<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/NCT03841344</url>
  </required_header>
  <id_info>
    <org_study_id>STH18285</org_study_id>
    <nct_id>NCT03841344</nct_id>
  </id_info>
  <brief_title>Repeatability and Sensitivity to Change of Non-invasive Endpoints in PAH</brief_title>
  <acronym>RESPIRE</acronym>
  <official_title>A Prospective Study Comparing the REpeatability and Sensitivity to Change of Non-invasive Endpoints in Pulmonary arterIal hypeRtEnsion</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Sheffield</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>GlaxoSmithKline</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Sheffield</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Pulmonary arterial hypertension (PAH) is progressive life limiting disease with a median&#xD;
      survival of less than 3 years without treatment. Current drug trials in PAH commonly use&#xD;
      simple tests for example the 6-minute walk test, blood tests such as N-terminal&#xD;
      pro-brain-type natriuretic peptide (NT-pro-BNP) and BNP, and haemodynamic measures such as&#xD;
      PAP and PVR obtained by RHC as endpoints. These tests are surrogate markers of disease&#xD;
      severity in patients with pulmonary hypertension. There is now evidence suggesting that&#xD;
      magnetic resonance imaging (MRI) may be helpful in the follow up of patients with PAH with&#xD;
      high accuracy for the detection of treatment failure, this is because MRI can track changes&#xD;
      occurring in the heart by direct visualisation of cardiopulmonary morphology and function, an&#xD;
      advantage over existing methods. However, the reproducible of MRI measurements in patients&#xD;
      with PAH is not known, and the comparative repeatability of MRI in relation to traditional&#xD;
      candidate endpoints such as walk tests and blood tests used in drug trials is not known.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      Pulmonary arterial hypertension (PAH) is a rare but severe and progressive disorder, with a&#xD;
      prevalence of approximately 50 in 1,000,000 of the population. The condition is incurable&#xD;
      with high morbidity and mortality despite the development of effective treatment options. The&#xD;
      emergence of goal orientated therapy initially focused interest on prognostic markers that&#xD;
      can both inform the clinician regarding disease severity at presentation and be used to&#xD;
      follow-up response to therapy and aid in decisions regarding listing for transplantation. A&#xD;
      number of effective therapies are available but are very expensive and there is an urgent&#xD;
      need for non-invasive and specific markers to assess treatment response and guide therapy.&#xD;
      Accurate follow up with reproducible measurements of the heart and pulmonary vasculature are&#xD;
      essential in order to accurately characterise treatment response.&#xD;
&#xD;
      Magnetic resonance imaging (MRI) a non-ionising and non-invasive technique provides accurate&#xD;
      and reproducible information on cardiac morphology and function. MR imaging is becoming an&#xD;
      established technique in the evaluation of patients with PAH, allowing direct visualisation&#xD;
      and accurate analysis of the structure and function of the right ventricle (RV). There is a&#xD;
      pressing need to validate and standardise MRI methods in pulmonary hypertension to allow&#xD;
      clinical translation nationally and internationally and to support trials of novel disease&#xD;
      modifying therapies.&#xD;
&#xD;
      Aims:&#xD;
&#xD;
      The aim of this study is to determine the repeatability and capability of detecting change of&#xD;
      MR imaging measurements in comparison with walk tests and blood tests in patients with PAH,&#xD;
      and define the optimal MRI analysis protocol for use in clinical practice and in future&#xD;
      studies in PAH.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
        -  Determine the inter-observer and inter-scan variability of MRI in healthy volunteers and&#xD;
           patients with PAH&#xD;
&#xD;
        -  Compare the inter-observer and inter-scan variability of MRI with walk tests and blood&#xD;
           tests, in healthy volunteers and patients with PAH&#xD;
&#xD;
        -  Determine the capability of MRI to detect change in PAH patients with start or change of&#xD;
           therapy in comparison to walk test and blood test data.&#xD;
&#xD;
        -  Compare MRI endpoints with associated clinical data including haemodynamic measures&#xD;
           obtained by right heart catheterisation&#xD;
&#xD;
      Plan of investigation:&#xD;
&#xD;
      Participants:&#xD;
&#xD;
      Participants from the following groups will be recruited:&#xD;
&#xD;
        -  Treatment naïve patients with PAH&#xD;
&#xD;
