................................................ 7 
3.4. 
Study Endpoints ....................................................................................................................... 7 
3.4.1. 
Primary Efficacy Endpoint .......................................................................................... 7 
3.4.2. 
Secondary Efficacy Endpoints ..................................................................................... 7 
3.4.3. 
Secondary Safety Endpoints ........................................................................................ 8 
4. 
Patient Populations .............................................................................................................................. 10 
4.1. 
Data Sets to be Analyzed ....................................................................................................... 10 
4.2. 
Protocol Deviations ................................................................................................................ 10 
5. 
Statistical Methods ............................................................................................................................... 11 
5.1. 
Determination of Sample Size ............................................................................................... 11 
5.2. 
General Considerations ......................................................................................................... 11 
5.2.1. 
General Methods........................................................................................................ 11 
5.2.2. 
Adjustments for Covariates ....................................................................................... 11 
5.2.3. 
Handling of Dropouts or Missing Data ...................................................................... 11 
5.2.4. 
Interim Analyses and Data Monitoring ..................................................................... 12 
5.2.5. 
Multicenter Studies .................................................................................................... 12 
5.2.6. 
Multiple Comparisons/Multiplicity ........................................................................... 13 
5.2.7. 
Examination of Subgroups ........................................................................................ 13 
5.2.8. 
Analysis Windows and Definitions ........................................................................... 13 
5.3. 
Patient Disposition, Demographics and Other Baseline Characteristics .......................... 14 
5.3.1. 
Listing of Individual Data .......................................................................................... 14 
5.4. 
Primary Endpoints ................................................................................................................ 14 
5.4.1. 
Primary Efficacy Endpoint ........................................................................................ 14 
5.5. 
Secondary Endpoints ............................................................................................................. 15 
5.5.1. 
Secondary Safety Endpoints ...................................................................................... 16 
5.5.2. 
Secondary Efficacy Endpoints ................................................................................... 16 
5.6. 
Blood Pressure ........................................................................................................................ 19 
5.7. 
Antihypertensive Medications .............................................................................................. 19 
5.8. 
Adverse Experiences .............................................................................................................. 19 
5.8.1. 
Adverse Events .......................................................................................................... 19 
5.9. 
Imaging Core Laboratory Findings ..................................................................................... 20 
5.9.1. 
MRA/CT Angiogram ................................................................................................. 20 
5.9.2. 
Duplex Ultrasound Findings ...................................................................................... 20 
5.10. 
Clinical Laboratory Evaluation ............................................................................................ 21 
5.10.1. Listing of Laboratory Values by Patient .................................................................... 21 
5.11. 
Physical Exam ........................................................................................................................ 21 
5.12. 
Electrocardiogram Findings ................................................................................................. 21 
5.13. 
Additional Concomitant Medications .................................................................................. 21 
5.14. 
Treatment Perception ............................................................................................................ 21 


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prior written permission from Ablative Solutions, Inc. 
5.15. 
Nephrologist Consult ............................................................................................................. 21 
6. 
Changes to Analyses Planned in the Protocol .................................................................................... 22 
7. 
Changes to the Statistical Analysis Plan ............................................................................................. 23 
8. 
References ............................................................................................................................................. 24 
9. 
Statistical Tables to Be Generated ...................................................................................................... 25 
10. 
Data Listings to Be Generated ............................................................................................................ 29 
11. 
Figures to Be Generated ...................................................................................................................... 30 
APPENDIX A – Table Shells ............................................................................................................................. 31 
 


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1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABP 
ambulatory blood pressure  
ABPM 
ambulatory blood pressure monitoring 
AE  
adverse event 
ANCOVA 
analysis of covariance 
ASI 
Ablative Solutions, Inc. 
BP  
blood pressure 
COVID-19 
coronavirus disease of 2019 
CRF 
Case Report Form 
CTA 
computed tomography angiography 
CVA 
cerebrovascular accident 
DSMB  
Data Safety Monitoring Board 
DDD  
defined daily dose 
DUS 
duplex ultrasound 
ECG 
electrocardiogram 
EF  
ejection fraction 
eGFR 
estimated glomerular filtration rate 
ITT 
Intent-to-Treat 
MAE 
major adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI  
myocardial infarction 
MRA 
magnetic resonance angiography 
NYHA 
New York Heart Association 
PP  
Per Protocol 
PT  
Preferred Term 
SAP 
statistical analysis plan 
SAE 
serious adverse event 
SOC 
System Organ Class 
TEAE 
treatment emergent adverse event 
UADE 
unanticipated adverse device effect 
WHO 
World Health Organization 


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2. 
INTRODUCTION 
This statistical analysis plan (SAP) in conjunction with the table shells is intended to 
prospectively (a priori) outline the analyses and presentations of data that will form the basis for 
conclusions to be reached to answer the study objectives outlined in the protocol, and to explain 
in detail how the data will be handled and analyzed, adhering to commonly accepted standards 
and practices of biostatistical analysis in clinical trials. Results obtained from the analyses 
outlined in this document will be the basis of the Clinical Study Report for this study. This plan 
is based on Version 6.0 of the study protocol dated 01 July 2020. 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Objective 
The primary objective of this proof-of-concept study is to evaluate the efficacy of renal 
denervation by alcohol-mediated neurolysis using the Peregrine System™ Kit (also referred to 
as Peregrine Kit) in hypertensive subjects, when used in the absence of antihypertensive 
medications, as evaluated by change in mean 24-hour ambulatory systolic blood pressure (SBP) 
from baseline to 8 weeks post-treatment. 
Secondary objectives are to evaluate the acute and chronic safety of renal denervation by 
alcohol-mediated neurolysis using the Peregrine Kit in hypertensive subjects, up to 2 years 
post-treatment and to evaluate the efficacy of renal denervation by alcohol-mediated neurolysis 
using the Peregrine Kit on blood pressure in hypertensive subjects, up to 1 year post-treatment. 
3.2. 
Overall Study Design and Plan 
This is a Phase 2, prospective, randomized, blinded, sham procedure-controlled, multicenter 
trial to assess the efficacy and safety of renal denervation by alcohol-mediated neurolysis using 
the Peregrine Kit. Subjects with a documented history of uncontrolled hypertension who are 
taking 0, 1, or 2 antihypertensive medications at enrollment will be recruited. Following 
screening, eligible subjects will enter a 4-week run in period during which they will take no 
antihypertensive medications. 
Subjects who continue to be eligible at the end of the run-in period will be randomized in a 1:1 
ratio to one of the following 2 groups via central randomization (stratified by study site): 
• Treatment Arm: renal denervation (using the Peregrine Kit) performed with alcohol 
(0.6 mL per treated renal artery) infused through the Peregrine Catheter (minimum 
treatment: the 2 main renal arteries [1 per side]; physician is also permitted to treat up to 
1 additional accessory artery on each side. Thus, the planned maximum total dose of 
alcohol is 4 x 0.6 mL = 2.4 mL.) 
• Sham Control Arm: only renal angiography will be performed. No renal denervation and 
no alcohol infusion will be performed. 
Subjects will be discharged from the study site the day after the procedure if there are no safety 
concerns, per the physician’s judgment. Subjects with an estimated glomerular filtration rate 
(eGFR) of >45 and <60 mL/min/1.73 m2 will return to provide a blood sample for measurement 
of serum creatinine 48 to 96 hours after the procedure. Subjects will continue to take no 
antihypertensive medications during the first 8 weeks after the procedure (except for 
emergencies, as defined in the protocol). After 8 weeks, antihypertensive medications are 
permitted according to the protocol-defined criteria and proposed titration scheme. 
Follow-up visits will be performed at 4 weeks, 8 weeks, 3 months, 6 months, 1 year, and 
2 years, as well as telephone contacts at 2 and 6 weeks in Ireland only. 
The study will be unblinded after the last subject has completed the 6-month visit. 
Crossover from the Sham Control Arm to the Treatment Arm may be allowed, at the discretion 
of the treating investigator, after the Data Safety Monitoring Board (DSMB) has reviewed the 
6-month data from all subjects, the study has been unblinded, and the subject has completed the 
1-year follow-up visit.  


