<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01673516</url>
  </required_header>
  <id_info>
    <org_study_id>2012/145/REK</org_study_id>
    <nct_id>NCT01673516</nct_id>
  </id_info>
  <brief_title>Effect of Renal Sympathetic Denervation on Resistant Hypertension and Cardiovascular Hemodynamic in Comparison to Intensive Medical Therapy Utilizing Impedance Cardiography</brief_title>
  <acronym>OsloRDN</acronym>
  <official_title>Effect of Renal Sympathetic Denervation on Resistant Hypertension and Cardiovascular Hemodynamic in Comparison to Intensive Medical Therapy Utilizing Impedance Cardiography</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Oslo University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Oslo University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to demonstrate that Renal Sympathetic Denervation (RDN) improves&#xD;
      the control of blood pressure (BP) in patients with treatment-resistant hypertension, as&#xD;
      compared to intensive medical therapy (IMT) using hemodynamic parameters and then applying a&#xD;
      predefined algorithm of drug selection (i.e. integrated hemodynamic management - IHM) during&#xD;
      6 months intensive treatment program (receiving antihypertensive care according to the 2007&#xD;
      ESH Guidelines). Working hypothesis: When it is possible to disrupt the sympatho-renal axis&#xD;
      by RDN - BP reduction occurs to a greater extent and more rapidly than applying intensive&#xD;
      medical therapy using IHM.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hypertension is the most common cardiovascular disease, affecting approximately 1 billion1&#xD;
      people worldwide. Hypertension is a major public health concern, because of its complications&#xD;
      (coronary artery disease, heart failure, renal disease, stroke). Early blood pressure control&#xD;
      in hypertensive patients guarantees the best prevention of cardiovascular events on the long&#xD;
      term (2007 ESH-ESC Guidelines on the Management of Hypertension; VALUE study). However, in&#xD;
      spite of education efforts and antihypertensive drugs, blood pressure control rates remain&#xD;
      low. The most common cause of uncontrolled BP is inadequate pharmacological treatment,&#xD;
      because the selection of antihypertensive agents is often done independently of the&#xD;
      hemodynamic status of the patient (volemic status, peripheral resistance, cardiac inotropy).&#xD;
&#xD;
      The sympatho-renal axis describes the dual role of the kidney as originator of some central&#xD;
      nervous system afferent signals and recipient of efferent sympathetic signals. Both the&#xD;
      contribution of the kidney to central sympathetic drive and the consequences of sympathetic&#xD;
      efferent drive to the kidney contribute to the development and sustenance of hypertension.&#xD;
      Poly-pharmacy strategies for the treatment of elevated blood pressure have identified&#xD;
      populations of patients with treatment resistant hypertension.&#xD;
&#xD;
      Treatment Resistant Hypertension(TRH) is a blood pressure that remains above goal in spite of&#xD;
      the concomitant use of antihypertensive medications from more than 3 drug classes. Patients&#xD;
      who require more than 4 drug classes to have their blood pressure controlled are also&#xD;
      considered to have resistant hypertension. Preferably, the regimen should include a diuretic&#xD;
      and all doses should be optimal2 .The true prevalence of treatment resistant hypertension is&#xD;
      unknown. In clinical trials from 20 to 40% of randomized patients did not reach blood&#xD;
      pressure targets3. In the National Health and Nutrition Examination Survey in USA&#xD;
      (2003-2008), non-pregnant adults with hypertension were classified as resistant if their&#xD;
      blood pressure was 140/90 mmHg or higher and if they reported using antihypertensive&#xD;
      medications from 3 different drug classes or drugs from 4 antihypertensive drug classes&#xD;
      regardless of blood pressure. The prevalence was 12.8% of the drug-treated hypertensive&#xD;
      population. Risk factors for treatment-resistant hypertension include older age and obesity .&#xD;
&#xD;
      Treatment-resistant patients are more likely to have albuminuria, reduced renal function, and&#xD;
      a history of diabetes mellitus, coronary heart disease, stroke or heart failure. They are at&#xD;
      increased risk of cardiovascular complications although the true incidence of death and&#xD;
      morbidity remains currently unknown.&#xD;
&#xD;
      In the Spanish Ambulatory Blood Pressure Monitoring Registry5, 8295 of 68045 treated patients&#xD;
