<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/NCT03809156</url>
  </required_header>
  <id_info>
    <org_study_id>15-3056</org_study_id>
    <nct_id>NCT03809156</nct_id>
  </id_info>
  <brief_title>Upfront Combination Pulmonary Arterial Hypertension Therapy</brief_title>
  <official_title>Upfront Riociguat and Ambrisentan Combination Therapy for Pulmonary Arterial Hypertension: A Safety and Efficacy Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Calgary</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bayer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Calgary</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>
      To evaluate the safety and efficacy of first-line combination therapy using riociguat with&#xD;
      ambrisentan in patients with Pulmonary Arterial Hypertension (PAH).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a prospective, multi-center, open-label, exploratory study with patients followed for&#xD;
      a period of one year. The treatment duration period in this study begins at the initiation of&#xD;
      ambrisentan plus riociguat and will continue for 12 months. Patients will come to clinic for&#xD;
      a visit at month 4 and 12. Assessments will include Right Heart Catheterization, 6 Minute&#xD;
      walk test, cardiac MRI, questionnaires and nt-Pro-BNP.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">April 26, 2016</start_date>
  <completion_date type="Anticipated">January 31, 2021</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2020</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>Pulmonary Vascular resistance</measure>
    <time_frame>4 and 12 months</time_frame>
    <description>Change from baseline to month 4 and month 12 in pulmonary vascular resistance (PVR) as assessed by Right Heart Catheterization.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Hemodynamic Variables</measure>
    <time_frame>4 and 12 months</time_frame>
    <description>Change in hemodynamic variables (mPAP, RAP, CI) from baseline to month 4 and month 12 as assessed by Right Heart Catheterization.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Echocardiographic parameters</measure>
    <time_frame>4 and 12 months</time_frame>
    <description>Change in echocardiographic parameters (TAPSE, RV strain, Tei index, Left ventricular Eccentricity index, RV:LV area ratio) as assessed by Echocardiogram.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>RV function</measure>
    <time_frame>4 and 12 months</time_frame>
    <description>Change from baseline to month 4 in RV function as assessed by cardiac MRI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NT-PRo-BNP</measure>
    <time_frame>4 and 12 Months</time_frame>
    <description>Change from baseline NT-PRo-BNP value from baseline to month 4 and month 12</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exercise capacity</measure>
    <time_frame>4 and 12 months</time_frame>
    <description>Change from baseline to month 4 and month 12 in exercise capacity assessed by the 6 minute walk test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dyspnea</measure>
    <time_frame>4 and 12 months</time_frame>
    <description>Change from baseline to month 4 and month 12 in dyspnea as assessed by study questionnaire.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life Assessment</measure>
    <time_frame>4 and 12 months</time_frame>
    <description>Change from baseline to month 4 and month 12 in quality of life as assessed by study questionnaire.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional Class</measure>
    <time_frame>4 and 12 months</time_frame>
    <description>Change from baseline to month 4 and month 12 in functional class as assessed by study questionnaire.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Survival</measure>
    <time_frame>12 months</time_frame>
    <description>Survival at 12 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical worsening</measure>
    <time_frame>12 months</time_frame>
    <description>Time to clinical worsening over 12 months</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Pulmonary Hypertension</condition>
  <arm_group>
    <arm_group_label>Combo Riociguat and Ambrisentan Therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Riociguat Oral Product and Ambrisentan Oral Product to be given in combination to de novo (untreated) patients.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Riociguat Oral Product</intervention_name>
    <description>Dual therapy of Riociguat and Ambrisentan at initiation of treatment.</description>
    <arm_group_label>Combo Riociguat and Ambrisentan Therapy</arm_group_label>
    <other_name>Ambrisentan Oral Product</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signed informed consent prior to initiation of any study mandated procedure;&#xD;
&#xD;
          2. Males or females ≥ 18 years of age i. Women of childbearing potential must have a&#xD;
             negative pre-treatment pregnancy test and must use reliable methods of contraception.&#xD;
&#xD;
             ii. Women not of childbearing potential are defined as postmenopausal (i.e.,&#xD;
             amenorrhea for at least 1 year), or documented surgically or naturally sterile.&#xD;
&#xD;
          3. Patients with symptomatic Functional Class III PAH in the following categories:&#xD;
&#xD;
             i. Idiopathic (IPAH) ii. Familial (FPAH) iii. Associated with connective tissue&#xD;
             disease iv. Associated with drugs or toxins;&#xD;
&#xD;
          4. PAH diagnosed by right heart catheterization, defined as:&#xD;
&#xD;
             i. Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg ii. PVR &gt; 3 mmHg/l/min (Wood&#xD;
