<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/NCT01691118</url>
  </required_header>
  <id_info>
    <org_study_id>2012-0229</org_study_id>
    <nct_id>NCT01691118</nct_id>
  </id_info>
  <brief_title>A Trial of Fimasartan for Early Diastolic Heart Failure</brief_title>
  <acronym>FINE</acronym>
  <official_title>Fimasartan for Improvement of Diastolic Dysfunction in Hypertensive Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Asan Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Boryung Pharmaceutical Co., Ltd</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>
      Approximately half of hypertensive patients have diastolic dysfunction and diastolic&#xD;
      dysfunction is associated with development of congestive heart failure and increased&#xD;
      mortality. Although diastolic heart failure associated with hypertension is a clinically&#xD;
      significant problem, few clinical trials have been conducted and there is no proven&#xD;
      pharmacological therapy to improve outcomes. To the best of the investigators knowledge,&#xD;
      there has been no randomized trial to demonstrate that an antihypertensive drug improves&#xD;
      diastolic function in hypertensive patients with diastolic dysfunction. The investigators&#xD;
      hypothesize that fimasartan added to standard therapy will be superior to placebo in&#xD;
      improving diastolic dysfunction in mildly symptomatic patients with hypertension and&#xD;
      diastolic dysfunction, and try to examine this hypothesis in a double-blind, randomized&#xD;
      comparison study using echocardiography.&#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 HF associated with hypertension is a clinically&#xD;
      significant problem, few clinical trials have been conducted and there is no proven&#xD;
      pharmacological therapy to improve outcomes.&#xD;
&#xD;
      Because the activation of rennin-angiotensin-aldosterone system (RAAS) has been shown to&#xD;
      induce LV hypertrophy and myocardial fibrosis, the RAAS may play a central role in the&#xD;
      pathogenic process from hypertension to diastolic HF. Inhibitors of RAAS have been considered&#xD;
      as a treatment option for these patients, and the angiotensin receptor blockers (ARB) have&#xD;
      been of interest because they antagonize the effects of angiotensin II more completely. The&#xD;
      largest clinical trial, the Irbesartan in Heart Failure with Preserved Systolic Function&#xD;
      (I-PRESERVE), recently reported that treatment with irbesartan did not reduce the risk of&#xD;
      death or hospitalization for cardiovascular causes among 4,128 patients who had HF with a&#xD;
      preserved LV ejection fraction. The negative result observed in the I-PRESERVE trial may have&#xD;
      been the consequence of the following possible factors. First, this trial may have targeted&#xD;
      patients in whom the disease process was too advanced for ARBs to be effective. Second,&#xD;
      irbesartan may not be an appropriate ARB for a HF trial, because ARBs are not all the same in&#xD;
      terms of clinical outcome data in patients with HF. Irbesartan did not have outcome data on&#xD;
      reducing HF hospitalization in high-risk hypertensive patients and telmisartan showed no&#xD;
      benefits compared to placebo in these patients, although candesartan and valsartan&#xD;
      significantly reduced endpoint in placebo-controlled trials. Telmisartan and irbesartan have&#xD;
      PPARγ activity and this activity might neutralize the beneficial effects of ARB on HF,&#xD;
      because it is well known that PPARγ agonist, rosiglitazone, increases the incidences of HF&#xD;
      significantly.&#xD;
&#xD;
      Evaluating the effect of treatments on diastolic dysfunction has been limited by difficulties&#xD;
      in non-invasive measure of LV diastolic pressure, but recent advances in echocardiography&#xD;
      have made it possible to assess diastolic dysfunction accurately and reproducibly. Thus,&#xD;
      additional clinical studies with the other ARBs are needed in hypertensive patients with&#xD;
      diastolic dysfunction and assessment of diastolic function by echocardiography will be&#xD;
      helpful to determine whether addition of ARB to standard therapy is beneficial to&#xD;
      hypertensive patients with diastolic dysfunction. Fimasartan is the first ARB developed in&#xD;
      Korea, and was felt to be particularly appropriate for examining the hypothesis that the ARB&#xD;
      can improve diastolic dysfunction associated with hypertension, because fimasartan is a&#xD;
      potent and well-tolerated ARB. To the best of our knowledge, there has been no randomized&#xD;
      trial to demonstrate that an antihypertensive drug improves diastolic function in&#xD;
      hypertensive patients with diastolic dysfunction. We hypothesize that fimasartan added to&#xD;
      standard therapy will be superior to placebo in improving diastolic dysfunction in mildly&#xD;
      symptomatic patients with hypertension and diastolic dysfunction, and try to examine this&#xD;
      hypothesis in a double-blind, randomized comparison study using echocardiography.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">August 2015</completion_date>
  <primary_completion_date type="Actual">August 2015</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in E/E' ratio</measure>
    <time_frame>10 months</time_frame>