      (12.2%) had treatment resistant hypertension, defined as an office blood pressure equal to or&#xD;
      exceeding 140 mm Hg systolic and/or 90 mm Hg diastolic.&#xD;
&#xD;
      RDN is a novel procedure which has been approved safe and gives a remarkable reduction of BP&#xD;
      in treatment-resistant hypertensive patients. The HOTMAN® System is a novel impedance&#xD;
      cardiographic device, measuring and calculating hemodynamic parameters. The HOTMAN® System&#xD;
      may help the physician to control blood pressure in patients with resistance hypertension.&#xD;
&#xD;
      * Our pilot study(Renal sympathetic denervation in patients with treatment-resistant&#xD;
      hypertension after witnessed intake of medication before qualifying ambulatory blood&#xD;
      pressure.Fadl Elmula FE, Hoffmann P, Fossum E, Brekke M, Gjønnæss E, Hjørnholm U, Kjær VN,&#xD;
      Rostrup M, Kjeldsen SE, Os I, Stenehjem AE, Høieggen A.Hypertension. 2013&#xD;
      Sep;62(3):526-32)has showed that The mean office and ambulatory BPs remained unchanged at 1,&#xD;
      3, and 6 months in the 6 patients, whereas there was no known change in antihypertensive&#xD;
      medication. Two patients, however, had a fall in both office and ambulatory BPs. Our findings&#xD;
      question whether BP falls in response to RDN in patients with true treatment-resistant&#xD;
      hypertension.That is why we intended to do an intrim analysis after inclusion of around 30%&#xD;
      of the total number planned to be included in the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>August 2012</start_date>
  <completion_date type="Anticipated">August 2022</completion_date>
  <primary_completion_date type="Actual">December 2013</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Absolute change in office systolic blood pressure(SBP)</measure>
    <time_frame>at 6 months</time_frame>
    <description>is the absolute change in office SBP, after a 6 months follow-up.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Short and long term safety of RDN as an interventional procedure</measure>
    <time_frame>up to10 years</time_frame>
    <description>Safety of RDN will be assessed at 1, 3, 5 and 10 years by clinical, laboratory and radiology examinations.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of normalization of blood pressure(BP) at office, home and ABPM</measure>
    <time_frame>at 6 months and later</time_frame>
    <description>This will include the percentage of normalization of daytime SBP at office, home and ABPM.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The normalization of hemodynamics.</measure>
    <time_frame>at 6 month and later</time_frame>
    <description>The normalization of hemodynamics: Cardiac Index (CI), Heart rate, Stroke systemic vascular resistance index (SSVRI), pulse wave velocity(PWV) and central BP.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost effectiveness</measure>
    <time_frame>At 6 month and later</time_frame>
    <description>It will be assessed the Cost effectiveness of Renal denervation as treatment of resistant hypertension compared to control group.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>The quality of life and side effects related to antihypertensive agents</measure>
    <time_frame>at 6 months and later</time_frame>
    <description>The quality of life and side effects related to antihypertensive agents</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Hypertension, Resistant to Conventional Therapy</condition>
  <arm_group>
    <arm_group_label>group Co</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>group Co receives intensive medical therapy utilizing integrated hemodynamic management calculated by impedance cardiography of &quot;The HOTMAN® System&quot;</description>
  </arm_group>
  <arm_group>
    <arm_group_label>group RDN</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>For patients who will be randomly assigned to undergo renal denervation by &quot;The SymplicityTM Renal Denervation System&quot;, the femoral artery will be accessed with the standard endovascular technique and the catheter will be advanced into the renal artery and connected to a radiofrequency generator. As in Symplicity HTN 1 and 2 trials, four-to-six discrete, low-power radiofrequency ablations lasting up to 2 min each and of 8 watts or less to obtain up to four-six ablations separated both longitudinally and rotationally within each renal artery. During ablation, the catheter system monitored tip temperature and impedance, altering radiofrequency energy delivery in response to a predetermined algorithm.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>The SymplicityTM Renal Denervation System</intervention_name>
