<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/NCT03782818</url>
  </required_header>
  <id_info>
    <org_study_id>CER-21724</org_study_id>
    <nct_id>NCT03782818</nct_id>
  </id_info>
  <brief_title>Olaparib for PAH: a Multicenter Clinical Trial</brief_title>
  <acronym>OPTION</acronym>
  <official_title>Olaparib for Pulmonary Arterial Hypertension: a Multicenter Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Laval University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Canadian Institutes of Health Research (CIHR)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Laval University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The main OBJECTIVE of this proposal is to extend our preclinical findings on the role of DNA&#xD;
      damage and poly(ADP-ribose) polymerases (PARP) inhibition as a therapy for a devastating&#xD;
      disease, pulmonary arterial hypertension (PAH), to early-phase clinical trials. We, and&#xD;
      others, have published strong evidence that DNA damage accounts for disease progression in&#xD;
      PAH and showed that PARP1 inhibition can reverse PAH in several animal models1.&#xD;
      Interestingly, PARP1 inhibition is also cardioprotective. Olaparib, an orally available PARP1&#xD;
      inhibitor, can reverse cancer growth in animals and humans with a good safety profile, and is&#xD;
      now approved for the treatment of ovarian cancer in Canada, Europe and the USA. The time is&#xD;
      thus right to translate our findings in human PAH.&#xD;
&#xD;
      The primary objective of this Phase 1B study is to confirm the safety of using olaparib in&#xD;
      PAH patients, and precise the sample size of a future Phase 2 trial. In addition to safety,&#xD;
      efficacy signals will thus be assessed.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Overall, 20 well-characterized PAH patients that have been stable for &gt;4 months on standard&#xD;
      PAH-therapies, as per guidelines will be recruited. The initial Health Canada approval will&#xD;
      be obtained. Olaparib will be provided by AstraZeneca Canada, but AZ had no input into the&#xD;
      trial design and will not be involved in the conduct of the trial, analysis, interpretation&#xD;
      of the results or the final manuscript.&#xD;
&#xD;
      A 4-week pre-treatment phase will allow ensuring that patients are on stable doses of PAH&#xD;
      medication.&#xD;
&#xD;
      Given that PAH is a chronic disease and that patients may be at higher risk for drug-related&#xD;
      adverse events (e.g. anemia), olaparib will be started at low-dose (100mg BID), then&#xD;
      up-titrated weekly by 100mg BID up to 200mg BID (n=5, group 1) or 300mg BID (n=15, group 2)&#xD;
      for a total treatment duration (including the up-titration phase) of 24 weeks. Using 100mg&#xD;
      and 150mg tablets will allow minimizing the number of tablets taken (e.g. 2 x 150mg tablets&#xD;
      BID) or adjusting the dose in case of drug-related adverse events (e.g. 250mg BID using 100mg&#xD;
      and 150mg tablets).&#xD;
&#xD;
      Patients will be regularly followed to assess whether side effects are observed and whether&#xD;
      olaparib can be up-titrated.&#xD;
&#xD;
      At baseline and week 24, a cardiac catheterization will assess changes in pulmonary&#xD;
      hemodynamics and RV function.&#xD;
&#xD;
      An end-of-study visit is planned at week 28 week.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 20, 2019</start_date>
  <completion_date type="Anticipated">March 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</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>
    <intervention_model_description>The design is open-label. A 4-week pre-treatment phase will allow ensuring that patients are on stable doses of medication. Patients will be given progressive doses of olaparib up to 300mg BID for 24 weeks.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Occurrence of treatment-emergent AEs at week 24</measure>
    <time_frame>Week 24</time_frame>
    <description>Description of treatment-emergent AEs leading to premature discontinuation of the study treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>6-min walk test (6MWT)</measure>
    <time_frame>At baseline and visits 1, 3, 4, 5 and 6.</time_frame>
    <description>The 6-minute walk test (6MWT) is a non-encouraged test which measures the distance in meters covered over a 6-minute walk.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>WHO functional class</measure>
    <time_frame>At baseline and visits 1, 3, 4, 5, 6 and 7.</time_frame>
    <description>WHO FC is a classification, which reflects disease severity based on symptoms. It is also a clinically relevant marker of prognosis and functional status.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NT-proBNP levels</measure>
    <time_frame>At baseline and visits 1, 3, 4, 5 and 6.</time_frame>
    <description>NT-proBNP correlates with severity of RV failure in PAH, elevated or increasing plasma levels being associated with a worse prognosis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health related Quality of Life (HRQoL)</measure>
    <time_frame>Visit 1 and visit 6</time_frame>