    <description>Change in the ratio of E velocity (Early mitral inflow velocity) to E' velocity (Early mitral annular velocity) from baseline to 10 months follow-up.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in BNP levels</measure>
    <time_frame>10 months</time_frame>
    <description>Change in BNP levels from baseline to 10 months follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in left ventricular mass</measure>
    <time_frame>10 months</time_frame>
    <description>Change in LV mass from baseline to 10 months follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in left atrial volume</measure>
    <time_frame>10 months</time_frame>
    <description>Change in left atrial volume from baseline to 10 months follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in global left ventricular strain</measure>
    <time_frame>10 months</time_frame>
    <description>Change in global left ventricular strain from baseline to 10 months follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in functional class</measure>
    <time_frame>10 months</time_frame>
    <description>Change in New York Heart Association (NYHA) functional class from baseline to 10 months follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in clinical composite</measure>
    <time_frame>10 months</time_frame>
    <description>The clinical composite assessment is based on a change in the NYHA functional class and occurrences of serious adverse events (SAE). Patients with an improvement in NYHA class and without SAE are classified as improved, and those as aggravated if they have SAE during treatment or report worsening of their NYHA class at the endpoint visit.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Hypertension</condition>
  <arm_group>
    <arm_group_label>Fimasartan</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Fimasartan 60mg qd added on conventional antihypertensive treatment for 10 months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Conventional antihypetensive treatment</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fimasartan</intervention_name>
    <arm_group_label>Fimasartan</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Antihypertensive treatment</intervention_name>
    <arm_group_label>Fimasartan</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Untreated hypertension: systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg or Treated&#xD;
             hypertension&#xD;
&#xD;
          -  Current heart failure symptoms with NYHA class II&#xD;
&#xD;
          -  Evidence of diastolic dysfunction showing any 2 of the following:&#xD;
&#xD;
        E/E' &gt; 10, LV posterior wall thickness &gt; 11 mm, BNP level &gt; 40 pg/mL&#xD;
&#xD;
        Exclusion Criteria:&#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;
          -  LV ejection fraction &lt; 50%&#xD;
&#xD;
          -  Hypertrophic or restrictive cardiomyopathy, moderate or severe valve disease,&#xD;
             constrictive pericarditis&#xD;
&#xD;
          -  Atrial fibrillation with a heart rate &gt; 120/min&#xD;
&#xD;
          -  Sitting systolic BP &lt; 100 mmHg&#xD;
&#xD;
          -  Sitting systolic BP &gt; 160 mmHg or diastolic BP &gt; 95 mmHg despite antihypertensive&#xD;
             therapy&#xD;
&#xD;
          -  Significant renal disease manifested by serum creatinine &gt; 2.5 mg/dL&#xD;
&#xD;
          -  Clinically significant pulmonary disease, coronary artery disease&#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;
      </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, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Asan Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Asan Medical Center</name>
      <address>
        <city>Seoul</city>
        <zip>138-736</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <verification_date>December 2015</verification_date>
  <study_first_submitted>September 20, 2012</study_first_submitted>
  <study_first_submitted_qc>September 21, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 24, 2012</study_first_posted>
  <last_update_submitted>December 29, 2015</last_update_submitted>
  <last_update_submitted_qc>December 29, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 31, 2015</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>
  <keyword>Hypertension</keyword>
  <keyword>Angiotensin Receptor Blocker</keyword>
  <keyword>Diastolic Dysfunction</keyword>
  <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>Antihypertensive Agents</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/NCT01691118
org study id: 2012-0229
nct id: NCT01691118
lead sponsor: 
collaborator: 
has dmc: No
Approximately half of hypertensive patients have diastolic dysfunction and diastolic
      dysfunction is associated with development of congestive heart failure and increased
      mortality. Although diastolic heart failure associated with hypertension is a clinically
      significant problem, few clinical trials have been conducted and there is no proven
      pharmacological therapy to improve outcomes. To the best of the investigators knowledge,
      there has been no randomized trial to demonstrate that an antihypertensive drug improves
      diastolic function in hypertensive patients with diastolic dysfunction. The investigators
      hypothesize that fimasartan added to standard therapy will be superior to placebo in
      improving diastolic dysfunction in mildly symptomatic patients with hypertension and
      diastolic dysfunction, and try to examine this hypothesis in a double-blind, randomized
      comparison study using echocardiography.
