<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/NCT01715207</url>
  </required_header>
  <id_info>
    <org_study_id>2009-10-025</org_study_id>
    <nct_id>NCT01715207</nct_id>
  </id_info>
  <brief_title>Comparison of Aliskiren vs Negative Controls on Aortic Stiffness in Patients With MFS</brief_title>
  <official_title>Comparison Study of the Effect of Aliskiren Versus Negative Controls on Aortic Stiffness in Patients With Marfan Syndrome Under Treatment With Atenolol</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Samsung Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Samsung Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Marfan syndrome (MFS) is an inherited disorder of connective tissue with morbidity and&#xD;
      mortality from aortic dilatation and dissection. The current standard of care is beta-blocker&#xD;
      (BB) treatment and therapeutic target is heart rate. The degree of aortic dilatation and&#xD;
      response to BB vary in adults with MFS. However, aortic stiffness is often present, and can&#xD;
      be a predictor of aortic dilatation and cardiovascular complications. Aortic stiffness is a&#xD;
      logical therapeutic target in adults with MFS.&#xD;
&#xD;
      Transforming growth factor beta(TGF-beta) mediates disease pathogenesis in MFS and&#xD;
      contributes to aortic stiffness. Cross-talk between TGF-beta system and renin-angiotensin&#xD;
      system (RAS) has been demonstrated. The angiotensin receptor blocker (ARB), losartan,&#xD;
      inhibits TGF-beta activity and reverses aortic wall pathology in a Marfan mouse model. In a&#xD;
      small cohort study, the use of ARB therapy (losartan or irbesartan) significantly slowed the&#xD;
      rate of progressive aortic dilatation in patients with MFS, after BB therapy had failed to&#xD;
      prevent aortic root dilatation. In another study, angiotensin converting enzyme inhibitor,&#xD;
      perindopril, reduced both aortic stiffness and aortic root diameter in patients with MFS&#xD;
      taking standard BB therapy. Renin inhibitor, aliskiren, has not been studied to reduce aortic&#xD;
      stiffness and attenuate aortic dilatation in patients with MFS.&#xD;
&#xD;
      This trial is a randomized, open-label trial of 32 patients with Marfan syndrome, treated&#xD;
      with 6 months of aliskiren vs. negative controls in patients with MFS under atenolol&#xD;
      treatment. MRI for aortic pulsed wave velocity (PWV) and distensibility, measurements of&#xD;
      central BP (CBP) and augmentation index (AIx) will be performed at the beginning and end of&#xD;
      treatment. A blood drawn for serum markers of TGF-beta, extracellular matrix turnover and&#xD;
      inflammation will also be performed at 0 and 6 months. We plan to determine whether aliskiren&#xD;
      decreases aortic stiffness significantly more than negative controls in patients with MFS&#xD;
      under atenolol treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study design and study population The study design was a prospective randomized intervention&#xD;
      study in a single center. A randomization process was performed to assign participants to&#xD;
      either the aliskiren-treatment group or the negative control group in an open-label design.&#xD;
      The duration of the study period was 24 weeks as the time frame for treatment. Duration of&#xD;
      treatment was decided based on previous studies using RAS inhibitor 13,25. Aliskiren was&#xD;
      administered to patients in the treatment group at an oral dose of 150-300 mg per day.&#xD;
      Medication administration started after a baseline study with a dose of 150 mg of aliskiren,&#xD;
      which was escalated to 300 mg of aliskiren at 4 weeks after evaluation of tolerability and&#xD;
      the presence of adverse effects as angioedema, gastrointestinal symptoms, rash, gout,&#xD;
      hypotension, and renal stones. The patients stopped taking aliskiren if serious adverse&#xD;
      events such as angioedema or allergic reactions definitely related to the medication&#xD;
      developed. Dose reduction was considered in cases with development of hyperkalemia, elevation&#xD;
      of serum creatinine to twice baseline, symptomatic hypotension, gout, or renal stones. Dose&#xD;
      reduction to 150 mg after escalation was performed on the decision of the investigators if&#xD;
      the patient complained of discomfort and side effects that were probably related to the&#xD;
      medication.&#xD;
&#xD;
      MFS patients were recruited at Samsung Medical Center from November 2009 to October 2014. All&#xD;
      patients were receiving atenolol as standard β-blocker therapy. All patients gave written&#xD;
      informed consent to participate in the study, which was approved by the Samsung Medical&#xD;
      Center Ethics Committee. This trial is registered at ClinicalTrial.gov. (Identifier:&#xD;
      NCT01715207) Inclusion criteria were age 14 to 55 years, a diagnosis of MFS by Ghent&#xD;
      criteria, β-blocker treatment for at least 3 months, and no chronic RAS inhibitor therapy&#xD;
      (i.e., angiotensin II receptor blockers or ACE inhibitors) for 90 days prior to screening.&#xD;