    <description>The CAMPHOR is a PAH-specific QoL measure validated for the Canadian English and French languages. It has been used in numerous PAH trials.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Pulmonary Arterial Hypertension</condition>
  <arm_group>
    <arm_group_label>Olaparib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>After a 4-week pre-treatment phase to ensure that patients are on stable doses of PAH medication, patients will be given progressive doses of olaparib up to 300 mg BID for 24 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Olaparib</intervention_name>
    <description>Olaparib up to 300 mg BID for 24 weeks</description>
    <arm_group_label>Olaparib</arm_group_label>
    <other_name>Lynparza</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Informed consent:&#xD;
&#xD;
               1. Capable of giving signed informed consent, which includes compliance with the&#xD;
                  requirements and restrictions listed in the informed consent form (ICF) and in&#xD;
                  this protocol.&#xD;
&#xD;
               2. Provision of signed and dated, written informed consent form prior to any&#xD;
                  mandatory study specific procedures, sampling, and analyses.&#xD;
&#xD;
          -  Type of patient and disease characteristics:&#xD;
&#xD;
               1. PAH of idiopathic/ hereditary/drug or toxin-induced origin or associated with&#xD;
                  connective tissue diseases;&#xD;
&#xD;
               2. Mean PA pressure ≥25mmHg, PA wedge pressure ≤15mmHg, PVR &gt;480 dyn.s.cm-5 and&#xD;
                  absence of acute vasoreactivity (we expect PARP1 inhibition will be most&#xD;
                  effective in patients with significant PA remodelling);&#xD;
&#xD;
               3. WHO functional class II or III, which is the traditional inclusion criteria in&#xD;
                  all PAH RCT);&#xD;
&#xD;
               4. Clinically stable with unchanged vasoactive therapy for ≥4 months; 5) two 6MWD of&#xD;
                  ≥150m and within ±15% of each other (the latter being used as baseline value);&#xD;
&#xD;
               5. Patients must have normal organ and bone marrow function measured within 28 days&#xD;
                  prior to administration of study treatment as defined below:&#xD;
&#xD;
                    -  Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days&#xD;
&#xD;
                    -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L&#xD;
&#xD;
                    -  Platelet count ≥ 100 x 109/L&#xD;
&#xD;
                    -  Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)&#xD;
&#xD;
                    -  Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase&#xD;
                       (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate&#xD;
                       Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal&#xD;
&#xD;
                    -  Patients must have creatinine clearance estimated of ≥51 mL/min using the&#xD;
                       Cockcroft-Gault equation or based on a 24 hour urine test :&#xD;
&#xD;
                  Estimated creatinine clearance =( [(140-age [years]) x weight (kg)] / [serum&#xD;
                  creatinine (mg/dL) x 72]) (x F); (where F=0.85 for females and F=1 for males).&#xD;
&#xD;
               6. Patients must have a life expectancy ≥ 28 weeks.&#xD;
&#xD;
          -  Weight: Body mass index (BMI) within the range 18-40 kg/m2 (inclusive).&#xD;
&#xD;
          -  Reproduction:&#xD;
&#xD;
               1. Postmenopausal or evidence of non-childbearing status for women of childbearing&#xD;
                  potential: negative urine or serum pregnancy test within 28 days of study&#xD;
                  treatment and confirmed prior to treatment on day 1.&#xD;
&#xD;
                  Postmenopausal is defined as:&#xD;
&#xD;
                    -  Amenorrheic for 1 year or more following cessation of exogenous hormonal&#xD;
                       treatments&#xD;
&#xD;
                    -  Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in&#xD;
                       the post menopausal range for women under 50&#xD;
&#xD;
                    -  surgical sterilisation (bilateral oophorectomy or hysterectomy)&#xD;
&#xD;
               2. Male patients must use a condom during treatment and for 3 months after the last&#xD;
                  dose of olaparib when having sexual intercourse with a pregnant woman or with a&#xD;
                  woman of childbearing potential. Female partners of male patients should also use&#xD;
                  a highly effective form of contraception if they are of childbearing potential.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Medical conditions&#xD;
&#xD;
               -  Other types of pulmonary hypertension [130], including pulmonary related to left&#xD;
                  heart diseases (group 2), lung diseases (group 3) or chronic thromboembolic&#xD;
                  disease (group 4);&#xD;
&#xD;
               -  Significant restrictive (total lung capacity &lt;60% predicted) or obstructive&#xD;
                  (FEV1/FVC&lt;60% after a bronchodilator) lung disease;&#xD;
&#xD;
               -  Systolic blood pressure &lt;90 mmHg;&#xD;
&#xD;
