First Clinical Experience With Targeted REnal Nerve Demodulation (TREND-1) Using a Neurotropic Agent for the Treatment of Sympathetic Hypertension

Abstract: Aims. To evaluate the feasibility and safety of a novel targeted neuromodulatory treatment for sympathetic hypertension involving a one-time local injection of neurotropic agents near renal nerves. Methods and Results. Seven patients suffering from uncontrolled hypertension per ESH-ESC guidelines were treated using a single dose of NW2013, a neurotropic Na⁺/K⁺ ATPase antagonist. A microneedle catheter was used to administer 1.2 mL of NW2013 (0.6 mL per artery) to the perivascular space surrounding renal arteries using percutaneous endovascular procedures under fluoroscopic guidance. All patients were successfully treated without any procedural complications. Patients were followed for 12 months post procedure, and office and 24-hour ambulatory blood pressure measurements were made. Both office and ambulatory blood pressures were lower at 24 hours, 1 month, and 3 months after treatment. The decrease in office blood pressure was greater than the decrease in ambulatory blood pressure. A reduction in medication regimen was also observed in 2 patients. One patient suffered a cerebrovascular event after 6-month follow-up and died from stroke, unrelated to the treatment. Overall, the reduction in office and ambulatory blood pressure was sustained over the course of 12 months. Conclusions. Treatment of hypertension using local administration of NW2013 near renal nerves appears to be feasible and safe. Large, controlled, randomized, and blinded clinical studies with monitoring of patient compliance to daily oral medication are recommended to further establish the efficacy of this novel treatment.

J INVASIVE CARDIOL 2017;29(3):97-103. EPub 2017 Jan 15

Key words: atherectomy, calcification, percutaneous coronary intervention, coronary artery disease, kidney disease

An increasing amount of animal and clinical data suggests that increased sympathetic nerve activity (SNA), specifically related to heart and kidney physiology, is a major contributor to chronic diseases like hypertension, atrial fibrillation, pulmonary hypertension, chronic obstructive pulmonary disease, sleep apnea, stroke, heart failure, kidney failure, and insulin resistance.^1-10 Among SNA-mediated diseases, hypertension is most common in the developed world, affecting up to 25% of the adult population.¹¹ Despite the availability of pharmacologic regimens, many patients fail to benefit from drug therapy due to their non-compliance with daily medication. In addition, about 10% of the patients with diagnosed hypertension are considered to be “uncontrolled” or “drug-resistant” and fail to achieve adequate control of blood pressure (BP), despite receiving three or more antihypertensive medications, including a diuretic.¹² Suboptimal BP control is responsible for approximately 62% of cerebrovascular disease and 49% of ischemic heart disease, and accounts for an estimated 7.1 million deaths a year.¹³ Because of the associated morbidity, mortality, and economic cost to society, the early diagnosis and effective treatment of hypertension is imperative.^14-16

One of the potential causes for uncontrolled hypertension is the overactive sympathetic nervous system. New therapies have focused on modulating the overactive nerve signals at two locations within the body – namely, the renal nerves and the carotid body. Device-based treatments using electrical stimulation, radiofrequency (RF) ablation, cryoablation, and ultrasound ablation are currently in development.^17-27 These involve implanting electrical generators with leads connecting to baroreceptors near the carotid body or using endovascular catheters that apply energy pulses to affect renal nerves near the kidney. 

Such non-specific energy-based treatments may cause collateral tissue damage, require investment in capital equipment, require operator training, and may be painful. Optical coherence tomographic imaging of renal artery walls after RF ablation showed endothelial-intimal edema, thrombus formation, and local tissue damage.²⁸ Moreover, results from the pivotal Symplicity HTN-3 study¹⁹ concluded that RF ablation, although acutely safe, was ineffective in reducing BP. Incomplete denervation was cited as one of the reasons for failure to meet the trial endpoints.^29-31

Herein, we present a new approach to treat sympathetic hypertension by the local administration of a Na⁺/K⁺ ATPase antagonist near renal arteries using an endovascular approach, targeting renal sympathetic nerves, to modulate nerve activity. The aim of this study was to evaluate the feasibility and safety of this local neuromodulation therapy to treat patients suffering from uncontrolled hypertension despite the use of three or more drugs.

