<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/NCT02973035</url>
  </required_header>
  <id_info>
    <org_study_id>YMC016</org_study_id>
    <nct_id>NCT02973035</nct_id>
  </id_info>
  <brief_title>Amlodipine Versus Valsartan for Improvement of Diastolic Dysfunction Associated With Hypertension</brief_title>
  <official_title>Effect of Add-on of Amlodipine Versus Valsartan on Diastolic Dysfunction Associated With Hypertension</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Asan Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Yuhan Corporation</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Asan Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hypertensive patients are at increased risk of developing LV hypertrophy and myocardial&#xD;
      fibrosis, which cause diastolic dysfunction. Because the activation of&#xD;
      rennin-angiotensin-aldosterone system (RAAS) has been shown to induce LV hypertrophy and&#xD;
      myocardial fibrosis, the RAAS may play a central role in the pathogenic process from&#xD;
      hypertension to diastolic HF. Inhibitors of RAAS have been considered as a treatment option&#xD;
      for these patients, and the angiotensin receptor blockers (ARB) have been of interest because&#xD;
      they antagonize the effects of angiotensin II more completely. However, the Irbesartan in&#xD;
      Heart Failure with Preserved Systolic Function (I-PRESERVE) trial reported that treatment&#xD;
      with irbesartan did not reduce the risk of death or hospitalization for cardiovascular causes&#xD;
      among 4,128 patients who had HF with a preserved LV ejection fraction. The degree of&#xD;
      improvement of diastolic dysfunction was associated with the extent of systolic blood&#xD;
      pressure reduction, whether a RAAS inhibitor or non-RAAS blood pressure lowering was used.&#xD;
      Amlodipine is a potent and well-tolerated calcium channel blocker, and seems to be&#xD;
      appropriate for achieving more aggressive systolic blood pressure target and improving&#xD;
      diastolic dysfunction in hypertensive patients, because amlodipine is clinically very useful&#xD;
      for controlling systolic blood pressure. Assessment of diastolic function by echocardiography&#xD;
      will be helpful to determine whether addition of amlodipine or an ARB to standard therapy is&#xD;
      more beneficial to hypertensive patients with diastolic dysfunction. The investigators&#xD;
      hypothesize that amlodipine added to standard therapy will be superior to valsartan in&#xD;
      improving diastolic dysfunction by lowering systolic blood pressure more effectively in&#xD;
      hypertensive patients, and try to examine this hypothesis in a prospective, open-label,&#xD;
      randomized comparison study using blinded echocardiographic evaluation for end point.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Approximately half of hypertensive patients have diastolic dysfunction and diastolic&#xD;
      dysfunction is associated with development of congestive heart failure and increased&#xD;
      mortality. The Framingham study reported that 51% of patients with HF have a preserved left&#xD;
      ventricular (LV) ejection fraction and hypertension is the strongest risk factor for HF with&#xD;
      preserved ejection fraction, also termed diastolic heart failure. The rates of death and&#xD;
      morbidity in these patients are as high as in patients with HF and a low LV ejection&#xD;
      fraction. Hypertensive patients are at increased risk of developing LV hypertrophy and&#xD;
      myocardial fibrosis, which cause relaxation abnormality and decreased compliance of LV with a&#xD;
      rise in the LV diastolic pressure. Although diastolic HF associated with hypertension is a&#xD;
      clinically significant problem, few clinical trials have been conducted and there is no&#xD;
      proven pharmacological therapy to improve outcomes. Because the activation of&#xD;
      rennin-angiotensin-aldosterone system (RAAS) has been shown to induce LV hypertrophy and&#xD;
      myocardial fibrosis, the RAAS may play a central role in the pathogenic process from&#xD;
      hypertension to diastolic HF. Inhibitors of RAAS have been considered as a treatment option&#xD;
      for these patients, and the angiotensin receptor blockers (ARB) have been of interest because&#xD;
      they antagonize the effects of angiotensin II more completely. However, the Irbesartan in&#xD;
      Heart Failure with Preserved Systolic Function (I-PRESERVE) trial reported that treatment&#xD;
      with irbesartan did not reduce the risk of death or hospitalization for cardiovascular causes&#xD;
      among 4,128 patients who had HF with a preserved LV ejection fraction.&#xD;
&#xD;
      The degree of improvement of diastolic dysfunction was associated with the extent of systolic&#xD;
