<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/NCT03251872</url>
  </required_header>
  <id_info>
    <org_study_id>CER-21658</org_study_id>
    <nct_id>NCT03251872</nct_id>
  </id_info>
  <brief_title>Olaparib for PAH: a Pilot Study</brief_title>
  <acronym>OPTION-p</acronym>
  <official_title>Olaparib for Pulmonary Arterial Hypertension: a Pilot Clinical Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Laval University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Laval University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </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. The industry-sponsored clinical research&#xD;
      on PARP1 inhibitor is currently entirely cancer-oriented. Nonetheless, AstraZeneca Canada&#xD;
      accepted to support an early phase clinical trial through in-kind contribution, but the&#xD;
      support from foundations and federal agencies is critical to catalyze early-stage development&#xD;
      of PARP1 inhibitors for other indications, especially for orphan diseases. A CIHR Project&#xD;
      Scheme grant will thus be submitted on September 15 2017, proposing a Phase 1, followed by a&#xD;
      Phase 2 trial that will be conducted in recognized PAH programs throughout Canada. At this&#xD;
      stage, however, we propose a pilot study to assess the feasibility of the proposed trials in&#xD;
      the PAH population. The overall HYPOTHESIS is that PARP1 inhibition with olaparib is a safe&#xD;
      and effective therapy for PAH.&#xD;
&#xD;
      The primary objective of the study is to confirm feasibility, to support the safety of using&#xD;
      olaparib in PAH patients, and precise the sample size of the coming Phase 1B trial. The&#xD;
      feasibility of the comprehensive patient phenotyping that will be proposed within the phase&#xD;
      1B trial will thus be assessed, in addition to adverse events and efficacy signals.&#xD;
&#xD;
      ***OPTION pilot trial was merged with the new OPTION multicenter trial (NCT03782818)***&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND PAH is a progressive and multifactorial condition characterized by the chronic&#xD;
      elevation of pulmonary artery (PA) pressure leading to RV failure. In spite of currently&#xD;
      approved therapies, patients with PAH have poor quality of life and the 3-year survival of&#xD;
      idiopathic PAH remains ~55%. The identification and characterization of new therapeutic&#xD;
      targets is thus an urgent need.&#xD;
&#xD;
      In recent years, it has become increasingly appreciated that, as in cancer cells, PAH-PA&#xD;
      smooth muscle cells (PASMCs) are exposed to stressful conditions, jeopardizing their&#xD;
      survival. To deal with these insults, these cells have developed complementary pathways,&#xD;
      allowing them to survive and proliferate and leading to intense remodelling of distal PA.&#xD;
      Central to these strategies are the activation of the DNA repair machinery. Survival of these&#xD;
      cells is associated with an over-efficient activation of PAPR1, a predominant mechanism&#xD;
      involved in DNA repair, and pharmacological inhibition of PARP1 reverses PAH in human cells&#xD;
      and clinically relevant animal models.&#xD;
&#xD;
      Recently, Olaparib, an orally available PARP1 inhibitor, was shown to be safe, well tolerated&#xD;
      and effective in treating cancers and was approved for the treatment of ovarian cancer.&#xD;
&#xD;
      OLAPARIB IN PAH: A PILOT STUDY The study population will include 6 well-characterized PAH&#xD;
      patients that have been stable for &gt;4 months on standard PAH-therapies, as per guidelines.&#xD;
&#xD;
      The primary objective of the study is to confirm the feasibility for a future early stage&#xD;
      clinical trial and provide early evidence that Olaparib may be effective in PAH.&#xD;
&#xD;
      Exploratory efficacy end-point: The exploratory efficacy endpoint will be the change in&#xD;
      pulmonary vascular resistance (PVR) at week 16. Other exploratory efficacy end-points will&#xD;
      include changes in: 1) additional haemodynamic data by catheterization; 2) 6-min walk&#xD;
      distance (6MWD); 3) RV volumes and mass (cardiac MRI) in eligible patients; 4) WHO functional&#xD;
      class; 5) NT-proBNP levels; 6) Quality of life assessed using the CAMPHOR questionnaire.&#xD;