               -  Acute RV failure within the last 3 months;&#xD;
&#xD;
               -  Received any investigational drug within 30 days;&#xD;
&#xD;
               -  Cardiopulmonary rehabilitation program planned or started ≤12 weeks prior to Day&#xD;
                  1;&#xD;
&#xD;
               -  Presence of ≥3 risk factors for heart failure with preserved ejection fraction,&#xD;
                  including: - BMI &gt;30 kg/m2, - Diabetes mellitus, - Hypertension, - Coronary&#xD;
                  artery disease;&#xD;
&#xD;
               -  Other organ dysfunction other than RV failure including Childs-Pugh class B-C&#xD;
                  liver cirrhosis;&#xD;
&#xD;
               -  Recent cancer (&lt;1yr)&#xD;
&#xD;
               -  Recent bacterial infection (&lt;30 days);&#xD;
&#xD;
               -  History of hypertensive crisis;&#xD;
&#xD;
               -  Stage ≥1 systemic hypertension, defined as a systolic blood pressure ≥140mmHg or&#xD;
                  a diastolic blood pressure ≥90mmHg, or requiring anti-hypertensive therapies;&#xD;
&#xD;
               -  Resting ECG indicating uncontrolled, potentially reversible cardiac conditions,&#xD;
                  as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic&#xD;
                  arrhythmia, congestive heart failure, QTcF prolongation &gt;500 ms, electrolyte&#xD;
                  disturbances, etc.), or patients with congenital long QT syndrome.&#xD;
&#xD;
               -  Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features&#xD;
                  suggestive of MDS/AML.&#xD;
&#xD;
               -  Patients considered a poor medical risk due to a serious, uncontrolled medical&#xD;
                  disorder, non-malignant systemic disease or active, uncontrolled infection.&#xD;
                  Examples include, but are not limited to, uncontrolled ventricular arrhythmia,&#xD;
                  recent (within 3 months) myocardial infarction, uncontrolled major seizure&#xD;
                  disorder, unstable spinal cord compression, superior vena cava syndrome,&#xD;
                  extensive interstitial bilateral lung disease on High Resolution Computed&#xD;
                  Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining&#xD;
                  informed consent.&#xD;
&#xD;
               -  Patients unable to swallow orally administered medication and patients with&#xD;
                  gastrointestinal disorders likely to interfere with absorption of the study&#xD;
                  medication.&#xD;
&#xD;
               -  Immunocompromised patients, e.g., patients who are known to be serologically&#xD;
                  positive for human immunodeficiency virus (HIV).&#xD;
&#xD;
               -  Patients with known active hepatitis (i.e. Hepatitis B or C). Active hepatitis B&#xD;
                  virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result.&#xD;
                  Patients with a past or resolved HBV infection (defined as the presence of&#xD;
                  hepatitis B core antibody and absence of HBsAg) are eligible. Patients positive&#xD;
                  for hepatitis C virus (HCV) antibody are eligible only if polymerase chain&#xD;
                  reaction is negative for HCV RNA.&#xD;
&#xD;
          -  Prior/concomitant therapy&#xD;
&#xD;
               -  Any previous treatment with PARP inhibitor, including Olaparib.&#xD;
&#xD;
               -  Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole,&#xD;
                  telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or&#xD;
                  cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or&#xD;
                  moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem,&#xD;
                  fluconazole, verapamil). The required washout period prior to starting olaparib&#xD;
                  is 2 weeks.&#xD;
&#xD;
               -  Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin,&#xD;
                  rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort&#xD;
                  ) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required&#xD;
                  washout period prior to starting olaparib is 5 weeks for enzalutamide or&#xD;
                  phenobarbital and 3 weeks for other agents.&#xD;
&#xD;
               -  Major surgery within 2 weeks of starting study treatment and patients must have&#xD;
                  recovered from any effects of any major surgery.&#xD;
&#xD;
               -  Previous allogenic bone marrow transplant or double umbilical cord blood&#xD;
                  transplantation (dUCBT).&#xD;
&#xD;
               -  Whole blood transfusions in the last 120 days prior to entry to the study (packed&#xD;
                  red blood cells and platelet transfusions are acceptable, for timing refer to&#xD;
                  inclusion criteria no.7).&#xD;
&#xD;
          -  Prior/concurrent clinical study experience:&#xD;
&#xD;
               -  Participation in another clinical study with an investigational product&#xD;
                  administered in the last 3 months&#xD;
&#xD;
               -  Patients with a known hypersensitivity to olaparib or any of the excipients of&#xD;
                  the product.&#xD;
