<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/NCT03037580</url>
  </required_header>
  <id_info>
    <org_study_id>TDE-HF-301</org_study_id>
    <nct_id>NCT03037580</nct_id>
  </id_info>
  <brief_title>Oral Treprostinil in Subjects With Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction</brief_title>
  <official_title>A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Oral Treprostinil in Subjects With Pulmonary Hypertension (PH) in Heart Failure With Preserved Ejection Fraction (HFpEF)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>United Therapeutics</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>United Therapeutics</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 was a multicenter, randomized (1:1; oral treprostinil to placebo), double-blind,&#xD;
      placebo-controlled study in subjects with World Health Organization (WHO) Group 2 pulmonary&#xD;
      hypertension (PH) associated with heart failure with preserved ejection fraction (HFpEF).&#xD;
      Once randomized, subjects took the initial dose of study drug at the study site on the day of&#xD;
      randomization. Subjects returned to the study site for visits scheduled at Weeks 6, 12, 18,&#xD;
      and 24. The duration of study participation was approximately 28 weeks from Screening until&#xD;
      study completion (includes a 30-day Screening Phase and 24-week Treatment Phase).&#xD;
&#xD;
      The study was discontinued by the Sponsor on 14 October 2019 due to slow enrollment. As only&#xD;
      a small portion of the anticipated total subjects had been enrolled, with many terminating&#xD;
      early due to the study termination, there was a limited ability to explore the effect of oral&#xD;
      treprostinil in this indication in this study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study TDE-HF-301 was a multicenter, randomized, double-blind, placebo-controlled study&#xD;
      designed to investigate the effect of oral treprostinil compared with placebo on exercise&#xD;
      capacity in subjects with WHO Group 2 PH associated with HFpEF.&#xD;
&#xD;
      Once randomized, subjects were dispensed study drug and took an initial dose (0.125 mg) at&#xD;
      the study site on the day of randomization. Dosing of study drug continued at 0.125 mg 3&#xD;
      times daily (TID; every 6 to 8 hours) with food. Dose increases could occur in 0.125-mg&#xD;
      increments every 72 hours at the discretion of the Investigator up to a maximum allowable&#xD;
      dose of 6 mg TID. Subjects received oral treprostinil as 0.125, 0.25, 1.0, or 2.5 mg&#xD;
      sustained-release osmotic tablets (maximum dose 6 mg TID) or matching placebo. Doses of study&#xD;
      drug were to be increased in the absence of dose-limiting drug-related adverse events (AEs)&#xD;
      to ensure that each subject received the optimal dose throughout the study. Subjects returned&#xD;
      for visits at Weeks 6, 12, 18, and 24. Subjects who terminated study drug early were asked to&#xD;
      complete all remaining study visits. The study had an adaptive design where the maximum&#xD;
      allowable dose was 2 mg until the Data Monitoring Committee had confirmed a satisfactory&#xD;
      safety profile. After this confirmation, the maximum allowable dose was increased to 4 mg&#xD;
      TID. This occurred after 45 subjects had been enrolled. A subsequent Data Monitoring&#xD;
      Committee meeting, which occurred after 75 subjects had been enrolled, increased the maximum&#xD;
      allowable dose to 6 mg TID.&#xD;
&#xD;
      Efficacy assessments consisted of 6-Minute Walk Distance (6MWD), blood collection for&#xD;
      N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, clinical worsening, WHO&#xD;
      Functional Class (FC), Borg dyspnea score, glycated hemoglobin (HbA1c), and Kansas City&#xD;
      Cardiomyopathy Questionnaire (KCCQ).&#xD;
&#xD;
      Safety assessments consisted of AEs, physical examinations, vital signs, 12-lead&#xD;
      electrocardiograms (ECGs), echocardiograms (ECHOs), heart failure signs and symptoms,&#xD;
      pregnancy testing, clinical laboratory tests, hospitalizations due to cardiopulmonary&#xD;
      indication, and worsening heart failure as demonstrated by outpatient administration of&#xD;
      intravenous (IV) diuretics. Subjects could have optionally provided samples for the&#xD;
      evaluation of biomarkers and pharmacogenomics.&#xD;
&#xD;
      Subjects that completed the 24-week treatment period on study drug were permitted to enter&#xD;
      the open-label extension study (Study TDE-HF-302).&#xD;
&#xD;
      The study was discontinued by the Sponsor on 14 October 2019 due to slow enrollment. As only&#xD;
      a small portion of the anticipated total subjects had been enrolled, with many terminating&#xD;
      early due to the study termination, there was a limited ability to explore the effect of oral&#xD;
      treprostinil in this indication in this study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Terminated by sponsor&#xD;
  </why_stopped>
  <start_date type="Actual">August 15, 2017</start_date>
  <completion_date type="Actual">December 3, 2019</completion_date>
  <primary_completion_date type="Actual">December 3, 2019</primary_completion_date>
  <phase>Phase 3</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in 6MWD From Baseline to Week 24</measure>
    <time_frame>Baseline to Week 24</time_frame>
    <description>The intent of the 6-Minute Walk Test (6MWT) is to evaluate exercise capacity associated with carrying out activities of daily living.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in NT-proBNP Levels From Baseline to Week 24</measure>
    <time_frame>Baseline to Week 24</time_frame>
    <description>The NT-proBNP concentration is a biomarker associated with changes in right heart morphology and function.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Subjects With First Clinical Worsening Event From Baseline to Week 24</measure>
    <time_frame>Baseline to Week 24</time_frame>