&#xD;
      Study design: This is a standard-design, dose-escalating pilot study. In line with most pilot&#xD;
      and safety studies, the design is open-label. A 4-week pre-treatment phase will allow&#xD;
      ensuring that patients are on stable doses of medication. Patients will be given progressive&#xD;
      doses of olaparib up to 400mg BID for 16 weeks. Patients will be regularly followed. At&#xD;
      baseline and week 16, a cardiac catheterization and MRI will assess changes in pulmonary&#xD;
      hemodynamics and RV function.&#xD;
&#xD;
      Toxicity monitoring/withdrawal: Based on experience to date with olaparib, doses up to 400mg&#xD;
      BID should be tolerated. Subjects may experience mild side effects or other events that the&#xD;
      investigator may consider related to study drug but not of sufficient clinical significance&#xD;
      to warrant withdrawal from treatment. At the investigators' discretion, olaparib may be&#xD;
      managed by dose reduction. If the lower dose is not tolerated, the patient will be withdrawn&#xD;
      from the study. Subjects who require a dose reduction should be maintained at the reduced&#xD;
      dose level through to the end of the 16-week treatment period. Adverse events will be&#xD;
      submitted to our ethics committees.&#xD;
&#xD;
      Analysis: This pilot study is not meant to prove efficacy. As a result, power calculations&#xD;
      were not determined. The safety and exploratory endpoint analysis will be only descriptive.&#xD;
      Nonetheless, it is hoped that olaparib will be associated with hemodynamic improvements,&#xD;
      giving precision about the dose to be tested and sample size calculation for subsequent&#xD;
      studies. Thus, there is a need for assessment of the exploratory efficacy endpoints. These&#xD;
      analyses will be based on the per protocol set (all treated patients who did not violate the&#xD;
      protocol in a way that might influence the evaluation of the effect of the study drug on the&#xD;
      primary endpoint).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    OPTION pilot trial merged with the new NCT03782818 - OPTION multicenter trial&#xD;
  </why_stopped>
  <start_date type="Actual">October 25, 2018</start_date>
  <completion_date type="Actual">December 1, 2019</completion_date>
  <primary_completion_date type="Actual">December 1, 2019</primary_completion_date>
  <phase>Early Phase 1</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 400mg BID for 16 weeks.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in pulmonary vascular resistance (PVR) at week 16</measure>
    <time_frame>16 weeks</time_frame>
    <description>At baseline and week 16, a cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function</description>
  </primary_outcome>
  <other_outcome>
    <measure>Additional haemodynamic data by catheterization</measure>
    <time_frame>At baseline and week 16</time_frame>
    <description>A cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function</description>
  </other_outcome>
  <other_outcome>
    <measure>6-min walk distance (6MWD)</measure>
    <time_frame>At baseline and week 16</time_frame>
    <description>The six-minute walk test (6MWT) measures the distance (6MWD) that a person can quickly walk on a flat, hard surface in 6 min.</description>
  </other_outcome>
  <other_outcome>
    <measure>RV volumes and mass (cardiac MRI)</measure>
    <time_frame>At baseline and week 16</time_frame>
    <description>A cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function</description>
  </other_outcome>
  <other_outcome>
    <measure>WHO functional class</measure>
    <time_frame>At baseline and week 16</time_frame>
    <description>Assesses the severity of the disease using a range of clinical assessments, exercise tests, biochemical markers, and echocardiographic and haemodynamic assessments. The clinical assessment of the patient has a pivotal role in the choice of the initial treatment, the evaluation of the response to therapy, and the possible escalation of therapy if needed. The clinical severity of PAH is classified by the World Health Organization (WHO) according to a system that grades PAH severity according to the functional status of the patient. The grades range from Functional Class (FC) I, where the patient's disease does not affect their day-to-day activities, to FC IV, where patients are severely functionally impaired, even at rest. This functional classification system links symptoms with activity limitations, and allows clinicians to quickly predict disease progression and prognosis, as well as the need for specific treatment regimens, irrespective of the underlying aetiology of PAH.</description>