Methods

Neuromodulation therapy. The neuromodulation therapy (developed by Northwind Medical, Inc) involves catheter-based local administration of neurotropic drugs, focally targeting renal nerves to reduce renal sympathetic nerve activity (RSNA) and treat hypertension.^26,27 The clinical procedure utilizes an endovascular catheter with a microneedle. The catheter is advanced to position inside the renal artery using standard endovascular techniques under fluoroscopy. The microneedle is advanced across the artery wall to reach the renal nerves, and a proprietary neurotropic drug is injected.

The proprietary formulation, NW2013, was selected after careful screening of various drugs and is based on a Food and Drug Administration (FDA)-approved drug and FDA-approved dose for injectable and oral use. NW2013 is a Na⁺/K⁺ ATPase antagonist that targets the ATPase receptors enriched on the axonal cytoplasmic membranes of neurons. Binding of NW2013 to the Na⁺/K⁺ ATPase blocks ion-pump function, inhibits membrane repolarization, and causes cessation of nerve firing or blocks nerve conductance. Prolonged nerve blockade induces cytosolic Ca²⁺ flux, disrupts ion homeostasis, triggers caspase 3 activation, and results in neuronal apoptosis.²⁷ We tested the hypothesis that overactive sympathetic neurons would be more susceptible to NW2013 and thus, a lower dose of drug could be effective in down-modulating nerve activity in situ. We further hypothesized that a dose response could be achieved whereby a higher dose can result in prolonged neuronal down-modulation and apoptosis, and a lower dose can cause nerve block. Indeed, in animal models, neuromodulation was observed, ranging between transient nerve block and apoptosis, and was dependent on the dose of NW2013 used.^26,27

Preclinical studies. Preclinical tests were conducted to establish the feasibility of modulating nerves and nerve function using local administration of neurotropic agents, and are described elsewhere.^26,27 Various formulations based on FDA-approved drugs, with a well-established toxicity profile, were screened for their potency to affect nerves in human neuronal cell cultures. Both single and combination formulations were tested, and then validated in small (rat sciatic-nerve block) and large (porcine renal-nerve block) animal models. Based on these results, the lead formulation, NW2013, was selected for clinical investigation. NW2013 was found to be safe and effective in neuromodulating and inducing nerve-specific degenerative changes with minimal damage to surrounding tissue. Degenerative changes in nerve structure and function were deemed permanent in the porcine model at 90 days, with neurons undergoing NW2013-mediated apoptosis within 14 days post procedure. Concurrent reductions in kidney tissue norepinephrine levels were also observed. 

Clinical study. The Targeted REnal Nerve Demodulation (TREND-1) study is a single-arm, open-label, first-in-human clinical feasibility study with 1-month, 3-month, 6-month, and 12-month follow-up. Seven patients were enrolled at a single site (The Center of Vascular and Heart Diseases, Tbilisi, Georgia) between January-May 2014. Institutional review board (IRB) and ethics committee approvals were obtained prior to the study. Written informed consent was obtained from all patients after explaining the clinical procedure and potential risks in their native language. The study was sponsored by Northwind Medical, Inc.

Patient screening and inclusion criteria. Patients were enrolled based on having high BP (office or ambulatory systolic blood pressure ≥160 mm Hg) despite the stable use of ≥3 antihypertensive drugs, one of which was a diuretic. No changes in medication were made 1 month prior to enrollment. Patients had to be older than 18 years and <85 years of age with good renal function (estimated glomerular filtration rate [eGFR] >45 mL/min/1.73 m²). Patients with type 1 diabetes mellitus, known causes of secondary hypertension, end-stage renal disease, ischemic or valvular heart disease, hemodynamically significant renal artery stenosis, or pregnancy were excluded. Patients were screened for renovascular anatomy and disease using 64-slice electron-beam computed tomography (CT) imaging. Patients with previous renal artery intervention (angioplasty, stent implantation), anatomic abnormalities (renal artery aneurysms, renal artery diameter <4 mm, excessive renal artery tortuosity), or aortic aneurysms were excluded.

