<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/NCT03273257</url>
  </required_header>
  <id_info>
    <org_study_id>PEA Bridging Study</org_study_id>
    <nct_id>NCT03273257</nct_id>
  </id_info>
  <brief_title>Riociguat in Patients With Operable CTEPH Prior to Pulmonary Endarterectomy (PEA Bridging Study)</brief_title>
  <official_title>A Phase 2, Randomised, Double-Blind, Placebo-Controlled, Multicentre, Prospective Study to Assess Efficacy of Riociguat in Patients With Operable CTEPH Prior to Pulmonary Endarterectomy With High Preoperative Pulmonary Vascular Resistance</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>International CTEPH Association</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>International CTEPH Association</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomised, double-blind, placebo-controlled, multicentre, multinational,&#xD;
      prospective study in patients with operable chronic thromboembolic pulmonary hypertension&#xD;
      (CTEPH) prior to pulmonary endarterectomy (PEA) with high preoperative pulmonary vascular&#xD;
      resistance (PVR). Patients will be randomised in a 1:1 ratio to receive riociguat or matching&#xD;
      placebo for 3 months before undergoing PEA. The primary objective of this study is to assess&#xD;
      the efficacy of riociguat on preoperative PVR compared to placebo in patients with operable&#xD;
      CTEPH.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    The study was stopped due to slower than expected recruitment and the additional limitations on&#xD;
    clinical research imposed by the COVID-19 pandemic, both of which made study completion within&#xD;
    a reasonable timeframe appear unlikely.&#xD;
  </why_stopped>
  <start_date type="Actual">August 17, 2018</start_date>
  <completion_date type="Actual">May 5, 2020</completion_date>
  <primary_completion_date type="Actual">May 5, 2020</primary_completion_date>
  <phase>Phase 2</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>Double (Participant, Investigator)</masking>
    <masking_description>Double-blind</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change From Baseline in Pulmonary Vascular Resistance (PVR) to Immediately Before Pulmonary Endarterectomy (Pre-PEA)</measure>
    <time_frame>90 days</time_frame>
    <description>Pulmonary vascular resistance (PVR) will be assessed at baseline and immediately before pulmonary endarterectomy. The change in PVR will be assessed as percentage.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Pulmonary Vascular Resistance (PVR) to 6 Months Post Pulmonary Endarterectomy (PEA)</measure>
    <time_frame>270 days</time_frame>
    <description>Pulmonary vascular resistance (PVR) will be assessed at baseline and 6 months post pulmonary endarterectomy (PEA). The change in PVR will be assessed as percentage.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Patients With Either All-cause Death, PH-related Hospitalization, Need for PAH-targeted Therapy or WHO Functional Class Unchanged or Worse Between Randomization and 6 Months Post Pulmonary Endarterectomy (Composite Endpoint)</measure>
    <time_frame>270 days</time_frame>
    <description>All deaths occurring post-randomization until the last visit will be included. All PH-related hospitalizations except the in-hospital care during and after pulmonary endarterectomy (PEA) from randomization until 6 months after PEA will be included.&#xD;
The worst value for World Health Organization (WHO) functional class after treatment will be used.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intraoperative Circulatory Arrest Time</measure>
    <time_frame>intraoperative</time_frame>
    <description>Circulatory arrest time will be measured in minutes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Patients With Intraoperative Surgery-related Complications (Composite Endpoint)</measure>
    <time_frame>intraoperative</time_frame>
    <description>The occurrence of any of the following complications will be assessed:&#xD;
Bleeding and/or blood loss &gt;1 L in 12 hours&#xD;
Airway bleed with need for extracorporeal membrane oxygenation&#xD;
Any use of extracorporeal membrane oxygenation for respiratory or hemodynamic support, specified as veno-venous or veno-arterial&#xD;
Prolonged ventilation &gt;96 hours&#xD;
Need for tracheostomy&#xD;
Need for drainage of pericardial effusion&#xD;
Neurological complications, ie, stroke, cerebral, subdural bleeding&#xD;
Reintubation or noninvasive ventilation for reperfusion response&#xD;
Hemoptysis requiring any intervention&#xD;
Renal failure requiring dialysis&#xD;
Wound infections&#xD;
Pneumonia&#xD;
Prolonged need for inotropic support (≥ 5 days)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Surgical Evaluation of Specimen: Stratification of Patients According to Ease of Dissection Plane</measure>
    <time_frame>intraoperative</time_frame>
    <description>Classed as easier than normal (1); normal (2); more difficult than normal (3)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Surgical Evaluation of Specimen: Stratification of Patients According to Completeness of Disease Clearance</measure>
    <time_frame>intraoperative</time_frame>
    <description>Classed as better than expected (1); as expected (2); worse than expected (3)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Surgical Evaluation of Specimen: Stratification of Patients According to Appearance of Clot and Vessel Wall</measure>
    <time_frame>intraoperative</time_frame>
    <description>Classed as more solid than usual (1); normal (2); more friable than usual (3)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Patients Who Died During the Course of the Study</measure>
    <time_frame>270 days</time_frame>
    <description>All deaths occurring during the whole course of the study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patients Who Withdraw During the Randomized Treatment Phase</measure>
    <time_frame>90 days</time_frame>
    <description>Only withdrawals after randomization but before PEA will be included</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in NT-proBNP From Baseline Until the End of Medical Treatment</measure>
    <time_frame>90 days</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in NT-proBNP From Baseline Until 6 Months Post-surgery</measure>
