<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/NCT03236818</url>
  </required_header>
  <id_info>
    <org_study_id>NL41878.029.13</org_study_id>
    <nct_id>NCT03236818</nct_id>
  </id_info>
  <brief_title>Goal Oriented Strategy to Preserve Ejection Fraction Trial</brief_title>
  <acronym>GOSPEL</acronym>
  <official_title>Raising the Bars in the Treatment of Pulmonary Arterial Hypertension: Goal Oriented Strategy to Preserve Ejection Fraction Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Amsterdam UMC, location VUmc</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Amsterdam UMC, location VUmc</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In this prospective long term feasibility study we examine whether a goal oriented&#xD;
      therapeutic strategy that is able to preserve right ventricular function will result in&#xD;
      improved clinical outcome in patients with pulmonary arterial hypertension. We hypothesize&#xD;
      that right ventricular function can only be preserved when early and aggressive medical&#xD;
      combination therapy not only reduces pulmonary vascular resistance but also pulmonary&#xD;
      pressures.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rationale:&#xD;
&#xD;
      The current strategy in patients with pulmonary arterial hypertension (PAH)is to improve&#xD;
      exercise capacity which can be achieved by decreasing pulmonary vascular resistance (PVR) and&#xD;
      subsequently increasing cardiac output (CO). Despite this load reduction, a substantial&#xD;
      proportion of patients show progressive right ventricular (RV) dysfunction leading to&#xD;
      clinical worsening and death. A possible explanation is that current therapies show a&#xD;
      relatively modest reduction in PVR, leaving mean pulmonary artery pressure (mPAP) unchanged.&#xD;
      As a consequence RV work, defined as the product of CO and mPAP increases, contributing to&#xD;
      progressive RV dysfunction.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      A goal oriented therapeutic strategy that is able to preserve RV function will result in&#xD;
      improved clinical outcome. RV function can only be preserved when early and aggressive&#xD;
      combination therapy not only reduces PVR but also mPAP.&#xD;
&#xD;
      Study questions:&#xD;
&#xD;
        1. Will a goal oriented strategy to preserve/improve RV function, measured by right&#xD;
           ventricular ejection fraction (RVEF) be effective?&#xD;
&#xD;
        2. Does early and aggressive combination therapy result in improved RV function and&#xD;
           survival during long term follow-up?&#xD;
&#xD;
        3. Does a strategy to preserve RVEF also translate into improvements of other clinically&#xD;
           meaningful parameters?&#xD;
&#xD;
        4. Can RVEF be replaced by more simple measures?&#xD;
&#xD;
        5. Will a goal oriented strategy to improve RVEF also lead to improvement of myocardial&#xD;
           performances and coupling of the RV to its load?&#xD;
&#xD;
      Study design and study population:&#xD;
&#xD;
      In this prospective longitudinal feasibility study, thirty newly diagnosed idiopathic or&#xD;
      heritable PAH patients with New York Heart Association (NYHA) functional class II or III will&#xD;
      be included. Maintenance/improvement of RVEF will be our primary outcome parameter and&#xD;
      therefore cardiac magnetic resonance imaging (CMR) will be performed at baseline and at 4, 8&#xD;
      , 12 and 24 months of follow-up. Six-minute walk testing (6MWT), quality of life&#xD;
      questionnaires and blood sampling (NT-proBNP) will be performed at similar follow-up&#xD;
      intervals. In addition, right heart catheterization (RHC) will be performed at baseline,&#xD;
      after 4, 12 and 24 months of follow-up.&#xD;
&#xD;
      NYHA II patients will start with single agent medical treatment whereas patients with NYHA&#xD;
      III will start on combination therapy (2 treatments). In case of a stable/improved RVEF&#xD;
      during each follow-up measurement (defined as no decrease in RVEF &gt;3% compared to previous&#xD;
      measurement), the treatment strategy will remain unchanged. In case of decreased RVEF &gt;3%,&#xD;
      additional medical therapy will be added. Our hypothesis will prove to be correct when the&#xD;
      additional medical treatment result in improved RVEF during the subsequent follow-up&#xD;
      measurement.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>May 2013</start_date>
  <completion_date type="Anticipated">September 2017</completion_date>
  <primary_completion_date type="Anticipated">September 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in right ventricular ejection fraction</measure>
    <time_frame>4,12, 24 months of follow-up</time_frame>
