Apabetalone for Pulmonary Arterial Hypertension


Study First Submitted Date 2021-05-19
Study First Posted Date 2021-06-07
Last Update Posted Date 2023-04-18
Start Month Year October 2023
Primary Completion Month Year March 2025
Verification Month Year April 2023
Verification Date 2023-04-30
Last Update Posted Date 2023-04-18

Detailed Descriptions

Sequence: 20764815
Description 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.


Sequence: 200472293
City Québec
Zip G1V 4G5
Country Canada

Facility Contacts

Sequence: 28160058
Facility Id 200472293
Contact Type primary
Name Luce Bouffard, RN
Email luce.bouffard@criucpq.ulaval.ca
Phone 418-656-8711
Phone Extension 2449

Facility Investigators

Sequence: 18362292
Facility Id 200472293
Role Principal Investigator
Name Steeve Provencher, MD, MSc


Sequence: 52282138
Name Pulmonary Arterial Hypertension
Downcase Name pulmonary arterial hypertension

Id Information

Sequence: 40238790
Id Source org_study_id
Id Value 2021-3625


Sequence: 42656916
Name Canada
Removed False

Design Groups

Sequence: 55717142 Sequence: 55717143
Group Type Active Comparator Group Type Placebo Comparator
Title Apabetalone Title Placebo
Description 100mg BID, 24-week (168±3 days) Treatment Period. Description 24-week (168±3 days) period.


Sequence: 52594344 Sequence: 52594345
Intervention Type Drug Intervention Type Drug
Name Apabetalone Name Placebo
Description Apabetalone 100mg p.o. (tablets) BID for 24 weeks treatment period. Description Placebo p.o. (tablets) BID for 24 weeks treatment period.


Sequence: 80025551 Sequence: 80025552 Sequence: 80025553 Sequence: 80025554 Sequence: 80025555 Sequence: 80025556 Sequence: 80025557
Name Bromodomain-Containing Protein 4 (BRD4) Name Apabetalone Name Pulmonary Arterial Hypertension Name BRD4 inhibitor Name Phase 2 clinical trial Name Double-blind trial Name Placebo-controlled trial
Downcase Name bromodomain-containing protein 4 (brd4) Downcase Name apabetalone Downcase Name pulmonary arterial hypertension Downcase Name brd4 inhibitor Downcase Name phase 2 clinical trial Downcase Name double-blind trial Downcase Name placebo-controlled trial

Design Outcomes

Sequence: 177787374 Sequence: 177787375 Sequence: 177787376 Sequence: 177787377 Sequence: 177787378 Sequence: 177787379 Sequence: 177787380 Sequence: 177787381 Sequence: 177787382 Sequence: 177787383 Sequence: 177787384 Sequence: 177787385 Sequence: 177787386 Sequence: 177787387 Sequence: 177787388 Sequence: 177787389
Outcome Type primary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type other Outcome Type other Outcome Type other Outcome Type other Outcome Type other Outcome Type other
Measure Placebo-corrected change from baseline in PVR at week 24 Measure Changes at week 24 in 6MWD Measure Changes at week 24 in plasma NT-proBNP concentration Measure Changes at week 24 in WHO functional class Measure Changes at week 24 in European Respiratory Society (ERS)/European Society of Cardiology (ESC) risk stratification score Measure Change at week 24 in mean Pulmonary Artery Pressure (mPAP), mmHg obtained from right heart catheterization Measure Change in cardiac output (L/min) Measure Change in right atrial pressure (RAP), mmHg Measure Change in mixed venous oxygen saturation (SvO2), % Measure Change at week 24 in HRQoL assessed using the EmPHasis-10 questionnaire Measure Change in clinical worsening events Measure Circulating levels change in whole blood markers of metabolism Measure Circulating levels change in whole blood markers of vascular calcification Measure Circulating levels change in whole blood markers of inflammation Measure Circulating levels change in whole blood markers of DNA damage Measure Change in PBMC expression of BMPR2
Time Frame Baseline, and 24 weeks later Time Frame Baseline, week 8 and week 24 Time Frame Baseline, week 8 and week 24 Time Frame Baseline, week 8 and week 24 Time Frame Screening and Week 24 Time Frame Screening and Week 24 Time Frame Screening and Week 24 Time Frame Screening and Week 24 Time Frame Screening and Week 24 Time Frame Screening and Week 24 Time Frame Baseline and Week 24 Time Frame Baseline and Week 24 Time Frame Baseline and Week 24 Time Frame Baseline and Week 24 Time Frame Baseline and Week 24 Time Frame Baseline and Week 24
Description 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. Description 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. Description 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. Description 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. Description 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. Description Catheterization Description Catheterization Description Catheterization Description 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. Description Win ratio methodology will be used to evaluate the effects of apabetalone compared to placebo on mortality and clinically relevant morbidity events. The pairwise comparison proceeds in hierarchical fashion, using 1) all-cause mortality, followed by 2) frequency of PAH-related hospitalization; 3) a placebo-corrected change from baseline 6-minute walk distance >35 meters and; 4) a >20% relative placebo-corrected change in NTproBNP levels from baseline using the win ratio methodology. This method is based on the principle that each patient is compared with every other patient in a pairwise manner. This method gives a higher importance to all-cause mortality, followed by frequency of PAH-related hospitalization, exercise capacity and natriuretic peptide when patients cannot be differentiated on the basis of mortality, hospitalizations and functional status, respectively. Description Adiponectin, ApoA-I, LDL-C and HDL-C Description Alkaline phosphatase, osteoprotegerin, osteopontin, RUNX2 Description C-reactive protein, fibrinogen, and inflammatory cytokines including IL-1 and IL-6 Description Comet assay, PARP1 expression Description The proportion of patients with mutations in BMPR2 and key genes of the HR repair pathway