    <time_frame>270 days</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in Cardiac Index From Baseline Until the End of Medical Treatment</measure>
    <time_frame>90 days</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in Cardiac Index From Baseline Until 6 Months Post-surgery</measure>
    <time_frame>270 days</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in Mean Right Atrial Pressure From Baseline Until the End of Medical Treatment</measure>
    <time_frame>90 days</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in Mean Right Atrial Pressure From Baseline Until 6 Months Post-surgery</measure>
    <time_frame>270 days</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in Mean Pulmonary Atrial Pressure From Baseline Until the End of Medical Treatment</measure>
    <time_frame>90 days</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in Mean Pulmonary Atrial Pressure From Baseline Until 6 Months Post-surgery</measure>
    <time_frame>270 days</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in Pulmonary Artery Wedge Pressure From Baseline Until the End of Medical Treatment</measure>
    <time_frame>90 days</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in Pulmonary Artery Wedge Pressure From Baseline Until 6 Months Post-surgery</measure>
    <time_frame>270 days</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <other_outcome>
    <measure>Length of Hospital Stay for Pulmonary Endarterectomy</measure>
    <time_frame>intraoperative</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <other_outcome>
    <measure>Length of Intensive Care Unit Stay for Pulmonary Endarterectomy</measure>
    <time_frame>intraoperative</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <other_outcome>
    <measure>WHO Functional Class at the End of Medical Treatment</measure>
    <time_frame>90 days</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <other_outcome>
    <measure>WHO Functional Class 6 Months Post Pulmonary Endarterectomy</measure>
    <time_frame>270 days</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <other_outcome>
    <measure>Need for PAH-targeted Therapy 6 Months Post-surgery</measure>
    <time_frame>270 days</time_frame>
    <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Chronic Thromboembolic Pulmonary Hypertension</condition>
  <condition>CTEPH</condition>
  <arm_group>
    <arm_group_label>Riociguat</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients will receive placebo for 3 months followed by pulmonary endarterectomy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Riociguat</intervention_name>
    <description>Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.&#xD;
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.</description>
    <arm_group_label>Riociguat</arm_group_label>
    <other_name>Adempas</other_name>
    <other_name>BAY 63-2521</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo will be given analogue to riociguat with matching tablets.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Pulmonary endarterectomy</intervention_name>
    <description>PEA will be performed at the end of medical treatment (Day 90)</description>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_label>Riociguat</arm_group_label>
    <other_name>PEA</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Is a male or nonpregnant and nonlactating female patient aged from 18 to 80 years,&#xD;
             both inclusive&#xD;
&#xD;
          -  Is diagnosed with operable CTEPH and anticipating symptomatic and/or prognostic&#xD;
             benefit from PEA&#xD;
&#xD;
          -  Has pulmonary vascular resistance (PVR) &gt;800 dyn·s·cm-5&#xD;
&#xD;
          -  Has undergone right heart catheterisation not more than 180 days before randomisation&#xD;
             visit&#xD;
&#xD;
          -  Has been treated with anticoagulants for at least 90 days before randomisation visit&#xD;
&#xD;
          -  Has ability to swallow oral medication&#xD;
&#xD;
          -  Has ability and willingness to participate and access the health facility&#xD;
&#xD;
          -  Is capable of understanding the written informed consent and provides signed and&#xD;
             witnessed written informed consent&#xD;
&#xD;
          -  Female patient must be either surgically sterile, postmenopausal (no menses for the&#xD;
             previous 12 months), or must be practicing an effective method of birth control as&#xD;
             determined by the investigator (eg, oral contraceptives, double barrier methods,&#xD;
             hormonal injectable or implanted contraceptives, tubal ligation, or male partner with&#xD;
             vasectomy or complete abstinence)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Has unstable disease in need of urgent PEA surgery as determined by the treating&#xD;
             physician&#xD;
&#xD;
          -  Has known hypersensitivity, allergic, or adverse reactions to riociguat or any of the&#xD;
             excipients comprising riociguat tablets.&#xD;
&#xD;
          -  Has known active hepatitis A IgM (HAV-IgM), hepatitis B surface antigen (HBsAg), or&#xD;
             hepatitis C antibody (HCV Ab)&#xD;
&#xD;
          -  Is human immunodeficiency virus positive&#xD;
&#xD;
          -  Has pulmonary veno-occlusive disease&#xD;
&#xD;
          -  Has symptomatic hypotension&#xD;
&#xD;
          -  Has symptomatic carotid disease&#xD;
&#xD;
          -  Has significant coronary atherosclerotic disease in need of intervention&#xD;
&#xD;
          -  Has severe left heart disease in need of intervention&#xD;
&#xD;
          -  Has redo sternotomy&#xD;
&#xD;
          -  Has received any background therapy for pulmonary arterial hypertension (PAH) in the&#xD;
             preceding 30 days before randomisation visit including endothelin receptor antagonists&#xD;
             (ERAs), phosphodiesterase 5 (PDE5) inhibitors, or prostanoids&#xD;
&#xD;
          -  Is receiving nitrates, nitric oxide donors (e.g. amyl nitrite), ERAs, prostanoids,&#xD;
             specific PDE5 inhibitors, nonspecific phosphodiesterase inhibitors (e.g. dipyridamole,&#xD;
             theophylline)&#xD;
&#xD;
          -  Is receiving strong cytochrome P450 (CYP) and P-glycoprotein/breast cancer resistance&#xD;
             protein inhibitors&#xD;
&#xD;
          -  Is receiving strong CYP3A inducers&#xD;
&#xD;
          -  Has creatinine clearance &lt;15 mL/min or on any form of dialysis&#xD;