      Exclusion criteria were previous medical history of aortic surgery and/or dissection,&#xD;
      significant valve disease requiring surgery, aortic root dimension &gt; 5.0 cm, renal&#xD;
      dysfunction (creatinine &gt; upper normal limit), pregnancy or planned pregnancy within 12&#xD;
      months of study entry or current breast feeding, known renal artery stenosis,&#xD;
      hypersensitivity to aliskiren or any of the excipients, elevation of serum creatinine during&#xD;
      follow-up (&gt; 30% of baseline), diarrhea resulting in severe dehydration, development of gout&#xD;
      or ureter stone, symptomatic hypotension (systolic blood pressure &lt;90 mmHg with symptoms),&#xD;
      hyperkalemia, and concomitant treatment with cyclosporin A.&#xD;
&#xD;
      Follow-up and outcomes All included patients were clinically followed to monitor adverse&#xD;
      effects of angioedema, gastrointestinal symptoms, rash, gout, hypotension, and renal stone at&#xD;
      initial examination, 1 week, 4 weeks, 8 weeks, 16 weeks, and 24 weeks. The following&#xD;
      laboratory data were collected during the same period: potassium, electrocardiogram,&#xD;
      creatinine, uric acid, and urine analysis. Echocardiographic evaluation, peripheral&#xD;
      tonometric measurements of peripheral PWV, central aortic blood pressure and augmentation&#xD;
      index, cardiac magnetic resonance imaging (cardiac MRI), and biomarkers were analyzed at&#xD;
      baseline and after 24 weeks of treatment.&#xD;
&#xD;
      Safety information was collected, including all adverse events and all serious adverse&#xD;
      events. Completion of a serious adverse event form was required for all serious adverse&#xD;
      events that occurred during the study period. All serious adverse events were assessed by&#xD;
      investigators and reported to the Novartis safety desk within 24 hours.&#xD;
&#xD;
      The primary end point was central aortic distensibility by cardiac MRI at 24 weeks, reported&#xD;
      as the change over the 24-week period after randomization. The secondary end points were&#xD;
      central aortic PWV by cardiac MRI, change in central aortic blood pressure (hereafter, aortic&#xD;
      BP), augmentation index, peripheral PWV by tonometry, aortic root diameter by&#xD;
      echocardiography, severity of aortic regurgitation by echocardiography, and&#xD;
      dissection/rupture/operation of aneurysm.&#xD;
&#xD;
      Cardiovascular imaging - echocardiography and cardiac MRI Cardiac MRI Cardiac MRI was&#xD;
      performed using a 1.5-Tesla scanner (Magnetom Avanto, Syngo MR; Siemens Medical Solutions,&#xD;
      Erlangen, Germany). Aortic diameters were measured at four landmark levels: level 1, the&#xD;
      ascending aorta at the level of bifurcation of the pulmonary artery; level 2, the upper&#xD;
      descending thoracic aorta at the level of bifurcation of the pulmonary artery; level 3, the&#xD;
      lower descending thoracic aorta at the level of the diaphragm; level 4, the abdominal aorta&#xD;
      just above the iliac bifurcation. Cine imaging was also performed at the same levels to&#xD;
      measure aortic stiffness.&#xD;
&#xD;
      Cardiac MRI analysis - central aortic distensibility and central aortic PWV Analyses of the&#xD;
      MRIs were performed using commercial software (Argus version 4.02, Siemens Medical Systems,&#xD;
      Germany) by experienced observers who were blinded to patient information. To measure central&#xD;
      aortic distensibility, the systolic and diastolic cross-sectional areas were measured by&#xD;
      manual contouring of the aorta through the cardiac cycle on the cine image. Distensibility at&#xD;
      the four regions was calculated as the mean of values obtained from the following equation:&#xD;
      Distensibility = (Amax - Amin)/[Amin × (Pmax - Pmin)](10-3mm/Hg), where Amax is the maximal&#xD;
      (systolic) aortic area, Amin is the minimal (diastolic) aortic area, Pmax is the systolic&#xD;
      blood pressure (SBP), and Pmin is the diastolic blood pressure (DBP). Central aortic blood&#xD;
      pressure measured non-invasively by SphygmoCor was used for systolic and diastolic blood&#xD;
      pressure.&#xD;
&#xD;
      Aortic PWV was measured according to the well-validated method using MRI 19. From the&#xD;
      velocity-encoded MRIs, aortic contours were automatically detected and manually adjusted in&#xD;
      each slice area throughout the cardiac cycle. The transit time between the flow curves of&#xD;
      each region of the aorta was determined from the midpoint of the systolic up-slope on the&#xD;
      flow versus time curve 26-28. The up-slopes were identified by drawing a line between the&#xD;
      points of 40% and 60% maximum velocity on the waveform. The distance between each aortic&#xD;
      level was measured on black blood images using a curved line along the center of the aorta.&#xD;
      Based on these data, the regional PWV was calculated as the ratio of the distance between&#xD;
      levels and the time differences between the arrival of the pulse wave at each level. The PWV&#xD;
