<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/NCT03809650</url>
  </required_header>
  <id_info>
    <org_study_id>AC-055E301</org_study_id>
    <nct_id>NCT03809650</nct_id>
  </id_info>
  <brief_title>A Clinical Study to Find Out if Macitentan is Effective and Safe in Japanese Patients With Chronic Thromboembolic Pulmonary Hypertension (CTEPH).</brief_title>
  <official_title>A Prospective, Multicenter, Open-label, Single Arm, Phase III Study to Assess the Efficacy and Safety of Macitentan (ACT-064992) in Subjects With Chronic Thromboembolic Pulmonary Hypertension (CTEPH)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Actelion</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>EPS Corporation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Imepro Inc.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>General Laboratory, BML, Inc.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Mitsubishi Logistics Corporation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Actelion</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The endothelin receptor antagonist macitentan showed significant improvement compared with&#xD;
      placebo in pulmonary vascular resistance (PVR) and 6-minute walking distance (6MWD) in&#xD;
      inoperable CTEPH patients in the phase II MERIT-1 trial (AC-055E201, NCT02021292). However,&#xD;
      in the MERIT-1 trial Japanese patients were not included. Therefore, in line with Japan's&#xD;
      medical environment, this phase III study is to confirm the efficacy and safety of macitentan&#xD;
      in Japanese CTEPH patients.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Due to a change in the development strategy&#xD;
  </why_stopped>
  <start_date type="Actual">January 8, 2019</start_date>
  <completion_date type="Actual">June 29, 2020</completion_date>
  <primary_completion_date type="Actual">June 29, 2020</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Evaluate the ratio in pulmonary vascular resistance (PVR) at rest from baseline to Week 16</measure>
    <time_frame>From Baseline to Week 16</time_frame>
    <description>The resistance in the artery carrying blood to the lungs is called PVR. The PVR is the resistance in the artery carrying blood to the lungs and that has to be overcome by the right ventricle in heart in order to let blood flow to the lungs occur. The ratio in PVR at rest indicates the efficacy of macitentan in patients with CTEPH. The ratio in PVR at rest is calculated as PVR at Week 16 divided by baseline PVR. The ratio in PVR at rest from baseline to Week 16 of administration of macitentan is evaluated in subjects with CTEPH who are not indicated for pulmonary endarterectomy (PEA) and/or subjects who have postoperative persistent or recurrent pulmonary hypertension (PH) after PEA and/or balloon pulmonary angioplasty (BPA).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change from baseline to Week 16 in PVR at rest</measure>
    <time_frame>From baseline to Week 16</time_frame>
    <description>The PVR at rest will be calculated to evaluate the change in PVR at rest from pre-dosing (baseline) to post-dosing (Week 16).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline to Week 16 in pulmonary vascular resistance index (PVRI) at rest</measure>
    <time_frame>From baseline to Week 16</time_frame>
    <description>The indexed PVR (PVRI) at rest will be calculated to evaluate the change in PVRI at rest from pre-dosing (baseline) to post-dosing (Week 16).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline to Week 24 in 6-minute walk distance (6MWD)</measure>
    <time_frame>From baseline to Week 24</time_frame>
    <description>The purpose of the 6-minute walk is to test exercise tolerance and capacity. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. This endpoint evaluates the change in 6MWD from pre-dosing (baseline) to post-dosing (Week 24).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline to Week 24 in Borg dyspnea index</measure>
    <time_frame>From baseline to Week 24</time_frame>
    <description>The Borg dyspnea index rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal'). A decrease in the Borg dyspnea index indicates an improvement. This endpoint evaluates the change in the Borg dyspnea index assessed at the end of measuring the 6MWD from pre-dosing (baseline) to post-dosing (Week 24).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline to Week 24 in WHO functional class (WHO FC)</measure>
    <time_frame>From baseline to Week 24</time_frame>
    <description>This endpoint evaluates the change of WHO functional class from pre-dosing (baseline) to post-dosing (Week 24). Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (e.g. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Chronic Thromboembolic Pulmonary Hypertension (CTEPH)</condition>