&#xD;
          -  Has severe hepatic impairment classified as Child-Pugh C&#xD;
&#xD;
          -  Has received an investigational drug within the past 4 weeks before randomisation&#xD;
             visit&#xD;
&#xD;
          -  Is a lactating or pregnant (as demonstrated by a serum pregnancy test) woman, and not&#xD;
             willing to take measures for not to become pregnant during the 3 months treatment&#xD;
             study period and one month after the last dose of study drug administered&#xD;
&#xD;
          -  Has smoked or used tobacco in any form, including snuff or chewing within 3 months&#xD;
             prior to randomisation visit&#xD;
&#xD;
          -  Has idiopathic interstitial pneumonitis&#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>David Jenkins, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Papworth Hospital NHS Foundation Trust, Cambridge, UK</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UC San Diego</name>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92037-7892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital de Bicêtre</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kerckhoff-Klinik GmbH</name>
      <address>
        <city>Bad Nauheim</city>
        <zip>61231</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Papworth Hospital</name>
      <address>
        <city>Cambridge</city>
        <zip>CB3 8RE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
    <country>Germany</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.cteph-association.org/</url>
    <description>Website of the International CTEPH Association</description>
  </link>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>August 25, 2017</study_first_submitted>
  <study_first_submitted_qc>September 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 6, 2017</study_first_posted>
  <results_first_submitted>May 5, 2021</results_first_submitted>
  <results_first_submitted_qc>May 31, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">June 22, 2021</results_first_posted>
  <last_update_submitted>May 31, 2021</last_update_submitted>
  <last_update_submitted_qc>May 31, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pulmonary endarterectomy</keyword>
  <keyword>PEA</keyword>
  <keyword>Medical therapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension, Pulmonary</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Riociguat</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>IPD sharing is not foreseen</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 26, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/57/NCT03273257/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 14, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/57/NCT03273257/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Eligible patients were recruited at 3 expert centers for CTEPH in France, Germany and the UK between August 2018 and May 2020.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Riociguat</title>
          <description>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.&#xD;
Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.&#xD;
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Patients will receive placebo for 3 months followed by pulmonary endarterectomy.&#xD;
Placebo will be given analogue to riociguat with matching tablets.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Started Treatment</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="6">Only 6 patients from the placebo group started treatment because 1 patient died after randomization (= study start), but before initiating treatment</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>Underwent PEA</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Inability to schedule PEA according to the protocol due to the COVID pandemic</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Study terminated</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>All participants who received at least one dose of randomized study drug</population>
      <group_list>
        <group group_id="B1">
          <title>Riociguat</title>
          <description>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.&#xD;
Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.&#xD;
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Patients will receive placebo for 3 months followed by pulmonary endarterectomy.&#xD;
Placebo will be given analogue to riociguat with matching tablets.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</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="7"/>
            <count group_id="B2" value="6"/>
            <count group_id="B3" value="13"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="66" lower_limit="48" upper_limit="75"/>
                    <measurement group_id="B2" value="67" lower_limit="52" upper_limit="74"/>
                    <measurement group_id="B3" value="66" lower_limit="48" upper_limit="75"/>
                  </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="4"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body mass index</title>
          <units>kg/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="31.2" spread="3.9"/>
                    <measurement group_id="B2" value="25.4" spread="1.7"/>
                    <measurement group_id="B3" value="28.8" spread="4.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>PVR at diagnosis</title>
          <units>dyn*sec/cm^5</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="944.0" spread="92.7"/>
                    <measurement group_id="B2" value="1007.5" spread="368.2"/>
                    <measurement group_id="B3" value="973.3" spread="248.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Mean pulmonary arterial pressure (mPAP) at diagnosis</title>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="50.3" spread="8.4"/>
                    <measurement group_id="B2" value="53.2" spread="4.8"/>
                    <measurement group_id="B3" value="51.5" spread="7.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Received beta blockers between enrollment and PEA</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Received vitamin K antagonists between enrollment and PEA</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Received new/direct oral anticoagulants between enrollment and PEA</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in Pulmonary Vascular Resistance (PVR) to Immediately Before Pulmonary Endarterectomy (Pre-PEA)</title>