      was measured at two regions: the proximal aorta (proximal PWV between level 1 and level 2)&#xD;
      and the entire aorta (PWV-total between level 1 and level 4).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2010</start_date>
  <completion_date type="Actual">December 2014</completion_date>
  <primary_completion_date type="Actual">October 2014</primary_completion_date>
  <phase>Phase 3</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>
    <masking_description>Open Label</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Central Aortic Distensibility by MRI</measure>
    <time_frame>6 months</time_frame>
    <description>Analyses of the MRIs were performed using commercial software (Argus version 4.02, Siemens Medical Systems, Germany) by experienced observers who were blinded to patient information. To measure central aortic distensibility, the systolic and diastolic cross-sectional areas were measured by manual contouring of the aorta through the cardiac cycle on the cine image. Distensibility at the four regions was calculated as the mean of values obtained from the following equation: Distensibility = (Amax - Amin)/[Amin × (Pmax - Pmin)](10-3mm/Hg), where Amax is the maximal (systolic) aortic area, Amin is the minimal (diastolic) aortic area, Pmax is the systolic blood pressure (SBP), and Pmin is the diastolic blood pressure (DBP). Central aortic blood pressure measured non-invasively by SphygmoCor was used for systolic and diastolic blood pressure.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Central Aortic PWV(Pulsed Wave Velocity)</measure>
    <time_frame>6 months</time_frame>
    <description>Aortic PWV was measured according to the well-validated method using MRI 19. From the velocity-encoded MRIs, aortic contours were automatically detected and manually adjusted in each slice area throughout the cardiac cycle. The transit time between the flow curves of each region of the aorta was determined from the midpoint of the systolic up-slope on the flow versus time curve 26-28. The up-slopes were identified by drawing a line between the points of 40% and 60% maximum velocity on the waveform. The distance between each aortic level was measured on black blood images using a curved line along the center of the aorta. Based on these data, the regional PWV was calculated as the ratio of the distance between levels and the time differences between the arrival of the pulse wave at each level. The PWV was measured at two regions: the proximal aorta (proximal PWV between level 1 and level 2) and the entire aorta (PWV-total between level 1 and level 4).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Marfan Syndrome</condition>
  <arm_group>
    <arm_group_label>Atenolol &amp; Aliskiren</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Atenolol tablet and Aliskiren 150mg or 300mg tablet by mouth per day for 6month</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Atenolol</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Atenolol tablet(Negative controls, Open-label)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aliskiren</intervention_name>
    <arm_group_label>Atenolol &amp; Aliskiren</arm_group_label>
    <other_name>Rasilez</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atenolol</intervention_name>
    <arm_group_label>Atenolol</arm_group_label>
    <arm_group_label>Atenolol &amp; Aliskiren</arm_group_label>
    <other_name>Tenormin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Diagnosis of MFS by Ghent criteria and/or genetically proven Fibrillin-1 (FBN1)&#xD;
             mutation&#xD;
&#xD;
          2. Age between 14 and 55 years&#xD;
&#xD;
          3. Beta-blocker treatment at least 3 months&#xD;
&#xD;
          4. subjects must not have been receiving chronic RAS inhibitor therapy (i.e. ARBs, or ACE&#xD;
             inhibitors)&gt;= 90days prior to screening&#xD;
&#xD;
          5. Written informed consent from the patients or authorized representatives must be&#xD;
             obtained&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. previous medical history of aortic surgery and/or dissection&#xD;
&#xD;
          2. significant valve disease requiring surgery&#xD;
&#xD;
          3. aortic root dimension &gt; 5.5 cm&#xD;
&#xD;
          4. renal dysfunction (creatinine &gt; upper normal limit)&#xD;
&#xD;
          5. pregnancy or planned pregnancy within 12 months of study entry or breast feeding women&#xD;
&#xD;
          6. Known renal artery stenosis&#xD;
&#xD;
          7. Hypersensitivity to the aliskiren or to any of the excipients&#xD;
&#xD;
          8. Elevation of serum creatinine during follow-up (&gt; 30% than baseline)&#xD;
&#xD;
          9. Diarrhea, resulting severe dehydration&#xD;
&#xD;
         10. Development of gout or ureter stone&#xD;
&#xD;
         11. Symptomatic hypotension (SBP&lt;90 with symptom)&#xD;
&#xD;
         12. Hyperkalemia&#xD;
&#xD;
         13. Concomitant use with ciclosporin A&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>14 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Duk-Kyung Kim, PhD MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Samsung Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Samsung Medical Center</name>
      <address>