    <description>For patients who will be randomly assigned to undergo renal denervation (group RDN), the femoral artery will be accessed with the standard endovascular technique and the catheter will be advanced into the renal artery and connected to a radiofrequency generator. As in Simplicity HTN 1 and 2 trials, four-to-six discrete, low-power radiofrequency ablations lasting up to 2 min each and of 8 watts or less to obtain up to four-six ablations separated both longitudinally and rotationally within each renal artery. During ablation, the catheter system monitored tip temperature and impedance, altering radiofrequency energy delivery in response to a predetermined algorithm.</description>
    <arm_group_label>group RDN</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>The HOTMAN® System</intervention_name>
    <description>Impedance Cardiography by HOTMAN system will evaluates non-invasively hemodynamic parameters in patients randomized to &quot;group Co&quot;</description>
    <arm_group_label>group Co</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Average SBP &gt;140mmHg, measured per guidelines&#xD;
&#xD;
          -  24 hour average ABPM daytime SBP &gt;135mm/Hg&#xD;
&#xD;
          -  On stable medication regimen of full tolerated doses of 3 or more antihypertensive&#xD;
             meds, with one being a diuretic&#xD;
&#xD;
          -  No changes for a minimum of 2 weeks prior to screening&#xD;
&#xD;
          -  No planned medication changes for 6 months&#xD;
&#xD;
          -  Age 18-80 years&#xD;
&#xD;
          -  At minimum, 3 antihypertensive medications must meet one or more of the following full&#xD;
             dose criteria:&#xD;
&#xD;
          -  Highest labeled dose according to medication's labeling&#xD;
&#xD;
          -  Highest usual dose per clinical guidelines-JNC-7&#xD;
&#xD;
          -  Highest tolerated dose&#xD;
&#xD;
          -  Highest appropriate dose for the patient per the PI's clinical judgment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Hemodynamically or anatomically significant renal artery abnormalities or stenosis&#xD;
             &gt;50% or prior renal artery intervention&#xD;
&#xD;
          -  eGFR &lt; 45 mL/min/1.73m2 (MDRD formula)&#xD;
&#xD;
          -  Albumin/creatinine ratio &gt; 50 mg/mmol&#xD;
&#xD;
          -  Type 1 diabetes mellitus&#xD;
&#xD;
          -  Known alcohol or drug abuse&#xD;
&#xD;
          -  Symptomatic orthostatic hypotension in past year&#xD;
&#xD;
          -  Stenotic valvular heart disease for which BP reduction would be hazardous&#xD;
&#xD;
          -  MI, unstable angina, or CVA in the prior 6 months&#xD;
&#xD;
          -  Known primary pulmonary HTN&#xD;
&#xD;
          -  Known pheochromocytoma, Cushing's disease, coarctation of the aorta, hyperthyroidism&#xD;
             or hyperparathyroidism&#xD;
&#xD;
          -  Known primary hyperaldosteronism not adequately treated.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Aud Høieggen, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Oslo University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Oslo University Hospital</name>
      <address>
        <city>Oslo</city>
        <zip>0424</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Norway</country>
  </location_countries>
  <verification_date>October 2015</verification_date>
  <study_first_submitted>August 17, 2012</study_first_submitted>
  <study_first_submitted_qc>August 27, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 28, 2012</study_first_posted>
  <last_update_submitted>October 29, 2015</last_update_submitted>
  <last_update_submitted_qc>October 29, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 30, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Renal sympathetic denervation</keyword>
  <keyword>Impedance cardiography</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01673516
org study id: 2012/145/REK
nct id: NCT01673516
lead sponsor: 
has dmc: Yes
The purpose of this study is to demonstrate that Renal Sympathetic Denervation (RDN) improves
      the control of blood pressure (BP) in patients with treatment-resistant hypertension, as
      compared to intensive medical therapy (IMT) using hemodynamic parameters and then applying a
      predefined algorithm of drug selection (i.e. integrated hemodynamic management - IHM) during
      6 months intensive treatment program (receiving antihypertensive care according to the 2007
      ESH Guidelines). Working hypothesis: When it is possible to disrupt the sympatho-renal axis
      by RDN - BP reduction occurs to a greater extent and more rapidly than applying intensive
      medical therapy using IHM.