      blood pressure reduction, whether a RAAS inhibitor or non-RAAS blood pressure lowering was&#xD;
      used. The Systolic Blood Pressure Intervention Trial (SPRINT) compared the benefit of&#xD;
      treatment of systolic blood pressure to a target of less than 120 mmHg with treatment to a&#xD;
      target of less than 140 mmHg, and recently reported that targeting a systolic blood pressure&#xD;
      of less than 120 mmHg, as compared with less than 140 mmHg, resulted in lower rates of fatal&#xD;
      and nonfatal major cardiovascular events and all-cause death. Amlodipine is a potent and&#xD;
      well-tolerated calcium channel blocker, and seems to be appropriate for achieving more&#xD;
      aggressive systolic blood pressure target and improving diastolic dysfunction in hypertensive&#xD;
      patients, because amlodipine is clinically very useful for controlling systolic blood&#xD;
      pressure. Evaluating the effect of treatments on diastolic dysfunction has been limited by&#xD;
      difficulties in non-invasive measure of LV diastolic pressure, but recent advances in&#xD;
      echocardiography have made it possible to assess diastolic dysfunction accurately and&#xD;
      reproducibly. Thus, assessment of diastolic function by echocardiography will be helpful to&#xD;
      determine whether addition of amlodipine or an ARB to standard therapy is more beneficial to&#xD;
      hypertensive patients with diastolic dysfunction. To the best of our knowledge, there has&#xD;
      been no randomized trial to compare the effect of amlodipine versus an ARB on improving&#xD;
      diastolic dysfunction in hypertensive patients. The investigators hypothesize that amlodipine&#xD;
      added to standard therapy will be superior to valsartan in improving diastolic dysfunction by&#xD;
      lowering systolic blood pressure more effectively in hypertensive patients, and try to&#xD;
      examine this hypothesis in a prospective, open-label, randomized comparison study using&#xD;
      blinded echocardiographic evaluation for end point.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2016</start_date>
  <completion_date type="Actual">January 6, 2020</completion_date>
  <primary_completion_date type="Actual">January 6, 2020</primary_completion_date>
  <phase>Phase 4</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>Change in the ratio of E velocity (Early mitral inflow velocity) to E' velocity (Early mitral annular velocity)</measure>
    <time_frame>24 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in systolic blood pressure</measure>
    <time_frame>24 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in global LV longitudinal strain</measure>
    <time_frame>24 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in LV mass</measure>
    <time_frame>24 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in left atrial volume</measure>
    <time_frame>24 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in clinical composite</measure>
    <time_frame>24 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">104</enrollment>
  <condition>Hypertension</condition>
  <arm_group>
    <arm_group_label>Amlodipine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Amlodipine 2.5mg added to antihypertensive therapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Valsartan</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Valsartan 40mg added to antihypertensive therapy</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Amlodipine</intervention_name>
    <arm_group_label>Amlodipine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Valsartan</intervention_name>
    <arm_group_label>Valsartan</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Controlled hypertension: systolic BP &lt; 150 and diastolic BP &lt; 90 mmHg in persons aged&#xD;
             60 years or older, systolic BP &lt; 140 and diastolic BP &lt; 90 mmHg in persons 40 through&#xD;
             59 years according to the JNC 8th guideline&#xD;
&#xD;
          -  Evidence of diastolic dysfunction showing E/E' &gt; 10&#xD;
&#xD;
          -  The patient agrees to the study protocol and the schedule of clinical and&#xD;
             echocardiographic follow-up, and provides informed, written consent, as approved by&#xD;
             the appropriate Institutional Review Board/Ethical Committee of the respective&#xD;
             clinical site&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Unwillingness or inability to comply with the procedures described in this protocol&#xD;
&#xD;
          -  Planned cardiac surgery or planned major non-cardiac surgery within the study period.&#xD;
&#xD;
          -  Stroke or coronary revascularization in the past 6 months.&#xD;
&#xD;
          -  Clinically significant pulmonary disease.&#xD;