        <city>Seoul</city>
        <zip>135-710</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <verification_date>May 2017</verification_date>
  <study_first_submitted>October 24, 2012</study_first_submitted>
  <study_first_submitted_qc>October 24, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 26, 2012</study_first_posted>
  <results_first_submitted>November 21, 2016</results_first_submitted>
  <results_first_submitted_qc>March 23, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">May 4, 2017</results_first_posted>
  <last_update_submitted>May 3, 2017</last_update_submitted>
  <last_update_submitted_qc>May 3, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">June 5, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Samsung Medical Center</investigator_affiliation>
    <investigator_full_name>Duk-Kyung Kim</investigator_full_name>
    <investigator_title>PhD, MD, Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Marfan Syndrome</mesh_term>
    <mesh_term>Arachnodactyly</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atenolol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>to contact the principal investigator</ipd_description>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>The study was premature termination due to the stop of supporting medication from company.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Atenolol &amp; Aliskiren</title>
          <description>Atenolol tablet and Aliskiren 150mg or 300mg tablet by mouth per day for 6month&#xD;
Aliskiren&#xD;
Atenolol</description>
        </group>
        <group group_id="P2">
          <title>Atenolol</title>
          <description>Atenolol tablet(Negative controls, Open-label)&#xD;
Atenolol</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Atenolol &amp; Aliskiren</title>
          <description>Atenolol tablet and Aliskiren 150mg or 300mg tablet by mouth per day for 6month&#xD;
Aliskiren&#xD;
Atenolol</description>
        </group>
        <group group_id="B2">
          <title>Atenolol</title>
          <description>Atenolol tablet(Negative controls, Open-label)&#xD;
Atenolol</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="14"/>
            <count group_id="B2" value="14"/>
            <count group_id="B3" value="28"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>yeaars</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="32.1" spread="9.3"/>
                    <measurement group_id="B2" value="33.2" spread="12.0"/>
                    <measurement group_id="B3" value="32.6" spread="9.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Central Aortic Distensibility by MRI</title>
        <description>Analyses of the MRIs were performed using commercial software (Argus version 4.02, Siemens Medical Systems, Germany) by experienced observers who were blinded to patient information. To measure central aortic distensibility, the systolic and diastolic cross-sectional areas were measured by manual contouring of the aorta through the cardiac cycle on the cine image. Distensibility at the four regions was calculated as the mean of values obtained from the following equation: Distensibility = (Amax - Amin)/[Amin × (Pmax - Pmin)](10-3mm/Hg), where Amax is the maximal (systolic) aortic area, Amin is the minimal (diastolic) aortic area, Pmax is the systolic blood pressure (SBP), and Pmin is the diastolic blood pressure (DBP). Central aortic blood pressure measured non-invasively by SphygmoCor was used for systolic and diastolic blood pressure.</description>
        <time_frame>6 months</time_frame>
        <population>MFS patients were recruited at Samsung Medical Center from November 2009 to October 2014. All patients were receiving atenolol as standard β-blocker therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Atenolol &amp; Aliskiren</title>
            <description>Atenolol tablet and Aliskiren 150mg or 300mg tablet by mouth per day for 6month&#xD;
Aliskiren&#xD;
Atenolol</description>
          </group>
          <group group_id="O2">
            <title>Atenolol</title>
            <description>Atenolol tablet(Negative controls, Open-label)&#xD;
Atenolol</description>
          </group>
        </group_list>
        <measure>
          <title>Central Aortic Distensibility by MRI</title>
          <description>Analyses of the MRIs were performed using commercial software (Argus version 4.02, Siemens Medical Systems, Germany) by experienced observers who were blinded to patient information. To measure central aortic distensibility, the systolic and diastolic cross-sectional areas were measured by manual contouring of the aorta through the cardiac cycle on the cine image. Distensibility at the four regions was calculated as the mean of values obtained from the following equation: Distensibility = (Amax - Amin)/[Amin × (Pmax - Pmin)](10-3mm/Hg), where Amax is the maximal (systolic) aortic area, Amin is the minimal (diastolic) aortic area, Pmax is the systolic blood pressure (SBP), and Pmin is the diastolic blood pressure (DBP). Central aortic blood pressure measured non-invasively by SphygmoCor was used for systolic and diastolic blood pressure.</description>