&#xD;
          -  Other exclusions&#xD;
&#xD;
               -  Judgment by the investigator that the patient should not participate in the study&#xD;
                  if the patient is unlikely to comply with study procedures, restrictions and&#xD;
                  requirements.&#xD;
&#xD;
               -  Breast feeding women.&#xD;
&#xD;
          -  Lifestyle restrictions:&#xD;
&#xD;
               -  Meals and dietary restrictions: It is prohibited to consume grapefruit juice&#xD;
                  while on olaparib therapy.&#xD;
&#xD;
               -  Activity: Women of childbearing potential and their partners, who are sexually&#xD;
                  active, must agree to the use of TWO highly effective forms of contraception in&#xD;
                  combination. This should be started from the signing of the informed consent and&#xD;
                  continue throughout the period of taking study treatment and for at least 1 month&#xD;
                  after last dose of study drug(s), or they must totally/truly abstain from any&#xD;
                  form of sexual intercourse.&#xD;
&#xD;
        Male patients must use a condom during treatment and for 3 months after the last dose of&#xD;
        olaparib when having sexual intercourse with a pregnant woman or with a woman of&#xD;
        childbearing potential. Female partners of male patients should also use a highly effective&#xD;
        form of contraception if they are of childbearing potential. Male patients should not&#xD;
        donate sperm throughout the period of taking olaparib and for 3 months following the last&#xD;
        dose of olaparib.&#xD;
&#xD;
        For details of acceptable methods of contraception refer to Appendix B Acceptable Birth&#xD;
        Control Methods.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Steeve Provencher, MD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>IUCPQ-UL</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Sébastien Bonnet, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>IUCPQ-UL</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Pascale Blais-Lecours, PhD</last_name>
    <role>Study Director</role>
    <affiliation>IUCPQ-UL</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Steeve Provencher, MD, MSc</last_name>
    <phone>418-656-4747</phone>
    <email>steve.provencher@criucpq.ulaval.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Pascale Blais-Lecours, PhD</last_name>
    <phone>418-656-8711</phone>
    <phone_ext>2651</phone_ext>
    <email>pascale.blais-lecours@criucpq.ulaval.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Alberta Hospital</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 2B7</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Linda Webster</last_name>
      <phone>780-407-8994</phone>
      <email>Linda.Webster@albertahealthservices.ca</email>
    </contact>
    <investigator>
      <last_name>Evangelos Michelakis, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UHN-Toronto General Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2C4</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Judy Lew</last_name>
      <phone>416-581-8586</phone>
      <email>judylew@uhnresearch.ca</email>
    </contact>
    <investigator>
      <last_name>John Granton, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>IUCPQ-UL</name>
      <address>
        <city>Quebec City</city>
        <state>Quebec</state>
        <zip>G1V4G5</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Luce Bouffard, RN</last_name>
      <phone>418-656-8711</phone>
      <phone_ext>2449</phone_ext>
      <email>luce.bouffard@criucpq.ulaval.ca</email>
    </contact>
    <investigator>
      <last_name>Steeve Provencher, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>December 17, 2018</study_first_submitted>
  <study_first_submitted_qc>December 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 20, 2018</study_first_posted>
  <last_update_submitted>April 17, 2023</last_update_submitted>
  <last_update_submitted_qc>April 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Laval University</investigator_affiliation>
    <investigator_full_name>Steeve Provencher</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Pulmonary Arterial Hypertension</keyword>
  <keyword>PAH</keyword>
  <keyword>poly (ADP-ribose) polymerases inhibition</keyword>
  <keyword>PARP-1 inhibition</keyword>
  <keyword>DNA damage</keyword>
  <keyword>Multicenter study</keyword>
  <keyword>Olaparib</keyword>
  <keyword>Safety and efficacy</keyword>
  <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>Olaparib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03782818
org study id: CER-21724
nct id: NCT03782818
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The main OBJECTIVE of this proposal is to extend our preclinical findings on the role of DNA
      damage and poly(ADP-ribose) polymerases (PARP) inhibition as a therapy for a devastating
      disease, pulmonary arterial hypertension (PAH), to early-phase clinical trials. We, and
      others, have published strong evidence that DNA damage accounts for disease progression in
      PAH and showed that PARP1 inhibition can reverse PAH in several animal models1.
