Apabetalone for Pulmonary Arterial Hypertension (APPROACH-2)

This is an interventional treatment trial for Pulmonary Arterial Hypertension focused on measuring Bromodomain-Containing Protein 4 (BRD4), Apabetalone, Pulmonary Arterial Hypertension, BRD4 inhibitor, Phase 2 clinical trial, Double-blind trial, Placebo-controlled trial Read More

Inclusion Criteria:

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.
3. Subject must be 18 to 75 years of age inclusive (18-80 years in case of PAH associated with scleroderma), at the time of signing the informed consent form.
4. PAH of idiopathic/hereditary/drug or toxin-induced origin; or associated with connective tissue diseases or simple congenital heart disease (atrial septal defect, ventricular septal defect, patent ductus arteriosus) corrected for >1 year;
5. Mean PA pressure >20mmHg, PVR >400 dyn.s.cm-5 with PA wedge pressure ≤15mmHg) and absence of acute vasoreactivity;
6. WHO functional class II or III;
7. Clinically stable with unchanged vasoactive therapy for ≥3 months;
8. Two 6MWD of ≥ 150m (the latter being used as baseline value);
9. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined as Absence of known liver cirrhosis, 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)) ≤ 3.0 x institutional upper limit of normal and creatinine clearance estimated of ≥30 mL/min.
10. Patients must have a life expectancy ≥ 28 weeks.
11. Body mass index (BMI) within the range 18-40 kg/m2 (inclusive).
12. Patients of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study treatment;
13. Patients must be postmenopausal, free from menses for >1 year, surgically sterilized, willing to use adequate contraception to prevent pregnancy, or agree to abstain from activities that could result in pregnancy; and agree to abstain lactating from enrollment through 3 months after the last dose of study treatment.
14. Male patients must use a condom during treatment and for 3 months after the last dose of apabetalone 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 (see appendix B for acceptable methods) if they are of childbearing potential.

Exclusion Criteria:

1. PAH related to HIV infection, portal hypertension;
2. Other types of pulmonary hypertension (Simonneau, Montani et al. 2019), including pulmonary related to left heart diseases, lung diseases, chronic thromboembolic disease or multifactorial mechanisms (PH groups 2-5, respectively);
3. Suspected pulmonary veno-occlusive disease;
4. A ventilation-perfusion lung scan or pulmonary angiography indicative of thromboembolic disease.
5. Significant restrictive (total lung capacity <70% predicted) or obstructive (FEV1/FVC<60% after a bronchodilator) lung disease;
6. DLCO <40%
7. Systolic blood pressure <90 mmHg;
8. Resting heart rate in the awake patient at rest <50 BPM or >110 BPM;
9. Acute RV failure or hospitalization within 30 days;
10. Received any investigational drug within 30 days;
11. Cardiopulmonary rehabilitation program planned or started ≤12 weeks prior to day 1;

12. Presence of ≥3 risk factors for heart failure with preserved ejection fraction, including:

    • BMI >30 kg/m2
    • Diabetes mellitus
    • Hypertension
    • Coronary artery disease
13. Recent cancer (<1yr, except for low grade and fully resolved non-melanoma skin cancer)
14. Recent bacterial infection (<30 days);
15. Anticipated survival less than 1 year due to concomitant disease.
16. Initiation of treatment with bosentan within 6 months (bosentan has been associated with a 5-10% risk or reversible raised in LFTs. This most commonly occurs within the first 6 months of treatment. Although there is no evidence of increased risk of apabetalone-related increases in LFTs amongst bosentan users, patients initiated on bosentan for <6 months will be excluded to minimize the risk of elevated LFTs falsely attributed to the study drug).
17. Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir). The required washout period prior to starting apabetalone is 2 weeks.*
18. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
19. 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).
20. Participation in another clinical study with an investigational product administered in the last 3 months
21. Patients with a known hypersensitivity to apabetalone or any of the excipients of their formulations.
22. Inability to consent
23. 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.
24. Breast feeding women.