          <population>MFS patients were recruited at Samsung Medical Center from November 2009 to October 2014. All patients were receiving atenolol as standard β-blocker therapy.</population>
          <units>(mmHg ^ -1) x 10 ^ -3</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>initial ascending aorta</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.7" spread="1.3"/>
                    <measurement group_id="O2" value="4.7" spread="2.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>initial upper descending aorta</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.7" spread="1.8"/>
                    <measurement group_id="O2" value="5.1" spread="2.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>initial lower descending aorta</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.5" spread="2.7"/>
                    <measurement group_id="O2" value="6.3" spread="2.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>initial abdominal aorta</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.4" spread="1.7"/>
                    <measurement group_id="O2" value="2.7" spread="1.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>follow up ascending aorta</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.2" spread="2.7"/>
                    <measurement group_id="O2" value="5.0" spread="2.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>follow up upper descending aorta</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.3" spread="4.7"/>
                    <measurement group_id="O2" value="6.0" spread="2.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>follow up lower descending aorta</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.7" spread="4.6"/>
                    <measurement group_id="O2" value="7.1" spread="2.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>follow up abdominal aorta</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.5" spread="3.4"/>
                    <measurement group_id="O2" value="3.5" spread="1.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Central Aortic PWV(Pulsed Wave Velocity)</title>
        <description>Aortic PWV was measured according to the well-validated method using MRI 19. From the velocity-encoded MRIs, aortic contours were automatically detected and manually adjusted in each slice area throughout the cardiac cycle. The transit time between the flow curves of each region of the aorta was determined from the midpoint of the systolic up-slope on the flow versus time curve 26-28. The up-slopes were identified by drawing a line between the points of 40% and 60% maximum velocity on the waveform. The distance between each aortic level was measured on black blood images using a curved line along the center of the aorta. Based on these data, the regional PWV was calculated as the ratio of the distance between levels and the time differences between the arrival of the pulse wave at each level. The PWV was measured at two regions: the proximal aorta (proximal PWV between level 1 and level 2) and the entire aorta (PWV-total between level 1 and level 4).</description>
        <time_frame>6 months</time_frame>
        <population>MFS patients were recruited at Samsung Medical Center from November 2009 to October 2014. All patients were receiving atenolol as standard β-blocker therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Atenolol and Aliskiren</title>
            <description>Aliskiren (Norvatis) 300mg oral tablet</description>
          </group>
          <group group_id="O2">
            <title>Atenolol</title>
            <description>Atenolol tablet(Negative controls, Open-label)&#xD;
Control group baseline 24 Weeks Central PWV (m/s)(26) by MRI regional PWV A (level 1-2) 3.8 (1.7) 3.6 (1.23) PWV-total (level 1-4) 5.0 (1.03) 4.9 (1.24)</description>
          </group>
        </group_list>
        <measure>
          <title>Central Aortic PWV(Pulsed Wave Velocity)</title>
          <description>Aortic PWV was measured according to the well-validated method using MRI 19. From the velocity-encoded MRIs, aortic contours were automatically detected and manually adjusted in each slice area throughout the cardiac cycle. The transit time between the flow curves of each region of the aorta was determined from the midpoint of the systolic up-slope on the flow versus time curve 26-28. The up-slopes were identified by drawing a line between the points of 40% and 60% maximum velocity on the waveform. The distance between each aortic level was measured on black blood images using a curved line along the center of the aorta. Based on these data, the regional PWV was calculated as the ratio of the distance between levels and the time differences between the arrival of the pulse wave at each level. The PWV was measured at two regions: the proximal aorta (proximal PWV between level 1 and level 2) and the entire aorta (PWV-total between level 1 and level 4).</description>
          <population>MFS patients were recruited at Samsung Medical Center from November 2009 to October 2014. All patients were receiving atenolol as standard β-blocker therapy.</population>
          <units>m/s</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline regional PWV A</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.3" spread="1.03"/>