        -  Patients with PAH undergoing changes in their treatment regime&#xD;
&#xD;
        -  Patients with PAH who are NOT undergoing changes in their treatment regime&#xD;
&#xD;
        -  Healthy volunteers will be recruited.&#xD;
&#xD;
      PAH treatment will be as per standard of care. No new therapies are being tested.&#xD;
&#xD;
      Sample sizes:&#xD;
&#xD;
      Recruit sufficient incident treatment naïve patients with PAH and patients with PAH on&#xD;
      monotherapy whose treatment is to be changed to achieve approximately 40 completers. This&#xD;
      number is based on prior MRI reproducibility studies investigating the reproducibility of&#xD;
      right ventricular measurements in healthy subjects and in those with cardiovascular disease.&#xD;
      It is planned that at least 30% of patients will be treatment naïve. 20 healthy volunteer&#xD;
      subjects will be recrited&#xD;
&#xD;
      Visit schedule Patients with pulmonary arterial hypertension Baseline study visit: During the&#xD;
      baseline visit, blood draw, 6 minute walk test (+/- shuttle walk test) and cardiopulmonary&#xD;
      MRI will be performed.&#xD;
&#xD;
      Follow-up visit: A follow-up visit will then occur at any time between 1 and 12 months after&#xD;
      baseline. Patients with PAH, will be admitted for a one or two day visit. Cardiopulmonary&#xD;
      MRI, blood draw, 6 minute walk test (+/- shuttle walk test) in the morning. Patients will&#xD;
      take their usual medications approximately 1 hour prior to their MRI. These investigations&#xD;
      will be repeated in the afternoon in the same way and in the same order. Patients will&#xD;
      refrain from, exercise, caffeinated drinks and alcohol, between investigations.&#xD;
&#xD;
      Healthy volunteers Recruited by open advertisement within the hospital and university. Male&#xD;
      or female subjects aged 18-60 years. Subjects will attend for a half day baseline visit for&#xD;
      MRI, walk tests and blood tests. The follow up visit, including MRI, blood draw and walk&#xD;
      test(s) will be as described for patients with PAH.&#xD;
&#xD;
      End points:&#xD;
&#xD;
      The MRI protocol will include measurement of candidate markers from the right heart and&#xD;
      pulmonary vasculature:&#xD;
&#xD;
      I. Biventricular volume, mass and function. Analysis from both the 4 chamber and short axis&#xD;
      images. Analyses will include and exclude trabecular mass.&#xD;
&#xD;
      II. Interventricular septal curvature and left ventricular eccentricity III. Pulmonary&#xD;
      arterial flow, pulmonary arterial area change and pulsatility IV. Dynamic contrast enhanced&#xD;
      perfusion imaging (first pass pulmonary transit time, full-width-half-maximum, delayed&#xD;
      enhancement washout time) V. Myocardial and pulmonary tissue characteristics pre and post&#xD;
      contrast T1 mapping of heart and lungs and myocardial late gadolinium enhancement pattern VI.&#xD;
      Other MRI endpoints including composite measures&#xD;
&#xD;
      Analysis of MRI will be undertaken blinded to the patient's covariate data (walk tests and&#xD;
      blood tests). Two experienced (one primary, one secondary) independent observers will analyse&#xD;
      all the MRI studies. In the event of discrepancy between observers, the images will be&#xD;
      reviewed by a third observer (radiologist) and all three observers should reach consensus.&#xD;
&#xD;
      Biomarker and walk test evaluation - The patient will be bled via a needle or cannula.&#xD;
      Whenever possible, blood tests will precede the walk test and MRI. Candidate prognostic&#xD;
      biomarkers, Pro NT BNP and BNP, will be tested. Incremental shuttle walk test and the 6&#xD;
      minute walk test will be performed &gt;45 minutes apart and both tests will be repeated in the&#xD;
      afternoon to determine the between measurement reproducibility for comparison with MRI. Walk&#xD;
      tests will be performed in accordance with standard protocols.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">September 15, 2015</start_date>
  <completion_date type="Anticipated">May 20, 2019</completion_date>
  <primary_completion_date type="Actual">September 24, 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>Single (Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Repeatability of endpoints</measure>
    <time_frame>Measurements repeated within 24 hours</time_frame>
    <description>Repeatability of MRI, 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Sensitivity to change of endpoints</measure>
    <time_frame>Follow up visits performed at 1-12 months</time_frame>
    <description>Sensitivity to change of MRI, 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP</description>
  </primary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">44</enrollment>
  <condition>Pulmonary Arterial Hypertension</condition>
