Studies
| 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. |
Facilities
| Sequence: | 200472293 |
| Name | IUCPQ-UL |
| City | Québec |
| Zip | G1V 4G5 |
| Country | Canada |
Facility Contacts
| Sequence: | 28160058 |
| Facility Id | 200472293 |
| Contact Type | primary |
| Name | Luce Bouffard, RN |
| 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 |
Conditions
| Sequence: | 52282138 |
| Name | Pulmonary Arterial Hypertension |
| Downcase Name | pulmonary arterial hypertension |
Id Information
| Sequence: | 40238790 |
| Id Source | org_study_id |
| Id Value | 2021-3625 |
Countries
| 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. |
Interventions
| 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. |
Keywords
| 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 |
Sponsors
| 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 |
| steeve.provencher@criucpq.ulaval.ca | 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 |
Eligibilities
| 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 |
Designs
| 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 |