&#xD;
          -  Untreated hyperthyroidism, or hypothyroidism.&#xD;
&#xD;
          -  A diagnosis of cancer (other than superficial squamous or basal cell skin cancer) in&#xD;
             the past 3 years or current treatment for the active cancer.&#xD;
&#xD;
          -  Female of child-bearing potential who do not use adequate contraception and women who&#xD;
             are pregnant or breast-feeding&#xD;
&#xD;
          -  Any clinically significant abnormality identified at the screening visit, physical&#xD;
             examination, laboratory tests, or electrocardiogram which, in the judgment of the&#xD;
             Investigator, would preclude safe completion of the study.&#xD;
&#xD;
          -  LV ejection fraction &lt; 50%.&#xD;
&#xD;
          -  Significant renal disease manifested by serum creatinine &gt; 2.5 mg/dL&#xD;
&#xD;
          -  Hepatic disease or biliary tract obstruction, or significant hepatic enzyme elevation&#xD;
             (ALT or AST &gt; 3 times upper limit of normal).&#xD;
&#xD;
          -  History of intolerance to ARB or amlodipine.&#xD;
&#xD;
          -  Hypertrophic or restrictive cardiomyopathy.&#xD;
&#xD;
          -  Moderate or severe valvular disease.&#xD;
&#xD;
          -  Constrictive pericarditis&#xD;
&#xD;
          -  Atrial fibrillation with a heart rate &gt; 120/min.&#xD;
&#xD;
          -  Sitting systolic BP &lt; 100 mmHg&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Duk-Hyun Kang, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Asan Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Busan Baik Hospital</name>
      <address>
        <city>Busan</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Busan University Hospital</name>
      <address>
        <city>Busan</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chungnam University Hospital</name>
      <address>
        <city>Daejeon</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Asan Medical Center</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>November 22, 2016</study_first_submitted>
  <study_first_submitted_qc>November 22, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 25, 2016</study_first_posted>
  <last_update_submitted>January 12, 2020</last_update_submitted>
  <last_update_submitted_qc>January 12, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 14, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Asan Medical Center</investigator_affiliation>
    <investigator_full_name>Duk-Hyun Kang</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Amlodipine</mesh_term>
    <mesh_term>Valsartan</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT02973035
org study id: YMC016
nct id: NCT02973035
lead sponsor: 
collaborator: 
has dmc: No
Hypertensive patients are at increased risk of developing LV hypertrophy and myocardial
      fibrosis, which cause diastolic dysfunction. Because the activation of
      rennin-angiotensin-aldosterone system (RAAS) has been shown to induce LV hypertrophy and
      myocardial fibrosis, the RAAS may play a central role in the pathogenic process from
      hypertension to diastolic HF. Inhibitors of RAAS have been considered as a treatment option
      for these patients, and the angiotensin receptor blockers (ARB) have been of interest because
      they antagonize the effects of angiotensin II more completely. However, the Irbesartan in
      Heart Failure with Preserved Systolic Function (I-PRESERVE) trial reported that treatment
      with irbesartan did not reduce the risk of death or hospitalization for cardiovascular causes
      among 4,128 patients who had HF with a preserved LV ejection fraction. The degree of
      improvement of diastolic dysfunction was associated with the extent of systolic blood
      pressure reduction, whether a RAAS inhibitor or non-RAAS blood pressure lowering was used.
      Amlodipine is a potent and well-tolerated calcium channel blocker, and seems to be
      appropriate for achieving more aggressive systolic blood pressure target and improving
      diastolic dysfunction in hypertensive patients, because amlodipine is clinically very useful
      for controlling systolic blood pressure. Assessment of diastolic function by echocardiography
      will be helpful to determine whether addition of amlodipine or an ARB to standard therapy is
      more beneficial to hypertensive patients with diastolic dysfunction. The investigators
      hypothesize that amlodipine added to standard therapy will be superior to valsartan in
      improving diastolic dysfunction by lowering systolic blood pressure more effectively in
      hypertensive patients, and try to examine this hypothesis in a prospective, open-label,
      randomized comparison study using blinded echocardiographic evaluation for end point.