    <description>Clinical worsening was defined as the occurrence of any 1 of the following clinical worsening events: hospitalization due to a cardiopulmonary indication (a non-elective hospitalization lasting at least 24 hours in duration caused by clinical conditions directly related to PH and/or heart failure), outpatient administration of IV diuretics, death (all causes), decrease in 6MWD &gt;15% from Baseline (or the subject was too ill to walk, and the cause was directly related to the disease under study) at 2 consecutive visits on different days (except Week 24).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in WHO FC From Baseline to Week 24</measure>
    <time_frame>Baseline to Week 24</time_frame>
    <description>The WHO functional classification ranges from I (subject's disease does not affect daily activities) to IV (subject's disease causes severe impairment).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">84</enrollment>
  <condition>Pulmonary Hypertension</condition>
  <condition>Heart Failure With Preserved Ejection Fraction</condition>
  <arm_group>
    <arm_group_label>Oral treprostinil</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Sustained-release oral tablets for TID administration</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo (sugar pill) for TID oral administration</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oral treprostinil</intervention_name>
    <description>Sustained-release oral tablets for TID administration</description>
    <arm_group_label>Oral treprostinil</arm_group_label>
    <other_name>Treprostinil diethanolamine, treprostinil diolamine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo (sugar pill) for TID oral administration</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Matching placebo (sugar pill)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. The subject voluntarily gave informed consent to participate in the study.&#xD;
&#xD;
          2. The subject was 18 to 85 years of age (inclusive) at Screening (ie, date of providing&#xD;
             written informed consent).&#xD;
&#xD;
          3. A subject could qualify if they had undergone a right heart catheterization (RHC)&#xD;
             within 180 days of Baseline.&#xD;
&#xD;
          4. The subject had a diagnosis of heart failure with a left ventricular ejection fraction&#xD;
             (LVEF) ≥45% by ECHO completed during Screening (prior to randomization).&#xD;
&#xD;
          5. The subject's baseline 6MWD was at least 150 meters.&#xD;
&#xD;
          6. The subject had pulmonary function tests conducted within 6 months of Screening or&#xD;
             during the Screening Phase.&#xD;
&#xD;
          7. Subjects on a chronic medication for heart failure were on a stable dose for ≥30 days&#xD;
             prior to randomization.&#xD;
&#xD;
          8. In the opinion of the Investigator, the subject was able to communicate effectively&#xD;
             with study personnel, and was considered reliable, willing, and likely to be&#xD;
             cooperative with protocol requirements, including attending all study visits.&#xD;
&#xD;
          9. Women of childbearing potential, including any female who had experienced menarche and&#xD;
             who had not undergone successful surgical sterilization or was not postmenopausal,&#xD;
             must have practiced true abstinence from intercourse when it was in line with their&#xD;
             preferred and usual lifestyle, or have used 2 different forms of highly effective&#xD;
             contraception for the duration of the study, and for at least 30 days after&#xD;
             discontinuing study drug. Male subjects with a partner of childbearing potential must&#xD;
             have used a condom during the length of the study, and for at least 48 hours after&#xD;
             discontinuing study drug.&#xD;
&#xD;
         10. Subjects on chronic medications (eg, inhaled corticosteroids, long-acting beta2&#xD;
             adrenergic agonist, long acting muscarinic antagonists, combination inhaled drugs,&#xD;
             anti-inflammatory drugs, oral/parenteral corticosteroids, or biologic agents) for any&#xD;
             underlying respiratory condition were on a stable dose for ≥30 days prior to&#xD;
             randomization.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. The subject was pregnant or lactating.&#xD;
&#xD;
          2. In the opinion of the Principal Investigator, the subject had a primary diagnosis of&#xD;
             PH other than WHO Group 2 PH.&#xD;
&#xD;
          3. The subject had shown intolerance or significant lack of efficacy to a prostacyclin or&#xD;
             prostacyclin analogue that resulted in discontinuation of therapy or inability to&#xD;
             effectively titrate that therapy.&#xD;
&#xD;
          4. The subject had received any approved pulmonary arterial hypertension (PAH) therapies&#xD;
             within 30 days of randomization. Chronic use of an approved phosphodiesterase type 5&#xD;
             inhibitor (PDE5-I) was allowed as long as the subject has been on a stable dose for at&#xD;
             least 90 days prior to randomization and had a RHC confirming the parameters necessary&#xD;
             for inclusion in the study after being on a stable PDE5-I dose for at least 30 days.&#xD;
&#xD;
          5. The subject had been hospitalized for a cardiopulmonary indication within 30 days of&#xD;
             randomization.&#xD;
&#xD;
          6. The subject had a myocardial infarction within 90 days of randomization.&#xD;
&#xD;
          7. The subject had cardiac resynchronization therapy within 90 days of randomization or&#xD;
             anticipated resynchronization therapy during the study treatment period.&#xD;
&#xD;
          8. The subject had liver function tests greater than 3 times the upper limit of normal at&#xD;
             Screening, clinically significant liver disease/dysfunction, known Child-Pugh Class C&#xD;
             hepatic disease, or noncirrhotic portal hypertension.&#xD;
&#xD;
          9. The subject had uncontrolled systemic hypertension, systolic blood pressure &lt;100 mmHg,&#xD;
             or a resting heart rate &gt;100 beats per minute at Baseline.&#xD;
&#xD;
         10. The subject had known genetic hypertrophic cardiomyopathy, sarcoidosis, or cardiac&#xD;