        <description>Pulmonary vascular resistance (PVR) will be assessed at baseline and immediately before pulmonary endarterectomy. The change in PVR will be assessed as percentage.</description>
        <time_frame>90 days</time_frame>
        <population>All participants who received at least one dose of randomized study drug and underwent PEA before study termination</population>
        <group_list>
          <group group_id="O1">
            <title>Riociguat</title>
            <description>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.&#xD;
Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.&#xD;
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Patients will receive placebo for 3 months followed by pulmonary endarterectomy.&#xD;
Placebo will be given analogue to riociguat with matching tablets.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Pulmonary Vascular Resistance (PVR) to Immediately Before Pulmonary Endarterectomy (Pre-PEA)</title>
          <description>Pulmonary vascular resistance (PVR) will be assessed at baseline and immediately before pulmonary endarterectomy. The change in PVR will be assessed as percentage.</description>
          <population>All participants who received at least one dose of randomized study drug and underwent PEA before study termination</population>
          <units>percentage of baseline PVR</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-28.4" spread="16.2"/>
                    <measurement group_id="O2" value="-6.9" spread="27.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis is that there is no difference between the treatment groups in percent change from baseline in PVR immediately before PEA.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.139</p_value>
            <method>2-sample Wilcoxon rank sum test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Pulmonary Vascular Resistance (PVR) to 6 Months Post Pulmonary Endarterectomy (PEA)</title>
        <description>Pulmonary vascular resistance (PVR) will be assessed at baseline and 6 months post pulmonary endarterectomy (PEA). The change in PVR will be assessed as percentage.</description>
        <time_frame>270 days</time_frame>
        <population>All participants who received at least one dose of randomized study drug and completed the study prior to study termination</population>
        <group_list>
          <group group_id="O1">
            <title>Riociguat</title>
            <description>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.&#xD;
Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.&#xD;
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Patients will receive placebo for 3 months followed by pulmonary endarterectomy.&#xD;
Placebo will be given analogue to riociguat with matching tablets.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Pulmonary Vascular Resistance (PVR) to 6 Months Post Pulmonary Endarterectomy (PEA)</title>
          <description>Pulmonary vascular resistance (PVR) will be assessed at baseline and 6 months post pulmonary endarterectomy (PEA). The change in PVR will be assessed as percentage.</description>
          <population>All participants who received at least one dose of randomized study drug and completed the study prior to study termination</population>
          <units>percentage of baseline PVR</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-68.1" spread="9.8"/>
                    <measurement group_id="O2" value="-83.0" spread="2.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients With Either All-cause Death, PH-related Hospitalization, Need for PAH-targeted Therapy or WHO Functional Class Unchanged or Worse Between Randomization and 6 Months Post Pulmonary Endarterectomy (Composite Endpoint)</title>
        <description>All deaths occurring post-randomization until the last visit will be included. All PH-related hospitalizations except the in-hospital care during and after pulmonary endarterectomy (PEA) from randomization until 6 months after PEA will be included.&#xD;
The worst value for World Health Organization (WHO) functional class after treatment will be used.</description>
        <time_frame>270 days</time_frame>
        <population>All participants who underwent PEA before study termination</population>
        <group_list>
          <group group_id="O1">
            <title>Riociguat</title>
            <description>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.&#xD;
Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.&#xD;
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Patients will receive placebo for 3 months followed by pulmonary endarterectomy.&#xD;
Placebo will be given analogue to riociguat with matching tablets.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients With Either All-cause Death, PH-related Hospitalization, Need for PAH-targeted Therapy or WHO Functional Class Unchanged or Worse Between Randomization and 6 Months Post Pulmonary Endarterectomy (Composite Endpoint)</title>
          <description>All deaths occurring post-randomization until the last visit will be included. All PH-related hospitalizations except the in-hospital care during and after pulmonary endarterectomy (PEA) from randomization until 6 months after PEA will be included.&#xD;
The worst value for World Health Organization (WHO) functional class after treatment will be used.</description>
          <population>All participants who underwent PEA before study termination</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Intraoperative Circulatory Arrest Time</title>
        <description>Circulatory arrest time will be measured in minutes</description>
        <time_frame>intraoperative</time_frame>
        <population>All participants who underwent PEA before study termination</population>
        <group_list>
          <group group_id="O1">
            <title>Riociguat</title>
            <description>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.&#xD;
Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.&#xD;
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Patients will receive placebo for 3 months followed by pulmonary endarterectomy.&#xD;
Placebo will be given analogue to riociguat with matching tablets.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
