<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/NCT04416750</url>
  </required_header>
  <id_info>
    <org_study_id>IRAS ID: 274093</org_study_id>
    <secondary_id>2020-001157-48</secondary_id>
    <secondary_id>20HH5896</secondary_id>
    <secondary_id>20/SC/0240</secondary_id>
    <nct_id>NCT04416750</nct_id>
  </id_info>
  <brief_title>Positioning Imatinib for Pulmonary Arterial Hypertension</brief_title>
  <acronym>PIPAH</acronym>
  <official_title>Positioning Imatinib for Pulmonary Arterial Hypertension</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Imperial College London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute for Health Research, United Kingdom</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Medical Research Council</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Cambridge</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Sheffield</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Imperial College London</source>
  <oversight_info>
    <has_dmc>Yes</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 a rare condition in which a narrowing of blood&#xD;
      vessels carrying blood through the lungs puts an increased work load on the heart; it has to&#xD;
      work harder to pump blood through the lungs. While current treatments relieve some of the&#xD;
      symptoms, they do not stop or reverse the disease in the affected blood vessels. Imatinib is&#xD;
      a medicine licensed for some types of cancers. A published study has shown that imatinib can&#xD;
      have beneficial effects on blood flow through the lungs and exercise capacity in patients&#xD;
      with PAH, even when added to existing treatments. However, there have been concerns about its&#xD;
      safety and tolerability. Imatinib continues to be prescribed occasionally on compassionate&#xD;
      grounds, usually when other treatment options have been exhausted, and some patients feel&#xD;
      better on the drug. To improve the investigator's understanding, the investigators of this&#xD;
      study re-visits the use of Imatinib as a potential treatment for patients with PAH.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      What does the study involve?&#xD;
&#xD;
      The study involves treatment of PAH patients with imatinib (study drug) for up to 24 weeks,&#xD;
      and clinical assessments and tests to assess the drug's safety and tolerability.&#xD;
&#xD;
      PAH patients will be seen at their local hospital by the PAH clinical research team. Before&#xD;
      someone can start study, the study doctor (or clinical study team) will describe the clinical&#xD;
      trial in detail. If a potential subject decides to participate, he/she will be asked to sign&#xD;
      the informed consent form before any study procedures are done.&#xD;
&#xD;
      Participants will be asked to come to their local hospital for clinical appointments. This&#xD;
      includes a screening visit, a baseline visit, three clinical assessments and an end-of-study&#xD;
      visit. In between, and at the very end of these, there will be six tele-visits (assessments&#xD;
      over the phone). Each clinical appointment will be on a weekday morning or afternoon. No&#xD;
      major lifestyle restrictions are required for these appointments.&#xD;
&#xD;
      Participants will undergo clinical examinations and tests to monitor the severity of PAH and&#xD;
      the response to the study drug. Clinical procedures include:&#xD;
&#xD;
        -  Questions about demographics, medical and medication history&#xD;
&#xD;
        -  Physical examination and record of vital signs (blood pressure, temperature, heart and&#xD;
           respiratory rate)&#xD;
&#xD;
        -  Questionnaire about quality of life,&#xD;
&#xD;
        -  Assessments of PAH severity (WHO Functional Class, six-minute walk test, and Borg&#xD;
           dyspnoea index)&#xD;
&#xD;
        -  Right heart catheterisation to assess response to the drug&#xD;
&#xD;
        -  Haematology and clinical chemistry blood tests to ensure safety&#xD;
&#xD;
        -  Serum pregnancy test and urine pregnancy tests (if applicable) to exclude pregnancy&#xD;
&#xD;
        -  Blood samples to measure the levels of the study drug in the circulation&#xD;
&#xD;
        -  Additional blood samples for future research on PAH and/or the mechanism of action of&#xD;
           the drug&#xD;
&#xD;
        -  Electrocardiogram (ECG), and echocardiogram to assess the size, shape, pumping action&#xD;
           and the extent of any damage to the heart&#xD;
&#xD;
        -  Brain MRI scan (or CT scan if MR is not indicated/tolerated) to exclude bleeding in the&#xD;
           brain&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 20, 2021</start_date>
  <completion_date type="Anticipated">July 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">July 1, 2024</primary_completion_date>
  <phase>Phase 2</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>
    <intervention_model_description>The highest tolerated dose of Imatinib will be determined using a Bayesian continual reassessment method. Treatment efficacy at the pre-determined highest tolerated dose will be assessed using a Simons two stage design.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Identifying the highest tolerated dose</measure>
    <time_frame>12 months</time_frame>