                    <measurement group_id="O2" value="3.8" spread="1.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>baseline PWV total</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.5" spread="0.77"/>
                    <measurement group_id="O2" value="5.0" spread="1.03"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>follow up regional PWV A</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.2" spread="0.8"/>
                    <measurement group_id="O2" value="3.6" spread="1.23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>follow up PWV total</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.7" spread="1.1"/>
                    <measurement group_id="O2" value="4.9" spread="1.24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>6months</time_frame>
      <desc>angioedema, GI symptom, rash, gout, hypotension, renal stone K, EKG, creatinine, uric acid, urine analysis Safety information will be collected including all AEs (adverse events) and all SAEs (Serious adverse events). Specially, a serious adverse event form should be completed for all serious adverse events during the study period. The serious adverse event will be checked by investigators. And investigators will report all SAEs to Novartis Safety desk within 24 hours since they know.</desc>
      <group_list>
        <group group_id="E1">
          <title>Atenolol &amp; Aliskiren</title>
          <description>Atenolol tablet and Aliskiren 150mg or 300mg tablet by mouth per day for 6month&#xD;
Treatment (n=14) Overall rate of adverse events 12 (85.7%) moderate to severe cases 0 generalized symptoms 8 (57.1%) gastrointestinal symptoms 4 (28.6%) lung problems 0 cardiovascular symptoms 3 (21.4%) central nervous system symptoms 5 (35.7%) Eye, nose, throat symptoms 4 (28.6%) gynecologic problems 1 (7.1%) problems of extremities 1 (7.1%)</description>
        </group>
        <group group_id="E2">
          <title>Atenolol</title>
          <description>Atenolol tablet(Negative controls, Open-label)&#xD;
Control (n=14) Overall rate of adverse events 10 (71.4%) moderate to severe cases 2 (14.3%) generalized symptoms 4 (28.6%) gastrointestinal symptoms 3 (21.4%) lung problems 1 (7.1%) cardiovascular symptoms 0 central nervous system symptoms 1 (7.1%) Eye, nose, throat symptoms 1 (7.1%) gynecologic problems 1 (7.1%) problems of extremities 2 (14.3%)</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>inguinal hernia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>pneumothorax</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>generalized symptoms</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="14"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Prof Duk-Kyung Kim</name_or_title>
      <organization>SamsungMC</organization>
      <phone>01099333413</phone>
      <email>dukkyung.kim@samsung.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01715207
org study id: 2009-10-025
nct id: NCT01715207
lead sponsor: 
has dmc: No
Marfan syndrome (MFS) is an inherited disorder of connective tissue with morbidity and
      mortality from aortic dilatation and dissection. The current standard of care is beta-blocker
      (BB) treatment and therapeutic target is heart rate. The degree of aortic dilatation and
      response to BB vary in adults with MFS. However, aortic stiffness is often present, and can
      be a predictor of aortic dilatation and cardiovascular complications. Aortic stiffness is a
      logical therapeutic target in adults with MFS.

      Transforming growth factor beta(TGF-beta) mediates disease pathogenesis in MFS and
      contributes to aortic stiffness. Cross-talk between TGF-beta system and renin-angiotensin
      system (RAS) has been demonstrated. The angiotensin receptor blocker (ARB), losartan,
      inhibits TGF-beta activity and reverses aortic wall pathology in a Marfan mouse model. In a
      small cohort study, the use of ARB therapy (losartan or irbesartan) significantly slowed the
      rate of progressive aortic dilatation in patients with MFS, after BB therapy had failed to
      prevent aortic root dilatation. In another study, angiotensin converting enzyme inhibitor,
      perindopril, reduced both aortic stiffness and aortic root diameter in patients with MFS
      taking standard BB therapy. Renin inhibitor, aliskiren, has not been studied to reduce aortic
      stiffness and attenuate aortic dilatation in patients with MFS.

      This trial is a randomized, open-label trial of 32 patients with Marfan syndrome, treated
      with 6 months of aliskiren vs. negative controls in patients with MFS under atenolol
      treatment. MRI for aortic pulsed wave velocity (PWV) and distensibility, measurements of
      central BP (CBP) and augmentation index (AIx) will be performed at the beginning and end of
      treatment. A blood drawn for serum markers of TGF-beta, extracellular matrix turnover and
      inflammation will also be performed at 0 and 6 months. We plan to determine whether aliskiren
      decreases aortic stiffness significantly more than negative controls in patients with MFS
      under atenolol treatment.