Study procedure and assessments. The primary endpoints for the study were technical success of the clinical procedure and safety of the procedure. Technical success was defined as the ability of the physician to access the renal artery using the catheter and successfully administer NW2013 near renal nerves. Acute safety of the procedure was defined as the overall rate of serious adverse events (SAEs), such as renal artery dissection, bleeding, or perforation that required stenting or surgery; renal artery infarction or embolus; cerebrovascular accidents; myocardial infarction; and sudden cardiac death at the time of procedure or within 24 hours of the procedure.

The secondary endpoints for the study were chronic safety of the procedure, defined as the overall rate of SAEs and adverse device effects at 6 months; chronic effectiveness of the procedure, defined as office systolic BP reduction >10 mm Hg at 6 months compared with baseline. Other secondary endpoints included measuring the changes from baseline in ambulatory BP at 6 months, in antihypertensive medication at 6 months, and in office systolic BP at 12 months.

Office and 24-hour ambulatory BP measurements were performed per Joint National Committee VII guidelines. Office BP measurements were taken using the cuff method; three data points were taken and the average office BP was reported. Ambulatory BP measurements were made using a fully programmable monitor (Microlife WhatchBP 03 model). Automated measurements were taken every 30 minutes during the day and every hour at night. Data were analyzed for the mean and standard deviation on the 24-hour, daytime and nighttime systolic BP, diastolic BP, and heart rate. Baseline and follow-up assessments included physical examination, CT scan, electrocardiogram, standard blood chemistry (renin, aldosterone), urinalysis, eGFR, and duplex Doppler scans (renal blood flow) at various time points after treatment (Table 1). Medication changes were allowed for clinical reasons based on physician discretion and standard of care at the hospital.

Treatment procedure. Access to the right common femoral artery was achieved by standard endovascular techniques using a 4-5 Fr diagnostic catheter and 0.035˝ guidewire under x-ray imaging guidance. The diagnostic catheter and wire were exchanged for a 7 Fr renal sheath and a 0.014˝ guidewire. A renal artery angiogram was obtained after advancing and positioning the sheath in the aorta at the ostium of the renal artery (Figure 1A). Then, a commercially available microneedle catheter (Bullfrog micro-infusion device; Mercator Medsystems) was advanced over the 0.014˝ wire and placed in the mid-section of the renal artery. The balloon segment was inflated and the microneedle was advanced to penetrate the renal artery wall and reach the perivascular space surrounding the artery (Figure 1B). Advancement of the needle was verified by balloon occlusion of the renal artery by contrast injection proximal to the device (Figure 1C). A small volume (0.3 mL) of NW2013 was injected through the microneedle of the catheter. The balloon was deflated, the microneedle was retracted, and an angiogram was obtained (Figure 1D).

Next, the catheter was pulled back and repositioned about 5 mm from the first injection. The balloon was inflated again to advance the microneedle across the renal artery wall, and another 0.3 mL of drug was injected. The balloon was deflated, microneedle retracted, and the catheter was pulled into the sheath. The steps were repeated in the second renal artery and a final angiogram was obtained. In total, ~1.2 mL of NW2013 were administered per patient in the mid-segment (middle third) of the renal artery (between the aortic ostium and kidney hilum). Based on preclinical tests, the drug distribution is expected to be confined to an approximately 10 mm-long cylindrical perivascular zone surrounding the renal artery and affect all nerves originating at the renal plexus and innervating the kidney.