    <description>Part 1: Discontinuation of the drug for more than 5 consecutive days due to Grade 2 or above Adverse Events, defined by NCI criteria (version 5.0, 2017) adapted for the study.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in pulmonary vascular resistance (PVR)</measure>
    <time_frame>24 months</time_frame>
    <description>Part 2: The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) &gt;1000 dynes·s·cm-5, success is defined by an absolute reduction in PVR of ≥300 dynes·s·cm-5 at 24 weeks. For patients with a baseline PVR ≤1000 dynes·s·cm-5, success is a 30% reduction in PVR at 24 weeks.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in exercise test</measure>
    <time_frame>24 weeks</time_frame>
    <description>Change in six minute walk distance (6MWD) at 24 weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in ejection fraction measures</measure>
    <time_frame>24 weeks</time_frame>
    <description>Change in right ventricular ejection fraction (RVEF) values, measured in echocardiogram (at screening visit and at 24 weeks).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in brain natriuretic peptide (BNP) values</measure>
    <time_frame>24 weeks</time_frame>
    <description>Change in plasma BNP (or proNT-BNP) levels from baseline at 24 weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in quality of life scores</measure>
    <time_frame>24 weeks</time_frame>
    <description>Change in Quality of Life (QoL) scores from baseline at 24 weeks.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Plasma proteome measures</measure>
    <time_frame>24 weeks</time_frame>
    <description>Change in plasma proteome from baseline at 24 weeks.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">43</enrollment>
  <condition>Pulmonary Arterial Hypertension</condition>
  <arm_group>
    <arm_group_label>Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Open label; Imatinib tablets administered once daily; Dosage: in the range of 100mg-400mg; Group evaluated: adults with PAH</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Imatinib Mesylate</intervention_name>
    <description>Treatment with Imatinib</description>
    <arm_group_label>Treatment</arm_group_label>
    <other_name>Oral treatment</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Subjects aged between 18-80 years old&#xD;
&#xD;
          2. PAH which is idiopathic; PAH heritable; PAH associated with connective tissue disease;&#xD;
             PAH after ≥ 1 year repair of congenital systemic to pulmonary shunt, or PAH associated&#xD;
             with anorexigens or other drugs&#xD;
&#xD;
          3. Subjects willing to be genotyped for genes that influence PDGF activity&#xD;
&#xD;
          4. Resting mean pulmonary artery pressure ≥25 mmHg, Pulmonary capillary wedge pressure&#xD;
             ≤15 mmHg, PVR &gt;5 wood units, and normal or reduced cardiac output , as measured by&#xD;
             right heart catheterisation (RHC) at entry&#xD;
&#xD;
          5. Six-minute walking distance &gt;50m at entry&#xD;
&#xD;
          6. Stable on an unchanged PAH therapeutic regime comprising at least 2 therapies licensed&#xD;
             for PAH (any combination of endothelin receptor antagonist, phosphodiesterase&#xD;
             inhibitor or prostacyclin analogue) for at least 1 month prior to screening&#xD;
&#xD;
          7. Able to provide written informed consent prior to any study mandated procedures&#xD;
&#xD;
          8. Contraception: Fertile females (women of childbearing potential) are eligible to&#xD;
             participate after a negative highly sensitive pregnancy test, if they are taking a&#xD;
             highly effective method of contraception during treatment and until the end of&#xD;
             relevant systemic exposure. Fertile males who make use of condom and contraception&#xD;
             methods during treatment and until the end of relevant systemic exposure in women of&#xD;
             childbearing potential -full details are in included in the research protocol-&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. Unable to provide informed consent and/or are non-fluent speakers of the English&#xD;
             language&#xD;
&#xD;
          2. Hypersensitivity to Imatinib or to any of the excipients&#xD;
&#xD;
          3. Clinically-significant renal disease (confirmed by creatinine clearance &lt;30 ml/min per&#xD;
             1.73m2)&#xD;
&#xD;
          4. Clinically-significant liver disease (confirmed by serum transaminases &gt;3 times than&#xD;
             upper normal limit)&#xD;
&#xD;
          5. Patients receiving oral and/or parenteral anticoagulants (this does not apply to&#xD;
             single antiplatelet therapy)&#xD;
&#xD;
          6. Anaemia confirmed by haemoglobin concentration &lt;10 g/dl&#xD;
&#xD;
          7. History of thrombocytopenia&#xD;
&#xD;
          8. Individuals known to have haemoglobinopathy sickle cell disease, thalassaemia&#xD;
&#xD;
          9. Hospital admission related to PAH or change in PAH therapy within 3 months prior to&#xD;
             screening&#xD;
&#xD;
         10. History of left-sided heart disease and/or clinically significant cardiac disease,&#xD;
             including but not limited to any of the following:&#xD;
&#xD;
               1. Aortic or mitral valve disease (stenosis or regurgitation) defined as greater&#xD;