  <arm_group>
    <arm_group_label>Open-label treatment period</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>oral administration of macitentan 10 mg once daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>macitentan 10 mg</intervention_name>
    <description>macitentan 10 mg, film-coated tablet, oral use</description>
    <arm_group_label>Open-label treatment period</arm_group_label>
    <other_name>ACT-064992, Opsumit®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent to participate in the study obtained from the subject or&#xD;
             legal representative a) prior to initiation of any study mandated procedure&#xD;
&#xD;
          -  Japanese subjects who have been diagnosed as having CTEPH:&#xD;
&#xD;
               1. Subjects who have not undergone balloon pulmonary angioplasty (BPA) and for whom&#xD;
                  the investigator determines not to implement pulmonary endarterectomy (PEA) at&#xD;
                  the time of the acquisition of informed consent due to the organized thrombosis&#xD;
                  localized in the peripheral regions, high risk (complications, old age, etc.) or&#xD;
                  for any other reasons.&#xD;
&#xD;
               2. Subjects who have postoperative persistent or recurrent pulmonary hypertension&#xD;
                  (PH) after undergoing pulmonary endarterectomy (PEA) and/or BPA.&#xD;
&#xD;
          -  PH subjects whose WHO FC is I to IV&#xD;
&#xD;
          -  6MWD measured during the screening period ranges from 150 m to 450 m&#xD;
&#xD;
          -  Subjects who meet the following conditions according to the right heart&#xD;
             catheterization (RHC) performed during the screening period or within 8 weeks before&#xD;
             the acquisition of the informed consent:&#xD;
&#xD;
               1. Resting mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg&#xD;
&#xD;
               2. Pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg (if PAWP cannot be measured or&#xD;
                  the value of PAWP is not reliable, left ventricular end-diastolic pressure ≤ 13&#xD;
                  mmHg)&#xD;
&#xD;
               3. Resting PVR ≥ 400 dyn*sec/cm5&#xD;
&#xD;
          -  Subjects treated with anti-coagulation agents, unfractionated heparin or low molecular&#xD;
             weight heparin at least 90 days prior to RHC at baseline&#xD;
&#xD;
          -  Women with childbearing potential with negative serum pregnancy test results and able&#xD;
             to follow the appropriate contraceptive methods from the date of starting the study&#xD;
             drug administration up to 30 days after the discontinuation or completion of the study&#xD;
             drug administration. Fertile male subjects able to use condom during the same period.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  BPA within 90 days prior to undergoing baseline RHC&#xD;
&#xD;
          -  PEA within 180 days prior to undergoing baseline RHC&#xD;
&#xD;
          -  Subjects with unstable pulmonary hemodynamics who have postoperative persistent or&#xD;
             recurrent PH after undergoing PEA and/or BPA&#xD;
&#xD;
          -  Recurrent thromboembolism undergoing treatment with oral anti-coagulation agents&#xD;
&#xD;
          -  Symptomatic acute pulmonary embolism within 180 days prior to the start of study drug&#xD;
             administration&#xD;
&#xD;
          -  Known moderate-to-severe restrictive lung disease or obstructive lung disease or known&#xD;
             significant chronic lung disease diagnosed by chest imaging (e.g., interstitial lung&#xD;
             disease, emphysema)&#xD;
&#xD;
          -  Acute myocardial infarction during Screening period&#xD;
&#xD;
          -  Severe liver impairment.&#xD;
&#xD;
          -  Systolic blood pressure (SBP) &lt; 90 mmHg at screening.&#xD;
&#xD;
          -  Any known factor or disease that may interfere with treatment compliance or full&#xD;
             participation in the study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>89 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Yoshinari Yokoyama, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Actelion Japan</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Fukuoka University Nishijin Hospital</name>
      <address>
        <city>Fukuoka</city>
        <zip>814-8522</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fukushima Medical University Hospital</name>
      <address>
        <city>Fukushima</city>
        <zip>960-1247</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kagoshima University Hospital</name>
      <address>
        <city>Kagoshima</city>
