<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/NCT02968901</url>
  </required_header>
  <id_info>
    <org_study_id>AC-055-405</org_study_id>
    <nct_id>NCT02968901</nct_id>
  </id_info>
  <brief_title>Clinical Study Evaluating the Effects of First-line Oral cOmbination theraPy of maciTentan and tadalafIl in Patients With Newly Diagnosed pulMonary Arterial Hypertension (OPTIMA)</brief_title>
  <acronym>OPTIMA</acronym>
  <official_title>Prospective, Multicenter, Open-label Study Evaluating the Effects of First-line Oral Combination Therapy of Macitentan and Tadalafil in Patients With Newly Diagnosed Pulmonary Arterial Hypertension (OPTIMA).</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Actelion</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Actelion</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of the study is to document the effect of first line dual oral combination&#xD;
      therapy with macitentan 10mg and tadalafil 40mg on pulmonary vascular resistance (PVR) in&#xD;
      treatment-naïve patients with newly diagnosed pulmonary arterial hypertension (PAH).&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <start_date type="Actual">September 1, 2015</start_date>
  <completion_date type="Actual">September 10, 2018</completion_date>
  <primary_completion_date type="Actual">September 10, 2018</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>pulmonary vascular resistance (PVR)</measure>
    <time_frame>16 weeks</time_frame>
    <description>Change from Baseline to Week 16 in percentage of patients with clinically meaningful improvement of PVR (decrease of 30% from baseline to Week 16)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>mean right atrial pressure (mRAP)</measure>
    <time_frame>Week 16</time_frame>
    <description>Change from Baseline to Week 16 in mean right atrial pressure (mRAP)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6MWD</measure>
    <time_frame>Week 16</time_frame>
    <description>Change from Baseline to Week 16 in 6MWD</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>level NT-proBNP</measure>
    <time_frame>Week 16</time_frame>
    <description>Change in NT-proBNP from baseline to Week 16</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>mean pulmonary arterial pressure (mPAP)</measure>
    <time_frame>Week 16</time_frame>
    <description>Change from Baseline to Week 16 in mean pulmonary arterial pressure (mPAP)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>cardiac index (CI)</measure>
    <time_frame>Week 16</time_frame>
    <description>Change from Baseline to Week 16 in cardiac index (CI).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>total pulmonary resistance (TPR)</measure>
    <time_frame>Week 16</time_frame>
    <description>Change from Baseline to Week 16 in total pulmonary resistance (TPR)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>mixed venous oxygen saturation (Sv02)</measure>
    <time_frame>Week 16</time_frame>
    <description>Change from Baseline to Week 16 in mixed venous oxygen saturation (Sv02)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>WHO functional class</measure>
    <time_frame>Week 16</time_frame>
    <description>Change from baseline to Week 16 in WHO functional class and Percentage of patients with improvement/worsening of WHO functional class from baseline to Week 16</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of treatment goals</measure>
    <time_frame>Week 16</time_frame>
    <description>Number of treatment goals (score 0 or 1 per goal, i.e. total score 0-5) met at Week 16: WHO-FC I or II; Cardiac index &gt; 2.8 L/min/m²; mRAP &lt; 8 mmHg; 6MWD &gt; 400 m; NT-proBNP &lt; 3xULN</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">46</enrollment>
  <condition>Pulmonary Arterial Hypertension</condition>
  <arm_group>
    <arm_group_label>bitherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Macitentan and tadalafil</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>macitentan</intervention_name>
    <description>used in open label</description>
    <arm_group_label>bitherapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>tadalafil</intervention_name>
    <description>used in open label</description>
    <arm_group_label>bitherapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria :&#xD;
&#xD;
          1. Signed informed consent prior to any study-mandated procedure.&#xD;
&#xD;
          2. Male or female ≥ 18 and ≤ 75 years of age at screening.&#xD;
&#xD;
          3. Initial PAH diagnosis &lt; 6 months prior to Day 1.&#xD;
&#xD;