                  than mild aortic insufficiency, mild aortic stenosis, mild mitral stenosis,&#xD;
                  moderate mitral regurgitation&#xD;
&#xD;
               2. Mechanical or bioprosthetic cardiac valve&#xD;
&#xD;
               3. Pericardial constriction, effusion with tamponade physiology, or abnormal left&#xD;
                  atrial size.&#xD;
&#xD;
               4. Restrictive or congestive cardiomyopathy&#xD;
&#xD;
               5. Left ventricular ejection fraction ≤50% (measured in echocardiogram at screening)&#xD;
&#xD;
               6. Symptomatic coronary disease&#xD;
&#xD;
               7. Significant (2+ for regurgitation) valvular disease other than tricuspid or&#xD;
                  pulmonary regurgitation&#xD;
&#xD;
               8. Acutely decompensated left heart failure within 1 month of screening&#xD;
&#xD;
               9. History of untreated obstructive sleep apnoea&#xD;
&#xD;
         11. Evidence of significant lung disease on high-resolution CT (if available) or recent&#xD;
             (performed within 12 months) lung function, where FEV1 &lt; 50% predicted and FVC &lt; 70%&#xD;
             predicted, and DLCO (or TLCO) &lt; 50% predicted if any CT abnormalities; judged by the&#xD;
             Site Physician&#xD;
&#xD;
         12. Patients with a history of uncontrolled systemic hypertension&#xD;
&#xD;
         13. Acute infection (including eye, dental, and skin infections)&#xD;
&#xD;
         14. Chronic inflammatory disease including HIV, and Hepatitis B&#xD;
&#xD;
         15. Women of childbearing potential who are pregnant or breastfeeding (if applicable)&#xD;
&#xD;
         16. Previous intracerebral haemorrhage&#xD;
&#xD;
         17. Patients who have received an Investigational Medicinal Product (IMP) within 5&#xD;
             half-lives of the last dose of the IMP or 1 month (whichever is greater) before the&#xD;
             baseline visit&#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>Martin R Wilkins, MD, FRCP</last_name>
    <role>Study Director</role>
    <affiliation>Imperial College London</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hammersmith Hospital, Imperial College Healthcare NHS Trust</name>
      <address>
        <city>London</city>
        <state>Greater London</state>
        <zip>W12 0HS</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal United Hospital, Royal United Hospitals Bath NHS Foundation Trust</name>
      <address>
        <city>Bath</city>
        <zip>BA1 3NG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Papworth Hospital, Royal Papworth Hospital NHS Foundation Trust</name>
      <address>
        <city>Cambridge</city>
        <zip>CB2 0AY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Golden Jubilee National Hospital, NHS Greater Glasgow and Clyde</name>
      <address>
        <city>Glasgow</city>
        <zip>G81 4DY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Free Hospital, Royal Free London NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>NW3 2QG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Brompton Hospital, Royal Brompton &amp; Harefield NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>SW3 6NP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Newcastle Freeman Hospital, The Newcastle Upon Tyne Hospitals NHS Foundation Trust</name>
      <address>
        <city>Newcastle Upon Tyne</city>
        <zip>NE7 7DN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation</name>
      <address>
        <city>Sheffield</city>
        <zip>S10 2JF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>May 28, 2020</study_first_submitted>
  <study_first_submitted_qc>June 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 4, 2020</study_first_posted>
  <last_update_submitted>June 5, 2023</last_update_submitted>
  <last_update_submitted_qc>June 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pulmonary Arterial Hypertension</keyword>
  <keyword>PAH</keyword>
  <keyword>Imatinib</keyword>
  <keyword>TKI</keyword>
  <keyword>Genotype</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>Imatinib Mesylate</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/NCT04416750
org study id: IRAS ID: 274093
secondary id: 2020-001157-48
secondary id: 20HH5896
secondary id: 20/SC/0240
nct id: NCT04416750
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Pulmonary Arterial Hypertension (PAH) is a rare condition in which a narrowing of blood
      vessels carrying blood through the lungs puts an increased work load on the heart; it has to
      work harder to pump blood through the lungs. While current treatments relieve some of the
      symptoms, they do not stop or reverse the disease in the affected blood vessels. Imatinib is
      a medicine licensed for some types of cancers. A published study has shown that imatinib can
      have beneficial effects on blood flow through the lungs and exercise capacity in patients
      with PAH, even when added to existing treatments. However, there have been concerns about its
      safety and tolerability. Imatinib continues to be prescribed occasionally on compassionate
      grounds, usually when other treatment options have been exhausted, and some patients feel
      better on the drug. To improve the investigator's understanding, the investigators of this
      study re-visits the use of Imatinib as a potential treatment for patients with PAH.
What does the study involve?