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A subject is considered enrolled once he/she signs the informed consent form. All enrolled 
subjects will then proceed to complete the screening and baseline tests. If they do not meet the 
study criteria, they will be withdrawn from the study (status Screen Failure) and will not count 
towards the treated study population.  
3.2.1. 
Blinding 
The subject, sponsor, and hypertensionist/nephrologist performing the screening and follow-up 
assessments are blinded. The interventionalist and cath lab staff are unblinded. Details of study 
blinding are contained in the study Randomization and Blinding Plan. 
3.3. 
Description of Study Hypotheses 
This study is designed as a proof-of-concept study. It is therefore not formally powered for the 
primary endpoint. The purpose of the trial is to determine if there is an adequate treatment effect 
to proceed to a pivotal study. It is planned to randomize approximately 90 subjects (45 per group) 
to achieve 80 evaluable subjects (for the primary efficacy endpoint analysis). 
Primary Efficacy Endpoint 
The primary efficacy endpoint of the change in mean 24-hour ambulatory SBP at 8 weeks 
post-treatment will be compared between the 2 treatment groups. 
The following table provides examples of observed treatment effects and standard deviations 
(SDs) that would be considered statistically significant at alpha = 0.05, for the change in mean 
24-hour ambulatory SBP at 8 weeks post-treatment with 80 evaluable subjects: 
Treatment Difference 
Standard Deviation 
3.5 mmHg 
8 mmHg 
4.4 mmHg 
10 mmHg 
5.3 mmHg 
12 mmHg 
A study of the planned size would be powered at 80% to detect a difference between intervention 
and control of 5.1 mmHg assuming a SD of 8 mmHg in each group and two-sided alpha of 0.05 
using the independent two-sample t-test. A difference between treatment and control of 5 mmHg 
is considered clinically meaningful and consistent with previous trials of renal denervation in a 
similar population (Townsend et al. 2017). An observed difference between groups of 5 mmHg 
with an observed SD as high as 11.2 mmHg per group would be considered statistically significant 
at a two-sided alpha level of 0.05. 
3.4. 
Study Endpoints 
3.4.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the change in mean 24-hour ambulatory SBP from 
baseline to 8 weeks post-treatment. This will be summarized and compared between the 
2 treatment groups using the independent two-sample t-test. 
3.4.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 


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• Change in mean 24-hour ambulatory diastolic blood pressure (DBP) from baseline to 
8 weeks 
• Change in mean 24-hour ambulatory SBP and DBP from baseline to 6 months and 1 year 
• Change in mean daytime (07:00 to 21:59) ambulatory SBP and DBP from baseline to 
8 weeks, 6 months, and 1 year 
• Change in mean nighttime (22:00 to 6:59) ambulatory SBP and DBP from baseline to 
8 weeks, 6 months, and 1 year 
• Change in mean office SBP and DBP from baseline to 8 weeks, 6 months, 1 year, and 
2 years 
• Percentage of subjects controlled to target blood pressure values. 
• Use of antihypertensive medication(s) from time of procedure to 8 weeks post-treatment 
(emergency use medication). 
• Use of antihypertensive medication(s) (including increases/decreases) from 8 weeks to 
6 months post-treatment (titrated according to standardized formula to maintain a target 
office SBP of <140 mmHg and ≥90 mmHg, see Section 7.2.2 of the protocol for more 
detail regarding medication titration). 
• Compliance with not taking antihypertensive medications, as assessed by blood and urine 
testing, through 8 weeks post-treatment. 
3.4.3. 
Secondary Safety Endpoints 
Secondary safety endpoints include: 
• 
Major adverse events (MAEs) through 30 days post-treatment, as adjudicated by the Clinical 
Events Committee (CEC). A MAE is defined as any of the following: 
o 
All-cause death 
o 
End-stage renal disease (ESRD) (eGFR <15 mL/min/1.73 m2 or need for renal 
replacement therapy) 
o 
Significant embolic event resulting in end-organ damage or requiring intervention to 
prevent it 
o 
Major vascular complications, including major renal artery dissection, renal artery 
aneurysm or pseudoaneurysm that required intervention or led to renal artery stenosis 
(>60% diameter stenosis) 
o 
Major bleeding related to renal denervation within the renal arteries, or related to the 
Peregrine Catheter when in the body (per protocol bleeding definition) 
o 
Significant acute (post-procedural) renal artery stenosis (>60% diameter stenosis) as 
indicated by the renal angiogram post renal denervation, and confirmed by the 
angiography core laboratory, which led to one of the following: (i) acute kidney injury 
per modified Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease 
(RIFLE) definition, as confirmed by renal function blood test, or (ii) percutaneous 
intervention. 
o 
Hypertensive crisis (hypertensive emergency only) 


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o 
Hypotensive crisis 
o 
Symptomatic hypotension that required a change in antihypertensive medications, or 
medications to increase blood pressure (e.g., persistent syncope, lightheadedness) 
• 
Changes in eGFR from baseline to 8 weeks and 6 months post-treatment. 
• 
Decreases in eGFR >25% from baseline to 8 weeks and 6 months post-treatment. 
• 
Rate of adverse events (AEs) (serious and non-serious), peri-procedurally, at discharge, and 
at each of the follow-up time points. 
• 
Device success (defined as the ability to insert the Peregrine Catheter into the lumen of the 
renal artery [target vessel], deploy the guide tubes inside the renal artery, deploy the needles 
through the arterial wall, deliver the intended dose of alcohol, retract the needles and the guide 
tubes back in the catheter, and remove the catheter from the access site without any related 
complications or events) 
• 
Procedure success (defined as device success with freedom from peri-procedural MAEs). 
Adverse events will be recorded from the time of signing the informed consent form through the 
end of study participation. Date of report; date of onset; whether the AE is serious or not; whether 
the AE is considered an MAE; whether the AE is considered a serious adverse device effect 
(SADE); whether the AE is considered a suspected unexpected adverse drug reaction; causal 
relationship (to Peregrine Catheter, study drug [alcohol], and study procedure, separately); action 
taken; outcome; date recovered/resolved; and date of death (if applicable) of each adverse event 
will be recorded.   


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4. 
PATIENT POPULATIONS 
4.1. 
Data Sets to be Analyzed 
The Intent-to-Treat (ITT) Analysis Set will include all subjects who were randomized regardless 
of whether treatment was received. Subjects will be analyzed according to their randomized 
treatment group, irrespective of treatment received. 
The Safety Analysis Set will include all subjects who received treatment. Subjects will be 
analyzed according to the actual treatment received, irrespective of treatment assignment. 
The Per-Protocol (PP) Analysis Set will include subjects with no important protocol deviations. 
Subjects will be analyzed according to the actual treatment received. Important protocol 
deviations include:  
• Not meeting inclusion/exclusion criteria 
• Not receiving bi-lateral treatment or an unsuccessful procedure 
• Receiving anti-hypertensive treatment prior to evaluation of the primary ambulatory blood 
pressure monitoring (ABPM) measurement 
• Not completing the primary ABPM measurement  
All deviations will be reviewed prior to unblinding to assess if additional exclusions will be 
applied. 
Unless otherwise noted, the ITT and PP Analysis Sets will be used for all efficacy analyses and 
safety analyses will be conducted in the Safety Analysis Set. 
4.2. 
Protocol Deviations 
This study will be conducted as described in the protocol, except for an emergency situation in 
which the protection, safety, and well-being of the patient require immediate intervention, based 
on the judgment of the investigator (or a responsible, appropriately trained professional 
designated by the investigator). All protocol deviations will be documented on the protocol 
specific deviation form of the eCRF. All protocol deviations will be summarized. Those 
protocol deviations associated with COVID-19 will be additionally summarized separately as 
indicated by the site and checked on the eCRF. 


