<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/NCT02238457</url>
  </required_header>
  <id_info>
    <org_study_id>Project 103-10</org_study_id>
    <nct_id>NCT02238457</nct_id>
  </id_info>
  <brief_title>Study of High Dosage of Losartan in Comparison to Low Dose of Losartan in Heart Failure Patients</brief_title>
  <official_title>Effects of Low-Dose vs High-dose Losartan on Sympathetic Hyperactivity in Patients With Congestive Heart Failure</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Baker Heart and Diabetes Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Baker Heart and Diabetes Institute</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The sympathetic nervous system, a part of the nervous system that stimulates the heart via&#xD;
      release of substances, noradrenaline and adrenaline (combined called catecholamines), becomes&#xD;
      activated in people with heart failure. As these people become sicker, the nervous system&#xD;
      becomes more active, causing further damage to the heart.&#xD;
&#xD;
      Large trials have shown that Angiotensin-converting enzyme (ACE) inhibitors reduce morbidity&#xD;
      and mortality in patients with heart failure. Higher doses of these drugs are more effective&#xD;
      than lower doses. Studies show that ACE-inhibitors decrease catecholamine levels. This could&#xD;
      be why congestive heart failure (CHF) patients taking this class of drugs show improvement in&#xD;
      heart function.&#xD;
&#xD;
      There are several ways of measuring the activity of the sympathetic nervous system. The most&#xD;
      common measurement is to test the blood for catecholamine levels. This is not very reliable&#xD;
      or reproducible. Microneurography is a new technique used to measure sympathetic nerve&#xD;
      activity. A small electrode (comparable to an acupuncture needle) is placed in a muscle nerve&#xD;
      and hooked up to a stimulator and a recorder. It produces direct recordings of skeletal&#xD;
      muscle nerve traffic. Both the rate and amplitude of the burst can be measured. The results&#xD;
      in this technique are highly reproducible. By using this technique we get a more accurate&#xD;
      picture of how the nervous system responds to medications given to treat heart failure.&#xD;
&#xD;
      Losartan (Cozaar) is an angiotensin II type 1 (AT1) receptor blocker. It blocks the binding&#xD;
      of angiotensin II, a hormone that constricts blood vessels. As a result the blood vessels&#xD;
      remain relaxed, leading to a reduction in the workload of the heart. Minor decreases in blood&#xD;
      catecholamine levels have been reported with a low dose of this drug. The purpose of this&#xD;
      study is to see whether a high dose of losartan (200 mg) has a greater effect on the&#xD;
      sympathetic nervous system than a low dose of losartan (50 mg) does.&#xD;
&#xD;
      A total of 30 participants will be recruited. Participants will be assigned to one of two&#xD;
      groups: high-dose, in which subjects will receive treatment of 200 mg/day of losartan, and&#xD;
      low-dose, in which subjects will receive treatment of 50 mg/day of losartan. Via&#xD;
      microneurography the investigators will measure the difference in sympathetic activity in&#xD;
      subjects in high-dose vs low-dose losartan. The investigators expect to see further decrease&#xD;
      in sympathetic activity in high-dose group than in low-dose group.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Difficulty recruiting patients&#xD;
  </why_stopped>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Effect of losartan on the sympathetic nervous system.</measure>
    <time_frame>10 weeks</time_frame>
    <description>Assessed by microneurographic recordings of muscle sympathetic nerve activity from the peroneal nerve.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in plasma catecholamines.</measure>
    <time_frame>10 weeks</time_frame>
    <description>Plasma catecholamines will be measured by High-performance liquid chromatography (HPLC). Samples will be collected for plasma aldosterone, plasma renin and plasma angiotensin II.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in central hemodynamics.</measure>
    <time_frame>10 weeks</time_frame>
    <description>Invasive measurement of central hemodynamic parameters; heart rate, blood pressure, cardiac output (CO), pulmonary capillary wedge pressure (PCWP), right arterial pressure (RAP).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Heart Failure</condition>
  <arm_group>
    <arm_group_label>Low dose losartan</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Low dose losartan</description>
  </arm_group>
  <arm_group>
    <arm_group_label>High dose losartan</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>High dose losartan</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Low dose losartan</intervention_name>
    <description>25 mg losartan bid for 10 weeks</description>
    <arm_group_label>Low dose losartan</arm_group_label>
    <other_name>losartan (Cozaar)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>High dose losartan</intervention_name>
    <description>50 mg, 75 mg, or 100 mg bid for 10 weeks. Dose will be determined by the medical doctor depending on patients' tolerability</description>
    <arm_group_label>High dose losartan</arm_group_label>
    <other_name>Losartan (Cozaar)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males and females age between 21 and 75 years&#xD;
&#xD;
          -  Diagnosis of mild to moderate congestive heart failure&#xD;
&#xD;
          -  Coronary angiography identifying coronary artery disease as the likely cause of&#xD;
             congestive heart failure&#xD;
&#xD;
          -  Left Ventricular (LV) ejection fraction between 20 to 40 percent on echocardiography&#xD;
             or RNA&#xD;
&#xD;
          -  Sinus rhythm&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Insulin-dependent diabetes mellitus&#xD;
&#xD;
          -  Hypertension (higher than 140/90 mmHg at rest)&#xD;
&#xD;
          -  Use of sympatholytic agents such as clonidine, methyldopa, reserpine&#xD;
&#xD;
          -  Significant non-cardiac disease, possibly affecting cardiovascular regulation&#xD;
&#xD;
          -  Autonomic neuropathy of any cause&#xD;
&#xD;
          -  Leg injuries with nerve damage&#xD;
&#xD;
          -  Poor bladder control&#xD;
&#xD;
          -  Recent history of alcoholism, drug abuse, significant psychiatric disorders&#xD;
&#xD;
          -  Known adverse events to AT1-receptor blockers&#xD;
&#xD;
          -  Unlikely to tolerate being off digoxin and off blockers of the RAS for a short period&#xD;
&#xD;
          -  Ischemic event within past 3 months&#xD;
&#xD;
          -  Serum creatinine higher than 200 mmol/L&#xD;
&#xD;
          -  Patients taking digoxin for atrial fibrillation&#xD;
&#xD;
          -  Patients who require treatment with aldactone&#xD;
&#xD;
          -  Patients with more than mild stable angina while on beta-blockers and/or calcium&#xD;
             antagonists&#xD;
&#xD;
          -  Patients on coumadin&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Markus P Schlaich</last_name>
    <role>Principal Investigator</role>
    <affiliation>Baker IDI Heart &amp; Diabetes Institute</affiliation>
  </overall_official>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>June 4, 2012</study_first_submitted>
  <study_first_submitted_qc>September 11, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 12, 2014</study_first_posted>
  <last_update_submitted>November 1, 2018</last_update_submitted>
  <last_update_submitted_qc>November 1, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">November 2, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Baker Heart and Diabetes Institute</investigator_affiliation>
    <investigator_full_name>Markus Schlaich</investigator_full_name>
    <investigator_title>A/Prof</investigator_title>
  </responsible_party>
  <keyword>Heart failure</keyword>
  <keyword>Losartan</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Losartan</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/NCT02238457
org study id: Project 103-10
nct id: NCT02238457
lead sponsor: 
has dmc: No
The sympathetic nervous system, a part of the nervous system that stimulates the heart via
      release of substances, noradrenaline and adrenaline (combined called catecholamines), becomes
      activated in people with heart failure. As these people become sicker, the nervous system
      becomes more active, causing further damage to the heart.