          4. Right heart catheterization (RHC) performed between Day -28 and Day 1 (RHC data&#xD;
             obtained at the study site within this time frame, but before the study, i.e., before&#xD;
             signed informed consent, are acceptable), meeting all the following criteria:&#xD;
&#xD;
               -  Resting mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg.&#xD;
&#xD;
               -  Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic&#xD;
                  pressure (LVEDP) ≤ 15 mmHg.&#xD;
&#xD;
               -  PVR ≥ 400 dyn·sec/cm5 (≥ 5 Wood units) if PCWP &lt; 12 mmHg OR PVR ≥ 500 dyn·sec/cm5&#xD;
                  (≥ 6.25 Wood units) if PCWP in [12-15] mmHg.&#xD;
&#xD;
               -  Negative vasoreactivity test mandatory in idiopathic PAH (at this or a previous&#xD;
                  RHC).&#xD;
&#xD;
          5. World Health Organization (WHO) Functional Class (FC) II to III.&#xD;
&#xD;
          6. PAH etiology belonging to one of the following groups:&#xD;
&#xD;
               -  Idiopathic.&#xD;
&#xD;
               -  Heritable.&#xD;
&#xD;
               -  Anorexigens induced.&#xD;
&#xD;
               -  Associated with one of the following:&#xD;
&#xD;
                    -  Connective tissue disease&#xD;
&#xD;
                    -  Congenital heart disease with simple systemic-to-pulmonary shunt (atrial&#xD;
                       septal defect, ventricular septal defect, patent ductus arteriosus) ≥1 year&#xD;
                       after surgical repair&#xD;
&#xD;
                    -  HIV infection&#xD;
&#xD;
          7. 6MWD ≥ 50 m at screening.&#xD;
&#xD;
          8. Woman of childbearing potential [see definition in Section 4.5.1] must:&#xD;
&#xD;
               -  Have a negative serum pregnancy test at the screening visit and a negative urine&#xD;
                  pregnancy test at the D1 visit, and&#xD;
&#xD;
               -  Agree to perform monthly pregnancy tests up to 30 days after EOT2, and&#xD;
&#xD;
               -  Agree to use reliable contraception [defined in Section 4.5.2] from screening up&#xD;
                  to 30 days after EOT2. Reliable contraception must be started at least 11 days&#xD;
                  prior to Day 1.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any PAH-specific drug therapy [e.g. any endothelin receptor antagonist,&#xD;
             phosphodiesterase-5 inhibitors (PDE-5i), soluble guanylate cyclase stimulator,&#xD;
             prostacyclin, prostacyclin analog, or prostacyclin receptor agonist] at any time prior&#xD;
             to Day 1 (single-dose administration for vasoreactivity testing is permitted; previous&#xD;
             iloprost used intermittently for the treatment of digital ulcers or Raynaud's&#xD;
             phenomenon is permitted if stopped &gt; 6 months prior to Day 1).&#xD;
&#xD;
          2. Subjects who changed the dose or discontinued calcium channel blockers within 1 week&#xD;
             prior to Day 1.&#xD;
&#xD;
          3. Initiation of diuretics within 1 week prior to RCH.&#xD;
&#xD;
          4. Subjects on oral diuretics in whom the dose has not been stable for at least 1 week&#xD;
             prior to RHC.&#xD;
&#xD;
          5. Treatment with other PDE-5i for erectile dysfunction.&#xD;
&#xD;
          6. Treatment with strong inducers of CYP3A4 (e.g., carbamazepine, rifampin, rifampicin,&#xD;
             rifabutin, rifapentin, phenobarbital, phenytoin, and St. John's wort) ≤ 28 days prior&#xD;
             to Day 1.&#xD;
&#xD;
          7. Treatment with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole,&#xD;
             voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, boceprevir,&#xD;
             telaprevir, saquinavir, lopinavir, fosamprenavir, darunavir, tipranavir, atazanavir,&#xD;
             nelfinavir, amprenavir, indinavir) ≤ 28 days prior to Day 1.&#xD;
&#xD;
          8. History of priapism.&#xD;
&#xD;
          9. Significant aortic and mitral valve disease requiring a specific treatment.&#xD;
&#xD;
         10. Pericardial constriction.&#xD;
&#xD;
         11. Life-threatening arrhythmia.&#xD;
&#xD;
         12. Uncontrolled hypertension.&#xD;
&#xD;
         13. Symptomatic coronary artery disease.&#xD;
&#xD;
         14. Cardio-pulmonary rehabilitation program based on exercise (planned, or started ≤ 12&#xD;
             weeks prior to Day 1).&#xD;
&#xD;
         15. Body mass index (BMI) &gt; 40 kg/m2 at screening.&#xD;
&#xD;
         16. Acute myocardial infarction ≤ 12 weeks prior to Day 1.&#xD;
&#xD;
         17. Known permanent atrial fibrillation.&#xD;
&#xD;