        </group_list>
        <measure>
          <title>Intraoperative Circulatory Arrest Time</title>
          <description>Circulatory arrest time will be measured in minutes</description>
          <population>All participants who underwent PEA before study termination</population>
          <units>minutes</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32" spread="9"/>
                    <measurement group_id="O2" value="40" spread="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients With Intraoperative Surgery-related Complications (Composite Endpoint)</title>
        <description>The occurrence of any of the following complications will be assessed:&#xD;
Bleeding and/or blood loss &gt;1 L in 12 hours&#xD;
Airway bleed with need for extracorporeal membrane oxygenation&#xD;
Any use of extracorporeal membrane oxygenation for respiratory or hemodynamic support, specified as veno-venous or veno-arterial&#xD;
Prolonged ventilation &gt;96 hours&#xD;
Need for tracheostomy&#xD;
Need for drainage of pericardial effusion&#xD;
Neurological complications, ie, stroke, cerebral, subdural bleeding&#xD;
Reintubation or noninvasive ventilation for reperfusion response&#xD;
Hemoptysis requiring any intervention&#xD;
Renal failure requiring dialysis&#xD;
Wound infections&#xD;
Pneumonia&#xD;
Prolonged need for inotropic support (≥ 5 days)</description>
        <time_frame>intraoperative</time_frame>
        <population>All participants who underwent PEA before study termination</population>
        <group_list>
          <group group_id="O1">
            <title>Riociguat</title>
            <description>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.&#xD;
Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.&#xD;
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Patients will receive placebo for 3 months followed by pulmonary endarterectomy.&#xD;
Placebo will be given analogue to riociguat with matching tablets.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients With Intraoperative Surgery-related Complications (Composite Endpoint)</title>
          <description>The occurrence of any of the following complications will be assessed:&#xD;
Bleeding and/or blood loss &gt;1 L in 12 hours&#xD;
Airway bleed with need for extracorporeal membrane oxygenation&#xD;
Any use of extracorporeal membrane oxygenation for respiratory or hemodynamic support, specified as veno-venous or veno-arterial&#xD;
Prolonged ventilation &gt;96 hours&#xD;
Need for tracheostomy&#xD;
Need for drainage of pericardial effusion&#xD;
Neurological complications, ie, stroke, cerebral, subdural bleeding&#xD;
Reintubation or noninvasive ventilation for reperfusion response&#xD;
Hemoptysis requiring any intervention&#xD;
Renal failure requiring dialysis&#xD;
Wound infections&#xD;
Pneumonia&#xD;
Prolonged need for inotropic support (≥ 5 days)</description>
          <population>All participants who underwent PEA before study termination</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Surgical Evaluation of Specimen: Stratification of Patients According to Ease of Dissection Plane</title>
        <description>Classed as easier than normal (1); normal (2); more difficult than normal (3)</description>
        <time_frame>intraoperative</time_frame>
        <population>All participants who underwent PEA</population>
        <group_list>
          <group group_id="O1">
            <title>Riociguat</title>
            <description>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.&#xD;
Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.&#xD;
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Patients will receive placebo for 3 months followed by pulmonary endarterectomy.&#xD;
Placebo will be given analogue to riociguat with matching tablets.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
        </group_list>
        <measure>
          <title>Surgical Evaluation of Specimen: Stratification of Patients According to Ease of Dissection Plane</title>
          <description>Classed as easier than normal (1); normal (2); more difficult than normal (3)</description>
          <population>All participants who underwent PEA</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Easier than normal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Normal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>More difficult than normal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Surgical Evaluation of Specimen: Stratification of Patients According to Completeness of Disease Clearance</title>
        <description>Classed as better than expected (1); as expected (2); worse than expected (3)</description>
        <time_frame>intraoperative</time_frame>
        <population>All participants who underwent PEA before study termination</population>
        <group_list>
          <group group_id="O1">
            <title>Riociguat</title>
            <description>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.&#xD;
Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.&#xD;
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Patients will receive placebo for 3 months followed by pulmonary endarterectomy.&#xD;
Placebo will be given analogue to riociguat with matching tablets.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
        </group_list>
        <measure>
          <title>Surgical Evaluation of Specimen: Stratification of Patients According to Completeness of Disease Clearance</title>
          <description>Classed as better than expected (1); as expected (2); worse than expected (3)</description>
          <population>All participants who underwent PEA before study termination</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Better than expected</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>As expected</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Worse than expected</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Surgical Evaluation of Specimen: Stratification of Patients According to Appearance of Clot and Vessel Wall</title>
        <description>Classed as more solid than usual (1); normal (2); more friable than usual (3)</description>
        <time_frame>intraoperative</time_frame>
        <population>All participants who underwent PEA before study termination</population>
        <group_list>
          <group group_id="O1">
            <title>Riociguat</title>
