<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/NCT01679652</url>
  </required_header>
  <id_info>
    <org_study_id>FHC-1-2012</org_study_id>
    <nct_id>NCT01679652</nct_id>
  </id_info>
  <brief_title>The Effects of Nebivolol on the NO-system in Patients With Essential Hypertension</brief_title>
  <acronym>NEBI</acronym>
  <official_title>The Effects of Nebivolol on the NO-system in Patients With Essential</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Erling Bjerregaard Pedersen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Regional Hospital Holstebro</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Investigators want investigate the following hypothesis:&#xD;
&#xD;
        1. Nebivolol increases nitric oxide activity in the systemic circulation and the kidney&#xD;
&#xD;
        2. The increased activity of nitric oxide during nebivolol treatment can be demonstrated by&#xD;
           inhibition of NO synthesis with L-NMMA. We expect increased responses in blood pressure&#xD;
           and sodium excretion is expected during nebivolol treatment compared to placebo.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Beta-blockers are no longer recommended as first line treatment in essential hypertension.&#xD;
      Evidence mainly based on clinical trails with the non-vasodilating beta-blockers atenolol and&#xD;
      propanolol points towards that beta-blockers have an increased risk of stroke compared to&#xD;
      ACE-inhibitors, calcium channel blockers and thiazides. However, this Nebivolol is a third&#xD;
      generation beta-blocker with vasodilating properties. Nebivolol decreases peripheral blood&#xD;
      pressure to the same extend as other beta-blockers but in contrast to atenolol nebivolol also&#xD;
      reduces central blood pressure. Furthermore nebivolol increases nitric oxide (NO)&#xD;
      availability in forearm vessels, maybe through activation of beta-3 receptors. The nitric&#xD;
      oxide system plays a central role in both renal sodium and water handling and regulation of&#xD;
      vascular tone and blood pressure. It has not been investigated if nebivolol changes NO&#xD;
      availability in the kidney.&#xD;
&#xD;
      Investigators want investigate the following hypothesis:&#xD;
&#xD;
        1. Nebivolol increases nitric oxide activity in the systemic circulation and the kidney&#xD;
&#xD;
        2. The increased activity of nitric oxide during nebivolol treatment can be demonstrated by&#xD;
           inhibition of NO synthesis with L-NMMA. Investigators expect increased responses in&#xD;
           blood pressure and sodium excretion is expected during nebivolol treatment compared to&#xD;
           placebo.&#xD;
&#xD;
      Purpose The purpose of this study is to investigate the effects of nebivolol on renal&#xD;
      handling of sodium and water (Glomerular filtration rate, urine production, free water&#xD;
      clearance, excretion of proteins from epithelial sodium channels (u-ENaCαβγ) and aquaporin&#xD;
      channels (u-AQP2) and sodium and potassium excretion), plasma concentrations of vasoactive&#xD;
      hormones (renin, angiotensin II, aldosterone, vasopressin, atrial natriuretic peptide, brain&#xD;
      natriuretic peptide and endothelin), central blood pressure, pulse wave velocity (PWV) and&#xD;
      augmentation index, under basal conditions and during inhibition of nitric oxide synthesis in&#xD;
      patients with essential hypertension.&#xD;
&#xD;
      Design 25 patients with essential hypertension are recruited in this randomised, cross over,&#xD;
      placebo-controlled, double blinded study with two treatment periods (nebivolol/placebo). Each&#xD;
      subject will attend to two examination days. Four days prior to each examination days and on&#xD;
      the morning of each examination day subjects are given either nebivolol 5 mg pr. day or&#xD;
      placebo. During treatment periods subject are given a standardized diet. On the examination&#xD;
      days subject are given L-NMMA, a nitric oxide synthase inhibitor, and renal function, central&#xD;
      hemodynamic and vasoactive hormones are evaluated during basal conditions and during&#xD;
      inhibition of nitric oxide synthesis.&#xD;
&#xD;
      Perspectives This study is expected to contribute to increasing the knowledge about the&#xD;
      mechanisms involved in the development and progression of cardiovascular disease.&#xD;
      Beta-blockers are not recommended as first line treatment in essential hypertension but the&#xD;
      results from this study may influence clinical treatment of essential hypertension in the&#xD;
      future.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">September 2013</completion_date>
  <primary_completion_date type="Actual">September 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>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Fractional excretion of sodium</measure>
    <time_frame>5 days</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Blood pressure</measure>
    <time_frame>5 days</time_frame>
    <description>Both ambulatory blood pressure and office and central blood pressure before and during L-NMMA infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pulse wave velocity</measure>
    <time_frame>5 days</time_frame>
    <description>before and during L-NMMA infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma renin concentration</measure>