      Large trials have shown that Angiotensin-converting enzyme (ACE) inhibitors reduce morbidity
      and mortality in patients with heart failure. Higher doses of these drugs are more effective
      than lower doses. Studies show that ACE-inhibitors decrease catecholamine levels. This could
      be why congestive heart failure (CHF) patients taking this class of drugs show improvement in
      heart function.

      There are several ways of measuring the activity of the sympathetic nervous system. The most
      common measurement is to test the blood for catecholamine levels. This is not very reliable
      or reproducible. Microneurography is a new technique used to measure sympathetic nerve
      activity. A small electrode (comparable to an acupuncture needle) is placed in a muscle nerve
      and hooked up to a stimulator and a recorder. It produces direct recordings of skeletal
      muscle nerve traffic. Both the rate and amplitude of the burst can be measured. The results
      in this technique are highly reproducible. By using this technique we get a more accurate
      picture of how the nervous system responds to medications given to treat heart failure.

      Losartan (Cozaar) is an angiotensin II type 1 (AT1) receptor blocker. It blocks the binding
      of angiotensin II, a hormone that constricts blood vessels. As a result the blood vessels
      remain relaxed, leading to a reduction in the workload of the heart. Minor decreases in blood
      catecholamine levels have been reported with a low dose of this drug. The purpose of this
      study is to see whether a high dose of losartan (200 mg) has a greater effect on the
      sympathetic nervous system than a low dose of losartan (50 mg) does.

      A total of 30 participants will be recruited. Participants will be assigned to one of two
      groups: high-dose, in which subjects will receive treatment of 200 mg/day of losartan, and
      low-dose, in which subjects will receive treatment of 50 mg/day of losartan. Via
      microneurography the investigators will measure the difference in sympathetic activity in
      subjects in high-dose vs low-dose losartan. The investigators expect to see further decrease
      in sympathetic activity in high-dose group than in low-dose group.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Effect of losartan on the sympathetic nervous system.
time frame: 10 weeks
description: Assessed by microneurographic recordings of muscle sympathetic nerve activity from the peroneal nerve.
measure: Change in plasma catecholamines.
time frame: 10 weeks
description: Plasma catecholamines will be measured by High-performance liquid chromatography (HPLC). Samples will be collected for plasma aldosterone, plasma renin and plasma angiotensin II.
measure: Change in central hemodynamics.
time frame: 10 weeks
description: Invasive measurement of central hemodynamic parameters; heart rate, blood pressure, cardiac output (CO), pulmonary capillary wedge pressure (PCWP), right arterial pressure (RAP).
arm group label: Low dose losartan
arm group type: Active Comparator
description: Low dose losartan
arm group label: High dose losartan
arm group type: Active Comparator
description: High dose losartan
intervention type: Drug
intervention name: Low dose losartan
description: 25 mg losartan bid for 10 weeks
arm group label: Low dose losartan
other name: losartan (Cozaar)
intervention type: Drug
intervention name: High dose losartan
description: 50 mg, 75 mg, or 100 mg bid for 10 weeks. Dose will be determined by the medical doctor depending on patients' tolerability
arm group label: High dose losartan
other name: Losartan (Cozaar)
criteria: 
gender: All
minimum age: 21 Years
maximum age: 75 Years
healthy volunteers: No
last name: Markus P Schlaich
role: Principal Investigator
affiliation: Baker IDI Heart & Diabetes Institute
responsible party type: Principal Investigator
investigator affiliation: Baker Heart and Diabetes Institute
investigator full name: Markus Schlaich
investigator title: A/Prof
mesh term: Heart Failure
mesh term: Losartan