Results

Acute results. A total of 7 patients (4 males and 3 females), between 45 and 72 years of age, were enrolled in the TREND study. All patients were on at least three antihypertensive medications; 1 patient was on five medications. Vascular access from the common femoral artery was used. Seven Fr sheaths were used to treat 6 patients and an 8 Fr guiding catheter was used in 1 patient. The NW2013 drug was successfully administered in the perivascular space surrounding renal arteries. Two injections were done at two locations, approximately 5 mm apart, per renal artery, first distally and then proximally. One patient had bilateral renal accessory branches and received therapy for both branches. Total interventional procedure times ranged between 60-90 minutes; actual treatment (catheter advancement to renal arteries, balloon inflation, drug injection, balloon deflation, and catheter removal) was completed within 15-20 minutes.

All 7 patients were successfully treated through local administration of NW2013 near renal nerves using the microneedle catheter. There were no procedure-related, device-related, or drug-related complications. Injury to the renal artery wall appeared to be minimal; no vessel spasm, dissections, or vessel perforations were observed. 

The first 2 patients were treated without administering pain medication. Mild to moderate pain, lasting about 1 minute, was reported during agent injection. The pain was tolerable and less severe compared with the procedural pain reported for energy-based renal denervation treatments. Subsequently, pain was managed by administering 0.5-1 mg of morphine before the procedure.

Follow-up results. Mean systolic/diastolic office BP and 24-hour ambulatory BP at baseline were 189/94 mm Hg and 160/101 mm Hg, respectively. At 1 month, 3 months, and 6 months following treatment, the average systolic/diastolic office BP reductions were 40/10 mm Hg, 47/11 mm Hg, and 36/1 mm Hg, respectively; equivalent decreases in ambulatory BP were 13/11 mm Hg, 18/13 mm Hg, and 6/6 mm Hg, respectively. A rise in both office BP and ambulatory BP was seen between 6 and 12 months. At 12 months, the average office BP and ambulatory BP values were 148/83 mm Hg and 155/94 mm Hg, respectively; equivalent average reductions, compared with baseline, were 45/8 mm Hg and 5/7 mm Hg for office and ambulatory BPs, respectively. 

It can be noted that office BP drops varying between 15-40 mm Hg were noted within 24 hours after treatment prior to discharge. The effect was sustained at 1 and 3 months, with a slight increase noted at 6 and 12 months. Primary care physicians and clinical research staff noted that some patients reported at follow-up visits that they were non-compliant with their drug regimens and continued to smoke. 

Similar trends were noted on ambulatory BP, with a drop in systolic ambulatory BP, compared with baseline, at 1 and 3 months after treatment. Although an increase in ambulatory BP was noted at 6 and 12 months, the ambulatory BP at 12 months was lower compared with baseline. As noted previously, one of the confounding factors may be related to the compliance of the patients to the prescribed drug regimen. However, the drop in ambulatory BP was lower compared with the drop in office BP for all time points. 

Mean heart rate was 78 ± 9.9 beats/min at baseline. At 1, 3, and 6 months following treatment, the heart rates were 71.4 ± 13.7 beats/min, 75.1 ± 12.2 beats/min, and 76.9 ± 11.0 beats/min, respectively. Apart from a slight decrease in heart rate at 1 month, no significant changes were observed. At 12 months, the heart rate was 76.5 ± 12.5 beats/min.

Two patients complained of fatigue during follow-up visits and their BP medication dose was reduced. Patient 001 was a 72-year-old male, taking 10 mg of prestance (amlodipine + perindopril, a calcium-channel blocker and angiotensin-converting enzyme inhibitor), 1.5 mg of indapamide, and 12.5 mg of hydrochlorothiazide (diuretics) daily, before enrollment in the study, with a 24-hour systolic ambulatory BP of 164 ± 18 mm Hg. At 1-month follow-up, the dose of prestance was reduced to 5 mg. At 6-month follow-up, the use of hydrochlorothiazide was stopped. At 1-year follow-up, he was stable on 5 mg of prestance and 1.5 mg of indapamide, with a 24-hour systolic ambulatory BP of 144 ± 14 mm Hg.