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5. 
STATISTICAL METHODS 
5.1. 
Determination of Sample Size 
The study is not powered for formal hypothesis testing.  
5.2. 
General Considerations 
5.2.1. 
General Methods 
Two unblinded team members (either two statisticians or a statistician and a statistical 
programmer) will be assigned for all analyses. This will allow for discussion of output and 
direct QC of statistical programming on the exact same dataset.  
In general, continuous variables will be summarized with descriptive statistics (n, mean, SD, 
range, median, and interquartile range). The difference between groups will be presented and 
the normal approximation will be used to calculate two-sided 95% confidence intervals (CIs). 
Change from baseline, when relevant, will be computed as the paired mean difference and 95% 
CI of the mean difference at each time point. 
For all continuous primary and secondary blood pressure endpoints, changes over time will be 
additionally explored in mixed effects repeated measures analyses, including the values at all 
time points. 
Categorical variables will be summarized as frequencies and percentages. Relative risks and 
95% CIs will be computed. 
All statistical analyses will be performed using SAS® Version 9.4 or higher (SAS Institute, 
Cary, NC 27513, USA). 
For each variable, the baseline value will be defined as the last value collected before the 
procedure.  
There will be no formal hypothesis testing conducted in the study. Ninety-five percent CIs, 
when presented, are intended to be descriptive in nature only. For binary variables, CIs will be 
calculated via exact binomial methods. For continuous variables, the CI of the mean will be 
constructed using the normal approximation. 
5.2.2. 
Adjustments for Covariates 
Analysis of changes in blood pressure measures will be adjusted for baseline values using 
analysis of covariance (ANCOVA). Raw mean values will be presented, however, comparisons 
between groups will include the baseline value of the associated measure as described below. 
There is no other planned adjustment for covariates. 
5.2.3. 
Handling of Dropouts or Missing Data 
For the primary efficacy endpoint analysis, all available data will be used. As additional 
analyses, patients who meet the protocol defined criteria for antihypertensive drug treatment 
within the 8 weeks prior to assessment of the primary endpoint will be assigned their baseline 
value of ABPM at 8 weeks. Additional sensitivity analyses will be conducted removing those 


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subjects who receive antihypertensive treatment within 8 weeks. Also, as a secondary sensitivity 
analysis, missing data will be imputed via multiple imputation techniques. 
There will be no imputation of data for secondary efficacy endpoints or other endpoints; only 
available data will be used, with the exception of analyses at 8 weeks for subjects receiving 
protocol defined antihypertensive therapy within 8 weeks. Analyses will be conducted with all 
available data and only in subjects who did not receive antihypertensive treatment between 
baseline and 8 weeks. 
This study allows for cross-over of control subjects once the participant has passed the 1-year 
study visit.  Subjects who cross-over will be considered withdrawn from the main study as of 
the day of their cross-over procedure and will no longer be analyzed with the main study cohort 
(i.e., their data will be missing for any subsequent scheduled study visits).  
5.2.4. 
Interim Analyses and Data Monitoring 
There are 2 planned interim analyses: a blinded 8-week interim analysis (conducted after all 
subjects have completed the 8-week visit), and an unblinded 6-month interim analysis 
(conducted after all subjects have completed the 6-month visit and the study has been 
unblinded).  
Neither of the planned interim analyses for this study is intended to be assessed with the purpose 
of altering the study design or sample size. 
The 8-week interim analysis will include available data through the 8-week assessment 
including, but not limited to, primary efficacy and safety data. The individual treatment 
assignments will remain blinded at this time. The 8-week interim analysis will be assessed by 
the unblinded DSMB in accordance with the DSMB charter. Analysis will be conducted by the 
independent unblinded DSMB statistician. Only aggregate data, by treatment group, will be 
provided outside of the DSMB. Data will be cleaned to the extent possible but not locked for 
this analysis. All outstanding adjudications for events occurring with 8-weeks should be 
resolved. A separate interim analysis plan will provide additional details as to the content and 
dissemination of these results. 
The 6-month interim analysis will include all available data through 6 months. The study will be 
unblinded for analysis at this time. The 6-month interim analysis results will help inform the 
appropriateness of the crossover. 
5.2.5. 
Multicenter Studies 
Consistency of the primary efficacy endpoint across study sites (centers) will be examined. 
Results will be presented by study site. There will be insufficient power to determine differences 
between sites, however, any notable differences between sites will be explored. Sites with less 
than 10 subjects may be combined by country in order to assess if there are statistical 
differences between sites. The interaction p-value from the ANOVA model for treatment by site 
will be calculated. A p-value < 0.15 will be viewed as evidence of differences between sites and 
will be discussed in the final study report. 


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Additionally, regions (US and Europe) will be pooled for the analysis by treatment group. 
Consistency of the effects by region will be explored by displaying the primary efficacy results 
by region. The interaction term for region by treatment will be calculated using analysis of 
variance. A treatment by region interaction p-value less than 0.15 will be explored further and 
described in the final study report. 
5.2.6. 
Multiple Comparisons/Multiplicity 
There is no formal hypothesis testing and thus no adjustment for alpha in necessary. In addition, 
there is a single primary endpoint in this study. Analyses of secondary endpoints are considered 
supportive. As such, there is no adjustment to alpha for multiplicity necessary to control Type I 
error. 
5.2.7. 
Examination of Subgroups 
The following subgroups will be presented for the primary efficacy endpoint in the ITT analysis 
set: 
• Age grouped according to the median age 
• Gender (male vs. female) 
• Region (US vs Europe) 
• Ethnicity (US only) 
• Race (US only) 
• Country 
• Subjects who require a change of antihypertensive drugs during the post-procedure 
follow-up period 
• Subjects with baseline ambulatory SBP >140 mmHg and DBP <90 mmHg versus all other 
subjects 
• Subjects with baseline eGFR within the following groupings 45-60, 61-75, and 
>75 mL/min/1.73 m2. Comparison of changes in eGFR will also be explored within this 
subgroup.  
The following subgroup will be presented for the secondary efficacy endpoints in the ITT 
Analysis Set: 
• Subjects with baseline daytime ambulatory SBP >140 mmHg and DBP <90 mmHg versus 
all other subjects. 
5.2.8. 
Analysis Windows and Definitions 
The following visit windows were defined per protocol for follow-up: 
Week -1 
(- 7 days) 
Week 4  
(28 days) 
Week 8  
(56 days) 
Month 3 
(90 days) 
Month 6 
(180 days)  
Year 1 and 2 
(365 and 730 days) 
± 2 days 
± 7 days 
± 7 days 
± 2 weeks  
(14 days) 
± 4 weeks 
(28 days) 
± 8 weeks 
(56 days) 
 


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For the day of the procedure (Day 0), flexibility in scheduling is permitted (up to 1 week), 
e.g., due to cath lab availability, based on physician discretion and with careful consideration of 
subject safety, thus data collected at the Week -1 visit will be acceptable if the day of procedure 
is extended by 1 week such that values up to 16 days (14+2 days) prior to procedure will be 
considered valid reading for analysis of baseline measures. If multiple baseline values are 
present prior to procedure, the valid reading that is closest to the day of procedure within 
window will be used.  
 
For the purposes of statistical analysis, the 8-week window will be extended to -15 and +30 days 
(i.e., the window for valid data will range from 41 to 86 days) allowing blood pressure measures 
collected within a reasonable time frame but beyond the protocol defined window to be 
analyzed, provided that the subject remains off antihypertensive medication prior to the visit 
assessments at 8 weeks.  
 