             amyloidosis.&#xD;
&#xD;
         11. The subject had a known history of any LVEF less than 40% by ECHO within 3 years of&#xD;
             randomization. Note: a transient decline in LVEF below 40% that occurred and recovered&#xD;
             more than 6 months before the start of Screening and was associated with an acute&#xD;
             intercurrent condition (eg, atrial fibrillation) was allowed.&#xD;
&#xD;
         12. The subject had hemodynamically significant valvular heart disease as determined by&#xD;
             the Investigator, including: greater than mild aortic and/or mitral stenosis or severe&#xD;
             mitral and/or aortic regurgitation (&gt;Grade 3)&#xD;
&#xD;
         13. The subject had a Body Mass Index &gt;45 kg/m^2.&#xD;
&#xD;
         14. The subject had any musculoskeletal disorder, or had any other condition that limited&#xD;
             ambulation.&#xD;
&#xD;
         15. The subject had end-stage renal disease requiring/receiving dialysis.&#xD;
&#xD;
         16. The subject participated in an investigational drug or device study within 30 days&#xD;
             prior to the first dose of study drug.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mardi Gomberg-Maitland, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>George Washington University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama at Birmingham</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35294</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Banner University Medical Center Phoenix</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85006</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Arizona</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85724</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VA Healthcare System of Greater Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90073</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California Los Angeles Pulmonary Division</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cedars-Sinai Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90211</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California - Davis Medical Center</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95817</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Santa Barbara Cottage Hospital</name>
      <address>
        <city>Santa Barbara</city>
        <state>California</state>
        <zip>93105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Aurora Denver Cardiology Associates</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80012</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Colorado Denver</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Jewish Health</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <zip>80206</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>South Denver Cardiology</name>
      <address>
        <city>Littleton</city>
        <state>Colorado</state>
        <zip>80120</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MedStar Georgetown University Hospital</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20007</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical Faculty Associates, George Washington University</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20037</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bay Area Cardiology Associates</name>
      <address>
        <city>Brandon</city>
        <state>Florida</state>
        <zip>33511</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic - Jacksonville</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Vincent's Lung, Sleep, and Critical Care Specialists</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>33204</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Central Florida Pulmonary Group, P.A.</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32803</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Florida Hospital</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32806</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of South Florida; Tampa General Hospital</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33606</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic of Florida</name>
      <address>
        <city>Weston</city>
        <state>Florida</state>
        <zip>33331</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emory University Hospital</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Augusta University</name>
      <address>
        <city>Augusta</city>
        <state>Georgia</state>
        <zip>30912</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Piedmont Physicians Georgia Lung</name>
      <address>
        <city>Austell</city>
        <state>Georgia</state>
        <zip>30309</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>WellStar Medical Group</name>
      <address>
        <city>Marietta</city>
        <state>Georgia</state>
        <zip>30060</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Illinois at Chicago Hospital</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Loyola University Medical Center</name>
      <address>
        <city>Maywood</city>
        <state>Illinois</state>
        <zip>60153</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Advocate Christ Medical Center</name>
      <address>
        <city>Oak Lawn</city>
        <state>Illinois</state>
        <zip>60453</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>OSF HealthCare</name>
      <address>
        <city>Peoria</city>
        <state>Illinois</state>
        <zip>61614</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Indiana University Health Methodist Research Institute, INC</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Community Physician Network, Heart and Vascular Care</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46250</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Vincent Hospital and Health Services</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46260</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Iowa Hospitals and Clinics</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>55242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Iowa Heart Center</name>