Browse Conditions

Sequence: 193911146 Sequence: 193911147 Sequence: 193911148 Sequence: 193911149 Sequence: 193911150 Sequence: 193911151 Sequence: 193911152 Sequence: 193911153
Mesh Term Pulmonary Arterial Hypertension Mesh Term Familial Primary Pulmonary Hypertension Mesh Term Hypertension Mesh Term Vascular Diseases Mesh Term Cardiovascular Diseases Mesh Term Hypertension, Pulmonary Mesh Term Lung Diseases Mesh Term Respiratory Tract Diseases
Downcase Mesh Term pulmonary arterial hypertension Downcase Mesh Term familial primary pulmonary hypertension Downcase Mesh Term hypertension Downcase Mesh Term vascular diseases Downcase Mesh Term cardiovascular diseases Downcase Mesh Term hypertension, pulmonary Downcase Mesh Term lung diseases Downcase Mesh Term respiratory tract diseases
Mesh Type mesh-list Mesh Type mesh-list Mesh Type mesh-list Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor


Sequence: 48423107 Sequence: 48423108 Sequence: 48423109
Agency Class OTHER Agency Class OTHER_GOV Agency Class INDUSTRY
Lead Or Collaborator lead Lead Or Collaborator collaborator Lead Or Collaborator collaborator
Name Laval University Name Canadian Institutes of Health Research (CIHR) Name Resverlogix Corp

Overall Officials

Sequence: 29345195 Sequence: 29345196
Role Principal Investigator Role Study Director
Name Steeve Provencher, MD, MSc Name Pascale Blais-Lecours, PhD
Affiliation IUCPQ-UL Affiliation IUCPQ-UL

Central Contacts

Sequence: 12035755 Sequence: 12035756
Contact Type primary Contact Type backup
Name Steeve Provencher, MD, MSc Name Pascale Blais-Lecours, PhD
Phone 418-656-4747 Phone 418-656-8711
Email steeve.provencher@criucpq.ulaval.ca Email pascale.blais-lecours@criucpq.ulaval.ca
Phone Extension 2651
Role Contact Role Contact

Design Group Interventions

Sequence: 68299007 Sequence: 68299008
Design Group Id 55717142 Design Group Id 55717143
Intervention Id 52594344 Intervention Id 52594345


Sequence: 30829850
Gender All
Minimum Age 18 Years
Maximum Age 75 Years
Healthy Volunteers No
Criteria 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.
Adult True
Child False
Older Adult True

Calculated Values

Sequence: 254131240
Number Of Facilities 1
Registered In Calendar Year 2021
Were Results Reported False
Has Us Facility False
Has Single Facility True
Minimum Age Num 18
Maximum Age Num 75
Minimum Age Unit Years
Maximum Age Unit Years
Number Of Primary Outcomes To Measure 1
Number Of Secondary Outcomes To Measure 9
Number Of Other Outcomes To Measure 6


Sequence: 30575773
Allocation Randomized
Intervention Model Parallel Assignment
Observational Model
Primary Purpose Treatment
Time Perspective
Masking Double
Intervention Model Description Randomized, double-blind, placebo-controlled study
Subject Masked True
Investigator Masked True

Responsible Parties

Sequence: 28942179
Responsible Party Type Principal Investigator
Name Steeve Provencher
Title Professor
Affiliation Institut universitaire de cardiologie et de pneumologie de Québec, University Laval