             units) or &gt; 240 dyn sec cm-5 iii. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg;&#xD;
&#xD;
          5. 150 m ≤ 6 Minute Walk Test (6MWT) distance ≤ 480 m&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. PAH associated with any other condition than those described in the inclusion criteria&#xD;
             (patients with PAH associated with portal hypertension, HIV and CHD should not be&#xD;
             included);&#xD;
&#xD;
          2. PAH associated with thyroid disorders, glycogen storage disease, Gaucher disease,&#xD;
             hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative&#xD;
             disorders and splenectomy;&#xD;
&#xD;
          3. Valvular disease with valvular lesions to be excluded by echocardiogram within 2 years&#xD;
             prior to randomization (i.e., patients with tricuspid or pulmonary insufficiency&#xD;
             secondary to PAH can be included);&#xD;
&#xD;
          4. Restrictive lung disease: total lung capacity (TLC) &lt; 60% of normal predicted value;&#xD;
&#xD;
          5. Obstructive lung disease: forced expiratory volume/forced vital capacity (FEV1/FVC) &lt;&#xD;
             0.5;&#xD;
&#xD;
          6. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C;&#xD;
&#xD;
          7. Pregnancy or breast-feeding;&#xD;
&#xD;
          8. Systolic blood pressure &lt; 95 mmHg;&#xD;
&#xD;
          9. Body weight &lt; 40 kg;&#xD;
&#xD;
         10. Hemoglobin &gt; 25% below the lower limit of the normal range;&#xD;
&#xD;
         11. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) &gt; 1.5 times the&#xD;
             upper limit of normal ranges;&#xD;
&#xD;
         12. Renal insufficiency as defined by creatinine clearance &lt; 30 mL/min or on dialysis&#xD;
&#xD;
         13. Treatment with phosphodiesterase type 5 inhibitors, any prostanoid (excluding acute&#xD;
             administration during a catheterization procedure to test vascular reactivity) or with&#xD;
             any other PH specific medication;&#xD;
&#xD;
         14. Treatment or planned treatment with calcineurin-inhibitors (i.e., cyclosporine A and&#xD;
             tacrolimus), CYP2C9 and CYP3A4 inhibitors (i.e., ketoconazole, fluconazole) within 1&#xD;
             week of study start;&#xD;
&#xD;
         15. Treatment or planned treatment with nitrate drugs, short acting nitrate-containing&#xD;
             medications, alpha blockers or protease inhibitors (i.e., ritonavir);&#xD;
&#xD;
         16. Known hypersensitivity to ambrisentan, riociguat or any of their excipients;&#xD;
&#xD;
         17. Patients with any contraindication to riociguat treatment or ERA treatment&#xD;
&#xD;
         18. Patients with syncope, a rapid rate of symptom progression or with high or rising&#xD;
             nt-BNP levels in the judgment of the investigators&#xD;
&#xD;
         19. Any contraindications specified in the product monographs of either ambrisentan or&#xD;
             riociguat, including:&#xD;
&#xD;
        1. Patients at increased risk of hypotension with concomitant or underlying conditions such&#xD;
        as coronary artery disease, hypovolemia, severe left ventricular outflow obstruction or&#xD;
        autonomic dysfunction; patients with resting hypotension 2. Patients with history of&#xD;
        serious hemoptysis or patients who have previously undergone bronchial arterial&#xD;
        embolization 20. Patients with pulmonary veno-occlusive disease 21. Ongoing participation&#xD;
        in any interventional clinical studies.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Naushad Hirani, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Calgary</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Naushad Hirani, MD</last_name>
    <phone>403 943 4759</phone>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Jean Marks, BN</last_name>
    <phone>(403) 943 4759</phone>
    <email>jean.marks@ahs.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Peter Lougheed Center</name>
      <address>
        <city>Calgary</city>
        <state>Alberta</state>
        <zip>T1Y 6J4</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Naushad Hirani, MD</last_name>
      <phone>403 943 4759</phone>
    </contact>
  </location>
  <location>
    <facility>
      <name>Vancouver General Hospital, The Lung Centre</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <zip>V5Z 1M9</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>John Swiston, MD</last_name>
      <phone>(604) 875 4122</phone>
      <email>swiston@mail.ubc.ca</email>
    </contact>
    <contact_backup>
      <last_name>Mami Okada</last_name>
      <phone>(604) 875 4111</phone>
      <phone_ext>69831</phone_ext>
      <email>mami.okada@vch.ca</email>
    </contact_backup>
    <investigator>
      <last_name>John Swiston, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>January 9, 2019</study_first_submitted>
  <study_first_submitted_qc>January 15, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 18, 2019</study_first_posted>
  <last_update_submitted>March 24, 2020</last_update_submitted>
  <last_update_submitted_qc>March 24, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 26, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pulmonary Hypertension</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension, Pulmonary</mesh_term>
    <mesh_term>Pulmonary Arterial 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>Ambrisentan</mesh_term>
    <mesh_term>Riociguat</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03809156
org study id: 15-3056
nct id: NCT03809156
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
To evaluate the safety and efficacy of first-line combination therapy using riociguat with
      ambrisentan in patients with Pulmonary Arterial Hypertension (PAH).