  </other_outcome>
  <other_outcome>
    <measure>NT-proBNP levels</measure>
    <time_frame>At baseline and week 16</time_frame>
    <description>Blood test. B-type natriuretic peptide (brain natriuretic peptide: BNP) is a small, ringed peptide secreted by the heart to regulate blood pressure and fluid balance. This peptide is stored in and secreted predominantly from membrane granules in the heart ventricles in a pro form (proBNP). Once released from the heart in response to ventricle volume expansion or pressure overload, the N-terminal (NT) piece of 76 amino acids (NT-proBNP) is rapidly cleaved by the enzymes corin and furin to release the active 32-amino acid peptide (BNP). Both BNP and NT-proBNP are markers of atrial and ventricular distension due to increased intracardiac pressure.</description>
  </other_outcome>
  <other_outcome>
    <measure>Quality of life - Clinical deterioration</measure>
    <time_frame>At baseline and week 16</time_frame>
    <description>Assessed using the CAMPHOR questionnaire</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Pulmonary Arterial Hypertension</condition>
  <arm_group>
    <arm_group_label>Drug: Olaparib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Olaparib up to 400 mg BID (100 to 400 mg) for 16 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Olaparib</intervention_name>
    <description>Olaparib tablets</description>
    <arm_group_label>Drug: Olaparib</arm_group_label>
    <other_name>Lynparza</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  1) adults (18-75 yrs) with PAH of idiopathic/ hereditary/drug or toxin-induced origin&#xD;
             or associated with connective tissue diseases; 2) mean PA pressure ≥25mmHg, PA wedge&#xD;
             pressure ≤15mmHg, PVR &gt;480 dyn.s.cm-5 and absence of acute vasoreactivity (we expect&#xD;
             PARP1 inhibition will be most effective in patients with significant PA remodelling);&#xD;
             3) WHO functional class II or III; 4) clinically stable with unchanged vasoactive&#xD;
             therapy for ≥4 months; 5) two 6MWD of 150-550m and within ±15% of each other (the&#xD;
             latter being used as baseline value); 6) a negative serum pregnancy test prior to&#xD;
             receiving the first dose of study treatment and willing to use adequate contraception&#xD;
             from enrolment through 3 months after the last dose of study treatment for patients of&#xD;
             childbearing potential&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  1) other types of pulmonary hypertension; 2) significant restrictive (total lung&#xD;
             capacity &lt;60% predicted) or obstructive (FEV1/FVC&lt;60% after a bronchodilator) lung&#xD;
             disease; 3) systolic blood pressure &lt;90 mmHg; 4) acute RV failure within the last 3&#xD;
             months; 5) received any investigational drug within 30 days; 6) BMI &lt;18 or &gt;40 kg/m2;&#xD;
             7) cardiopulmonary rehabilitation program planned or started ≤12 weeks prior to Day 1;&#xD;
             8) presence of ≥3 risk factors for heart failure with preserved ejection fraction (BMI&#xD;
             &gt;30 kg/m2, diabetes mellitus, hypertension or coronary artery disease); 9) organ&#xD;
             dysfunction other than RV failure; 10) anticipated survival &lt;1 year due to concomitant&#xD;
             disease&#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, FAHA</last_name>
    <role>Principal Investigator</role>
    <affiliation>IUCPQ-UL</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>IUCPQ-UL</name>
      <address>
        <city>Quebec City</city>
        <state>Quebec</state>
        <zip>G1V 4G5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <link>
    <url>https://clinicaltrials.gov/ct2/show/NCT03782818?term=NCT03782818&amp;draw=2&amp;rank=1</url>
    <description>OPTION pilot trial merged to a new multicenter trial (OPTION multicenter - NTC03782818)</description>