  <arm_group>
    <arm_group_label>Healthy volunteers</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>MRI 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment naive patients</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>MRI 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP&#xD;
Patients diagnosed with PAH initiating PAH therapy for the first time</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment change patients</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>MRI 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP&#xD;
Patients diagnosed with PAH, currently on PAH therapy who are undergoing an escalation of PAH therapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stable patients</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>MRI 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP&#xD;
Patients with PAH who are NOT undergoing changes in their treatment regime</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>MRI</intervention_name>
    <description>Evaluation of the utility of candidate endpoints in PAH trials</description>
    <arm_group_label>Healthy volunteers</arm_group_label>
    <arm_group_label>Stable patients</arm_group_label>
    <arm_group_label>Treatment change patients</arm_group_label>
    <arm_group_label>Treatment naive patients</arm_group_label>
    <other_name>6 minute walk test, incremental shuttle walk test, NT-ProBNP and BNP</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Patients with PAH&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  PAH subject is diagnosed with Group 1 pulmonary arterial hypertension, including IPAH,&#xD;
             hereditable and CTD, and PAH associated with portal hypertension&#xD;
&#xD;
          -  Mean pulmonary arterial pressure ≥ 25 mmHg&#xD;
&#xD;
          -  Pulmonary arterial wedge pressure ≤ 15 mmHg&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inability to perform the study protocol&#xD;
&#xD;
          -  Significant comorbidity where in the opinion of the clinician this is a significant&#xD;
             contributor to the patients PAH&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Allergy to contrast medium&#xD;
&#xD;
          -  Contraindication to MRI (as per standard screening questionnaire)&#xD;
&#xD;
          -  Significant lung disease.&#xD;
&#xD;
          -  Known Hep B,C, HIV&#xD;
&#xD;
        Healthy volunteers&#xD;
&#xD;
        Inclusion criteria:&#xD;
&#xD;
          -  Male or female aged between 18 years and 60 years&#xD;
&#xD;
          -  Currently healthy as determined by a responsible physician&#xD;
&#xD;
          -  No significant history of lung or cardiac disease and normal BNP.&#xD;
&#xD;
          -  Capable of giving written informed consent.&#xD;
&#xD;
          -  Subject is &gt;50kg with a body mass index within the range 18.0 to 32kg/m2.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>February 8, 2019</study_first_submitted>
  <study_first_submitted_qc>February 11, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 15, 2019</study_first_posted>
  <last_update_submitted>February 14, 2019</last_update_submitted>
  <last_update_submitted_qc>February 14, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 18, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Sheffield</investigator_affiliation>
    <investigator_full_name>Andy J Swift</investigator_full_name>
    <investigator_title>Wellcome Trust Clincial Research Career Development Fellow - principle investigator</investigator_title>
  </responsible_party>
  <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>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03841344
org study id: STH18285
nct id: NCT03841344
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Pulmonary arterial hypertension (PAH) is progressive life limiting disease with a median
      survival of less than 3 years without treatment. Current drug trials in PAH commonly use
      simple tests for example the 6-minute walk test, blood tests such as N-terminal
      pro-brain-type natriuretic peptide (NT-pro-BNP) and BNP, and haemodynamic measures such as
      PAP and PVR obtained by RHC as endpoints. These tests are surrogate markers of disease
      severity in patients with pulmonary hypertension. There is now evidence suggesting that
      magnetic resonance imaging (MRI) may be helpful in the follow up of patients with PAH with
      high accuracy for the detection of treatment failure, this is because MRI can track changes
      occurring in the heart by direct visualisation of cardiopulmonary morphology and function, an
      advantage over existing methods. However, the reproducible of MRI measurements in patients
      with PAH is not known, and the comparative repeatability of MRI in relation to traditional
      candidate endpoints such as walk tests and blood tests used in drug trials is not known.
Background:

      Pulmonary arterial hypertension (PAH) is a rare but severe and progressive disorder, with a
      prevalence of approximately 50 in 1,000,000 of the population. The condition is incurable
      with high morbidity and mortality despite the development of effective treatment options. The
      emergence of goal orientated therapy initially focused interest on prognostic markers that
      can both inform the clinician regarding disease severity at presentation and be used to
      follow-up response to therapy and aid in decisions regarding listing for transplantation. A
      number of effective therapies are available but are very expensive and there is an urgent
      need for non-invasive and specific markers to assess treatment response and guide therapy.
      Accurate follow up with reproducible measurements of the heart and pulmonary vasculature are
      essential in order to accurately characterise treatment response.

      Magnetic resonance imaging (MRI) a non-ionising and non-invasive technique provides accurate
      and reproducible information on cardiac morphology and function. MR imaging is becoming an
      established technique in the evaluation of patients with PAH, allowing direct visualisation
      and accurate analysis of the structure and function of the right ventricle (RV). There is a
      pressing need to validate and standardise MRI methods in pulmonary hypertension to allow
      clinical translation nationally and internationally and to support trials of novel disease
      modifying therapies.

      Aims:

      The aim of this study is to determine the repeatability and capability of detecting change of
      MR imaging measurements in comparison with walk tests and blood tests in patients with PAH,
      and define the optimal MRI analysis protocol for use in clinical practice and in future
      studies in PAH.

      Objectives:

        -  Determine the inter-observer and inter-scan variability of MRI in healthy volunteers and
           patients with PAH

        -  Compare the inter-observer and inter-scan variability of MRI with walk tests and blood
           tests, in healthy volunteers and patients with PAH

        -  Determine the capability of MRI to detect change in PAH patients with start or change of
           therapy in comparison to walk test and blood test data.

        -  Compare MRI endpoints with associated clinical data including haemodynamic measures
           obtained by right heart catheterisation

      Plan of investigation:

      Participants:

      Participants from the following groups will be recruited:

        -  Treatment naïve patients with PAH

        -  Patients with PAH undergoing changes in their treatment regime

        -  Patients with PAH who are NOT undergoing changes in their treatment regime

        -  Healthy volunteers will be recruited.

      PAH treatment will be as per standard of care. No new therapies are being tested.

      Sample sizes:

      Recruit sufficient incident treatment naïve patients with PAH and patients with PAH on
      monotherapy whose treatment is to be changed to achieve approximately 40 completers. This
      number is based on prior MRI reproducibility studies investigating the reproducibility of
      right ventricular measurements in healthy subjects and in those with cardiovascular disease.
      It is planned that at least 30% of patients will be treatment naïve. 20 healthy volunteer
      subjects will be recrited

      Visit schedule Patients with pulmonary arterial hypertension Baseline study visit: During the
      baseline visit, blood draw, 6 minute walk test (+/- shuttle walk test) and cardiopulmonary
      MRI will be performed.