      <address>
        <city>West Des Moines</city>
        <state>Iowa</state>
        <zip>50266</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Medical Center</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>66160</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kentucky Medical Center</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40536</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kentuckiana Pulmonary Associates</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Louisville Physicians Outpatient Center</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chest Medicine Associates</name>
      <address>
        <city>South Portland</city>
        <state>Maine</state>
        <zip>04106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tufts Medical Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Brigham and Women's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Elizabeth's Medical Center</name>
      <address>
        <city>Brighton</city>
        <state>Massachusetts</state>
        <zip>02135</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Henry Ford Health System</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Spectrum Health Medical Group</name>
      <address>
        <city>Grand Rapids</city>
        <state>Michigan</state>
        <zip>49503</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Minnesota</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Luke's Hospital</name>
      <address>
        <city>Chesterfield</city>
        <state>Missouri</state>
        <zip>63017</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Luke's Hospital of Kansas City</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dartmouth Hitchcock Medical Center</name>
      <address>
        <city>Lebanon</city>
        <state>New Hampshire</state>
        <zip>03756</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Barnabas Health Lung Center</name>
      <address>
        <city>Newark</city>
        <state>New Jersey</state>
        <zip>07112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Albany Medical College</name>
      <address>
        <city>Albany</city>
        <state>New York</state>
        <zip>12208</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Montefiore Medical Center</name>
      <address>
        <city>Bronx</city>
        <state>New York</state>
        <zip>10461</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mount Sinai Medical Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pulmonary Health Physicians, PC</name>
      <address>
        <city>Syracuse</city>
        <state>New York</state>
        <zip>13066</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Asheville Cardiology Associates</name>
      <address>
        <city>Asheville</city>
        <state>North Carolina</state>
        <zip>28803</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pinehurst Medical Clinic</name>
      <address>
        <city>Pinehurst</city>
        <state>North Carolina</state>
        <zip>28374</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Lindner Research Center The Christ Hospital Health Network</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45219</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Ohio State University Wexner Medical Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Toledo Medical Center</name>
      <address>
        <city>Toledo</city>
        <state>Ohio</state>
        <zip>43614</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Oregon Clinic</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97225</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lancaster General Hospital</name>
      <address>
        <city>Lancaster</city>
        <state>Pennsylvania</state>
        <zip>17601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Allegheny General Hospital</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15212</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AnMed Health Pulmonary and Sleep Medicine</name>
      <address>
        <city>Anderson</city>
        <state>South Carolina</state>
        <zip>29621</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VitaLink Research - Anderson</name>
      <address>
        <city>Anderson</city>
        <state>South Carolina</state>
        <zip>29621</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical University of South Carolina</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <zip>29425</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stern Cardiovascular Foundation</name>
      <address>
        <city>Germantown</city>
        <state>Tennessee</state>
        <zip>38138</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Summit Medical Group</name>
      <address>
        <city>Knoxville</city>
        <state>Tennessee</state>
        <zip>37909</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanderbilt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baylor University Medical Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75246</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Houston Methodist Research Institute</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The University of Texas Health Science Center at Houston</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Tech University Health Sciences Center</name>
      <address>
        <city>Lubbock</city>
        <state>Texas</state>
        <zip>79905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Intermountain Medical Center</name>
      <address>
        <city>Murray</city>
        <state>Utah</state>
        <zip>84157-7000</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Inova Heart and Vascular Institute</name>
      <address>
        <city>Falls Church</city>
        <state>Virginia</state>
        <zip>22042</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sentara Cardiovascular Research Institute</name>
      <address>
        <city>Norfolk</city>
        <state>Virginia</state>
        <zip>23507</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Virginia Commonwealth University</name>
      <address>
        <city>Richmond</city>
        <state>Virginia</state>
