Apabetalone for Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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Throughout the past twenty years, numerous specific pharmacologic agents targeting the endothelial dysfunction associated with PAH have emerged. Short term placebo-controlled randomized trials assessing PAH-specific monotherapy with these molecules have reported improvements in pulmonary hemodynamics and exercise capacity. A recent meta-analysis also documented a reduction in short-term mortality of about ≈40% with such therapies. Several randomized clinical trials evaluating PAH-specific combination therapy have been conducted. Our recent meta-analysis showed that combination therapy was associated with a 35% risk reduction for the occurrence of clinical worsening compared to monotherapy. Nonetheless, the investigators also showed 17% of PAH patients receiving combination therapy still experienced clinical worsening over a median exposure of 16 weeks. Moreover, long-term survival on PAH-specific also therapy remains poor in the modern era, with a yearly mortality rate of 15 % in incident idiopathic PAH. The identification of innovative therapeutic targets and validation of these complementary therapeutic interventions are thus urgently needed in PAH. The investigators and others (K. Stenmark, University of Colorado and H. Bogaard, VU University Medical Center, Amsterdam, personal communications), have published strong evidence that BRD4 plays a key role in the pathological phenotype in PAH accounting for disease progression and showed that BRD4 inhibition can reverse PAH in several animal models. Intriguingly, coronary artery disease (CAD) and metabolic syndrome are more prevalent in PAH compared with the global population, suggesting a link between these diseases. Interestingly, BRD4 is also a trigger for calcification and remodeling processes and regulates transcription of lipoprotein and inflammatory factors, all of which are important in PAH and CAD. Apabetalone, an orally available BRD4 inhibitor, is now in a clinical development stage with a good safety profile. The overall objective of the study is to explore the efficacy and safety of apabetalone as an add-on therapy for adult PAH patients and to inform the conduct and the design of a Phase 3 trial. The primary objective of the study is to assess the efficacy of apabetalone as evaluated by the change in PVR over a period of 24 weeks compared to placebo in adult subjects with PAH on stable background therapy. Secondary objectives include changes at week 24 in 6MWD, plasma NT-proBNP concentration, WHO functional class, ESC/ERS risk stratification score, health-related quality of life and additional hemodynamic data from right heart. Exploratory objectives are to evaluate the effects of apabetalone compared to placebo in adult subjects with PAH on mortality and clinically relevant morbidity events, and on circulating levels and transcription changes in whole blood markers of metabolism, vascular calcification, inflammation, DNA damage and leucocyte expression of BMPR2.

Detailed Description
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This is a standard-design, double-blind, parallel-group, placebo-controlled trial. Overall, 72 well-characterized PAH patients, 36 subjects in each treatment group (apabetalone 100 mg BID or matching placebo), that have been stable for >4 months on standard PAH-therapies, as per guidelines (Galie, Humbert et al. 2015) will be recruited in 8-15 participating centres (site selection currently ongoing). The participating centres will be recruited if they have the same approach to PAH patients in terms of choice and timing of treatments, and have expertise in performing trials in PAH. The initial Health Canada approval will be obtained. Apabetalone will be provided by Resverlogix Corp. Canada, but Resverlogix 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. Patients will be given apabetalone 100mg BID or placebo. Patients will be regularly followed to assess whether side effects. 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.

Official Title
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Apabetalone for Pulmonary Arterial Hypertension: a Phase 2 Clinical Study