  </link>
  <reference>
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    <citation>Federici C, Drake KM, Rigelsky CM, McNelly LN, Meade SL, Comhair SA, Erzurum SC, Aldred MA. Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2015 Jul 15;192(2):219-28. doi: 10.1164/rccm.201411-2128OC.</citation>
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    <citation>Happe CM, Szulcek R, Voelkel NF, Bogaard HJ. Reconciling paradigms of abnormal pulmonary blood flow and quasi-malignant cellular alterations in pulmonary arterial hypertension. Vascul Pharmacol. 2016 Aug;83:17-25. doi: 10.1016/j.vph.2016.01.004. Epub 2016 Jan 22.</citation>
    <PMID>26804008</PMID>
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    <citation>Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, Langleben D, Manes A, Satoh T, Torres F, Wilkins MR, Badesch DB. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D42-50. doi: 10.1016/j.jacc.2013.10.032.</citation>
    <PMID>24355641</PMID>
  </reference>
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    <citation>Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012 Apr 12;366(15):1382-92. doi: 10.1056/NEJMoa1105535. Epub 2012 Mar 27.</citation>
    <PMID>22452356</PMID>
  </reference>
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    <citation>Li M, Vattulainen S, Aho J, Orcholski M, Rojas V, Yuan K, Helenius M, Taimen P, Myllykangas S, De Jesus Perez V, Koskenvuo JW, Alastalo TP. Loss of bone morphogenetic protein receptor 2 is associated with abnormal DNA repair in pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2014 Jun;50(6):1118-28. doi: 10.1165/rcmb.2013-0349OC.</citation>
    <PMID>24433082</PMID>
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    <citation>Meloche J, Le Guen M, Potus F, Vinck J, Ranchoux B, Johnson I, Antigny F, Tremblay E, Breuils-Bonnet S, Perros F, Provencher S, Bonnet S. miR-223 reverses experimental pulmonary arterial hypertension. Am J Physiol Cell Physiol. 2015 Sep 15;309(6):C363-72. doi: 10.1152/ajpcell.00149.2015. Epub 2015 Jun 17.</citation>
    <PMID>26084306</PMID>
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    <citation>Meloche J, Pflieger A, Vaillancourt M, Paulin R, Potus F, Zervopoulos S, Graydon C, Courboulin A, Breuils-Bonnet S, Tremblay E, Couture C, Michelakis ED, Provencher S, Bonnet S. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation. 2014 Feb 18;129(7):786-97. doi: 10.1161/CIRCULATIONAHA.113.006167. Epub 2013 Nov 22.</citation>
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    <citation>Park ES, Kang DH, Kang JC, Jang YC, Lee MJ, Chung HJ, Yi KY, Kim DE, Kim B, Shin HS. Cardioprotective effect of KR-33889, a novel PARP inhibitor, against oxidative stress-induced apoptosis in H9c2 cells and isolated rat hearts. Arch Pharm Res. 2017 May;40(5):640-654. doi: 10.1007/s12272-017-0912-3. Epub 2017 Apr 4.</citation>
    <PMID>28378219</PMID>
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    <citation>Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014 Jun 20;115(1):165-75. doi: 10.1161/CIRCRESAHA.113.301141.</citation>
    <PMID>24951765</PMID>
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    <citation>Ramsey BW, Nepom GT, Lonial S. Academic, Foundation, and Industry Collaboration in Finding New Therapies. N Engl J Med. 2017 May 4;376(18):1762-1769. doi: 10.1056/NEJMra1612575. No abstract available.</citation>
    <PMID>28467868</PMID>
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    <citation>Ranchoux B, Meloche J, Paulin R, Boucherat O, Provencher S, Bonnet S. DNA Damage and Pulmonary Hypertension. Int J Mol Sci. 2016 Jun 22;17(6):990. doi: 10.3390/ijms17060990.</citation>
    <PMID>27338373</PMID>
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    <citation>Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D34-41. doi: 10.1016/j.jacc.2013.10.029. Erratum In: J Am Coll Cardiol. 2014 Feb 25;63(7):746. J Am Coll Cardiol. 2014 Feb 25;63(7):746.</citation>
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  <verification_date>August 2020</verification_date>
  <study_first_submitted>August 13, 2017</study_first_submitted>
  <study_first_submitted_qc>August 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 16, 2017</study_first_posted>
  <last_update_submitted>August 24, 2020</last_update_submitted>