A table summarizing visit compliance will be included as part of the overall subject disposition.  
5.3. 
Patient Disposition, Demographics and Other Baseline Characteristics 
A tabulation of patient disposition will be presented including number treated, number 
completing each visit and number of withdrawals and lost to follow-up, including primary 
reason for withdrawal as documented on the case report form. 
Baseline demographics and medical history will be summarized for the ITT, PP and Safety 
analysis sets. 
5.3.1. 
Listing of Individual Data 
A by-patient listing of key demographic data and medical history will be presented. 
5.4. 
Primary Endpoints 
The primary efficacy endpoint will be summarized in the ITT analysis set and the PP analysis 
set (if it differs from ITT). For the primary efficacy endpoint analysis, the primary population 
for analysis is ITT, while the PP population is considered supportive (for sensitivity analyses). 
5.4.1. 
Primary Efficacy Endpoint 
The mean change in 24-hour ambulatory SBP from baseline to 8 weeks post-treatment will be 
presented in each group. The difference between groups will be summarized and compared using 
ANCOVA with adjustment for the baseline 24-hour ambulatory SBP.  
The protocol defined window for the 8-week (56 day) visit is ±7 days. For the purposes of 
analysis, measurements obtained within -15 days or +30 days (i.e., between 41 and 86 days) will 
be considered valid and will be analyzed as part of the primary endpoint analysis, provided that 
the subject remained off antihypertensive medication prior to collection of ABPM.    
For the primary analysis, all available data will be used. There will be no imputation of data at 8 
weeks. This analysis will be repeated in the PP analysis set. 
In addition to the primary analysis, the following secondary and sensitivity analyses will be 
conducted: 


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1. Subjects who meet the protocol defined criteria for antihypertensive drug treatment and 
receive treatment within the 8 weeks prior to assessment of the primary endpoint will 
have their 8-week value imputed with their baseline value of ABPM.   
2. Subjects who meet the protocol defined criteria for antihypertensive drug treatment and 
receive treatment within 8 weeks will be removed from the analysis.  
3. Subjects who receive antihypertensive treatment within 8 weeks for any reason or in 
whom antihypertensive medications are detected via compliance samples will be 
removed from the analysis.  
4. Missing data at 8 weeks will be imputed via multiple imputation techniques. The 
following covariates will be considered for the imputation: treatment group, age, gender, 
history of diabetes, BMI, anatomy defined by length from ostium to bifurcation, number 
of medications at baseline, baseline office systolic pressure, 8-week office systolic 
pressure, baseline 24-hour ambulatory SBP. These factors were chosen based on clinical 
experience and recent literature (Fengler, 2016) (Id, 2016) (Kandzari, 2015). 
5. Missing data at 8 weeks and data for those subjects who meet the protocol defined 
criteria for antihypertensive drug treatment and receive treatment within 8 weeks will be 
imputed via multiple imputation techniques. 
An additional exploratory analysis will be conducted, which combines the treatment failures 
(subjects receiving rescue medication) with the continuous 24-hour ambulatory SBP 
measurement in a hierarchical fashion using the approach described in Finkelstein and 
Schoenfeld (1999) and later adapted to the Win Ratio by Pocock (2012). Using this approach, 
each subject is compared to every other subject first as to whether or not the subject received 
rescue medication. If both subjects did or did not receive rescue medication (i.e., there is a tie), 
then the subjects will have their change in 24-hour ambulatory SBP at 8 weeks compared. A 
score of -1 will be assigned to a loss and a score of +1 will be assigned to a win. For example:  
• If Subject A receives rescue medication within 8 weeks and Subject B does not, Subject 
A loses (score -1), and Subject B wins (score +1) 
• If neither receive rescue medication within 8 weeks, then if Subject A has a larger 
reduction in 24-hour ambulatory SBP at 8 weeks compared to Subject B, then Subject A 
wins (score +1) and Subject B loses (score -1).  
After all between-subject comparisons have been performed, scores will be summed to obtain a 
cumulative score for each subject, and the scores between treatment groups will be compared 
using the Mann-Whitney U test. The resulting p-value will be presented. The win ratio will also 
be presented. It is calculated as number of "wins" divided by the number of losses out of all 
comparisons of intervention to sham subjects.     
5.5. 
Secondary Endpoints 
In general, all secondary efficacy endpoints will be summarized in the ITT Analysis Set and the 
PP Analysis Set (if it differs from ITT). All secondary safety endpoints, with the exception of 


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Device and Procedure Success, will be summarized in the Safety Analysis Set. Device and 
Procedure Success will be summarized in the ITT Analysis Set. 
5.5.1. 
Secondary Safety Endpoints 
5.5.1.1. MAE within 30 days 
The number and percent of subjects experiencing any MAE within 30 days as adjudicated by the 
clinical events committee will be summarized and two-sided 95% exact CIs will be reported. 
The difference between groups will be summarized, two-sided 95% exact Cis will be reported 
and the groups will be compared via the Fisher’s Exact test. Only subjects who have 
experienced an MAE within 30 days or who have at least 21 days of follow-up (includes 
subjects who have had their 4 weeks visit minus the allowable visit window). These analyses 
will be conducted in the Safety Analysis Set. 
5.5.1.2. Changes in eGFR from Baseline to 8 weeks and 6 months Post-Treatment 
The change in eGFR will be summarized between baseline and 8 weeks and baseline and 
6 months. Changes in eGFR at 8 weeks and 6 months will be compared between groups using 
the independent two-sample t-test. These analyses will be conducted in the Safety Analysis Set. 
5.5.1.3. Decreases in eGFR >25% from Baseline to 8 weeks and 6 months Post-Treatment  
The number and percent of patients with greater than a 25% reduction in eGFR will be 
summarized at 8 weeks and 6 months. Groups will be compared using Fisher’s Exact test. These 
analyses will be conducted in the Safety Analysis Set. 
5.5.1.4. Rate of Adverse Events (Serious and Non-Serious), Peri-Procedurally, at Discharge, and at 
Each of the Follow-up Time Points. 
Coded AEs will be summarized at each follow-up time period (any events occurring prior to and 
including the follow-up time) and overall according to system organ class (SOC) and Preferred 
Term (PT) by treatment group as described in Section 5.8.1 below. 
5.5.1.5. Device Success 
Device success is defined as the ability to insert the Peregrine Catheter into the lumen of the 
renal artery [target vessel], deploy the guide tubes inside the renal artery, deploy the needles 
through the arterial wall, deliver the intended dose of alcohol, retract the needles and the guide 
tubes back in the catheter, and remove the catheter from the access site without any related 
complications or events. The number and percent of devices used successfully will be 
summarized in the treated group. Devices opened but not used (i.e. no attempt was made to 
insert the device into the body) will not be included in the summary. These analyses will be 
conducted in the ITT analysis set.  
5.5.1.6. Procedure Success 
Procedure success is defined as device success with freedom from peri-procedural MAEs and 
will be summarized at the subject level. The number and percent of subjects who experience 
procedure success will be summarized in the treatment group. These analyses will be conducted 
in the ITT Analysis Set.  
5.5.2. 
Secondary Efficacy Endpoints 


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5.5.2.1. Change in Mean 24-hour, Daytime, and Nighttime Ambulatory SBP and DBP from Baseline to 
Time Points Post-Treatment. 
The mean change in ambulatory blood pressures at all collected time points will be reported 
with 95% CIs as described in Section 5.6. These analyses will be conducted in the ITT and PP 
analysis sets. 
The sensitivity analyses as proposed in Section 5.4.1 for the primary mean 24-hour SBP will be 
additionally conducted for the 8-week daytime and nighttime SBP. 
5.5.2.2. Change in Mean Office SBP and DBP from Baseline to Time Points Post-Treatment. 
The mean change in office blood pressures at all collected time points will be reported with 95% 
CIs as described in Section 5.6. These analyses will be conducted in the ITT and PP analysis 
sets. 
The sensitivity analyses as proposed in Section 5.4.1 for the primary mean 24-hour SBP will be 
additionally conducted for the 8-week office SBP. 
5.5.2.3. Percentage of Subjects Controlled to Target Blood Pressure Values. 
The number and percent of patients controlled to target office blood pressure of <140 and 
>90 mmHg will be summarized by treatment group and compared via Fisher’s Exact test. These 
analyses will be conducted in the ITT and PP analysis sets. 
5.5.2.4. Use of Antihypertensive Medication(s) from Time of Procedure to 8 weeks Post-Treatment 
(Emergency Use Medication). 
The mean change in the number of antihypertensive medications will be summarized as described 
in Section 5.7 along with 95% CIs for the mean change in number of medications. The addition 
of new antihypertensive drugs will be considered an intensification of the antihypertensive 
regimen. Discontinuation of one or more of the baseline antihypertensive medications without an 
increase in dose of remaining drugs or addition of new drugs will be considered a reduction in 
antihypertensive drug regimen. 
Antihypertensive dose titration will be scored according to the protocol as defined in the tables 
below. The mean treatment score will be reported by treatment group and the groups compared 
via Fisher’s Exact test. These analyses will be conducted in the ITT and PP analysis sets. 