      Follow-up visit: A follow-up visit will then occur at any time between 1 and 12 months after
      baseline. Patients with PAH, will be admitted for a one or two day visit. Cardiopulmonary
      MRI, blood draw, 6 minute walk test (+/- shuttle walk test) in the morning. Patients will
      take their usual medications approximately 1 hour prior to their MRI. These investigations
      will be repeated in the afternoon in the same way and in the same order. Patients will
      refrain from, exercise, caffeinated drinks and alcohol, between investigations.

      Healthy volunteers Recruited by open advertisement within the hospital and university. Male
      or female subjects aged 18-60 years. Subjects will attend for a half day baseline visit for
      MRI, walk tests and blood tests. The follow up visit, including MRI, blood draw and walk
      test(s) will be as described for patients with PAH.

      End points:

      The MRI protocol will include measurement of candidate markers from the right heart and
      pulmonary vasculature:

      I. Biventricular volume, mass and function. Analysis from both the 4 chamber and short axis
      images. Analyses will include and exclude trabecular mass.

      II. Interventricular septal curvature and left ventricular eccentricity III. Pulmonary
      arterial flow, pulmonary arterial area change and pulsatility IV. Dynamic contrast enhanced
      perfusion imaging (first pass pulmonary transit time, full-width-half-maximum, delayed
      enhancement washout time) V. Myocardial and pulmonary tissue characteristics pre and post
      contrast T1 mapping of heart and lungs and myocardial late gadolinium enhancement pattern VI.
      Other MRI endpoints including composite measures

      Analysis of MRI will be undertaken blinded to the patient's covariate data (walk tests and
      blood tests). Two experienced (one primary, one secondary) independent observers will analyse
      all the MRI studies. In the event of discrepancy between observers, the images will be
      reviewed by a third observer (radiologist) and all three observers should reach consensus.

      Biomarker and walk test evaluation - The patient will be bled via a needle or cannula.
      Whenever possible, blood tests will precede the walk test and MRI. Candidate prognostic
      biomarkers, Pro NT BNP and BNP, will be tested. Incremental shuttle walk test and the 6
      minute walk test will be performed >45 minutes apart and both tests will be repeated in the
      afternoon to determine the between measurement reproducibility for comparison with MRI. Walk
      tests will be performed in accordance with standard protocols.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: Single (Investigator)
measure: Repeatability of endpoints
time frame: Measurements repeated within 24 hours
description: Repeatability of MRI, 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP
measure: Sensitivity to change of endpoints
time frame: Follow up visits performed at 1-12 months
description: Sensitivity to change of MRI, 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP
arm group label: Healthy volunteers
arm group type: Active Comparator
description: MRI 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP
arm group label: Treatment naive patients
arm group type: Active Comparator
description: MRI 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP
Patients diagnosed with PAH initiating PAH therapy for the first time
arm group label: Treatment change patients
arm group type: Active Comparator
description: MRI 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP
Patients diagnosed with PAH, currently on PAH therapy who are undergoing an escalation of PAH therapy
arm group label: Stable patients
arm group type: Active Comparator
description: MRI 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP
Patients with PAH who are NOT undergoing changes in their treatment regime
intervention type: Device
intervention name: MRI
description: Evaluation of the utility of candidate endpoints in PAH trials
arm group label: Healthy volunteers
arm group label: Stable patients
arm group label: Treatment change patients
arm group label: Treatment naive patients
other name: 6 minute walk test, incremental shuttle walk test, NT-ProBNP and BNP
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
responsible party type: Principal Investigator
investigator affiliation: University of Sheffield
investigator full name: Andy J Swift
investigator title: Wellcome Trust Clincial Research Career Development Fellow - principle investigator
mesh term: Pulmonary Arterial Hypertension
mesh term: Familial Primary Pulmonary Hypertension
mesh term: Hypertension
sharing ipd: Undecided