      The study involves treatment of PAH patients with imatinib (study drug) for up to 24 weeks,
      and clinical assessments and tests to assess the drug's safety and tolerability.

      PAH patients will be seen at their local hospital by the PAH clinical research team. Before
      someone can start study, the study doctor (or clinical study team) will describe the clinical
      trial in detail. If a potential subject decides to participate, he/she will be asked to sign
      the informed consent form before any study procedures are done.

      Participants will be asked to come to their local hospital for clinical appointments. This
      includes a screening visit, a baseline visit, three clinical assessments and an end-of-study
      visit. In between, and at the very end of these, there will be six tele-visits (assessments
      over the phone). Each clinical appointment will be on a weekday morning or afternoon. No
      major lifestyle restrictions are required for these appointments.

      Participants will undergo clinical examinations and tests to monitor the severity of PAH and
      the response to the study drug. Clinical procedures include:

        -  Questions about demographics, medical and medication history

        -  Physical examination and record of vital signs (blood pressure, temperature, heart and
           respiratory rate)

        -  Questionnaire about quality of life,

        -  Assessments of PAH severity (WHO Functional Class, six-minute walk test, and Borg
           dyspnoea index)

        -  Right heart catheterisation to assess response to the drug

        -  Haematology and clinical chemistry blood tests to ensure safety

        -  Serum pregnancy test and urine pregnancy tests (if applicable) to exclude pregnancy

        -  Blood samples to measure the levels of the study drug in the circulation

        -  Additional blood samples for future research on PAH and/or the mechanism of action of
           the drug

        -  Electrocardiogram (ECG), and echocardiogram to assess the size, shape, pumping action
           and the extent of any damage to the heart

        -  Brain MRI scan (or CT scan if MR is not indicated/tolerated) to exclude bleeding in the
           brain
allocation: N/A
intervention model: Single Group Assignment
intervention model description: The highest tolerated dose of Imatinib will be determined using a Bayesian continual reassessment method. Treatment efficacy at the pre-determined highest tolerated dose will be assessed using a Simons two stage design.
primary purpose: Treatment
masking: None (Open Label)
measure: Identifying the highest tolerated dose
time frame: 12 months
description: Part 1: Discontinuation of the drug for more than 5 consecutive days due to Grade 2 or above Adverse Events, defined by NCI criteria (version 5.0, 2017) adapted for the study.
measure: Change in pulmonary vascular resistance (PVR)
time frame: 24 months
description: Part 2: The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) >1000 dynes·s·cm-5, success is defined by an absolute reduction in PVR of ≥300 dynes·s·cm-5 at 24 weeks. For patients with a baseline PVR ≤1000 dynes·s·cm-5, success is a 30% reduction in PVR at 24 weeks.
measure: Change in exercise test
time frame: 24 weeks
description: Change in six minute walk distance (6MWD) at 24 weeks.
measure: Change in ejection fraction measures
time frame: 24 weeks
description: Change in right ventricular ejection fraction (RVEF) values, measured in echocardiogram (at screening visit and at 24 weeks).
measure: Change in brain natriuretic peptide (BNP) values
time frame: 24 weeks
description: Change in plasma BNP (or proNT-BNP) levels from baseline at 24 weeks.
measure: Change in quality of life scores
time frame: 24 weeks
description: Change in Quality of Life (QoL) scores from baseline at 24 weeks.
measure: Plasma proteome measures
time frame: 24 weeks
description: Change in plasma proteome from baseline at 24 weeks.
arm group label: Treatment
arm group type: Experimental
description: Open label; Imatinib tablets administered once daily; Dosage: in the range of 100mg-400mg; Group evaluated: adults with PAH
intervention type: Drug
intervention name: Imatinib Mesylate
description: Treatment with Imatinib
arm group label: Treatment
other name: Oral treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Martin R Wilkins, MD, FRCP
role: Study Director
affiliation: Imperial College London
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Pulmonary Arterial Hypertension
mesh term: Familial Primary Pulmonary Hypertension
mesh term: Hypertension
mesh term: Imatinib Mesylate