Hypertension is the most common cardiovascular disease, affecting approximately 1 billion1
      people worldwide. Hypertension is a major public health concern, because of its complications
      (coronary artery disease, heart failure, renal disease, stroke). Early blood pressure control
      in hypertensive patients guarantees the best prevention of cardiovascular events on the long
      term (2007 ESH-ESC Guidelines on the Management of Hypertension; VALUE study). However, in
      spite of education efforts and antihypertensive drugs, blood pressure control rates remain
      low. The most common cause of uncontrolled BP is inadequate pharmacological treatment,
      because the selection of antihypertensive agents is often done independently of the
      hemodynamic status of the patient (volemic status, peripheral resistance, cardiac inotropy).

      The sympatho-renal axis describes the dual role of the kidney as originator of some central
      nervous system afferent signals and recipient of efferent sympathetic signals. Both the
      contribution of the kidney to central sympathetic drive and the consequences of sympathetic
      efferent drive to the kidney contribute to the development and sustenance of hypertension.
      Poly-pharmacy strategies for the treatment of elevated blood pressure have identified
      populations of patients with treatment resistant hypertension.

      Treatment Resistant Hypertension(TRH) is a blood pressure that remains above goal in spite of
      the concomitant use of antihypertensive medications from more than 3 drug classes. Patients
      who require more than 4 drug classes to have their blood pressure controlled are also
      considered to have resistant hypertension. Preferably, the regimen should include a diuretic
      and all doses should be optimal2 .The true prevalence of treatment resistant hypertension is
      unknown. In clinical trials from 20 to 40% of randomized patients did not reach blood
      pressure targets3. In the National Health and Nutrition Examination Survey in USA
      (2003-2008), non-pregnant adults with hypertension were classified as resistant if their
      blood pressure was 140/90 mmHg or higher and if they reported using antihypertensive
      medications from 3 different drug classes or drugs from 4 antihypertensive drug classes
      regardless of blood pressure. The prevalence was 12.8% of the drug-treated hypertensive
      population. Risk factors for treatment-resistant hypertension include older age and obesity .

      Treatment-resistant patients are more likely to have albuminuria, reduced renal function, and
      a history of diabetes mellitus, coronary heart disease, stroke or heart failure. They are at
      increased risk of cardiovascular complications although the true incidence of death and
      morbidity remains currently unknown.

      In the Spanish Ambulatory Blood Pressure Monitoring Registry5, 8295 of 68045 treated patients
      (12.2%) had treatment resistant hypertension, defined as an office blood pressure equal to or
      exceeding 140 mm Hg systolic and/or 90 mm Hg diastolic.

      RDN is a novel procedure which has been approved safe and gives a remarkable reduction of BP
      in treatment-resistant hypertensive patients. The HOTMAN® System is a novel impedance
      cardiographic device, measuring and calculating hemodynamic parameters. The HOTMAN® System
      may help the physician to control blood pressure in patients with resistance hypertension.