Approximately half of hypertensive patients have diastolic dysfunction and diastolic
      dysfunction is associated with development of congestive heart failure and increased
      mortality. The Framingham study reported that 51% of patients with HF have a preserved left
      ventricular (LV) ejection fraction and hypertension is the strongest risk factor for HF with
      preserved ejection fraction, also termed diastolic heart failure. The rates of death and
      morbidity in these patients are as high as in patients with HF and a low LV ejection
      fraction. Hypertensive patients are at increased risk of developing LV hypertrophy and
      myocardial fibrosis, which cause relaxation abnormality and decreased compliance of LV with a
      rise in the LV diastolic pressure. Although diastolic HF associated with hypertension is a
      clinically significant problem, few clinical trials have been conducted and there is no
      proven pharmacological therapy to improve outcomes. Because the activation of
      rennin-angiotensin-aldosterone system (RAAS) has been shown to induce LV hypertrophy and
      myocardial fibrosis, the RAAS may play a central role in the pathogenic process from
      hypertension to diastolic HF. Inhibitors of RAAS have been considered as a treatment option
      for these patients, and the angiotensin receptor blockers (ARB) have been of interest because
      they antagonize the effects of angiotensin II more completely. However, the Irbesartan in
      Heart Failure with Preserved Systolic Function (I-PRESERVE) trial reported that treatment
      with irbesartan did not reduce the risk of death or hospitalization for cardiovascular causes
      among 4,128 patients who had HF with a preserved LV ejection fraction.

      The degree of improvement of diastolic dysfunction was associated with the extent of systolic
      blood pressure reduction, whether a RAAS inhibitor or non-RAAS blood pressure lowering was
      used. The Systolic Blood Pressure Intervention Trial (SPRINT) compared the benefit of
      treatment of systolic blood pressure to a target of less than 120 mmHg with treatment to a
      target of less than 140 mmHg, and recently reported that targeting a systolic blood pressure
      of less than 120 mmHg, as compared with less than 140 mmHg, resulted in lower rates of fatal
      and nonfatal major cardiovascular events and all-cause death. Amlodipine is a potent and
      well-tolerated calcium channel blocker, and seems to be appropriate for achieving more
      aggressive systolic blood pressure target and improving diastolic dysfunction in hypertensive
      patients, because amlodipine is clinically very useful for controlling systolic blood
      pressure. Evaluating the effect of treatments on diastolic dysfunction has been limited by
      difficulties in non-invasive measure of LV diastolic pressure, but recent advances in
      echocardiography have made it possible to assess diastolic dysfunction accurately and
      reproducibly. Thus, assessment of diastolic function by echocardiography will be helpful to
      determine whether addition of amlodipine or an ARB to standard therapy is more beneficial to
      hypertensive patients with diastolic dysfunction. To the best of our knowledge, there has
      been no randomized trial to compare the effect of amlodipine versus an ARB on improving
      diastolic dysfunction in hypertensive patients. The investigators hypothesize that amlodipine
      added to standard therapy will be superior to valsartan in improving diastolic dysfunction by
      lowering systolic blood pressure more effectively in hypertensive patients, and try to
      examine this hypothesis in a prospective, open-label, randomized comparison study using
      blinded echocardiographic evaluation for end point.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in the ratio of E velocity (Early mitral inflow velocity) to E' velocity (Early mitral annular velocity)
time frame: 24 weeks
measure: Change in systolic blood pressure
time frame: 24 weeks
measure: Change in global LV longitudinal strain
time frame: 24 weeks
measure: Change in LV mass
time frame: 24 weeks
measure: Change in left atrial volume
time frame: 24 weeks
measure: Change in clinical composite
time frame: 24 weeks
arm group label: Amlodipine
arm group type: Experimental
description: Amlodipine 2.5mg added to antihypertensive therapy
arm group label: Valsartan
arm group type: Experimental
description: Valsartan 40mg added to antihypertensive therapy
intervention type: Drug
intervention name: Amlodipine
arm group label: Amlodipine
intervention type: Drug
intervention name: Valsartan
arm group label: Valsartan
criteria: 
gender: All
minimum age: 40 Years
maximum age: 80 Years
healthy volunteers: No
last name: Duk-Hyun Kang, M.D.
role: Principal Investigator
affiliation: Asan Medical Center
facility: 
facility: 
facility: 
facility: 
country: Korea, Republic of
responsible party type: Principal Investigator
investigator affiliation: Asan Medical Center
investigator full name: Duk-Hyun Kang
investigator title: Professor
mesh term: Hypertension
mesh term: Amlodipine
mesh term: Valsartan
sharing ipd: No