        <zip>23298</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Carilion Clinic</name>
      <address>
        <city>Roanoke</city>
        <state>Virginia</state>
        <zip>24014</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Providence Medical Research Center</name>
      <address>
        <city>Spokane</city>
        <state>Washington</state>
        <zip>99204</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>West Virginia University Hospital</name>
      <address>
        <city>Morgantown</city>
        <state>West Virginia</state>
        <zip>26506</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Aurora St. Luke's Medical Center</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical College of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>January 27, 2017</study_first_submitted>
  <study_first_submitted_qc>January 30, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 31, 2017</study_first_posted>
  <results_first_submitted>September 25, 2020</results_first_submitted>
  <results_first_submitted_qc>September 25, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">October 22, 2020</results_first_posted>
  <last_update_submitted>October 20, 2020</last_update_submitted>
  <last_update_submitted_qc>October 20, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 10, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pulmonary Hypertension</keyword>
  <keyword>6-Minute Walk Test</keyword>
  <keyword>HFpEF</keyword>
  <keyword>Oral Treprostinil</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>
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Treprostinil</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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>August 12, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/80/NCT03037580/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>September 18, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/80/NCT03037580/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Oral Treprostinil</title>
          <description>Sustained-release oral tablets for TID administration&#xD;
Oral treprostinil: Sustained-release oral tablets for TID administration</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Placebo (sugar pill) for TID oral administration&#xD;
Placebo: Placebo (sugar pill) for TID oral administration</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="41"/>
                <participants group_id="P2" count="43"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="25"/>
                <participants group_id="P2" count="27"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Study Terminated by Sponsor</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </drop_withdraw_reason>
            <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_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Oral Treprostinil</title>
          <description>Sustained-release oral tablets for TID administration&#xD;
Oral treprostinil: Sustained-release oral tablets for TID administration</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Placebo (sugar pill) for TID oral administration&#xD;
Placebo: Placebo (sugar pill) for TID oral administration</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="41"/>
            <count group_id="B2" value="43"/>
            <count group_id="B3" value="84"/>
          </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="74.0" lower_limit="53" upper_limit="85"/>
                    <measurement group_id="B2" value="74.0" lower_limit="46" upper_limit="82"/>
                    <measurement group_id="B3" value="74.0" lower_limit="46" upper_limit="85"/>
                  </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="27"/>
                    <measurement group_id="B2" value="31"/>
                    <measurement group_id="B3" value="58"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="26"/>
                  </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="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="39"/>
                    <measurement group_id="B2" value="43"/>
                    <measurement group_id="B3" value="82"/>
                  </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="7"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="40"/>
                    <measurement group_id="B2" value="36"/>
                    <measurement group_id="B3" value="76"/>
                  </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>Etiology of HFpEF</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hypertension</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="28"/>
                    <measurement group_id="B3" value="49"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Coronary artery disease</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Obesity</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Diabetes</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in 6MWD From Baseline to Week 24</title>
        <description>The intent of the 6-Minute Walk Test (6MWT) is to evaluate exercise capacity associated with carrying out activities of daily living.</description>
        <time_frame>Baseline to Week 24</time_frame>
        <population>Safety Population</population>
        <group_list>
          <group group_id="O1">
            <title>Oral Treprostinil</title>
            <description>Sustained-release oral tablets for TID administration&#xD;
Oral treprostinil: Sustained-release oral tablets for TID administration</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo (sugar pill) for TID oral administration&#xD;
Placebo: Placebo (sugar pill) for TID oral administration</description>
          </group>
        </group_list>
        <measure>
          <title>Change in 6MWD From Baseline to Week 24</title>
          <description>The intent of the 6-Minute Walk Test (6MWT) is to evaluate exercise capacity associated with carrying out activities of daily living.</description>
          <population>Safety Population</population>
          <units>meters</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.0" lower_limit="-195" upper_limit="62"/>