Study design and study population The study design was a prospective randomized intervention
      study in a single center. A randomization process was performed to assign participants to
      either the aliskiren-treatment group or the negative control group in an open-label design.
      The duration of the study period was 24 weeks as the time frame for treatment. Duration of
      treatment was decided based on previous studies using RAS inhibitor 13,25. Aliskiren was
      administered to patients in the treatment group at an oral dose of 150-300 mg per day.
      Medication administration started after a baseline study with a dose of 150 mg of aliskiren,
      which was escalated to 300 mg of aliskiren at 4 weeks after evaluation of tolerability and
      the presence of adverse effects as angioedema, gastrointestinal symptoms, rash, gout,
      hypotension, and renal stones. The patients stopped taking aliskiren if serious adverse
      events such as angioedema or allergic reactions definitely related to the medication
      developed. Dose reduction was considered in cases with development of hyperkalemia, elevation
      of serum creatinine to twice baseline, symptomatic hypotension, gout, or renal stones. Dose
      reduction to 150 mg after escalation was performed on the decision of the investigators if
      the patient complained of discomfort and side effects that were probably related to the
      medication.

      MFS patients were recruited at Samsung Medical Center from November 2009 to October 2014. All
      patients were receiving atenolol as standard β-blocker therapy. All patients gave written
      informed consent to participate in the study, which was approved by the Samsung Medical
      Center Ethics Committee. This trial is registered at ClinicalTrial.gov. (Identifier:
      NCT01715207) Inclusion criteria were age 14 to 55 years, a diagnosis of MFS by Ghent
      criteria, β-blocker treatment for at least 3 months, and no chronic RAS inhibitor therapy
      (i.e., angiotensin II receptor blockers or ACE inhibitors) for 90 days prior to screening.
      Exclusion criteria were previous medical history of aortic surgery and/or dissection,
      significant valve disease requiring surgery, aortic root dimension > 5.0 cm, renal
      dysfunction (creatinine > upper normal limit), pregnancy or planned pregnancy within 12
      months of study entry or current breast feeding, known renal artery stenosis,
      hypersensitivity to aliskiren or any of the excipients, elevation of serum creatinine during
      follow-up (> 30% of baseline), diarrhea resulting in severe dehydration, development of gout
      or ureter stone, symptomatic hypotension (systolic blood pressure <90 mmHg with symptoms),
      hyperkalemia, and concomitant treatment with cyclosporin A.

      Follow-up and outcomes All included patients were clinically followed to monitor adverse
      effects of angioedema, gastrointestinal symptoms, rash, gout, hypotension, and renal stone at
      initial examination, 1 week, 4 weeks, 8 weeks, 16 weeks, and 24 weeks. The following
      laboratory data were collected during the same period: potassium, electrocardiogram,
      creatinine, uric acid, and urine analysis. Echocardiographic evaluation, peripheral
      tonometric measurements of peripheral PWV, central aortic blood pressure and augmentation
      index, cardiac magnetic resonance imaging (cardiac MRI), and biomarkers were analyzed at
      baseline and after 24 weeks of treatment.

      Safety information was collected, including all adverse events and all serious adverse
      events. Completion of a serious adverse event form was required for all serious adverse
      events that occurred during the study period. All serious adverse events were assessed by
      investigators and reported to the Novartis safety desk within 24 hours.

      The primary end point was central aortic distensibility by cardiac MRI at 24 weeks, reported
      as the change over the 24-week period after randomization. The secondary end points were
      central aortic PWV by cardiac MRI, change in central aortic blood pressure (hereafter, aortic
      BP), augmentation index, peripheral PWV by tonometry, aortic root diameter by
      echocardiography, severity of aortic regurgitation by echocardiography, and
      dissection/rupture/operation of aneurysm.

      Cardiovascular imaging - echocardiography and cardiac MRI Cardiac MRI Cardiac MRI was
      performed using a 1.5-Tesla scanner (Magnetom Avanto, Syngo MR; Siemens Medical Solutions,
      Erlangen, Germany). Aortic diameters were measured at four landmark levels: level 1, the
      ascending aorta at the level of bifurcation of the pulmonary artery; level 2, the upper
      descending thoracic aorta at the level of bifurcation of the pulmonary artery; level 3, the
      lower descending thoracic aorta at the level of the diaphragm; level 4, the abdominal aorta
      just above the iliac bifurcation. Cine imaging was also performed at the same levels to
      measure aortic stiffness.

