An Early Phase 1 interventional study of Apabetalone in Pulmonary Arterial Hypertension, sponsored by Steeve Provencher. Completed at 2 sites in Canada. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2022-04-25.
Sponsored by Steeve Provencher · Early Phase 1, Interventional, and Screening
The main OBJECTIVE of this proposal is to extend the investigator's preclinical findings on the role of epigenetics and DNA damage and Bromodomain-Containing Protein 4 (BRD4) inhibition as a therapy for a devastating disease, pulmonary arterial hypertension (PAH).
There is strong evidence that BRD4 plays a key role in the pathological phenotype in PAH accounting for disease progression and 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.
At this stage, the investigators propose a pilot study to assess the feasibility of a Phase 2 clinical trial assessing apabetalone in the PAH population. The overall HYPOTHESIS is that BRD4 inhibition with apabetalone is a safe and effective therapy for PAH.
In line with most pilot and safety studies, this is a two-centre (Quebec and Calgary) open-label trial. A 4-week pre-treatment phase will allow ensuring that patients are on stable doses of medication. Patients will be given doses of apabetalone 100mg BID for 16 weeks. Patients will be regularly followed. At baseline and week 16, a cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function.
761 studies on the registry are indexed under Pulmonary Arterial Hypertension; 142 are open to participants now.
This study's enrollment of 7 is below the median of 38 across 509 interventional studies indexed under Pulmonary Arterial Hypertension.
Browse Pulmonary Arterial Hypertension studies →This is the only study on the registry with Steeve Provencher as lead sponsor.
Counted across the registry records on this site, refreshed daily.
Mean PA pressure ≥25mmHg, with pulmonary artery wedge pressure ≤15mmHg. In addition, subjects will be required meet the following hemodynamic criteria:
Exclusion Criteria:
Presence of ≥3 of the following risk factors for heart failure with preserved ejection fraction at screening:
i. History of stable angina ii. More than 50% stenosis in a coronary artery (by coronary angiography) iii. History of myocardial infarction iv. History of or planned coronary artery bypass grafting and/or coronary artery stenting.
Evidence of organ dysfunction other than right heart failure, including:
Forbidden concomitant therapy:
100mg BID for 16 weeks.
Drug: Apabetalone
A 4-week pre-treatment phase will allow ensuring that patients are on stable doses of medication. Patients will be given doses of apabetalone 100mg BID for 16 weeks. Patients will be regularly followed (Fig.1). At baseline and week 16, a cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function.
Also known as: BRD4 inhibitor
Change in Pulmonary Vascular Resistance (PVR), dyn·s·cm-5
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.
Time frame: Baseline,and 16 weeks later
Change in mean Pulmonary Artery Pressure (mPAP), mmHg
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.
Time frame: At screening and 16 weeks later
Change in cardiac output (L/min)
Catheterization
Time frame: At screening and 16 weeks later
Change in right atrial pressure (RAP), mmHg
Catheterization
Time frame: At screening and 16 weeks later
Change in mixed venous oxygen saturation (SvO2), %
Catheterization
Time frame: At screening and 16 weeks later
Change in the 6-min walk distance (6MWD), meters
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.
Time frame: Screening, Week 0 (baseline), Week 4, Week 8 and Week 16
Change 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.
Time frame: Screening, Week 0 (baseline), Week 4, Week 8, Week 16 and end of study
Change in plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration
To assess changes in inflammatory/calcification mediators (mRNA \& serum proteins) of PAH patients with apabetalone treatment and demonstrate on-target beneficial effects, plasma (EDTA tubes) and whole blood (mRNA; PAXgene tubes) samples will be collected in subjects at visits 0 (baseline), 8 weeks, and 16 weeks. Blood draws at the 8 and 16 week visits should occur 4-6 hours post apabetalone dose to optimize capture of apabetalone's impact on gene expression (mRNA analysis). The plasma samples (EDTA tubes) will be processed and stored at -80°C until shipment on dry ice for future exploratory biomarker analysis relevant to lipid and inflammatory pathways. Whole blood samples (PAXgene tubes) will be stored at -20°C until shipment on dry ice to evaluate gene expression changes.
Time frame: Week 0 (baseline), Week 8, and Week 16
Change in Quality of life (QoL) using 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.
Time frame: Week 0 (baseline), and Week 16
Change in biomarker samples
circulating levels and transcription (messenger RNA) changes in whole blood of vascular calcification markers (alkaline phosphatase, osteoprotegerin), inflammation (C-reactive protein, fibrinogen, and inflammatory cytokines), complement, acute phase response, fibrogenesis and metabolism (adiponectin, ApoA-I, LDL-C and HDL-C)
Time frame: Week 0 (baseline), Week 8, and Week 16
Plan to share: No
This study is completed, as verified in Apr 2022. You cannot join it, but the record below documents what was studied.
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