            <description>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.&#xD;
Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.&#xD;
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Patients will receive placebo for 3 months followed by pulmonary endarterectomy.&#xD;
Placebo will be given analogue to riociguat with matching tablets.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
        </group_list>
        <measure>
          <title>Surgical Evaluation of Specimen: Stratification of Patients According to Appearance of Clot and Vessel Wall</title>
          <description>Classed as more solid than usual (1); normal (2); more friable than usual (3)</description>
          <population>All participants who underwent PEA before study termination</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>More solid than usual</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Normal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>More friable than usual</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients Who Died During the Course of the Study</title>
        <description>All deaths occurring during the whole course of the study</description>
        <time_frame>270 days</time_frame>
        <population>All participants who underwent PEA before study termination</population>
        <group_list>
          <group group_id="O1">
            <title>Riociguat</title>
            <description>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.&#xD;
Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.&#xD;
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Patients will receive placebo for 3 months followed by pulmonary endarterectomy.&#xD;
Placebo will be given analogue to riociguat with matching tablets.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients Who Died During the Course of the Study</title>
          <description>All deaths occurring during the whole course of the study</description>
          <population>All participants who underwent PEA before study termination</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Patients Who Withdraw During the Randomized Treatment Phase</title>
        <description>Only withdrawals after randomization but before PEA will be included</description>
        <time_frame>90 days</time_frame>
        <population>All participants who received at least one dose of randomized study drug</population>
        <group_list>
          <group group_id="O1">
            <title>Riociguat</title>
            <description>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.&#xD;
Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.&#xD;
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Patients will receive placebo for 3 months followed by pulmonary endarterectomy.&#xD;
Placebo will be given analogue to riociguat with matching tablets.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
          </group>
        </group_list>
        <measure>
          <title>Patients Who Withdraw During the Randomized Treatment Phase</title>
          <description>Only withdrawals after randomization but before PEA will be included</description>
          <population>All participants who received at least one dose of randomized study drug</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in NT-proBNP From Baseline Until the End of Medical Treatment</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>90 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in NT-proBNP From Baseline Until 6 Months Post-surgery</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>270 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Cardiac Index From Baseline Until the End of Medical Treatment</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>90 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Cardiac Index From Baseline Until 6 Months Post-surgery</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>270 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Mean Right Atrial Pressure From Baseline Until the End of Medical Treatment</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>90 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Mean Right Atrial Pressure From Baseline Until 6 Months Post-surgery</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>270 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Mean Pulmonary Atrial Pressure From Baseline Until the End of Medical Treatment</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>90 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Mean Pulmonary Atrial Pressure From Baseline Until 6 Months Post-surgery</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>270 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Pulmonary Artery Wedge Pressure From Baseline Until the End of Medical Treatment</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>90 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Pulmonary Artery Wedge Pressure From Baseline Until 6 Months Post-surgery</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>270 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Length of Hospital Stay for Pulmonary Endarterectomy</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>intraoperative</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Length of Intensive Care Unit Stay for Pulmonary Endarterectomy</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>intraoperative</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>WHO Functional Class at the End of Medical Treatment</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>90 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>WHO Functional Class 6 Months Post Pulmonary Endarterectomy</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>270 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Need for PAH-targeted Therapy 6 Months Post-surgery</title>
        <description>Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study</description>
        <time_frame>270 days</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From informed consent until study completion (typically 9-12 months) or early termination</time_frame>
      <desc>Events reported are treatment-emergent adverse events, i.e. any event not present before exposure to study drug or any event already present that worsened in either intensity or frequency after exposure to study drug, in patients who actually received any study drug. Events were identified by investigator assessment at each visit, and from study data. All-cause mortality is reported based on all patients enrolled, including one patient who died prior to initiating treatment.</desc>