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Step (Target SBP 
<140 mmHg and 
≥90 mmHg)1 
Drug 
Treatment Score2 
0 (not needed) 
None 
0 
1 (if needed) 
CCB: mid-dose 
1 
2 (if needed) 
ACE inhibitor or ARB: full dose 
2 
3 (if needed) 
Hydrochlorothiazide 12.5 mg 
3 
4 (if needed) 
Hydrochlorothiazide 25 mg 
4 
5 (if needed) 
CCB: increase to full dose 
5 
6 (if needed) 
Spironolactone or beta-blocker or clonidine 
6 
7 (if needed) 
Spironolactone or beta-blocker or clonidine 
7 
8 (if needed) 
Spironolactone or beta-blocker or clonidine 
8 
Abbreviations: ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BP = blood pressure; 
CCB = calcium channel blocker; SBP = systolic blood pressure. 
1. There will usually be 2 to 3 weeks between steps. If the target is reached, there are no further steps even if BP 
fluctuates above the target. If initial systolic blood pressure (SBP) is ≥160 mmHg, Steps 1 and 2 can be 
combined. Fixed-combination drug products can be used to decrease pill burden. 
2. The treatment score will be used for the purpose of the statistical analysis. 
Source: Weber et al. 2015 
5.5.2.5. Use of Antihypertensive Medication(s) (including Increases/Decreases) from 8 weeks to 
6 months Post-Treatment (Titrated According to Standardized Formula to Maintain a Target 
SBP of <140 mmHg and ≥90 mmHg). 
The mean change in the number of antihypertensive medications will be summarized as described 
in Section 5.7 along with 95% CIs for the mean change in number of medications. The addition 
of new antihypertensive drugs will be considered an intensification of the antihypertensive 
regimen. Discontinuation of one or more of the baseline antihypertensive medications without an 
increase in dose of remaining drugs or addition of new drugs will be considered a reduction in 
antihypertensive drug regimen. 
The mean treatment score will be reported by treatment group and the groups compared via 
Fisher’s Exact test. These analyses will be conducted in the ITT and PP analysis sets. 
5.5.2.6. Compliance with Not Taking Antihypertensive Medications Through 8 weeks Post-Treatment. 
The number and percent of patients in whom no antihypertensive medications are detected 
according to urine compliance results will be summarized by treatment group and compared 
using Fisher’s Exact test. Subjects who meet the protocol defined criteria for antihypertensive 
drug treatment and receive treatment within 8 weeks will be excluded from the analysis. These 
analyses will be conducted in the ITT and PP analysis sets. 
5.5.2.7. Use of Antihypertensive Medication(s) according to Defined Daily Dose. 
In addition to the protocol specified analyses as described above, prescribed medications will be 
summarized according to the sum of the defined daily dose (DDD) in order to assess and 


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compare total drug consumption between groups (World Health Organization Collaborating 
Centre for Drug Statistics, 2019). The data will be expressed as DDD/100 patient days. 
5.6. 
Blood Pressure 
Blood pressure will be summarized at each visit for the various blood pressure measures: office 
BP (Screening (Week -8), run-in (Week -2), baseline (Week -1), 4 weeks, 8 weeks, 3 months, 
6 months, 1 year and 2 years), 24-hour ABPM (baseline [Week -1], 8 weeks, 6 months and 1 
year), daytime ABPM (baseline [Week -1], 8 weeks, 6 months and 1 year) and nighttime ABPM 
(baseline [Week -1], 8 weeks, 6 months and 1 year). Both systolic and diastolic blood pressure 
will be presented separately. The mean values at each visit will be presented along with the 
mean change from baseline (and the matched baseline data for each visit).  
The number and percentage of subjects with any decrease from baseline in the various blood 
pressure measures will be presented. The number and percentage of subjects with any, 
≥5 mmHg, ≥10 mmHg, and ≥20 mmHg decreases in blood pressure at each time point will be 
presented. 
Ninety-five percent CIs for the change in mean blood pressure will be computed as well as the 
95% CI for the percentage of subjects with any decrease in blood pressure. 
These analyses will be conducted in the ITT analysis set. 
In order to assess the totality of the data over time, changes in blood pressure at the 8-week, 
3-month, 6-month, and 1-year and 2-year (office BP only) visits will be plotted over time by 
treatment group and assessed via a mixed effects repeated measures model. All available data at 
the time of analysis will be included in the model. This analysis will be conducted in the ITT 
analysis set with available data. 
 
5.7. 
Antihypertensive Medications 
The mean number of antihypertensive medications will be summarized at baseline, 8 weeks, 
6 months, 1 year and 2 years. The number and percentage of patients on 0 to 3, and >3 
medications will additionally be presented. The mean change from baseline in the number of 
antihypertensive medications at each visit will be presented along with the matched baseline 
mean values. Antihypertensive medications will also be summarized by class. These analyses 
will be conducted in the ITT Analysis Set. 
5.8. 
Adverse Experiences 
5.8.1. 
 Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) per the data management plan for the study. Summary statistics for AEs will be 
presented by MedDRA system organ class and preferred term.  
Treatment-emergent AEs (TEAEs) are defined as AEs that meet one of the following criteria: 
• Have a start date and time during or after the procedure 
• Have a missing start date, and the stop date is after the procedure 


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• Have a start date and time before the procedure, but have a worsening severity during or 
after the procedure. 
Overall summary statistics (number of events, and number and percentage of subjects) will be 
prepared by treatment group for the following treatment-emergent events: TEAEs, related 
TEAEs, SAEs, related SAEs, MAEs, related MAEs (per investigator and CEC adjudication), 
AEs leading to study discontinuation, AEs leading to procedure interruption/discontinuation, 
and deaths. 
Related AEs are those AEs that are recorded as being related to the study procedure/treatment. 
Events for which the relationship is not recorded will be considered as related for the purpose of 
the tabular summaries. 
Rates of AEs (serious and non-serious), peri-procedurally, at discharge, and at each of the 
follow-up time points will be summarized cumulatively as follows: 
• Frequency (number and percentage of subjects) with TEAEs, overall and by MedDRA 
system organ class and preferred term 
• Frequency (number and percentage of subjects) with treatment-emergent SAEs, overall 
and by MedDRA system organ class and preferred term  
• Frequency 
(number 
and 
percentage 
of 
subjects) 
with 
each 
site-reported 
treatment-emergent AE or SAE, by relationship to the investigational device or procedure 
according to both the investigator and the CEC (SAEs only) 
• Frequency (number and percentage of subjects) with each site-reported treatment-
emergent AE or SAE, by severity. 
These analyses will be conducted in the Safety Analysis Set. 
AEs and SAEs that start before the procedure (i.e. which are not treatment-emergent) will also 
be listed for all enrolled subjects, including screen failures. 
5.8.1.1. Listing of Adverse Events by Patient 
A by-patient listing of all adverse events reported, including date started/stopped, seriousness, 
intensity, relationship to study drug, action taken, and outcome will be presented in the data 
listings. TEAEs will be flagged in the listing. 
5.8.1.2. Listing of Device Deficiencies by Patient  
A by-patient listing of any device deficiency reported will be included in the data listings. 
5.9. 
Imaging Core Laboratory Findings 
5.9.1. 
MRA/CT Angiogram 
Results of the magnetic resonance angiography (MRA)/computed tomography (CT) assessments 
will be summarized at each imaging visit (baseline and 6 months) for all subjects by treatment 
group. These analyses will be conducted in the ITT Analysis Set. 
5.9.2. 
Duplex Ultrasound Findings 