        <zip>890-8520</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nara Medical University Hospital</name>
      <address>
        <city>Kashihara</city>
        <zip>634-8522</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kokura Kinen Hospital</name>
      <address>
        <city>Kitakyushu</city>
        <zip>802-8555</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kobe University Hospital</name>
      <address>
        <city>Kobe</city>
        <zip>650-0017</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saitama Cardiovascular and Respiratory Center</name>
      <address>
        <city>Kumagaya</city>
        <zip>360-0197</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kure Kyosai Hospital</name>
      <address>
        <city>Kure</city>
        <zip>737-8505</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kurume University Hospital</name>
      <address>
        <city>Kurume</city>
        <zip>830-0011</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Toho University Ohashi Medical Center</name>
      <address>
        <city>Meguro-ku</city>
        <zip>153-8515</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IIUHW Mita Hospital</name>
      <address>
        <city>Minato-ku</city>
        <zip>108-8329</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kyorin University Hospital</name>
      <address>
        <city>Mitaka</city>
        <zip>181-8611</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nagasaki University Hospital</name>
      <address>
        <city>Nagasaki</city>
        <zip>852-8501</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Hospital Organization Okayama Medical Center</name>
      <address>
        <city>Okayama</city>
        <zip>701-1192</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sapporo Medical University Hospital</name>
      <address>
        <city>Sapporo</city>
        <zip>060-8543</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hokkaido University Hospital</name>
      <address>
        <city>Sapporo</city>
        <zip>060-8648</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sasebo City General Hospital</name>
      <address>
        <city>Sasebo</city>
        <zip>857-8511</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Keio University Hospital</name>
      <address>
        <city>Shinjuku-ku</city>
        <zip>160-0016</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Cerebral and Cardiovascular Center Hospital</name>
      <address>
        <city>Suita</city>
        <zip>565-8565</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Tsukuba Hospital</name>
      <address>
        <city>Tsukuba</city>
        <zip>305-8576</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mie University Hospital</name>
      <address>
        <city>Tsu</city>
        <zip>514-8507</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yamagata University Hospital</name>
      <address>
        <city>Yamagata</city>
        <zip>990-0828</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yokohama City University Hospital</name>
      <address>
        <city>Yokohama</city>
        <zip>236-0004</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
  </location_countries>
  <link>
    <url>https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217051&amp;amp;parentIdentifier=AC-055E301&amp;amp;attachmentIdentifier=aa227840-255d-4f06-8064-e8ebb89a846a&amp;amp;fileName=AC-055E301_CSR_Synopsis.pdf&amp;amp;versionIdentifier=</url>
    <description>A Prospective, Multicenter, Open-label, Single Arm, Phase III Study to Assess the Efficacy and Safety of Macitentan (ACT-064992) in Subjects With Chronic Thromboembolic Pulmonary Hypertension (CTEPH)</description>
  </link>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>January 10, 2019</study_first_submitted>
  <study_first_submitted_qc>January 17, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 18, 2019</study_first_posted>
  <last_update_submitted>June 16, 2021</last_update_submitted>
  <last_update_submitted_qc>June 16, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 18, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>CTEPH</keyword>
  <keyword>chronic thromboembolic pulmonary hypertension</keyword>
  <keyword>macitentan</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension, Pulmonary</mesh_term>
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Macitentan</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The data sharing policy of the Janssen Pharmaceutical Companies of Johnson &amp; Johnson is available at www.janssen.com/clinical-trials\transparency. As noted on this site, requests for access to the study data can be submitted through Yale open Access (YODA) Project site at yoda.yale.edu</ipd_description>