      <group_list>
        <group group_id="E1">
          <title>Riociguat</title>
          <description>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.&#xD;
Riociguat will be initiated at 1 mg. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.&#xD;
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Patients will receive placebo for 3 months followed by pulmonary endarterectomy.&#xD;
Placebo will be given analogue to riociguat with matching tablets.&#xD;
PEA will be performed at the end of medical treatment (Day 90)</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 20.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Upper gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Mediastinitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pulmonary hypertension</sub_title>
                <description>Worsening symptoms of CTEPH, including increased NT-proBNP, peripheral oedema and breathlessness</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 20.1</default_vocab>
        <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="7" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Bradycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Cardiac failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Tachyarrhythmia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="4" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Retinal artery occlusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Eructation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Discomfort</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Feeling cold</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Seasonal allergy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lower respiratory tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Post procedural infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Procedural haemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Vaccination complication</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Inflammatory marker increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Weight increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypomagnesaemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dyslipidaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Joint swelling</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Chest wall haematoma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Musculoskeletal chest pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lethargy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Memory impairment</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Sleep disorder</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Anxiety disorder</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Confusional state</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Delirium</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Restlessness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Renal failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Menorrhagia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="4" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dyspnoea exertional</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Rhinorrhoea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Drug therapy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>Both the International CTEPH Association and the financial sponsor can review results communications prior to public release and can embargo communications regarding trial results for up to 180 days from submission for review</restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>The study was terminated after enrolling only 14 out of 88 planned patients, due to slower than expected recruitment and the additional limitations on clinical research imposed by the COVID-19 pandemic. No firm conclusions can be drawn based on the study data due to the limited sample size.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>David Jenkins, MD; Principal Investigator and ICA Board member</name_or_title>
      <organization>Papworth Hospital NHS Foundation Trust</organization>
      <phone>+44 1223 638000</phone>
      <email>david.jenkins1@nhs.net</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/NCT03273257
org study id: PEA Bridging Study
nct id: NCT03273257
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a randomised, double-blind, placebo-controlled, multicentre, multinational,
      prospective study in patients with operable chronic thromboembolic pulmonary hypertension
      (CTEPH) prior to pulmonary endarterectomy (PEA) with high preoperative pulmonary vascular
      resistance (PVR). Patients will be randomised in a 1:1 ratio to receive riociguat or matching
      placebo for 3 months before undergoing PEA. The primary objective of this study is to assess
      the efficacy of riociguat on preoperative PVR compared to placebo in patients with operable
      CTEPH.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: Double-blind
measure: Change From Baseline in Pulmonary Vascular Resistance (PVR) to Immediately Before Pulmonary Endarterectomy (Pre-PEA)
time frame: 90 days
description: Pulmonary vascular resistance (PVR) will be assessed at baseline and immediately before pulmonary endarterectomy. The change in PVR will be assessed as percentage.
measure: Change From Baseline in Pulmonary Vascular Resistance (PVR) to 6 Months Post Pulmonary Endarterectomy (PEA)
time frame: 270 days
description: Pulmonary vascular resistance (PVR) will be assessed at baseline and 6 months post pulmonary endarterectomy (PEA). The change in PVR will be assessed as percentage.
measure: Number of Patients With Either All-cause Death, PH-related Hospitalization, Need for PAH-targeted Therapy or WHO Functional Class Unchanged or Worse Between Randomization and 6 Months Post Pulmonary Endarterectomy (Composite Endpoint)
time frame: 270 days
description: All deaths occurring post-randomization until the last visit will be included. All PH-related hospitalizations except the in-hospital care during and after pulmonary endarterectomy (PEA) from randomization until 6 months after PEA will be included.