         18. Low blood pressure &lt; 90/50 mmHg at screening or Day 1.&#xD;
&#xD;
         19. Ongoing or planned treatment with nitrates and/or doxazosin.&#xD;
&#xD;
         20. DLCO &lt; 40% of predicted value (eligible only if no sign of veno-occlusive disease&#xD;
             according to adjudication committee);&#xD;
&#xD;
         21. Presence of ≥ 1 of the following signs of relevant lung disease at any time prior to&#xD;
             Day 1:&#xD;
&#xD;
               -  FEV1/FVC &lt; 70% and FEV1 &lt; 65% of predicted after bronchodilator administration;&#xD;
&#xD;
               -  Total Lung Capacity (TLC) &lt; 60% of predicted.&#xD;
&#xD;
         22. Known or suspicion of pulmonary veno-occlusive disease (PVOD).&#xD;
&#xD;
         23. Severe renal insufficiency (estimated creatinine clearance ≤ 30 mL/min/1.73m²)&#xD;
             assessed by central laboratory at screening.&#xD;
&#xD;
         24. Ongoing or planned dialysis.&#xD;
&#xD;
         25. Documented severe hepatic impairment (with or without cirrhosis) according to National&#xD;
             Cancer Institute organ dysfunction working group criteria, defined as total bilirubin&#xD;
             &gt; 3 x ULN accompanied by AST &gt; ULN (assessed by central laboratory at screening)&#xD;
             and/or Child-Pugh Class C.&#xD;
&#xD;
         26. Serum AST and/or ALT &gt; 3 x ULN (assessed by central laboratory at screening).&#xD;
&#xD;
         27. Porto-pulmonary hypertension.&#xD;
&#xD;
         28. Hemoglobin &lt; 100 g/L assessed by central laboratory at screening.&#xD;
&#xD;
         29. Hypersensitivity to any active substance or excipient of macitentan or tadalafil&#xD;
             formulation.&#xD;
&#xD;
         30. Loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy&#xD;
             (NAION), regardless of whether or not this episode was in connection with previous&#xD;
             PDE-5i exposure.&#xD;
&#xD;
         31. Hereditary degenerative retinal disorders, including retinitis pigmentosa.&#xD;
&#xD;
         32. Pregnancy, breast-feeding, intention to become pregnant during the study or woman of&#xD;
             childbearing potential not agree to use reliable method of contraception from&#xD;
             screening up to 30 days after EOT2.&#xD;
&#xD;
         33. Hereditary problems of galactose intolerance, Lapp lactase deficiency,&#xD;
             glucosegalactose malabsorption.&#xD;
&#xD;
         34. Any factor or condition likely to affect protocol compliance of the patient as judged&#xD;
             by the investigator.&#xD;
&#xD;
         35. Treatment with another investigational drug (planned, or taken ≤ 12 weeks prior to Day&#xD;
             1).&#xD;
&#xD;
         36. Concomitant life-threatening disease with a life expectancy &lt; 12 months.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Hôpital Jean Minjoz</name>
      <address>
        <city>Besançon</city>
        <zip>25030</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital de Haut Levêque</name>
      <address>
        <city>Bordeaux</city>
        <zip>33604</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Côte de Nacre</name>
      <address>
        <city>Caen</city>
        <zip>14033</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Site du Bocage</name>
      <address>
        <city>Dijon</city>
        <zip>21079</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Albert Michallon</name>
      <address>
        <city>Grenoble</city>
        <zip>38700</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Bicètre</name>
      <address>
        <city>Le Kremlin-Bicêtre</city>
        <zip>94270</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Dupuytren</name>
      <address>
        <city>Limoges</city>
        <zip>87042</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Louis Pradel</name>
      <address>
        <city>Lyon</city>
        <zip>69677</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Timone Adultes</name>
      <address>
        <city>Marseille</city>
        <zip>13005</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Arnaud de Villeneuve</name>
      <address>
        <city>Montpellier</city>
        <zip>34929</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHR La Miletrie</name>
      <address>
        <city>Poitiers</city>
        <zip>86021</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Robert Debré</name>
      <address>
        <city>Reims</city>
        <zip>51092</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Pontchaillou</name>
      <address>
        <city>Rennes</city>