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Results of the duplex ultrasound (DUS) will be summarized at 6 months for all subjects by 
treatment group. These analyses will be conducted in the ITT Analysis Set. 
5.10. 
Clinical Laboratory Evaluation 
Laboratory measurements, including chemistry, hematology, coagulation panel, and urinalysis, 
will be summarized at each visit, as applicable, and shift tables will be presented for changes 
from baseline to post-baseline at 8 weeks, 6 months, 1 year and 2 years. These analyses will be 
conducted in the Safety Analysis Set. 
5.10.1. Listing of Laboratory Values by Patient 
A by-patient listing of all laboratory values will be included. 
5.11. 
Physical Exam 
Physical exam will be summarized at each visit (baseline, discharge, 4 weeks, 8 weeks, 
6 months, 1 year and 2 years). These analyses will be conducted in the ITT Analysis Set. 
5.12. 
Electrocardiogram Findings 
Electrocardiogram findings will be summarized at screening and 6 months. Any new 
abnormality at 6 months will summarized.   
5.13. 
Additional Concomitant Medications 
5.13.1.1. Listing of Concomitant Medications by Patient 
A by-patient listing of all concomitant medications reported, drug name, indication, date 
started/stopped, dose, and route of administration, will be presented in the data listings. This 
listing will include all antihypertensive medications as well as any other medications reported 
during the trial. 
5.14. 
Treatment Perception 
The treatment perception questionnaire will be summarized at procedure and 8 weeks. The Bang 
(Bang, 2004) and James (James, 1996) blinding indices will be calculated and provided along 
with 95% CIs. These analyses will be conducted in the ITT Analysis Set. 
5.15. 
Nephrologist Consult 
The nephrologist consult comments will be provided as a data listing.  
 


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6. 
CHANGES TO ANALYSES PLANNED IN THE PROTOCOL 
There are no changes to the planned analyses in the protocol.   
 


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7. 
CHANGES TO THE STATISTICAL ANALYSIS PLAN 
 
Version / Date 
Old Analysis 
New Analysis 
Reason for change 
2.0 28Sep2020 
n/a 
Telephone contacts at 2 and 
6 weeks in Ireland only 
added. 
Updated per Protocol V6.0 
 
 
Those protocol deviations 
associated with COVID-19 
will be additionally 
summarized separately. 
Per FDA guidance 
 
 
Subgroups added: 
• Region (US vs Europe) 
• Ethnicity (US only) 
• Race (US only) 
Updated per Protocol V6.0 
 
 
Analysis windows clarified 
and description expanded 
Clarification 
 
 
Added repeated measures 
analysis of blood pressure. 
Oversight 
3.0 08Dec2020 
8-week primary analysis 
window not defined, 
assumed to be per the 
protocol 
8-week primary analysis 
window expanded.  
Addition, clarification 
 
No imputation specified for 
primary analysis 
Imputation of data for 
subjects who meet the 
criteria for antihypertensive 
drug treatment for the 
primary analysis clarified. 
Clarification 
 
n/a 
Sensitivity analyses added 
for all 8-week BP measures 
Addition 
 
n/a 
Exploratory hierarchical 
analysis added  
Addition 
 
Comparison between 
groups for BP 
measurements via t-test 
Comparison between group 
for BP measures by 
ANCOVA adjusting for 
baseline BP 
Per FDA guidance for the 
Target BPI study, and for 
consistency between the 2 
studies 
4.0 19Nov2021 
n/a 
Two unblinded team 
members (either two 
statisticians or a statistician 
and a statistical programmer) 
will be assigned for all 
analyses.  
CAPA-00012 
 


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8. 
REFERENCES 
Bang H, Ni L, Davis CE (2004). Assessment of blinding in clinical trials. Control Clin Trials, 
25:143–56. 
 
Fengler K, Rommel KP, Okon T, et al. (2016, August 26). Renal sympathetic denervation in 
therapy resistant hypertension - pathophysiological aspects and predictors for treatment success. 
World J Cardiol, 8(8): 436-446. 
 
Finkelstein DM and Schoenfeld DA. (1999) Combining mortality and longitudinal measures in 
clinical trials. Statistics in medicine,18:1341-54. 
 
Id D, Bertog SC, Ziegler AK, et al. (2016). Predictors of Blood Pressure Response: Obesity Is 
Associated With a Less Pronounced Treatment Response After Renal Denervation. 
Catheterization and Cardiovascular Interventions, 87: E30–E38. 
 
James KE, Bloch DA, Lee KK, et al. (1996). An index for assessing blindness in a multicentre 
clinical trial: Disulfiram for alcohol cessation – a VA cooperative study. Stat Med., 15:1421–34. 
 
Kandzari DE, Bhatt DL, Brar S, et al. (2015). Predictors of blood pressure response in the 
SYMPLICITY HTN-3 trial. European Heart Journal, 36: 219–227. 
 
Little R, Rubin D (1989). Statistical Analysis with Missing Data. New York: Wiley. 
 
Pocock SJ, Ariti CA, Collier TJ and Wang D. (2012) The win ratio: a new approach to the 
analysis of composite endpoints in clinical trials based on clinical priorities. Eur Heart J., 
33:176-82. 
 
Townsend RR, Mahfoud F, Kandzari DE, et al. (2017) Catheter-based renal denervation in 
patients with uncontrolled hypertension in the absence of antihypertensive medications 
(SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial. Lancet, 
390(10108): 2160-70. 
 
Weber MA, Kirtane A, Mauri L, et al. (2015) Renal denervation for the treatment of 
hypertension: making a new start, getting it right (editorial). J Clin Hypertens, 38(8): 447-54. 
 
World Health Organization Collaborating Centre for Drug Statistics Methodology. ATC 
Classification Index with DDDs. Accessed [2019 February 25]; Available from: 
https://www.whocc.no/use_of_atc_ddd/. 
 


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9. 
STATISTICAL TABLES TO BE GENERATED 
Disposition/Demographics 
Table 14.1.1 Subject Disposition (Main Study) 
Table 14.1.1 Subject Disposition (Crossover Phase) 
Table 14.1.1-2 Screen Failures 
Table 14.1.2-1 Baseline Demographics and Medical/Surgical History - ITT Analysis Set 
Table 14.1.2-2 Baseline Demographics and Medical/Surgical History – Safety Analysis Set 
Table 14.1.2-3 Baseline Demographics and Medical/Surgical History – PP Analysis Set 
Table 14.1.3-1 Procedure Information - ITT Analysis Set 
Table 14.1.3-2 Procedure Information - ITT Analysis Set 
Table 14.1.3-3 Procedure Information RENAL ARTERY TREATMENT - ITT Analysis Set 
Efficacy 
Table 14.2.1-1 Primary Endpoint: 24-Hour Systolic Ambulatory Blood Pressure at 8 weeks - ITT 
Analysis Set 
Table 14.2.1-2 Primary Endpoint: 24-Hour Systolic Ambulatory Blood Pressure at 8 weeks - PP 
Analysis Set 
Table 14.2.1-3 Primary Endpoint: 24-Hour Systolic Ambulatory Blood Pressure at 8 weeks, by Site - 
ITT Analysis Set 
Table 14.2.1-4 Primary Endpoint: 24-Hour Systolic Ambulatory Blood Pressure at 8 weeks, by Age - 
ITT Analysis Set 
Table 14.2.1-5 Primary Endpoint: 24-Hour Systolic Ambulatory Blood Pressure at 8 weeks, by Gender 
- ITT Analysis Set 
Table 14.2.1-6 Primary Endpoint: 24-Hour Systolic Ambulatory Blood Pressure at 8 weeks, by Region 
(US vs Europe) – ITT Analysis Set 
Table 14.2.1-7 Primary Endpoint: 24-Hour Systolic Ambulatory Blood Pressure at 8 weeks, by 
Ethnicity (US only) – ITT Analysis Set 
Table 14.2.1-8 Primary Endpoint: 24-Hour Systolic Ambulatory Blood Pressure at 8 weeks, by Race 
(US only) – ITT Analysis Set 
Table 14.2.1-9 Primary Endpoint: 24-Hour Systolic Ambulatory Blood Pressure at 8 weeks, by Country 
– ITT Analysis Set 
Table 14.2.1-10 Primary Endpoint: 24-Hour Systolic Ambulatory Blood Pressure at 8 weeks, by 
Subjects Receiving Treatment – ITT Analysis Set 
Table 14.2.1-11 Primary Endpoint: 24-Hour Systolic Ambulatory Blood Pressure at 8 weeks, by 
Baseline Ambulatory SBP>140mmHg and DBP<90mmHg – ITT Analysis Set 
Table 14.2.1-12 Primary Endpoint: 24-Hour Systolic Ambulatory Blood Pressure at 8 weeks, by eGFR 
– ITT Analysis Set 
Table 14.2.2-1 24-Hour Ambulatory Blood Pressure at 8 weeks, 6 months and 1 Year ALL 
AVAILABLE DATA - ITT Analysis Set 
Table 14.2.2-2 24-Hour Ambulatory Blood Pressure at 8 weeks, 6 months and 1 Year ALL 
AVAILABLE DATA - PP Analysis Set 
Table 14.2.2-3 24-Hour Ambulatory Blood Pressure at 8 weeks, 6 months and 1 Year, by baseline 
daytime ambulatory SBP >140 mmHg and DBP <90 mmHg - ITT Analysis Set 
Table 14.2.2-4 Exploratory analysis of 24-Hour Systolic Ambulatory Blood Pressure at 8 weeks 
HIERARCHICAL MODEL - ITT Analysis Set 
Table 14.2.2-5 Exploratory analysis of 24-Hour Systolic Ambulatory Blood Pressure at 8 weeks 
HIERARCHICAL MODEL - PP Analysis Set 
Table 14.2.3-1 Daytime Ambulatory Blood Pressure at 8 weeks, 6 months and 1 Year ALL 
AVAILABLE DATA - ITT Analysis Set 
Table 14.2.3-2 Daytime Ambulatory Blood Pressure at 8 weeks, 6 months and 1 Year ALL 
AVAILABLE DATA - PP Analysis Set 