Patient 002 was a 43-year-old female on 10 mg of enalapril (angiotensin-converting enzyme inhibitor), 10 mg of amlodipine (calcium-channel blocker), and 20 mg of hydrochlorothiazide (diuretic), with a 24-hour systolic ambulatory BP of 176 ± 13 mm Hg before treatment. At 1-month follow-up, her medication dosage was reduced in half (5 mg of enalapril + 5 mg of amlodipine + 10 mg of hydrochlorothiazide). At 3-month follow-up, she was taken off medications. She was stable at 1-year follow-up, with a 24-hour systolic ambulatory BP of 127 ± 14 mm Hg. 

Adverse events. All patients completed their 1-month, 3-month, and 6-month follow-up exams. No complications or adverse events were reported during the 6-month period following treatment. Between 6 and 12 months, 1 patient suffered an ischemic stroke with paralyzed left arm and leg and aphasia. The patient was reported to have a transient ischemic attack 2 years prior to enrollment, and was admitted to the neurological clinic with stable but high BP. He subsequently died due to stroke from cerebrovascular complications and the death was ascertained to be unrelated to the treatment procedure. The remaining 6 patients completed their 12 months of follow-up.

All other parameters were normal including heart function (electrocardiogram, echocardiogram), renal function (serum creatinine, estimated glomerular filtration rate, renin, aldosterone), and urinalysis (specific gravity and protein concentration). Blood flow to renal arteries under duplex Doppler ultrasound examination indicated patent renal arteries for all follow-up time points. Six-month CT scans were normal.

Discussion

The acute and chronic clinical results from the present study demonstrate that treatment of uncontrolled hypertension by endovascular catheter-mediated, one-time, local administration of a neuromodulatory drug targeting renal sympathetic nerves is safe and feasible. No adverse events were reported and the mechanical damage caused by microneedle puncture of the renal artery wall appeared to be minimal. No bleeding or dissections in the artery were observed. All patients survived the 6-month endpoint and the reduction in systolic office BP was >10 mm Hg at 6 and 12 months compared with baseline. Smaller reductions were observed in ambulatory BP, suggesting that measurement bias might play a role in quantifying the benefit from this treatment. 

The local administration of drug near renal nerves offers an alternative to other interventional approaches, such as energy-based ablation or implants, to treat hypertension. The one-time administration of a single dose of drug within the perivascular tissue surrounding renal arteries may be sufficient to reach and affect renal nerves. In preclinical tests, we observed the drug effects circumferentially around the adventitia of the renal artery, as far as 7-10 mm away, with minimal damage to the artery wall and surrounding tissue. The procedure is simple, similar to renal angioplasty, and appears to be less painful. Low-dose morphine was sufficient to mitigate the mild to moderate pain experienced during treatment compared with strong sedatives used during energy-based renal nerve ablation. 

The reductions in office and ambulatory BPs seen in this study are consistent with results from previous studies on catheter-based RF and ultrasound ablation of renal nerves.^17-25 An average decrease in office BP of ~30 mm Hg at 3-year follow-up in patients with drug-resistant hypertension was reported;¹⁷ reductions in ambulatory BP were reported to be smaller.

However, interest in interventional treatment of hypertension waned following results from Medtronic’s pivotal Symplicity HTN-3 study, where patients suffering from drug-resistant hypertension were randomized to RF ablation of renal nerves vs sham-procedural treatment controls.¹⁹ The study met the primary safety endpoint, but failed to meet the efficacy endpoint. At 6 months, the treated group had 14.1 mm Hg decrease in systolic BP compared with 11.7 mm Hg decrease in the sham group, which was not statistically significant. Ineffective denervation, medication regimen (changes and compliance), and lack of biomarkers to screen patients with sympathetic (overactive sympathetic-nerve activity driven or neurogenic) hypertension were identified as factors responsible for failure of Symplicity HTN-3.^29-31 More recently, a meta-analysis of 148 clinical trials suggested that trial design factors play a significant role in overestimating the decrease in BP after renal denervation.³² Asymmetric data handling and non-denervation effects alone accounted for a drop of 19 mm Hg in BP after renal denervation; regression to the mean had a small effect. These factors must be considered in designing future bias-resistant clinical trials to validate the efficacy of this treatment.