        <zip>35033</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Charles Nicolle</name>
      <address>
        <city>Rouen</city>
        <zip>76031</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Nord</name>
      <address>
        <city>Saint-Priest-en-Jarez</city>
        <zip>42277</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Civil</name>
      <address>
        <city>Strasbourg</city>
        <zip>67091</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Larrey</name>
      <address>
        <city>Toulouse</city>
        <zip>31059</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Bretonneau</name>
      <address>
        <city>Tours</city>
        <zip>37044</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <link>
    <url>https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-002078-19/results</url>
    <description>Clinical study evaluating the effects of first-line oral combination therapy of macitentan and tadalafil in patients with newly diagnosed pulmonary arterial hypertension (OPTIMA)</description>
  </link>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>November 14, 2016</study_first_submitted>
  <study_first_submitted_qc>November 17, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 21, 2016</study_first_posted>
  <last_update_submitted>October 4, 2019</last_update_submitted>
  <last_update_submitted_qc>October 4, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 8, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pulmonary Arterial Hypertension</mesh_term>
    <mesh_term>Familial Primary Pulmonary Hypertension</mesh_term>
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tadalafil</mesh_term>
    <mesh_term>Macitentan</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02968901
org study id: AC-055-405
nct id: NCT02968901
lead sponsor: 
has dmc: No
The purpose of the study is to document the effect of first line dual oral combination
      therapy with macitentan 10mg and tadalafil 40mg on pulmonary vascular resistance (PVR) in
      treatment-naïve patients with newly diagnosed pulmonary arterial hypertension (PAH).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: pulmonary vascular resistance (PVR)
time frame: 16 weeks
description: Change from Baseline to Week 16 in percentage of patients with clinically meaningful improvement of PVR (decrease of 30% from baseline to Week 16)
measure: mean right atrial pressure (mRAP)
time frame: Week 16
description: Change from Baseline to Week 16 in mean right atrial pressure (mRAP)
measure: 6MWD
time frame: Week 16
description: Change from Baseline to Week 16 in 6MWD
measure: level NT-proBNP
time frame: Week 16
description: Change in NT-proBNP from baseline to Week 16
measure: mean pulmonary arterial pressure (mPAP)
time frame: Week 16
description: Change from Baseline to Week 16 in mean pulmonary arterial pressure (mPAP)
measure: cardiac index (CI)
time frame: Week 16
description: Change from Baseline to Week 16 in cardiac index (CI).
measure: total pulmonary resistance (TPR)
time frame: Week 16
description: Change from Baseline to Week 16 in total pulmonary resistance (TPR)
measure: mixed venous oxygen saturation (Sv02)
time frame: Week 16
description: Change from Baseline to Week 16 in mixed venous oxygen saturation (Sv02)
measure: WHO functional class
time frame: Week 16
description: Change from baseline to Week 16 in WHO functional class and Percentage of patients with improvement/worsening of WHO functional class from baseline to Week 16
measure: Number of treatment goals
time frame: Week 16
description: Number of treatment goals (score 0 or 1 per goal, i.e. total score 0-5) met at Week 16: WHO-FC I or II; Cardiac index > 2.8 L/min/m²; mRAP < 8 mmHg; 6MWD > 400 m; NT-proBNP < 3xULN
arm group label: bitherapy
arm group type: Experimental
description: Macitentan and tadalafil
intervention type: Drug
intervention name: macitentan
description: used in open label
arm group label: bitherapy
intervention type: Drug
intervention name: tadalafil
description: used in open label
arm group label: bitherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: France
url: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-002078-19/results
description: Clinical study evaluating the effects of first-line oral combination therapy of macitentan and tadalafil in patients with newly diagnosed pulmonary arterial hypertension (OPTIMA)
responsible party type: Sponsor
mesh term: Pulmonary Arterial Hypertension
mesh term: Familial Primary Pulmonary Hypertension
mesh term: Hypertension
mesh term: Tadalafil
mesh term: Macitentan
sharing ipd: Undecided