  <last_update_submitted_qc>August 24, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 26, 2020</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>Early-phase clinical trial pilot 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>
  <!-- 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/NCT03251872
org study id: CER-21658
nct id: NCT03251872
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: 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 industry-sponsored clinical research
      on PARP1 inhibitor is currently entirely cancer-oriented. Nonetheless, AstraZeneca Canada
      accepted to support an early phase clinical trial through in-kind contribution, but the
      support from foundations and federal agencies is critical to catalyze early-stage development
      of PARP1 inhibitors for other indications, especially for orphan diseases. A CIHR Project
      Scheme grant will thus be submitted on September 15 2017, proposing a Phase 1, followed by a
      Phase 2 trial that will be conducted in recognized PAH programs throughout Canada. At this
      stage, however, we propose a pilot study to assess the feasibility of the proposed trials in
      the PAH population. The overall HYPOTHESIS is that PARP1 inhibition with olaparib is a safe
      and effective therapy for PAH.

      The primary objective of the study is to confirm feasibility, to support the safety of using
      olaparib in PAH patients, and precise the sample size of the coming Phase 1B trial. The
      feasibility of the comprehensive patient phenotyping that will be proposed within the phase
      1B trial will thus be assessed, in addition to adverse events and efficacy signals.

      ***OPTION pilot trial was merged with the new OPTION multicenter trial (NCT03782818)***
BACKGROUND PAH is a progressive and multifactorial condition characterized by the chronic
      elevation of pulmonary artery (PA) pressure leading to RV failure. In spite of currently
      approved therapies, patients with PAH have poor quality of life and the 3-year survival of
      idiopathic PAH remains ~55%. The identification and characterization of new therapeutic
      targets is thus an urgent need.

      In recent years, it has become increasingly appreciated that, as in cancer cells, PAH-PA
      smooth muscle cells (PASMCs) are exposed to stressful conditions, jeopardizing their
      survival. To deal with these insults, these cells have developed complementary pathways,
      allowing them to survive and proliferate and leading to intense remodelling of distal PA.
      Central to these strategies are the activation of the DNA repair machinery. Survival of these
      cells is associated with an over-efficient activation of PAPR1, a predominant mechanism
      involved in DNA repair, and pharmacological inhibition of PARP1 reverses PAH in human cells
      and clinically relevant animal models.

      Recently, Olaparib, an orally available PARP1 inhibitor, was shown to be safe, well tolerated
      and effective in treating cancers and was approved for the treatment of ovarian cancer.

      OLAPARIB IN PAH: A PILOT STUDY The study population will include 6 well-characterized PAH
      patients that have been stable for >4 months on standard PAH-therapies, as per guidelines.

      The primary objective of the study is to confirm the feasibility for a future early stage
      clinical trial and provide early evidence that Olaparib may be effective in PAH.

      Exploratory efficacy end-point: The exploratory efficacy endpoint will be the change in
      pulmonary vascular resistance (PVR) at week 16. Other exploratory efficacy end-points will
      include changes in: 1) additional haemodynamic data by catheterization; 2) 6-min walk
      distance (6MWD); 3) RV volumes and mass (cardiac MRI) in eligible patients; 4) WHO functional
      class; 5) NT-proBNP levels; 6) Quality of life assessed using the CAMPHOR questionnaire.

      Study design: This is a standard-design, dose-escalating pilot study. In line with most pilot
      and safety studies, 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 400mg BID for 16 weeks. Patients will be regularly followed. At
      baseline and week 16, a cardiac catheterization and MRI will assess changes in pulmonary
      hemodynamics and RV function.