    <description>The primary endpoint will be change in right ventricular ejection fraction (RVEF) during 2 years of follow-up.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>pulmonary vascular resistance</measure>
    <time_frame>4,12, 24 months of follow-up</time_frame>
    <description>Change in pulmonary vascular resistance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>mPAP</measure>
    <time_frame>4,12, 24 months of follow-up</time_frame>
    <description>Change in mPAP</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac output in L/min (Thermodilution method)</measure>
    <time_frame>4,8, 12, 24 months of follow-up</time_frame>
    <description>Change in cardiac output</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exercise capacity</measure>
    <time_frame>4,8, 12, 24 months of follow-up</time_frame>
    <description>Change in exercise capacity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New York Heart Association functional class</measure>
    <time_frame>4,8, 12, 24 months of follow-up</time_frame>
    <description>Change in New York Heart Association functional class</description>
  </secondary_outcome>
  <other_outcome>
    <measure>NT-proBNP</measure>
    <time_frame>4,8, 12, 24 months of follow-up</time_frame>
    <description>Change in NT-proBNP</description>
  </other_outcome>
  <other_outcome>
    <measure>Quality of Life by SF-36 questionnaire</measure>
    <time_frame>4,8, 12, 24 months of follow-up</time_frame>
    <description>Change in Quality of Life</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Pulmonary Arterial Hypertension</condition>
  <arm_group>
    <arm_group_label>Upfront combination therapy</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Combination of an ERA and PDE-5I (Sildenafil, Tadalafil, Bosentan, Macitentan)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ERA and PDE-5I (Sildenafil, Tadalafil, Bosentan, Macitentan)</intervention_name>
    <description>Combination of an ERA and PDE-5I (Sildenafil, Tadalafil, Bosentan, Macitentan)</description>
    <arm_group_label>Upfront combination therapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Idiopathic or heritable pulmonary arterial hypertension&#xD;
&#xD;
          -  New York Heart Association (NYHA) functional class II or III&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Other causes of pulmonary arterial hypertension (i.e. collagen vascular disease,&#xD;
             congenital heart disease, chrono-thromboembolic pulmonary hypertension, pulmonary&#xD;
             venous hypertension, left heart failure, hypoxemic lung disease)&#xD;
&#xD;
          -  Pulmonary arterial hypertension targeted therapies before study inclusion&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Anton Vonk Noordegraaf, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>VU University Medical Center, department of pulmonary diseases</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>VU University Medical Center, dept Pulmonary diseases</name>
      <address>
        <city>Amsterdam</city>
        <zip>1081 HV</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>July 2017</verification_date>
  <study_first_submitted>March 18, 2013</study_first_submitted>
  <study_first_submitted_qc>August 1, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 2, 2017</study_first_posted>
  <last_update_submitted>August 1, 2017</last_update_submitted>
  <last_update_submitted_qc>August 1, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 2, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Amsterdam UMC, location VUmc</investigator_affiliation>
    <investigator_full_name>A. Vonk Noordegraaf</investigator_full_name>
    <investigator_title>Clinical Professor, Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>pulmonary arterial hypertension</keyword>
  <keyword>right ventricle</keyword>
  <keyword>MRI</keyword>
  <keyword>medical combination therapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pulmonary Arterial Hypertension</mesh_term>
    <mesh_term>Familial Primary Pulmonary Hypertension</mesh_term>
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bosentan</mesh_term>
    <mesh_term>Sildenafil Citrate</mesh_term>
    <mesh_term>Tadalafil</mesh_term>
    <mesh_term>Macitentan</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/NCT03236818
org study id: NL41878.029.13
nct id: NCT03236818
lead sponsor: 
has dmc: No
In this prospective long term feasibility study we examine whether a goal oriented
      therapeutic strategy that is able to preserve right ventricular function will result in
      improved clinical outcome in patients with pulmonary arterial hypertension. We hypothesize
      that right ventricular function can only be preserved when early and aggressive medical
      combination therapy not only reduces pulmonary vascular resistance but also pulmonary
      pressures.
Rationale:

      The current strategy in patients with pulmonary arterial hypertension (PAH)is to improve
      exercise capacity which can be achieved by decreasing pulmonary vascular resistance (PVR) and
      subsequently increasing cardiac output (CO). Despite this load reduction, a substantial
      proportion of patients show progressive right ventricular (RV) dysfunction leading to
      clinical worsening and death. A possible explanation is that current therapies show a
      relatively modest reduction in PVR, leaving mean pulmonary artery pressure (mPAP) unchanged.
      As a consequence RV work, defined as the product of CO and mPAP increases, contributing to
      progressive RV dysfunction.

      Hypothesis:

      A goal oriented therapeutic strategy that is able to preserve RV function will result in
      improved clinical outcome. RV function can only be preserved when early and aggressive
      combination therapy not only reduces PVR but also mPAP.

      Study questions:

        1. Will a goal oriented strategy to preserve/improve RV function, measured by right
           ventricular ejection fraction (RVEF) be effective?

        2. Does early and aggressive combination therapy result in improved RV function and
           survival during long term follow-up?

        3. Does a strategy to preserve RVEF also translate into improvements of other clinically
           meaningful parameters?

        4. Can RVEF be replaced by more simple measures?

        5. Will a goal oriented strategy to improve RVEF also lead to improvement of myocardial
           performances and coupling of the RV to its load?

      Study design and study population:

      In this prospective longitudinal feasibility study, thirty newly diagnosed idiopathic or
      heritable PAH patients with New York Heart Association (NYHA) functional class II or III will
      be included. Maintenance/improvement of RVEF will be our primary outcome parameter and
      therefore cardiac magnetic resonance imaging (CMR) will be performed at baseline and at 4, 8
      , 12 and 24 months of follow-up. Six-minute walk testing (6MWT), quality of life
      questionnaires and blood sampling (NT-proBNP) will be performed at similar follow-up
      intervals. In addition, right heart catheterization (RHC) will be performed at baseline,
      after 4, 12 and 24 months of follow-up.

      NYHA II patients will start with single agent medical treatment whereas patients with NYHA
      III will start on combination therapy (2 treatments). In case of a stable/improved RVEF
      during each follow-up measurement (defined as no decrease in RVEF >3% compared to previous
      measurement), the treatment strategy will remain unchanged. In case of decreased RVEF >3%,
      additional medical therapy will be added. Our hypothesis will prove to be correct when the
      additional medical treatment result in improved RVEF during the subsequent follow-up
      measurement.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in right ventricular ejection fraction
time frame: 4,12, 24 months of follow-up
description: The primary endpoint will be change in right ventricular ejection fraction (RVEF) during 2 years of follow-up.
measure: pulmonary vascular resistance
time frame: 4,12, 24 months of follow-up
description: Change in pulmonary vascular resistance
measure: mPAP
time frame: 4,12, 24 months of follow-up
description: Change in mPAP
measure: Cardiac output in L/min (Thermodilution method)
time frame: 4,8, 12, 24 months of follow-up
description: Change in cardiac output
measure: Exercise capacity
time frame: 4,8, 12, 24 months of follow-up
description: Change in exercise capacity
measure: New York Heart Association functional class
time frame: 4,8, 12, 24 months of follow-up
description: Change in New York Heart Association functional class
measure: NT-proBNP
time frame: 4,8, 12, 24 months of follow-up
description: Change in NT-proBNP
measure: Quality of Life by SF-36 questionnaire
time frame: 4,8, 12, 24 months of follow-up
description: Change in Quality of Life
arm group label: Upfront combination therapy
arm group type: Other
description: Combination of an ERA and PDE-5I (Sildenafil, Tadalafil, Bosentan, Macitentan)
intervention type: Drug
intervention name: ERA and PDE-5I (Sildenafil, Tadalafil, Bosentan, Macitentan)
description: Combination of an ERA and PDE-5I (Sildenafil, Tadalafil, Bosentan, Macitentan)
arm group label: Upfront combination therapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Anton Vonk Noordegraaf, MD, PhD
role: Principal Investigator
affiliation: VU University Medical Center, department of pulmonary diseases
facility: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: Amsterdam UMC, location VUmc
investigator full name: A. Vonk Noordegraaf
investigator title: Clinical Professor, Principal Investigator
mesh term: Pulmonary Arterial Hypertension
mesh term: Familial Primary Pulmonary Hypertension
mesh term: Hypertension
mesh term: Bosentan
mesh term: Sildenafil Citrate
mesh term: Tadalafil
mesh term: Macitentan