      * Our pilot study(Renal sympathetic denervation in patients with treatment-resistant
      hypertension after witnessed intake of medication before qualifying ambulatory blood
      pressure.Fadl Elmula FE, Hoffmann P, Fossum E, Brekke M, Gjønnæss E, Hjørnholm U, Kjær VN,
      Rostrup M, Kjeldsen SE, Os I, Stenehjem AE, Høieggen A.Hypertension. 2013
      Sep;62(3):526-32)has showed that The mean office and ambulatory BPs remained unchanged at 1,
      3, and 6 months in the 6 patients, whereas there was no known change in antihypertensive
      medication. Two patients, however, had a fall in both office and ambulatory BPs. Our findings
      question whether BP falls in response to RDN in patients with true treatment-resistant
      hypertension.That is why we intended to do an intrim analysis after inclusion of around 30%
      of the total number planned to be included in the study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Absolute change in office systolic blood pressure(SBP)
time frame: at 6 months
description: is the absolute change in office SBP, after a 6 months follow-up.
measure: Short and long term safety of RDN as an interventional procedure
time frame: up to10 years
description: Safety of RDN will be assessed at 1, 3, 5 and 10 years by clinical, laboratory and radiology examinations.
measure: Percentage of normalization of blood pressure(BP) at office, home and ABPM
time frame: at 6 months and later
description: This will include the percentage of normalization of daytime SBP at office, home and ABPM.
measure: The normalization of hemodynamics.
time frame: at 6 month and later
description: The normalization of hemodynamics: Cardiac Index (CI), Heart rate, Stroke systemic vascular resistance index (SSVRI), pulse wave velocity(PWV) and central BP.
measure: Cost effectiveness
time frame: At 6 month and later
description: It will be assessed the Cost effectiveness of Renal denervation as treatment of resistant hypertension compared to control group.
measure: The quality of life and side effects related to antihypertensive agents
time frame: at 6 months and later
description: The quality of life and side effects related to antihypertensive agents
arm group label: group Co
arm group type: Active Comparator
description: group Co receives intensive medical therapy utilizing integrated hemodynamic management calculated by impedance cardiography of "The HOTMAN® System"
arm group label: group RDN
arm group type: Active Comparator
description: For patients who will be randomly assigned to undergo renal denervation by "The SymplicityTM Renal Denervation System", the femoral artery will be accessed with the standard endovascular technique and the catheter will be advanced into the renal artery and connected to a radiofrequency generator. As in Symplicity HTN 1 and 2 trials, four-to-six discrete, low-power radiofrequency ablations lasting up to 2 min each and of 8 watts or less to obtain up to four-six ablations separated both longitudinally and rotationally within each renal artery. During ablation, the catheter system monitored tip temperature and impedance, altering radiofrequency energy delivery in response to a predetermined algorithm.
intervention type: Procedure
intervention name: The SymplicityTM Renal Denervation System
description: For patients who will be randomly assigned to undergo renal denervation (group RDN), the femoral artery will be accessed with the standard endovascular technique and the catheter will be advanced into the renal artery and connected to a radiofrequency generator. As in Simplicity HTN 1 and 2 trials, four-to-six discrete, low-power radiofrequency ablations lasting up to 2 min each and of 8 watts or less to obtain up to four-six ablations separated both longitudinally and rotationally within each renal artery. During ablation, the catheter system monitored tip temperature and impedance, altering radiofrequency energy delivery in response to a predetermined algorithm.
arm group label: group RDN
intervention type: Device
intervention name: The HOTMAN® System
description: Impedance Cardiography by HOTMAN system will evaluates non-invasively hemodynamic parameters in patients randomized to "group Co"
arm group label: group Co
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Aud Høieggen, MD, PhD
role: Study Chair
affiliation: Oslo University Hospital
facility: 
country: Norway
responsible party type: Sponsor
mesh term: Hypertension