      Cardiac MRI analysis - central aortic distensibility and central aortic PWV Analyses of the
      MRIs were performed using commercial software (Argus version 4.02, Siemens Medical Systems,
      Germany) by experienced observers who were blinded to patient information. To measure central
      aortic distensibility, the systolic and diastolic cross-sectional areas were measured by
      manual contouring of the aorta through the cardiac cycle on the cine image. Distensibility at
      the four regions was calculated as the mean of values obtained from the following equation:
      Distensibility = (Amax - Amin)/[Amin × (Pmax - Pmin)](10-3mm/Hg), where Amax is the maximal
      (systolic) aortic area, Amin is the minimal (diastolic) aortic area, Pmax is the systolic
      blood pressure (SBP), and Pmin is the diastolic blood pressure (DBP). Central aortic blood
      pressure measured non-invasively by SphygmoCor was used for systolic and diastolic blood
      pressure.

      Aortic PWV was measured according to the well-validated method using MRI 19. From the
      velocity-encoded MRIs, aortic contours were automatically detected and manually adjusted in
      each slice area throughout the cardiac cycle. The transit time between the flow curves of
      each region of the aorta was determined from the midpoint of the systolic up-slope on the
      flow versus time curve 26-28. The up-slopes were identified by drawing a line between the
      points of 40% and 60% maximum velocity on the waveform. The distance between each aortic
      level was measured on black blood images using a curved line along the center of the aorta.
      Based on these data, the regional PWV was calculated as the ratio of the distance between
      levels and the time differences between the arrival of the pulse wave at each level. The PWV
      was measured at two regions: the proximal aorta (proximal PWV between level 1 and level 2)
      and the entire aorta (PWV-total between level 1 and level 4).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
masking description: Open Label
measure: Central Aortic Distensibility by MRI
time frame: 6 months
description: Analyses of the MRIs were performed using commercial software (Argus version 4.02, Siemens Medical Systems, Germany) by experienced observers who were blinded to patient information. To measure central aortic distensibility, the systolic and diastolic cross-sectional areas were measured by manual contouring of the aorta through the cardiac cycle on the cine image. Distensibility at the four regions was calculated as the mean of values obtained from the following equation: Distensibility = (Amax - Amin)/[Amin × (Pmax - Pmin)](10-3mm/Hg), where Amax is the maximal (systolic) aortic area, Amin is the minimal (diastolic) aortic area, Pmax is the systolic blood pressure (SBP), and Pmin is the diastolic blood pressure (DBP). Central aortic blood pressure measured non-invasively by SphygmoCor was used for systolic and diastolic blood pressure.
measure: Central Aortic PWV(Pulsed Wave Velocity)
time frame: 6 months
description: Aortic PWV was measured according to the well-validated method using MRI 19. From the velocity-encoded MRIs, aortic contours were automatically detected and manually adjusted in each slice area throughout the cardiac cycle. The transit time between the flow curves of each region of the aorta was determined from the midpoint of the systolic up-slope on the flow versus time curve 26-28. The up-slopes were identified by drawing a line between the points of 40% and 60% maximum velocity on the waveform. The distance between each aortic level was measured on black blood images using a curved line along the center of the aorta. Based on these data, the regional PWV was calculated as the ratio of the distance between levels and the time differences between the arrival of the pulse wave at each level. The PWV was measured at two regions: the proximal aorta (proximal PWV between level 1 and level 2) and the entire aorta (PWV-total between level 1 and level 4).
arm group label: Atenolol & Aliskiren
arm group type: Experimental
description: Atenolol tablet and Aliskiren 150mg or 300mg tablet by mouth per day for 6month
arm group label: Atenolol
arm group type: Other
description: Atenolol tablet(Negative controls, Open-label)
intervention type: Drug
intervention name: Aliskiren
arm group label: Atenolol & Aliskiren
other name: Rasilez
intervention type: Drug
intervention name: Atenolol
arm group label: Atenolol
arm group label: Atenolol & Aliskiren
other name: Tenormin
criteria: 
gender: All
minimum age: 14 Years
maximum age: 55 Years
healthy volunteers: No
last name: Duk-Kyung Kim, PhD MD
role: Principal Investigator
affiliation: Samsung Medical Center
facility: 
country: Korea, Republic of
responsible party type: Principal Investigator
investigator affiliation: Samsung Medical Center
investigator full name: Duk-Kyung Kim
investigator title: PhD, MD, Professor
mesh term: Marfan Syndrome
mesh term: Arachnodactyly
mesh term: Syndrome
mesh term: Atenolol
sharing ipd: No
ipd description: to contact the principal investigator
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 