Overall, we note that the present feasibility study shows that the local chemo-neuromodulation procedure is safe. A reduction in BP was noted at 1 month and 3 months when compared with baseline. A slight increase in BP was seen between 6 months and 12 months. Two patients reduced their dependence on hypertensive medications and others had no change. Various factors may contribute to the rise in BP after 6 months, including waning of the placebo effect from study design, BP measurement, and patient non-compliance to medications. Effect of the drug may reduce over time and an additional dose or higher dose of drug may be needed. Also, uncontrolled hypertension in patients may not entirely be neurogenic in origin and secondary factors may be involved. 

Study limitations. The present study has significant limitations. It is not randomized, blinded, or controlled, and a very small number of patients were enrolled. As identified by Howard et al,³² this small study may be influenced by potentially high BP estimates before treatment during patient selection (regression to the mean or big-day effect), potentially low BP estimates after therapy (asymmetric data handling), and non-denervation or placebo effects such as better adherence to daily medication after treatment. We also did not monitor patient compliance to daily medication using pill counts or urinalysis before or after the procedure. 

Larger clinical studies with bias-resistant trial designs are therefore required to establish the clinical evidence for this novel therapy. Adding a control group, blinding the physician, automating the data collection process, and blinding the patient (through a sham procedure) may address these limitations. Biologic markers and assays to identify patients with sympathetic nerve overactivity and real-time feedback/indicators to assess the completeness of neuromodulation treatment during the clinical procedure may be helpful in developing this novel interventional therapy to treat hypertension.

Conclusion

Local administration of neurotropic neuromodulatory drugs to tissues surrounding the renal arteries using an endovascular microneedle catheter appears to be a safe and feasible clinical procedure to treat hypertension. Large, sham-procedure controlled, randomized, and blinded clinical studies are needed to evaluate the efficacy of this treatment. 

Acknowledgments. The authors would like to thank and acknowledge the help of Drs Renu Virmani (CVPath Institute, Gaithersburg, Maryland) and Narayana Raju (Pathology Research Labs, South San Francisco, California) for assistance with preclinical studies and histopathology; Cindy Harris and Mike Daniel for assistance with conducting the clinical study.

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From ¹New York Cardiovascular Research, New York, New York; ²CardioVascular Center Frankfurt, Frankfurt, Germany; ³Anglia Ruskin University, Chelmsford, United Kingdom; ⁴University of Texas at San Antonio, San Antonio, Texas; ⁵Center for Vascular and Heart Disease, Tbilisi, Georgia; and ⁶Northwind Medical, Inc, San Jose, California.

Funding: The TREND-1 study was sponsored by Northwind Medical, San Jose, California.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Sievert, Dr Kipshidze, Dr Konstantin Kipiani, Dr Vakhtang Kipiani, and Dr Mukhuradze are clinical investigators. Dr Sievert, Dr Kipshidze, and Dr Michael Wholey are scientific advisors to Northwind Medical. Dr Mark Wholey, Dr Michael Wholey, Dr Stein, and Dr Venkateswara Rao are stockholders of Northwind Medical.

Manuscript submitted July 7, 2016, provisional acceptance given July 11, 2016, manuscript accepted October 6, 2016.

Address for correspondence: Nicholas Kipshidze, MD, PhD, Director, Molecular and Endoluminal Coronary Interventions, Interventional Cardiology, 130 E. 77th Street, New York, NY 10021. Email: nkipshidze@lenoxhill.net