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Physiological Study of the Efficacy and Mechanistic Effects of Alcohol Renal Denervation

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ClinicalTrials.gov Identifier: NCT03465917
Recruitment Status : Completed
First Posted : March 14, 2018
Last Update Posted : May 11, 2020
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
University of Texas Southwestern Medical Center

Brief Summary:

Hypertension is a major risk factor for heart disease and stroke, two of the leading causes of death in the United States. Hypertension is a common and widespread problem; unfortunately, current treatment strategies fail to adequately control blood pressure in up to 50% of patients either because of failure to take prescribed medications (because of cost, side effects, inconvenience etc.) or lack of therapeutic response. Indeed, it is estimated that 50% of patients stop taking antihypertensive medication within 6-12 months after the initiation of drug therapy.

Despite enthusiasm for a novel approach called renal denercation, presently there are no integrative studies of the antihypertensive effect of renal denervation on the multiple regulatory pathways it may consequentially affect. Experimental evidence from pre-clinical models suggests the effects are due to reducing efferent sympathetic activity and thus lowering blood pressure by altering the renin-angiotensin system. Uncontrolled clinical studies in humans suggest that when effective, this procedure may also lower renal sympathetic nerve activity. However the sympathetic response to monopolar radiofrequency therapy has been highly variable. Moreover, there have been no assessments of procedural efficacy performed in humans. Thus the actual mechanism by which this type of procedure reduces BP in humans is largely unknown, making it extremely difficult to identify the appropriate patients for this invasive procedure.

Recently, chemical renal denervation using ethanol (EtOH), was demonstrated to markedly lower blood pressure in small numbers of patients with resistant hypertension. However the mechanisms by which blood pressure is altered using this novel technique in humans is entirely unknown, and procedural efficacy has also not been assessed. Therefore it is unclear, whether in humans renal sympathetic nerve activity is lowered following renal denervation using this new approach. The Investigators propose to use high resolution physiological testing to determine the effects of chemical renal artery denervation on sympathetic activity.

Therefore the global objective of this physiological study is to provide the first detailed assessment of the integrated mechanistic effects of chemical renal nerve denervation in humans with hypertension that is uncontrolled by conventional treatment (because of lack of adherence or response to therapy).


Condition or disease Intervention/treatment Phase
Hypertension Combination Product: Renal Denervation Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Physiological Study of the Efficacy and Mechanistic Effects of Alcohol Renal Denervation
Actual Study Start Date : March 1, 2018
Actual Primary Completion Date : March 6, 2019
Actual Study Completion Date : November 12, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Renal Denervation
Renal denervation using the Peregrine Catheter for extravascular administration of ethanol
Combination Product: Renal Denervation
Bilateral denervation of the renal arteries using extravascular administration of neurolytic alcohol




Primary Outcome Measures :
  1. Renal sympathetic activity [ Time Frame: Change in renal sympathetic activity at 8 weeks ]
    18F-Fluorodopamine scanning of the kidney


Secondary Outcome Measures :
  1. Blood pressure [ Time Frame: Change in ambulatory blood pressure 24 hours, 1 week, 8 weeks, 6 months and 12 months after denervation. ]
    24-hour ambulatory blood pressure

  2. Muscle sympathetic activity [ Time Frame: Change in Muscle sympathetic nervous system activity 8 weeks, 6 months after renal denervation ]
    Muscle sympathetic nervous system activity at rest and during autonomic function testing

  3. Vascular function [ Time Frame: Change in flow mediated dilation 8 weeks, 6 months after renal denervation ]
    Flow mediated dilation

  4. Vascular stiffness [ Time Frame: Change in pulswave velocity at 8 weeks, 6 months after renal denervation ]
    Pulse wave velocity



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

9.1 Please indicate the inclusion criteria for enrollment: Six patients will participate in this study. Patients who present with uncontrolled hypertension (classified as clinic systolic blood pressure not at target level >140mmHg) to their primary care provider, emergency room (ER), specialist hypertension clinic or urgent care center will be asked to participate.

Inclusion criteria include:

  1. Patient presents with treated or untreated hypertension.
  2. Adults aged 18-75 years, male or female
  3. Patient has a clinic systolic blood pressure >140mmHg (average of 3 measurements), or >135mmHg in patients with type II diabetes
  4. Patient has a daytime mean systolic blood pressure of ≥135 and diastolic blood pressure ≥85mHg based on 24 hours ambulatory blood pressure monitoring
  5. Investigator judges that the subject can be managed safely for up to 12 weeks (4 weeks run-in plus 8 weeks post-treatment) with the use of standard background regimen of losartan/hydrochlorothiazide; patients with true resistant hypertension will be required to maintaining current antihypertensive regime for the duration of the study.

Exclusion Criteria. Any patient who meets any of the following exclusion criteria will not be eligible for the study.