                    <measurement group_id="O2" value="23.3" lower_limit="-140" upper_limit="104"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in NT-proBNP Levels From Baseline to Week 24</title>
        <description>The NT-proBNP concentration is a biomarker associated with changes in right heart morphology and function.</description>
        <time_frame>Baseline to Week 24</time_frame>
        <population>Safety Population</population>
        <group_list>
          <group group_id="O1">
            <title>Oral Treprostinil</title>
            <description>Sustained-release oral tablets for TID administration&#xD;
Oral treprostinil: Sustained-release oral tablets for TID administration</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo (sugar pill) for TID oral administration&#xD;
Placebo: Placebo (sugar pill) for TID oral administration</description>
          </group>
        </group_list>
        <measure>
          <title>Change in NT-proBNP Levels From Baseline to Week 24</title>
          <description>The NT-proBNP concentration is a biomarker associated with changes in right heart morphology and function.</description>
          <population>Safety Population</population>
          <units>pmol/L</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="28"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.5" lower_limit="-133" upper_limit="499"/>
                    <measurement group_id="O2" value="11.5" lower_limit="-231" upper_limit="172"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Subjects With First Clinical Worsening Event From Baseline to Week 24</title>
        <description>Clinical worsening was defined as the occurrence of any 1 of the following clinical worsening events: hospitalization due to a cardiopulmonary indication (a non-elective hospitalization lasting at least 24 hours in duration caused by clinical conditions directly related to PH and/or heart failure), outpatient administration of IV diuretics, death (all causes), decrease in 6MWD &gt;15% from Baseline (or the subject was too ill to walk, and the cause was directly related to the disease under study) at 2 consecutive visits on different days (except Week 24).</description>
        <time_frame>Baseline to Week 24</time_frame>
        <population>Safety Population</population>
        <group_list>
          <group group_id="O1">
            <title>Oral Treprostinil</title>
            <description>Sustained-release oral tablets for TID administration&#xD;
Oral treprostinil: Sustained-release oral tablets for TID administration</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo (sugar pill) for TID oral administration&#xD;
Placebo: Placebo (sugar pill) for TID oral administration</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects With First Clinical Worsening Event From Baseline to Week 24</title>
          <description>Clinical worsening was defined as the occurrence of any 1 of the following clinical worsening events: hospitalization due to a cardiopulmonary indication (a non-elective hospitalization lasting at least 24 hours in duration caused by clinical conditions directly related to PH and/or heart failure), outpatient administration of IV diuretics, death (all causes), decrease in 6MWD &gt;15% from Baseline (or the subject was too ill to walk, and the cause was directly related to the disease under study) at 2 consecutive visits on different days (except Week 24).</description>
          <population>Safety Population</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="41"/>
                <count group_id="O2" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>First Clinical Worsening Event</title>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No clinical worsening event</title>
                  <measurement_list>
                    <measurement group_id="O1" value="35"/>
                    <measurement group_id="O2" value="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in WHO FC From Baseline to Week 24</title>
        <description>The WHO functional classification ranges from I (subject's disease does not affect daily activities) to IV (subject's disease causes severe impairment).</description>
        <time_frame>Baseline to Week 24</time_frame>
        <population>Safety Population</population>
        <group_list>
          <group group_id="O1">
            <title>Oral Treprostinil</title>
            <description>Sustained-release oral tablets for TID administration&#xD;
Oral treprostinil: Sustained-release oral tablets for TID administration</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo (sugar pill) for TID oral administration&#xD;
Placebo: Placebo (sugar pill) for TID oral administration</description>
          </group>
        </group_list>
        <measure>
          <title>Change in WHO FC From Baseline to Week 24</title>
          <description>The WHO functional classification ranges from I (subject's disease does not affect daily activities) to IV (subject's disease causes severe impairment).</description>
          <population>Safety Population</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="41"/>
                <count group_id="O2" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <title>WHO FC I</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>WHO FC II</title>
                  <measurement_list>
                    <measurement group_id="O1" value="19"/>
                    <measurement group_id="O2" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>WHO FC III</title>
                  <measurement_list>
                    <measurement group_id="O1" value="21"/>
                    <measurement group_id="O2" value="24"/>
                  </measurement_list>
                </category>
                <category>
                  <title>WHO FC IV</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not analyzed</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 24</title>
              <category_list>
                <category>
                  <title>WHO FC I</title>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>WHO FC II</title>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                    <measurement group_id="O2" value="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>WHO FC III</title>