This is a prospective, multi-center, open-label, exploratory study with patients followed for
      a period of one year. The treatment duration period in this study begins at the initiation of
      ambrisentan plus riociguat and will continue for 12 months. Patients will come to clinic for
      a visit at month 4 and 12. Assessments will include Right Heart Catheterization, 6 Minute
      walk test, cardiac MRI, questionnaires and nt-Pro-BNP.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Pulmonary Vascular resistance
time frame: 4 and 12 months
description: Change from baseline to month 4 and month 12 in pulmonary vascular resistance (PVR) as assessed by Right Heart Catheterization.
measure: Hemodynamic Variables
time frame: 4 and 12 months
description: Change in hemodynamic variables (mPAP, RAP, CI) from baseline to month 4 and month 12 as assessed by Right Heart Catheterization.
measure: Echocardiographic parameters
time frame: 4 and 12 months
description: Change in echocardiographic parameters (TAPSE, RV strain, Tei index, Left ventricular Eccentricity index, RV:LV area ratio) as assessed by Echocardiogram.
measure: RV function
time frame: 4 and 12 months
description: Change from baseline to month 4 in RV function as assessed by cardiac MRI.
measure: NT-PRo-BNP
time frame: 4 and 12 Months
description: Change from baseline NT-PRo-BNP value from baseline to month 4 and month 12
measure: Exercise capacity
time frame: 4 and 12 months
description: Change from baseline to month 4 and month 12 in exercise capacity assessed by the 6 minute walk test
measure: Dyspnea
time frame: 4 and 12 months
description: Change from baseline to month 4 and month 12 in dyspnea as assessed by study questionnaire.
measure: Quality of Life Assessment
time frame: 4 and 12 months
description: Change from baseline to month 4 and month 12 in quality of life as assessed by study questionnaire.
measure: Functional Class
time frame: 4 and 12 months
description: Change from baseline to month 4 and month 12 in functional class as assessed by study questionnaire.
measure: Survival
time frame: 12 months
description: Survival at 12 months
measure: Clinical worsening
time frame: 12 months
description: Time to clinical worsening over 12 months
arm group label: Combo Riociguat and Ambrisentan Therapy
arm group type: Experimental
description: Riociguat Oral Product and Ambrisentan Oral Product to be given in combination to de novo (untreated) patients.
intervention type: Drug
intervention name: Riociguat Oral Product
description: Dual therapy of Riociguat and Ambrisentan at initiation of treatment.
arm group label: Combo Riociguat and Ambrisentan Therapy
other name: Ambrisentan Oral Product
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Naushad Hirani, MD
role: Principal Investigator
affiliation: University of Calgary
last name: Naushad Hirani, MD
phone: 403 943 4759
last name: Jean Marks, BN
phone: (403) 943 4759
email: jean.marks@ahs.ca
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: Canada
responsible party type: Sponsor
mesh term: Hypertension, Pulmonary
mesh term: Pulmonary Arterial Hypertension
mesh term: Hypertension
mesh term: Ambrisentan
mesh term: Riociguat
sharing ipd: No