    <time_frame>5 days</time_frame>
    <description>before and during L-NMMA infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma aldosterone concentration</measure>
    <time_frame>5 days</time_frame>
    <description>Before and during L-NMMA infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma angiotensin II concentration</measure>
    <time_frame>5 days</time_frame>
    <description>Before and during L-NMMA infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Endothelin concentration</measure>
    <time_frame>5 days</time_frame>
    <description>Before and during L-NMMA infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma brain natriuretic peptide concentration</measure>
    <time_frame>5 days</time_frame>
    <description>Before and during L-NMMA infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma vasopressin concentration</measure>
    <time_frame>5 days</time_frame>
    <description>Before and during L-NMMA infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glomerular filtration rate</measure>
    <time_frame>5 days</time_frame>
    <description>Before and during L-NMMA infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urinary excretions of epithelial sodium channels</measure>
    <time_frame>5 days</time_frame>
    <description>Before and during L-NMMA infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urinary excretions of aquaprorin-2</measure>
    <time_frame>5 days</time_frame>
    <description>Before and during L-NMMA infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>24-hour ambulatory blood pressure</measure>
    <time_frame>5 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Free water clearance</measure>
    <time_frame>5 days</time_frame>
    <description>Before and during L-NMMA infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine flow</measure>
    <time_frame>5 days</time_frame>
    <description>Before and during L-NMMA infusion</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Essential Hypertension</condition>
  <arm_group>
    <arm_group_label>Nebivolol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tablet Nebivolol 5 mg (oral use) for 5 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Inactive placebo given as tablet for 5 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nebivolol</intervention_name>
    <description>Tablet i blinded in capsula</description>
    <arm_group_label>Nebivolol</arm_group_label>
    <other_name>Tradename in Denmark: Hypoloc</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Increased blood pressure (above 135 mmHg systolic or 85 mmHg diastolic in day time in&#xD;
             24 hour blood pressure measurement taking 5 or 10 mg amlodipine&#xD;
&#xD;
          -  Men and women&#xD;
&#xD;
          -  age 40 - 70 years&#xD;
&#xD;
          -  informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  diabetes mellitus&#xD;
&#xD;
          -  glomerular filtration rate &lt; 30 ml/min&#xD;
&#xD;
          -  albuminuria &gt; 1,5 g/l&#xD;
&#xD;
          -  renogram which suggests secondary hypertension&#xD;
&#xD;
          -  clinical signs of pheochromocytoma or increased p-metanephrines&#xD;
&#xD;
          -  clinical important sign og heart, lung, liver, thyroid or neoplastic diseases&#xD;
&#xD;
          -  clinical important deviations in routine blood samples or ECG&#xD;
&#xD;
          -  drug or alcohol abuse&#xD;
&#xD;
          -  pregnancy or nursery&#xD;
&#xD;
          -  intolerance to nebivolol&#xD;
&#xD;
          -  blood donation with a month of the first examination day&#xD;
&#xD;
          -  inacceptable increase in blood pressure durin L-NMMA infusion (200/120)&#xD;
&#xD;
          -  inacceptable side effects to amlodipine&#xD;
&#xD;
          -  blood pressure increase above 170/105 on highest dose amlodipine (10 mg)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Erling B Pedersen, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Department of medical Research, Holstebro Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Frank H Mose, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Medical Research, Holstebro Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Medical Research, Holstebro Hospital</name>
      <address>
        <city>Holstebro</city>
        <zip>7500</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>March 2014</verification_date>
  <study_first_submitted>September 1, 2012</study_first_submitted>
  <study_first_submitted_qc>September 5, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 6, 2012</study_first_posted>
  <last_update_submitted>March 1, 2014</last_update_submitted>
  <last_update_submitted_qc>March 1, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">March 4, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Regional Hospital Holstebro</investigator_affiliation>
    <investigator_full_name>Erling Bjerregaard Pedersen</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <keyword>Essential hypertension</keyword>
  <keyword>Nitric oxide</keyword>
  <keyword>Nebivolol</keyword>
  <keyword>Fractional excretion of sodium</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</mesh_term>
    <mesh_term>Essential Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nebivolol</mesh_term>
  </intervention_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/NCT01679652
org study id: FHC-1-2012
nct id: NCT01679652
lead sponsor: 
has dmc: Yes
Investigators want investigate the following hypothesis:

        1. Nebivolol increases nitric oxide activity in the systemic circulation and the kidney

        2. The increased activity of nitric oxide during nebivolol treatment can be demonstrated by
           inhibition of NO synthesis with L-NMMA. We expect increased responses in blood pressure
           and sodium excretion is expected during nebivolol treatment compared to placebo.
Beta-blockers are no longer recommended as first line treatment in essential hypertension.
      Evidence mainly based on clinical trails with the non-vasodilating beta-blockers atenolol and
      propanolol points towards that beta-blockers have an increased risk of stroke compared to
      ACE-inhibitors, calcium channel blockers and thiazides. However, this Nebivolol is a third
      generation beta-blocker with vasodilating properties. Nebivolol decreases peripheral blood
      pressure to the same extend as other beta-blockers but in contrast to atenolol nebivolol also
      reduces central blood pressure. Furthermore nebivolol increases nitric oxide (NO)
      availability in forearm vessels, maybe through activation of beta-3 receptors. The nitric
      oxide system plays a central role in both renal sodium and water handling and regulation of
      vascular tone and blood pressure. It has not been investigated if nebivolol changes NO
      availability in the kidney.

      Investigators want investigate the following hypothesis:

        1. Nebivolol increases nitric oxide activity in the systemic circulation and the kidney

        2. The increased activity of nitric oxide during nebivolol treatment can be demonstrated by
           inhibition of NO synthesis with L-NMMA. Investigators expect increased responses in
           blood pressure and sodium excretion is expected during nebivolol treatment compared to
           placebo.

      Purpose The purpose of this study is to investigate the effects of nebivolol on renal
      handling of sodium and water (Glomerular filtration rate, urine production, free water
      clearance, excretion of proteins from epithelial sodium channels (u-ENaCαβγ) and aquaporin
      channels (u-AQP2) and sodium and potassium excretion), plasma concentrations of vasoactive
      hormones (renin, angiotensin II, aldosterone, vasopressin, atrial natriuretic peptide, brain
      natriuretic peptide and endothelin), central blood pressure, pulse wave velocity (PWV) and
      augmentation index, under basal conditions and during inhibition of nitric oxide synthesis in
      patients with essential hypertension.

      Design 25 patients with essential hypertension are recruited in this randomised, cross over,
      placebo-controlled, double blinded study with two treatment periods (nebivolol/placebo). Each
      subject will attend to two examination days. Four days prior to each examination days and on
      the morning of each examination day subjects are given either nebivolol 5 mg pr. day or
      placebo. During treatment periods subject are given a standardized diet. On the examination
      days subject are given L-NMMA, a nitric oxide synthase inhibitor, and renal function, central
      hemodynamic and vasoactive hormones are evaluated during basal conditions and during
      inhibition of nitric oxide synthesis.

      Perspectives This study is expected to contribute to increasing the knowledge about the
      mechanisms involved in the development and progression of cardiovascular disease.
      Beta-blockers are not recommended as first line treatment in essential hypertension but the
      results from this study may influence clinical treatment of essential hypertension in the
      future.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Fractional excretion of sodium
time frame: 5 days
measure: Blood pressure
time frame: 5 days
description: Both ambulatory blood pressure and office and central blood pressure before and during L-NMMA infusion
measure: Pulse wave velocity
time frame: 5 days
description: before and during L-NMMA infusion
measure: Plasma renin concentration
time frame: 5 days
description: before and during L-NMMA infusion
measure: Plasma aldosterone concentration
time frame: 5 days
description: Before and during L-NMMA infusion
measure: Plasma angiotensin II concentration
time frame: 5 days
description: Before and during L-NMMA infusion
measure: Plasma Endothelin concentration
time frame: 5 days
description: Before and during L-NMMA infusion
measure: Plasma brain natriuretic peptide concentration
time frame: 5 days
description: Before and during L-NMMA infusion
measure: Plasma vasopressin concentration
time frame: 5 days
description: Before and during L-NMMA infusion
measure: Glomerular filtration rate
time frame: 5 days
description: Before and during L-NMMA infusion
measure: Urinary excretions of epithelial sodium channels
time frame: 5 days
description: Before and during L-NMMA infusion
measure: Urinary excretions of aquaprorin-2
time frame: 5 days
description: Before and during L-NMMA infusion
measure: 24-hour ambulatory blood pressure
time frame: 5 days
measure: Free water clearance
time frame: 5 days
description: Before and during L-NMMA infusion
measure: Urine flow
time frame: 5 days
description: Before and during L-NMMA infusion
arm group label: Nebivolol
arm group type: Experimental
description: Tablet Nebivolol 5 mg (oral use) for 5 days
arm group label: Placebo
arm group type: Placebo Comparator
description: Inactive placebo given as tablet for 5 days
intervention type: Drug
intervention name: Nebivolol
description: Tablet i blinded in capsula
arm group label: Nebivolol
other name: Tradename in Denmark: Hypoloc
intervention type: Drug
intervention name: placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 40 Years
maximum age: 70 Years
healthy volunteers: No
last name: Erling B Pedersen, MD
role: Study Chair
affiliation: Department of medical Research, Holstebro Hospital
last name: Frank H Mose, MD
role: Principal Investigator
affiliation: Department of Medical Research, Holstebro Hospital
facility: 
country: Denmark
responsible party type: Sponsor-Investigator
investigator affiliation: Regional Hospital Holstebro
investigator full name: Erling Bjerregaard Pedersen
investigator title: MD
mesh term: Hypertension
mesh term: Essential Hypertension
mesh term: Nebivolol