      Interestingly, PARP1 inhibition is also cardioprotective. Olaparib, an orally available PARP1
      inhibitor, can reverse cancer growth in animals and humans with a good safety profile, and is
      now approved for the treatment of ovarian cancer in Canada, Europe and the USA. The time is
      thus right to translate our findings in human PAH.

      The primary objective of this Phase 1B study is to confirm the safety of using olaparib in
      PAH patients, and precise the sample size of a future Phase 2 trial. In addition to safety,
      efficacy signals will thus be assessed.
Overall, 20 well-characterized PAH patients that have been stable for >4 months on standard
      PAH-therapies, as per guidelines will be recruited. The initial Health Canada approval will
      be obtained. Olaparib will be provided by AstraZeneca Canada, but AZ had no input into the
      trial design and will not be involved in the conduct of the trial, analysis, interpretation
      of the results or the final manuscript.

      A 4-week pre-treatment phase will allow ensuring that patients are on stable doses of PAH
      medication.

      Given that PAH is a chronic disease and that patients may be at higher risk for drug-related
      adverse events (e.g. anemia), olaparib will be started at low-dose (100mg BID), then
      up-titrated weekly by 100mg BID up to 200mg BID (n=5, group 1) or 300mg BID (n=15, group 2)
      for a total treatment duration (including the up-titration phase) of 24 weeks. Using 100mg
      and 150mg tablets will allow minimizing the number of tablets taken (e.g. 2 x 150mg tablets
      BID) or adjusting the dose in case of drug-related adverse events (e.g. 250mg BID using 100mg
      and 150mg tablets).

      Patients will be regularly followed to assess whether side effects are observed and whether
      olaparib can be up-titrated.

      At baseline and week 24, a cardiac catheterization will assess changes in pulmonary
      hemodynamics and RV function.

      An end-of-study visit is planned at week 28 week.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: The design is open-label. A 4-week pre-treatment phase will allow ensuring that patients are on stable doses of medication. Patients will be given progressive doses of olaparib up to 300mg BID for 24 weeks.
primary purpose: Treatment
masking: None (Open Label)
measure: Occurrence of treatment-emergent AEs at week 24
time frame: Week 24
description: Description of treatment-emergent AEs leading to premature discontinuation of the study treatment.
measure: 6-min walk test (6MWT)
time frame: At baseline and visits 1, 3, 4, 5 and 6.
description: The 6-minute walk test (6MWT) is a non-encouraged test which measures the distance in meters covered over a 6-minute walk.
measure: WHO functional class
time frame: At baseline and visits 1, 3, 4, 5, 6 and 7.
description: WHO FC is a classification, which reflects disease severity based on symptoms. It is also a clinically relevant marker of prognosis and functional status.
measure: NT-proBNP levels
time frame: At baseline and visits 1, 3, 4, 5 and 6.
description: NT-proBNP correlates with severity of RV failure in PAH, elevated or increasing plasma levels being associated with a worse prognosis.
measure: Health related Quality of Life (HRQoL)
time frame: Visit 1 and visit 6
description: The CAMPHOR is a PAH-specific QoL measure validated for the Canadian English and French languages. It has been used in numerous PAH trials.
arm group label: Olaparib
arm group type: Experimental
description: After a 4-week pre-treatment phase to ensure that patients are on stable doses of PAH medication, patients will be given progressive doses of olaparib up to 300 mg BID for 24 weeks.
intervention type: Drug
intervention name: Olaparib
description: Olaparib up to 300 mg BID for 24 weeks
arm group label: Olaparib
other name: Lynparza
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Steeve Provencher, MD, MSc
role: Principal Investigator
affiliation: IUCPQ-UL
last name: Sébastien Bonnet, PhD
role: Principal Investigator
affiliation: IUCPQ-UL
last name: Pascale Blais-Lecours, PhD
role: Study Director
affiliation: IUCPQ-UL
last name: Steeve Provencher, MD, MSc
phone: 418-656-4747
email: steve.provencher@criucpq.ulaval.ca
last name: Pascale Blais-Lecours, PhD
phone: 418-656-8711
phone ext: 2651
email: pascale.blais-lecours@criucpq.ulaval.ca
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: Laval University
investigator full name: Steeve Provencher
investigator title: Professor
mesh term: Pulmonary Arterial Hypertension
mesh term: Familial Primary Pulmonary Hypertension
mesh term: Hypertension
mesh term: Olaparib
sharing ipd: No