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Table 14.2.3-3 Daytime Ambulatory Blood Pressure at 8 weeks, 6 months and 1 Year, by baseline 
daytime ambulatory SBP >140 mmHg and DBP <90 mmHg - ITT Analysis Set 
Table 14.2.3-4 Daytime Ambulatory Systolic Blood Pressure at 8 weeks SENSITIVITY ANALYSES – 
ITT Analysis Set 
Table 14.2.3-5 Daytime Ambulatory Systolic Blood Pressure at 8 weeks SENSITIVITY ANALYSES – 
PP Analysis Set 
Table 14.2.4-1 Nighttime Ambulatory Blood Pressure at 8 weeks, 6 months and 1 Year ALL 
AVAILABLE DATA - ITT Analysis Set 
Table 14.2.4-2 Nighttime Ambulatory Blood Pressure at 8 weeks, 6 months and 1 Year ALL 
AVAILABLE DATA - PP Analysis Set 
Table 14.2.4-3 Nighttime Ambulatory Blood Pressure at 8 weeks, 6 months and 1 Year, by baseline 
daytime ambulatory SBP >140 mmHg and DBP <90 mmHg - ITT Analysis Set 
Table 14.2.4-4 Nighttime Ambulatory Systolic Blood Pressure at 8 weeks SENSITIVITY ANALYSES 
– ITT Analysis Set 
Table 14.2.4-5 Nighttime Ambulatory Systolic Blood Pressure at 8 weeks SENSITIVITY ANALYSES 
– PP Analysis Set 
Table 14.2.5-1 Office Blood Pressure at 8 weeks, 6 months, 1 Year and 2 Years - ITT Analysis Set 
Table 14.2.5-2 Office Blood Pressure at 8 weeks, 6 months and 1 Year ALL AVAILABLE DATA - PP 
Analysis Set  
Table 14.2.5-3 Office Blood Pressure at 8 weeks, 6 months and 1 Year, by baseline daytime ambulatory 
SBP >140 mmHg and DBP <90 mmHg - ITT Analysis Set 
Table 14.2.5-4 Office Blood Pressure at 8 weeks SENSITIVITY ANALYSES – ITT Analysis Set 
Table 14.2.5-5 Office Blood Pressure at 8 weeks SENSITIVITY ANALYSES – PP Analysis Set 
Table 14.2.6-1 Antihypertensive Medication Use EMERGENCY USE MEDICATIONS - ITT Analysis 
Set 
Table 14.2.6-2 Antihypertensive Medication Use EMERGENCY USE MEDICATIONS – PP Analysis 
Set 
Table 14.2.6-3 Antihypertensive Medication Use EMERGENCY USE MEDICATIONS, by baseline 
daytime ambulatory SBP >140 mmHg and DBP <90 mmHg - ITT Analysis Set 
Table 14.2.7-1 Antihypertensive Medication Use beyond 8 weeks - ITT Analysis Set 
Table 14.2.7-2 Antihypertensive Medication Use beyond 8 weeks - PP Analysis Set 
Table 14.2.8-1.1 Office Systolic Blood Pressure at all time points - ITT Analysis Set 
Table 14.2.8-1.2 Office Diastolic Blood Pressure at all time points - ITT Analysis Set 
Table 14.2.8-2.1 24-Hour Systolic ABP at all time points - ITT Analysis Set 
Table 14.2.8-2.2 24-Hour Diastolic ABP at all time points - ITT Analysis Set 
Table 14.2.8-3.1 Daytime Systolic ABP at all time points - ITT Analysis Set 
Table 14.2.8-3.2 Daytime Diastolic ABP at all time points - ITT Analysis Set 
Table 14.2.8-4.1 Nighttime Systolic ABP at all time points - ITT Analysis Set 
Table 14.2.8-4.2 Nighttime Diastolic ABP at all time points - ITT Analysis Set 
Table 14.2.9 Anti-Hypertensive Medications at all time points by Class - ITT Analysis Set 
Table 14.2.10 Anti-Hypertensive Medication Compliance1 - ITT Analysis Set 
Safety 
Table 14.3.1-1 Summary of Treatment Emergent Adverse Events (TEAE) – Safety Analysis Set 
Table 14.3.1-2.1 Treatment Emergent Adverse Events at any time during the study, by Relationship - 
Safety Analysis Set 
Table 14.3.1-2.2 Treatment Emergent Adverse Events Peri-procedural, by Relationship - Safety 
Analysis Set 
Table 14.3.1-2.3 Treatment Emergent Adverse Events through Discharge, by Relationship - Safety 
Analysis Set 


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Table 14.3.1-2.4 Treatment Emergent Adverse Events within 8 weeks, by Relationship - Safety 
Analysis Set 
Table 14.3.1-2.5 Treatment Emergent Adverse Events within 6 months, by Relationship - Safety 
Analysis Set 
Table 14.3.1-2.6 Treatment Emergent Adverse Events within 1 Year, by Relationship - Safety Analysis 
Set 
Table 14.3.1-3.1 Treatment Emergent Adverse Events at any time during the study, by Severity - Safety 
Analysis Set 
Table 14.3.1-3.2 Treatment Emergent Adverse Events Peri-procedural, by Severity - Safety Analysis 
Set 
Table 14.3.1-3.3 Treatment Emergent Adverse Events through Discharge, by Severity - Safety Analysis 
Set 
Table 14.3.1-3.4 Treatment Emergent Adverse Events within 8 weeks, by Severity - Safety Analysis 
Set 
Table 14.3.1-3.5 Treatment Emergent Adverse Events within 6 months, by Severity - Safety Analysis 
Set 
Table 14.3.1-3.6 Treatment Emergent Adverse Events within 1 Year, by Severity - Safety Analysis Set 
Table 14.3.2-1.1 Treatment Emergent Serious Adverse Events at any time during the study, by 
Relationship - Safety Analysis Set 
Table 14.3.2-1.2 Treatment Emergent Serious Adverse Events Peri-procedural, by Relationship - Safety 
Analysis Set 
Table 14.3.2-1.3 Treatment Emergent Serious Adverse Events through Discharge, by Relationship - 
Safety Analysis Set 
Table 14.3.2-1.4 Treatment Emergent Serious Adverse Events within 8 weeks, by Relationship - Safety 
Analysis Set 
Table 14.3.2-1.5 Treatment Emergent Serious Adverse Events within 6 months, by Relationship - 
Safety Analysis Set 
Table 14.3.2-1.6 Treatment Emergent Serious Adverse Events within 1 Year, by Relationship - Safety 
Analysis Set 
Table 14.3.2-2.1 Treatment Emergent Serious Adverse Events at any time during the study, by Severity 
- Safety Analysis Set 
Table 14.3.2-2.2 Treatment Emergent Serious Adverse Events Peri-procedural, by Severity - Safety 
Analysis Set 
Table 14.3.2-2.3 Treatment Emergent Serious Adverse Events through Discharge, by Severity - Safety 
Analysis Set 
Table 14.3.2-2.4 Treatment Emergent Serious Adverse Events within 8 weeks, by Severity - Safety 
Analysis Set 
Table 14.3.2-2.5 Treatment Emergent Serious Adverse Events within 6 months, by Severity - Safety 
Analysis Set 
Table 14.3.2-2.6 Treatment Emergent Serious Adverse Events within 1 Year, by Severity - Safety 
Analysis Set 
Table 14.3.3-1.1 Treatment Emergent Non-Serious Adverse Events at any time during the study, by 
Relationship - Safety Analysis Set 
Table 14.3.3-1.2 Treatment Emergent Non-Serious Adverse Events Peri-procedural, by Relationship - 
Safety Analysis Set 
Table 14.3.3-1.3 Treatment Emergent Non-Serious Adverse Events through Discharge, by Relationship 
- Safety Analysis Set 
Table 14.3.3-1.4 Treatment Emergent Non-Serious Adverse Events within 8 weeks, by Relationship - 
Safety Analysis Set 