The worst value for World Health Organization (WHO) functional class after treatment will be used.
measure: Intraoperative Circulatory Arrest Time
time frame: intraoperative
description: Circulatory arrest time will be measured in minutes
measure: Number of Patients With Intraoperative Surgery-related Complications (Composite Endpoint)
time frame: intraoperative
description: The occurrence of any of the following complications will be assessed:
Bleeding and/or blood loss >1 L in 12 hours
Airway bleed with need for extracorporeal membrane oxygenation
Any use of extracorporeal membrane oxygenation for respiratory or hemodynamic support, specified as veno-venous or veno-arterial
Prolonged ventilation >96 hours
Need for tracheostomy
Need for drainage of pericardial effusion
Neurological complications, ie, stroke, cerebral, subdural bleeding
Reintubation or noninvasive ventilation for reperfusion response
Hemoptysis requiring any intervention
Renal failure requiring dialysis
Wound infections
Pneumonia
Prolonged need for inotropic support (≥ 5 days)
measure: Surgical Evaluation of Specimen: Stratification of Patients According to Ease of Dissection Plane
time frame: intraoperative
description: Classed as easier than normal (1); normal (2); more difficult than normal (3)
measure: Surgical Evaluation of Specimen: Stratification of Patients According to Completeness of Disease Clearance
time frame: intraoperative
description: Classed as better than expected (1); as expected (2); worse than expected (3)
measure: Surgical Evaluation of Specimen: Stratification of Patients According to Appearance of Clot and Vessel Wall
time frame: intraoperative
description: Classed as more solid than usual (1); normal (2); more friable than usual (3)
measure: Number of Patients Who Died During the Course of the Study
time frame: 270 days
description: All deaths occurring during the whole course of the study
measure: Patients Who Withdraw During the Randomized Treatment Phase
time frame: 90 days
description: Only withdrawals after randomization but before PEA will be included
measure: Change in NT-proBNP From Baseline Until the End of Medical Treatment
time frame: 90 days
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
measure: Change in NT-proBNP From Baseline Until 6 Months Post-surgery
time frame: 270 days
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
measure: Change in Cardiac Index From Baseline Until the End of Medical Treatment
time frame: 90 days
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
measure: Change in Cardiac Index From Baseline Until 6 Months Post-surgery
time frame: 270 days
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
measure: Change in Mean Right Atrial Pressure From Baseline Until the End of Medical Treatment
time frame: 90 days
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
measure: Change in Mean Right Atrial Pressure From Baseline Until 6 Months Post-surgery
time frame: 270 days
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
measure: Change in Mean Pulmonary Atrial Pressure From Baseline Until the End of Medical Treatment
time frame: 90 days
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
measure: Change in Mean Pulmonary Atrial Pressure From Baseline Until 6 Months Post-surgery
time frame: 270 days
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
measure: Change in Pulmonary Artery Wedge Pressure From Baseline Until the End of Medical Treatment
time frame: 90 days
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
measure: Change in Pulmonary Artery Wedge Pressure From Baseline Until 6 Months Post-surgery
time frame: 270 days
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
measure: Length of Hospital Stay for Pulmonary Endarterectomy
time frame: intraoperative
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
measure: Length of Intensive Care Unit Stay for Pulmonary Endarterectomy
time frame: intraoperative
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
measure: WHO Functional Class at the End of Medical Treatment
time frame: 90 days
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
measure: WHO Functional Class 6 Months Post Pulmonary Endarterectomy
time frame: 270 days
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
measure: Need for PAH-targeted Therapy 6 Months Post-surgery
time frame: 270 days
description: Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
arm group label: Riociguat
arm group type: Active Comparator
description: Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.
arm group label: Placebo
arm group type: Placebo Comparator
description: Patients will receive placebo for 3 months followed by pulmonary endarterectomy.
intervention type: Drug
intervention name: Riociguat
description: Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid.
Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.
arm group label: Riociguat
other name: Adempas
other name: BAY 63-2521
intervention type: Drug
intervention name: Placebo
description: Placebo will be given analogue to riociguat with matching tablets.
arm group label: Placebo
intervention type: Procedure
intervention name: Pulmonary endarterectomy
description: PEA will be performed at the end of medical treatment (Day 90)
arm group label: Placebo
arm group label: Riociguat
other name: PEA
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: David Jenkins, MD
role: Principal Investigator
affiliation: Papworth Hospital NHS Foundation Trust, Cambridge, UK
facility: 
facility: 
facility: 
facility: 
country: France
country: Germany
country: United Kingdom
country: United States
url: https://www.cteph-association.org/
description: Website of the International CTEPH Association
responsible party type: Sponsor
mesh term: Hypertension, Pulmonary
mesh term: Riociguat
sharing ipd: No
ipd description: IPD sharing is not foreseen
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: The study was terminated after enrolling only 14 out of 88 planned patients, due to slower than expected recruitment and the additional limitations on clinical research imposed by the COVID-19 pandemic. No firm conclusions can be drawn based on the study data due to the limited sample size.
point of contact: 