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 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. The
      largest clinical trial, the Irbesartan in Heart Failure with Preserved Systolic Function
      (I-PRESERVE), recently 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 negative result observed in the I-PRESERVE trial may have
      been the consequence of the following possible factors. First, this trial may have targeted
      patients in whom the disease process was too advanced for ARBs to be effective. Second,
      irbesartan may not be an appropriate ARB for a HF trial, because ARBs are not all the same in
      terms of clinical outcome data in patients with HF. Irbesartan did not have outcome data on
      reducing HF hospitalization in high-risk hypertensive patients and telmisartan showed no
      benefits compared to placebo in these patients, although candesartan and valsartan
      significantly reduced endpoint in placebo-controlled trials. Telmisartan and irbesartan have
      PPARγ activity and this activity might neutralize the beneficial effects of ARB on HF,
      because it is well known that PPARγ agonist, rosiglitazone, increases the incidences of HF
      significantly.

      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,
      additional clinical studies with the other ARBs are needed in hypertensive patients with
      diastolic dysfunction and assessment of diastolic function by echocardiography will be
      helpful to determine whether addition of ARB to standard therapy is beneficial to
      hypertensive patients with diastolic dysfunction. Fimasartan is the first ARB developed in
      Korea, and was felt to be particularly appropriate for examining the hypothesis that the ARB
      can improve diastolic dysfunction associated with hypertension, because fimasartan is a
      potent and well-tolerated ARB. To the best of our knowledge, there has been no randomized
      trial to demonstrate that an antihypertensive drug improves diastolic function in
      hypertensive patients with diastolic dysfunction. We hypothesize that fimasartan added to
      standard therapy will be superior to placebo in improving diastolic dysfunction in mildly
      symptomatic patients with hypertension and diastolic dysfunction, and try to examine this
      hypothesis in a double-blind, randomized comparison study using echocardiography.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in E/E' ratio
time frame: 10 months
description: Change in the ratio of E velocity (Early mitral inflow velocity) to E' velocity (Early mitral annular velocity) from baseline to 10 months follow-up.
measure: Change in BNP levels
time frame: 10 months
description: Change in BNP levels from baseline to 10 months follow-up.
measure: Change in left ventricular mass
time frame: 10 months
description: Change in LV mass from baseline to 10 months follow-up.
measure: Change in left atrial volume
time frame: 10 months
description: Change in left atrial volume from baseline to 10 months follow-up.
measure: Change in global left ventricular strain
time frame: 10 months
description: Change in global left ventricular strain from baseline to 10 months follow-up.
measure: Change in functional class
time frame: 10 months
description: Change in New York Heart Association (NYHA) functional class from baseline to 10 months follow-up.
measure: Change in clinical composite
time frame: 10 months
description: The clinical composite assessment is based on a change in the NYHA functional class and occurrences of serious adverse events (SAE). Patients with an improvement in NYHA class and without SAE are classified as improved, and those as aggravated if they have SAE during treatment or report worsening of their NYHA class at the endpoint visit.
arm group label: Fimasartan
arm group type: Active Comparator
description: Fimasartan 60mg qd added on conventional antihypertensive treatment for 10 months.
arm group label: Placebo
arm group type: Placebo Comparator
description: Conventional antihypetensive treatment
intervention type: Drug
intervention name: Fimasartan
arm group label: Fimasartan
intervention type: Drug
intervention name: Antihypertensive treatment
arm group label: Fimasartan
arm group label: Placebo
criteria: 
gender: All
minimum age: 40 Years
maximum age: 80 Years
healthy volunteers: No
last name: Duk-Hyun Kang, MD, PhD
role: Principal Investigator
affiliation: Asan Medical Center
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: Antihypertensive Agents