Olaparib for PAH: a Multicenter Clinical Trial

• Informed consent:

  1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  2. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.

• Type of patient and disease characteristics:

  1. PAH of idiopathic/ hereditary/drug or toxin-induced origin or associated with connective tissue diseases;
  2. Mean PA pressure ≥25mmHg, PA wedge pressure ≤15mmHg, PVR >480 dyn.s.cm-5 and absence of acute vasoreactivity (we expect PARP1 inhibition will be most effective in patients with significant PA remodelling);
  3. WHO functional class II or III, which is the traditional inclusion criteria in all PAH RCT);
  4. Clinically stable with unchanged vasoactive therapy for ≥4 months; 5) two 6MWD of ≥150m and within ±15% of each other (the latter being used as baseline value);

  5. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:

     • Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days
     • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
     • Platelet count ≥ 100 x 109/L
     • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
     • Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal
     • Patients must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test :

     Estimated creatinine clearance =( [(140-age [years]) x weight (kg)] / [serum creatinine (mg/dL) x 72]) (x F); (where F=0.85 for females and F=1 for males).

  6. Patients must have a life expectancy ≥ 28 weeks.
• Weight: Body mass index (BMI) within the range 18-40 kg/m2 (inclusive).

• Reproduction:

  1. Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1.

     Postmenopausal is defined as:

     • Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
     • Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50
     • surgical sterilisation (bilateral oophorectomy or hysterectomy)
  2. Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential.

Exclusion Criteria:

• Medical conditions

  • Other types of pulmonary hypertension [130], including pulmonary related to left heart diseases (group 2), lung diseases (group 3) or chronic thromboembolic disease (group 4);
  • Significant restrictive (total lung capacity \<60% predicted) or obstructive (FEV1/FVC\<60% after a bronchodilator) lung disease;
  • Systolic blood pressure \<90 mmHg;
  • Acute RV failure within the last 3 months;
  • Received any investigational drug within 30 days;
  • Cardiopulmonary rehabilitation program planned or started ≤12 weeks prior to Day 1;
  • Presence of ≥3 risk factors for heart failure with preserved ejection fraction, including: - BMI >30 kg/m2, - Diabetes mellitus, - Hypertension, - Coronary artery disease;
  • Other organ dysfunction other than RV failure including Childs-Pugh class B-C liver cirrhosis;
  • Recent cancer (\<1yr)
  • Recent bacterial infection (\<30 days);
  • History of hypertensive crisis;
  • Stage ≥1 systemic hypertension, defined as a systolic blood pressure ≥140mmHg or a diastolic blood pressure ≥90mmHg, or requiring anti-hypertensive therapies;
  • Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
  • Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.
  • Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
  • Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
  • Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
  • Patients with known active hepatitis (i.e. Hepatitis B or C). Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

• Prior/concomitant therapy

  • Any previous treatment with PARP inhibitor, including Olaparib.
  • Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
  • Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
  • Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
  • Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
  • Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria no.7).

• Prior/concurrent clinical study experience:

  • Participation in another clinical study with an investigational product administered in the last 3 months
  • Patients with a known hypersensitivity to olaparib or any of the excipients of the product.

• Other exclusions

  • Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
  • Breast feeding women.

• Lifestyle restrictions:

  • Meals and dietary restrictions: It is prohibited to consume grapefruit juice while on olaparib therapy.
  • Activity: Women of childbearing potential and their partners, who are sexually active, must agree to the use of TWO highly effective forms of contraception in combination. This should be started from the signing of the informed consent and continue throughout the period of taking study treatment and for at least 1 month after last dose of study drug(s), or they must totally/truly abstain from any form of sexual intercourse.

Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential. Male patients should not donate sperm throughout the period of taking olaparib and for 3 months following the last dose of olaparib.

For details of acceptable methods of contraception refer to Appendix B Acceptable Birth Control Methods.