                  <measurement_list>
                    <measurement group_id="O1" value="15"/>
                    <measurement group_id="O2" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>WHO FC IV</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not analyzed</title>
                  <measurement_list>
                    <measurement group_id="O1" value="12"/>
                    <measurement group_id="O2" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>The Treatment Phase was 24 weeks for each subject. The study was discontinued by the Sponsor on 14 October 2019 due to slow enrollment.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Oral Treprostinil</title>
          <description>Sustained-release oral tablets for TID administration&#xD;
Oral treprostinil: Sustained-release oral tablets for TID administration</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Placebo (sugar pill) for TID oral administration&#xD;
Placebo: Placebo (sugar pill) for TID oral administration</description>
        </group>
      </group_list>
      <serious_events>
        <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="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Cardiac failure acute</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Cardio-respiratory arrest</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gastritis erosive</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Upper gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchitis viral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Fluid overload</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Fibromyalgia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="43"/>
              </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="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <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="37" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="38" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="23" subjects_affected="19" subjects_at_risk="41"/>
                <counts group_id="E2" events="19" subjects_affected="16" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="14" subjects_affected="13" subjects_at_risk="41"/>
                <counts group_id="E2" events="7" subjects_affected="6" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="41"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="10" subjects_affected="8" subjects_at_risk="41"/>
                <counts group_id="E2" events="13" subjects_affected="10" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="41"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Viral upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>N-terminal prohormone brain natriuretic peptide increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Weight increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="43"/>
              </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="41"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Gout</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="10" subjects_affected="7" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="8" subjects_affected="5" subjects_at_risk="41"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Pain in jaw</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="27" subjects_affected="22" subjects_at_risk="41"/>
                <counts group_id="E2" events="14" subjects_affected="12" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="41"/>
                <counts group_id="E2" events="10" subjects_affected="9" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="43"/>
              </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="7" subjects_affected="7" subjects_at_risk="41"/>
                <counts group_id="E2" events="10" subjects_affected="9" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="43"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="41"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="43"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="43"/>
              </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>Institution and/or Principal Investigator agree not to publish or publicly present any interim results of the study without the prior written consent of Sponsor, not to be unreasonably withheld or delayed. Institution and/or Principal Investigator further agree to provide Sponsor with drafts of any such publication or presentation for review and approval no less than 30 days prior to submission for publication or the date of public presentation.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Louis Holdstock</name_or_title>
      <organization>United Therapeutics</organization>
      <phone>919-425-8866</phone>
      <email>lholdstock@unither.com</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/NCT03037580
org study id: TDE-HF-301
nct id: NCT03037580
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This was a multicenter, randomized (1:1; oral treprostinil to placebo), double-blind,
      placebo-controlled study in subjects with World Health Organization (WHO) Group 2 pulmonary
      hypertension (PH) associated with heart failure with preserved ejection fraction (HFpEF).
      Once randomized, subjects took the initial dose of study drug at the study site on the day of
      randomization. Subjects returned to the study site for visits scheduled at Weeks 6, 12, 18,
      and 24. The duration of study participation was approximately 28 weeks from Screening until
      study completion (includes a 30-day Screening Phase and 24-week Treatment Phase).

      The study was discontinued by the Sponsor on 14 October 2019 due to slow enrollment. As only
      a small portion of the anticipated total subjects had been enrolled, with many terminating
      early due to the study termination, there was a limited ability to explore the effect of oral
      treprostinil in this indication in this study.
Study TDE-HF-301 was a multicenter, randomized, double-blind, placebo-controlled study
      designed to investigate the effect of oral treprostinil compared with placebo on exercise
      capacity in subjects with WHO Group 2 PH associated with HFpEF.