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Apabetalone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses. 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. 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; Mean PA pressure >20mmHg, PVR >400 dyn.s.cm-5 with PA wedge pressure ≤15mmHg) and absence of acute vasoreactivity; WHO functional class II or III; Clinically stable with unchanged vasoactive therapy for ≥3 months; Two 6MWD of ≥ 150m (the latter being used as baseline value); 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. Patients must have a life expectancy ≥ 28 weeks. Body mass index (BMI) within the range 18-40 kg/m2 (inclusive). Patients of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study treatment; 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. 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: PAH related to HIV infection, portal hypertension; 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); Suspected pulmonary veno-occlusive disease; A ventilation-perfusion lung scan or pulmonary angiography indicative of thromboembolic disease. Significant restrictive (total lung capacity <70% predicted) or obstructive (FEV1/FVC<60% after a bronchodilator) lung disease; DLCO <40% Systolic blood pressure <90 mmHg; Resting heart rate in the awake patient at rest <50 BPM or >110 BPM; Acute RV failure or hospitalization within 30 days; 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 Recent cancer (<1yr, except for low grade and fully resolved non-melanoma skin cancer) Recent bacterial infection (<30 days); Anticipated survival less than 1 year due to concomitant disease. 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). 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.* Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. 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). Participation in another clinical study with an investigational product administered in the last 3 months Patients with a known hypersensitivity to apabetalone or any of the excipients of their formulations. Inability to consent 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind, placebo-controlled study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Apabetalone<br>100mg BID, 24-week (168±3 days) Treatment Period. | Drug: Apabetalone<br>* Apabetalone 100mg p.o. (tablets) BID for 24 weeks treatment period.<br>|
| Placebo Comparator: Placebo<br>24-week (168±3 days) period. | Drug: Placebo<br>* Placebo p.o. (tablets) BID for 24 weeks treatment period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Placebo-corrected change from baseline in PVR at week 24 | Right heart catheterization: Measuring PVR is performed in a standardized manner in catheterization laboratories of the participating centres, according to recommendations. Printed copies of waveforms will be kept for monitoring visits and documentation of the accuracy of the pressures and calculations. | Baseline, and 24 weeks later | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes at week 24 in 6MWD | The 6-min walk test (6 MWT) is a submaximal exercise test that entails measurement of distance walked over a span of 6 minutes. The 6-minute walk distance (6 MWD) provides a measure for integrated global response of multiple cardiopulmonary and musculoskeletal systems involved in exercise. | Baseline, week 8 and week 24 | 
| Changes at week 24 in plasma NT-proBNP concentration |  | Baseline, week 8 and week 24 | 
| Changes at week 24 in WHO functional class | There are four functional classes that are used to rate how ill PH patients are. Class I: No symptoms of pulmonary arterial hypertension with exercise or at rest. Class II: No symptoms at rest but uncomfortable and short of breath with normal activity such as climbing a flight of stairs, grocery shopping, or making the bed. Class III: May not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: Symptoms at rest and severe symptoms with any activity. | Baseline, week 8 and week 24 | 
| Changes at week 24 in European Respiratory Society (ERS)/European Society of Cardiology (ESC) risk stratification score | The ERS/ESC risk stratification strategy will be used to categorize patients as low, intermediate or high risk. The cut-off values proposed in the guidelines will be graded 1-3 (1: low-, 2: intermediate- and 3: high-risk). For each patient, the sum of all grades will be divided by the number of variables and rounded to the next integer to define the risk group. The number of low-risk criteria per patients will also be assessed. | Screening and Week 24 | 
| Change at week 24 in mean Pulmonary Artery Pressure (mPAP), mmHg obtained from right heart catheterization | The hemodynamic definition of pulmonary arterial hypertension (PAH) is a mean pulmonary artery pressure at rest greater than or equal to 25 mmHg in the presence of a pulmonary capillary wedge pressure less than or equal to 15 mmHg. These measurements can only be taken accurately during a right heart catheterization. | Screening and Week 24 | 
| Change in cardiac output (L/min) | Catheterization | Screening and Week 24 | 
| Change in right atrial pressure (RAP), mmHg | Catheterization | Screening and Week 24 | 
| Change in mixed venous oxygen saturation (SvO2), % | Catheterization | Screening and Week 24 | 
| Change at week 24 in HRQoL assessed using the EmPHasis-10 questionnaire | The Emphasis-10 questionnaire is a short questionnaire for assessing HRQoL in pulmonary arterial hypertension. It has excellent measurement properties and is sensitive to differences in relevant clinical parameters. | Screening and Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bromodomain-Containing Protein 4 (BRD4), Apabetalone, Pulmonary Arterial Hypertension, BRD4 inhibitor, Phase 2 clinical trial, Double-blind trial, Placebo-controlled trial