  1. Patient has known or suspected secondary hypertension
  2. Use of systemic drugs that may be used for the treatment of hypertension, for a non-hypertension indication for the trial, (e.g. atrial fibrillation/atrial flutter, heart failure, or calcium channel blocker for heart rate control).
  3. Renal artery stenosis ≥ 50% diameter stenosis, or aneurysm(s)
  4. Patients with atrial fibrillation.
  5. Patient has type 1 diabetes
  6. Patient has type 2 diabetes and evidence of peripheral neuropathy
  7. History of previous stenting or balloon angioplasty of the renal arteries.
  8. Untreated hypothyroid or hypo-parathyroid.
  9. Orthostatic hypotension defined as >20 mmHg of systolic blood pressure and/or more than 10 mmHg in diastolic blood pressure fall after standing for 3mins
  10. Renal artery anatomy as assessed by imaging (CT-angiogram or, MR angiogram or renal angiogram) meeting the following criteria:

    1. Single renal artery or two renal arteries, if either has a diameter of < 5 mm or > 7 mm or a length of < 11 mm,
    2. Accessory renal arteries with diameter > 2.0 mm and < 5.0 mm,
    3. Excessive renal artery tortuosity based on Investigator judgment,
    4. Moderate or severe, and diffuse renal artery calcification, and/or
    5. Renal anatomic renovascular abnormalities (as assessed by renal imaging) that would increase the risk of renal catheterization.
  11. Occlusive peripheral vascular disease that would preclude percutaneous access for the procedure.
  12. Patient is known to have a unilateral non-functioning kidney or unequal renal size (> 2cm difference in renal length between kidneys).
  13. Single kidney, kidney tumor, urinary tract obstruction, or other anatomic abnormality. Note: Simple renal cysts are not an exclusion.
  14. Previous renal denervation.
  15. History of renal transplantation.
  16. Estimated eGFR (by the CKD-Epi formula) ≤45 mL/min per 1.73 m2, or on chronic renal replacement therapy. Patients with eGFR of <60 mL/min per 1.73 m2 will undergo additional renal function monitoring post procedure and/or contrast exsposure.
  17. Unexplained hypokalemia (i.e. K < 3.5 mEq/L in patients not on a potassium-wasting diuretic).
  18. Patient in whom an ABPM device cannot be used due to arm size (>50 cm arm circumference) or other reasons as identified by the Investigator or study coordinator.
  19. Patient with severe cardiac valve stenosis for which, in the opinion of the Investigator, a significant reduction of blood pressure is contraindicated.
  20. Heart failure greater than asymptomatic, New York Heart Association Functional Classification, class I, stage B heart failure
  21. Patient with history of myocardial infarction, unstable angina pectoris, or stroke during the 6 months prior to screening
  22. Known primary or secondary pulmonary hypertension.
  23. Active infection.
  24. Patient requiring chronic oxygen support or has severe COPD.
  25. Patient has known hypersensitivity to contrast agents that cannot be adequately pre-medicated
  26. A known hypersensitivity to Dehydrated Alcohol Injection.
  27. Platelet count < 75,000/microliter and/or known bleeding diathesis or coagulopathy at time of screening.
  28. Receiving anticoagulant drugs (e.g., warfarin, dabigatran, rivaroxaban, apixaban, edoxaban, or low molecular weight heparins), that in the opinion of the investigator, would affect the safety of the trial procedure. Use of antiplatelet drugs such as aspirin and/or thienopyridines (e.g., clopidogrel) are permitted.
  29. Patient has current problems with substance abuse (e.g. alcohol, illegal drugs, etc.).
  30. Patient on high dose of steroids or immunosuppressant therapy.
  31. Patient has a history of myocardial infarction, unstable angina pectoris, or stroke during the 3 months prior to screening.
  32. Patients with a history of pre-eclampsia
  33. patients with fibromuscular dysplasia
  34. patients with history of pyelonephritis within 6 months
  35. patients with history of recurrent (> one episode) kidney stones or history of kidney stones within the last year
  36. Pregnant or nursing or planning to become pregnant during the trial time period.

    Note: If subject is of childbearing potential, as defined in the protocol, agrees to use of contraception.

  37. Any 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03465917


Locations
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United States, Texas
The Institute for Exercise and Environmental Medicine
Dallas, Texas, United States, 75231
Sponsors and Collaborators
University of Texas Southwestern Medical Center
National Institute of Neurological Disorders and Stroke (NINDS)
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Responsible Party: University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT03465917    
Other Study ID Numbers: STU 112014-023
First Posted: March 14, 2018    Key Record Dates
Last Update Posted: May 11, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Additional relevant MeSH terms:
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Hypertension
Vascular Diseases
Cardiovascular Diseases