      Once randomized, subjects were dispensed study drug and took an initial dose (0.125 mg) at
      the study site on the day of randomization. Dosing of study drug continued at 0.125 mg 3
      times daily (TID; every 6 to 8 hours) with food. Dose increases could occur in 0.125-mg
      increments every 72 hours at the discretion of the Investigator up to a maximum allowable
      dose of 6 mg TID. Subjects received oral treprostinil as 0.125, 0.25, 1.0, or 2.5 mg
      sustained-release osmotic tablets (maximum dose 6 mg TID) or matching placebo. Doses of study
      drug were to be increased in the absence of dose-limiting drug-related adverse events (AEs)
      to ensure that each subject received the optimal dose throughout the study. Subjects returned
      for visits at Weeks 6, 12, 18, and 24. Subjects who terminated study drug early were asked to
      complete all remaining study visits. The study had an adaptive design where the maximum
      allowable dose was 2 mg until the Data Monitoring Committee had confirmed a satisfactory
      safety profile. After this confirmation, the maximum allowable dose was increased to 4 mg
      TID. This occurred after 45 subjects had been enrolled. A subsequent Data Monitoring
      Committee meeting, which occurred after 75 subjects had been enrolled, increased the maximum
      allowable dose to 6 mg TID.

      Efficacy assessments consisted of 6-Minute Walk Distance (6MWD), blood collection for
      N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, clinical worsening, WHO
      Functional Class (FC), Borg dyspnea score, glycated hemoglobin (HbA1c), and Kansas City
      Cardiomyopathy Questionnaire (KCCQ).

      Safety assessments consisted of AEs, physical examinations, vital signs, 12-lead
      electrocardiograms (ECGs), echocardiograms (ECHOs), heart failure signs and symptoms,
      pregnancy testing, clinical laboratory tests, hospitalizations due to cardiopulmonary
      indication, and worsening heart failure as demonstrated by outpatient administration of
      intravenous (IV) diuretics. Subjects could have optionally provided samples for the
      evaluation of biomarkers and pharmacogenomics.

      Subjects that completed the 24-week treatment period on study drug were permitted to enter
      the open-label extension study (Study TDE-HF-302).

      The study was discontinued by the Sponsor on 14 October 2019 due to slow enrollment. As only
      a small portion of the anticipated total subjects had been enrolled, with many terminating
      early due to the study termination, there was a limited ability to explore the effect of oral
      treprostinil in this indication in this study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in 6MWD From Baseline to Week 24
time frame: Baseline to Week 24
description: The intent of the 6-Minute Walk Test (6MWT) is to evaluate exercise capacity associated with carrying out activities of daily living.
measure: Change in NT-proBNP Levels From Baseline to Week 24
time frame: Baseline to Week 24
description: The NT-proBNP concentration is a biomarker associated with changes in right heart morphology and function.
measure: Number of Subjects With First Clinical Worsening Event From Baseline to Week 24
time frame: Baseline to Week 24
description: Clinical worsening was defined as the occurrence of any 1 of the following clinical worsening events: hospitalization due to a cardiopulmonary indication (a non-elective hospitalization lasting at least 24 hours in duration caused by clinical conditions directly related to PH and/or heart failure), outpatient administration of IV diuretics, death (all causes), decrease in 6MWD >15% from Baseline (or the subject was too ill to walk, and the cause was directly related to the disease under study) at 2 consecutive visits on different days (except Week 24).
measure: Change in WHO FC From Baseline to Week 24
time frame: Baseline to Week 24
description: The WHO functional classification ranges from I (subject's disease does not affect daily activities) to IV (subject's disease causes severe impairment).
arm group label: Oral treprostinil
arm group type: Experimental
description: Sustained-release oral tablets for TID administration
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo (sugar pill) for TID oral administration
intervention type: Drug
intervention name: Oral treprostinil
description: Sustained-release oral tablets for TID administration
arm group label: Oral treprostinil
other name: Treprostinil diethanolamine, treprostinil diolamine
intervention type: Drug
intervention name: Placebo
description: Placebo (sugar pill) for TID oral administration
arm group label: Placebo
other name: Matching placebo (sugar pill)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Mardi Gomberg-Maitland, MD
role: Principal Investigator
affiliation: George Washington University
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country: United States
responsible party type: Sponsor
mesh term: Hypertension, Pulmonary
mesh term: Hypertension
mesh term: Heart Failure
mesh term: Treprostinil
sharing ipd: No
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