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Table 14.3.3-1.5 Treatment Emergent Non-Serious Adverse Events within 6 months, by Relationship - 
Safety Analysis Set 
Table 14.3.3-1.6 Treatment Emergent Non-Serious Adverse Events within 1 Year, by Relationship - 
Safety Analysis Set 
Table 14.3.3-2.1 Treatment Emergent Non-Serious Adverse Events at any time during the study, by 
Severity - Safety Analysis Set 
Table 14.3.3-2.2 Treatment Emergent Non-Serious Adverse Events Peri-procedural, by Severity - 
Safety Analysis Set 
Table 14.3.3-2.3 Treatment Emergent Non-Serious Adverse Events through Discharge, by Severity - 
Safety Analysis Set 
Table 14.3.3-2.4 Treatment Emergent Non-Serious Adverse Events within 8 weeks, by Severity - 
Safety Analysis Set 
Table 14.3.3-2.5 Treatment Emergent Non-Serious Adverse Events within 6 months, by Severity - 
Safety Analysis Set 
Table 14.3.3-2.6 Treatment Emergent Non-Serious Adverse Events within 1 Year, by Severity - Safety 
Analysis Set 
Table 14.3.4 Listing of Adverse Events Prior to Study Procedure – All Enrolled Subjects  
Table 14.3.5 CEC Adjudicated MAE - Safety Analysis Set 
Table 14.3.6 Device / Procedure Success – ITT Analysis Set 
Table 14.3.7-1 eGFR (mL/min/1.73m3) - Safety Analysis Set 
Table 14.3.7-2.1 Summary of Laboratory Parameters (Serum Chemistry) - Safety Analysis Set 
Table 14.3.7-2.2 Summary of Laboratory Parameters (Liver Panel) - Safety Analysis Set 
Table 14.3.7-2.3 Summary of Laboratory Parameters (Hematology) - Safety Analysis Set 
Table 14.3.7-2.4 Summary of Laboratory Parameters (Coagulation) - Safety Analysis Set 
Table 14.3.7-2.5 Summary of Laboratory Parameters (Urinalysis) - Safety Analysis Set 
Table 14.3.7-2.6 Summary of Laboratory Parameters (Other) - Safety Analysis Set 
Table 14.3.7-3.1 Shifts in Laboratory Parameters (Chemistry) from Baseline to Follow-up Visits - 
Safety Analysis Set 
Table 14.3.7-3.2 Shifts in Laboratory Parameters (Liver Panel) - Safety Analysis Set 
Table 14.3.7-3.3 Shifts in Laboratory Parameters (Hematology) - Safety Analysis Set 
Table 14.3.7-3.4 Shifts in Laboratory Parameters (Coagulation) - Safety Analysis Set 
Table 14.3.7-3.5 Shifts in Laboratory Parameters (Urinalysis) - Safety Analysis Set 
Table 14.3.7-3.6 Shifts in Laboratory Parameters (Other) - Safety Analysis Set 
Table 14.3.8 Physical Examination – ITT Analysis Set 
Table 14.3.9 Electrocardiogram – ITT Analysis Set 
Table 14.3.10 Procedural Angiogram Core Lab Analysis - ITT Analysis Set 
Table 14.3.11-1 Renal Imaging Core Lab Analysis – ITT Analysis Set 
Table 14.3.11-2 Renal Imaging Core Lab Analysis - ITT Analysis Set 
Table 14.3.12 Renal Duplex Ultrasound (RDUS) at 6 Months – ITT Analysis Set 
Table 14.4 Protocol Deviations - ITT Analysis Set 
Table 14.5.1 Treatment Perception - ITT Analysis Set 
Table 14.5.2 Treatment Perception BANG and JAMES BLINDING INDICES - ITT Analysis Set 


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10. 
DATA LISTINGS TO BE GENERATED 
Listing 16.2.1-1 Randomized Subjects and Visits  
Listing 16.2.1-2 Discontinued Subjects 
Listing 16.2.2 Protocol Deviations 
Listing 16.2.3 Patients excluded from efficacy analysis 
Listing 16.2.4 Demographics and Medical/Surgical History 
Listing 16.2.5 Procedure 
Listing 16.2.6 Blood Pressure 
Listing 16.2.7-1 All Adverse Events 
Listing 16.2.7-2 Serious Adverse Events 
Listing 16.2.7-3 Deaths 
Listing 16.2.8 Laboratories 
Listing 16.2.9-1 Anti-Hypertensive Medications 
Listing 16.2.9-2 Other Concomitant Medications 
Listing 16.2.10 Device Deficiency 
Listing 16.2.11 ECG and MR/CT Angiogram 
Listing 16.2.12 DUS 
Listing 16.2.13 Nephrologist Consult 
 


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11. 
FIGURES TO BE GENERATED 
Figure Number 
Title 
Figure 1.1 
Mean Office SBP and DBP by Visit 
Figure 1.2 
Mean Change from Baseline in Office SBP and DBP by Visit 
Figure 1.3 
Office SBP over time by Subject 
Figure 1.4 
Office DBP over time by Subject 
Figure 2.1 
Mean 24-hour Systolic and Diastolic ABPM by Visit 
Figure 2.2 
Mean Change from Baseline in 24-H Mean Systolic and Diastolic ABPM 
by Visit 
Figure 2.3 
24-hour Systolic ABPM over time by Subject 
Figure 2.4 
24-hour Diastolic ABPM over time by Subject 
Figure 2.5 
Hourly Systolic and Diastolic ABPM by Visit 
Figure 3.1 
Mean Daytime Systolic and Diastolic ABPM by Visit 
Figure 3.2 
Mean Change from Baseline in Daytime Systolic and Diastolic ABPM by 
Visit 
Figure 3.3 
Daytime Systolic ABPM over time by Subject 
Figure 3.4 
Daytime Diastolic ABPM over time by Subject 
Figure 4.1 
Mean Nighttime Systolic and Diastolic ABPM by Visit 
Figure 4.2 
Mean Change from Baseline in Nighttime Systolic and Diastolic ABPM by 
Visit 
Figure 4.3 
Nighttime Systolic ABPM over time by Subject 
Figure 4.4 
Nighttime Diastolic ABPM over time by Subject 
Figure 5 
Mean eGFR (mL/min/1.73m2) over time 
Figure 6 
Kaplan Meier plot of CEC Adjudicated MAE  


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APPENDIX A – TABLE SHELLS