    <ipd_url>https://www.janssen.com/clinical-trials/transparency</ipd_url>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03809650
org study id: AC-055E301
nct id: NCT03809650
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
The endothelin receptor antagonist macitentan showed significant improvement compared with
      placebo in pulmonary vascular resistance (PVR) and 6-minute walking distance (6MWD) in
      inoperable CTEPH patients in the phase II MERIT-1 trial (AC-055E201, NCT02021292). However,
      in the MERIT-1 trial Japanese patients were not included. Therefore, in line with Japan's
      medical environment, this phase III study is to confirm the efficacy and safety of macitentan
      in Japanese CTEPH patients.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Evaluate the ratio in pulmonary vascular resistance (PVR) at rest from baseline to Week 16
time frame: From Baseline to Week 16
description: The resistance in the artery carrying blood to the lungs is called PVR. The PVR is the resistance in the artery carrying blood to the lungs and that has to be overcome by the right ventricle in heart in order to let blood flow to the lungs occur. The ratio in PVR at rest indicates the efficacy of macitentan in patients with CTEPH. The ratio in PVR at rest is calculated as PVR at Week 16 divided by baseline PVR. The ratio in PVR at rest from baseline to Week 16 of administration of macitentan is evaluated in subjects with CTEPH who are not indicated for pulmonary endarterectomy (PEA) and/or subjects who have postoperative persistent or recurrent pulmonary hypertension (PH) after PEA and/or balloon pulmonary angioplasty (BPA).
measure: Change from baseline to Week 16 in PVR at rest
time frame: From baseline to Week 16
description: The PVR at rest will be calculated to evaluate the change in PVR at rest from pre-dosing (baseline) to post-dosing (Week 16).
measure: Change from baseline to Week 16 in pulmonary vascular resistance index (PVRI) at rest
time frame: From baseline to Week 16
description: The indexed PVR (PVRI) at rest will be calculated to evaluate the change in PVRI at rest from pre-dosing (baseline) to post-dosing (Week 16).
measure: Change from baseline to Week 24 in 6-minute walk distance (6MWD)
time frame: From baseline to Week 24
description: The purpose of the 6-minute walk is to test exercise tolerance and capacity. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. This endpoint evaluates the change in 6MWD from pre-dosing (baseline) to post-dosing (Week 24).
measure: Change from baseline to Week 24 in Borg dyspnea index
time frame: From baseline to Week 24
description: The Borg dyspnea index rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal'). A decrease in the Borg dyspnea index indicates an improvement. This endpoint evaluates the change in the Borg dyspnea index assessed at the end of measuring the 6MWD from pre-dosing (baseline) to post-dosing (Week 24).
measure: Change from baseline to Week 24 in WHO functional class (WHO FC)
time frame: From baseline to Week 24
description: This endpoint evaluates the change of WHO functional class from pre-dosing (baseline) to post-dosing (Week 24). Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (e.g. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure.
arm group label: Open-label treatment period
arm group type: Experimental
description: oral administration of macitentan 10 mg once daily
intervention type: Drug
intervention name: macitentan 10 mg
description: macitentan 10 mg, film-coated tablet, oral use
arm group label: Open-label treatment period
other name: ACT-064992, Opsumit®
criteria: 
gender: All
minimum age: 18 Years
maximum age: 89 Years
healthy volunteers: No
last name: Yoshinari Yokoyama, PhD
role: Study Director
affiliation: Actelion Japan
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Japan
url: https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217051&amp;parentIdentifier=AC-055E301&amp;attachmentIdentifier=aa227840-255d-4f06-8064-e8ebb89a846a&amp;fileName=AC-055E301_CSR_Synopsis.pdf&amp;versionIdentifier=
description: A Prospective, Multicenter, Open-label, Single Arm, Phase III Study to Assess the Efficacy and Safety of Macitentan (ACT-064992) in Subjects With Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
responsible party type: Sponsor
mesh term: Hypertension, Pulmonary
mesh term: Hypertension
mesh term: Macitentan
sharing ipd: Yes
ipd description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials\transparency. As noted on this site, requests for access to the study data can be submitted through Yale open Access (YODA) Project site at yoda.yale.edu
ipd url: https://www.janssen.com/clinical-trials/transparency