      Toxicity monitoring/withdrawal: Based on experience to date with olaparib, doses up to 400mg
      BID should be tolerated. Subjects may experience mild side effects or other events that the
      investigator may consider related to study drug but not of sufficient clinical significance
      to warrant withdrawal from treatment. At the investigators' discretion, olaparib may be
      managed by dose reduction. If the lower dose is not tolerated, the patient will be withdrawn
      from the study. Subjects who require a dose reduction should be maintained at the reduced
      dose level through to the end of the 16-week treatment period. Adverse events will be
      submitted to our ethics committees.

      Analysis: This pilot study is not meant to prove efficacy. As a result, power calculations
      were not determined. The safety and exploratory endpoint analysis will be only descriptive.
      Nonetheless, it is hoped that olaparib will be associated with hemodynamic improvements,
      giving precision about the dose to be tested and sample size calculation for subsequent
      studies. Thus, there is a need for assessment of the exploratory efficacy endpoints. These
      analyses will be based on the per protocol set (all treated patients who did not violate the
      protocol in a way that might influence the evaluation of the effect of the study drug on the
      primary endpoint).
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 400mg BID for 16 weeks.
primary purpose: Treatment
masking: None (Open Label)
measure: Change in pulmonary vascular resistance (PVR) at week 16
time frame: 16 weeks
description: At baseline and week 16, a cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function
measure: Additional haemodynamic data by catheterization
time frame: At baseline and week 16
description: A cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function
measure: 6-min walk distance (6MWD)
time frame: At baseline and week 16
description: The six-minute walk test (6MWT) measures the distance (6MWD) that a person can quickly walk on a flat, hard surface in 6 min.
measure: RV volumes and mass (cardiac MRI)
time frame: At baseline and week 16
description: A cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function
measure: WHO functional class
time frame: At baseline and week 16
description: Assesses the severity of the disease using a range of clinical assessments, exercise tests, biochemical markers, and echocardiographic and haemodynamic assessments. The clinical assessment of the patient has a pivotal role in the choice of the initial treatment, the evaluation of the response to therapy, and the possible escalation of therapy if needed. The clinical severity of PAH is classified by the World Health Organization (WHO) according to a system that grades PAH severity according to the functional status of the patient. The grades range from Functional Class (FC) I, where the patient's disease does not affect their day-to-day activities, to FC IV, where patients are severely functionally impaired, even at rest. This functional classification system links symptoms with activity limitations, and allows clinicians to quickly predict disease progression and prognosis, as well as the need for specific treatment regimens, irrespective of the underlying aetiology of PAH.
measure: NT-proBNP levels
time frame: At baseline and week 16
description: Blood test. B-type natriuretic peptide (brain natriuretic peptide: BNP) is a small, ringed peptide secreted by the heart to regulate blood pressure and fluid balance. This peptide is stored in and secreted predominantly from membrane granules in the heart ventricles in a pro form (proBNP). Once released from the heart in response to ventricle volume expansion or pressure overload, the N-terminal (NT) piece of 76 amino acids (NT-proBNP) is rapidly cleaved by the enzymes corin and furin to release the active 32-amino acid peptide (BNP). Both BNP and NT-proBNP are markers of atrial and ventricular distension due to increased intracardiac pressure.
measure: Quality of life - Clinical deterioration
time frame: At baseline and week 16
description: Assessed using the CAMPHOR questionnaire
arm group label: Drug: Olaparib
arm group type: Experimental
description: Olaparib up to 400 mg BID (100 to 400 mg) for 16 weeks
intervention type: Drug
intervention name: Olaparib
description: Olaparib tablets
arm group label: Drug: 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, FAHA
role: Principal Investigator
affiliation: IUCPQ-UL
facility: 
country: Canada
url: https://clinicaltrials.gov/ct2/show/NCT03782818?term=NCT03782818&draw=2&rank=1
description: OPTION pilot trial merged to a new multicenter trial (OPTION multicenter - NTC03782818)
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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