Apabetalone for Pulmonary Arterial Hypertension: a Pilot Study (APPRoAcH-p)
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|ClinicalTrials.gov Identifier: NCT03655704|
Recruitment Status : Not yet recruiting
First Posted : August 31, 2018
Last Update Posted : May 7, 2019
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.
|Condition or disease||Intervention/treatment||Phase|
|Pulmonary Arterial Hypertension||Drug: Apabetalone||Early Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||10 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||Pilot study to assess the feasibility of a Phase 2 clinical trial assessing apabetalone in 10 PAH patients|
|Masking:||None (Open Label)|
|Official Title:||Apabetalone for Pulmonary Arterial Hypertension: a Pilot Study|
|Estimated Study Start Date :||August 2019|
|Estimated Primary Completion Date :||December 2020|
|Estimated Study Completion Date :||December 2020|
100mg BID for 16 weeks.
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.
Other Name: BRD4 inhibitor
- Change in Pulmonary Vascular Resistance (PVR), dyn·s·cm−5 [ Time Frame: Baseline,and 16 weeks later ]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.
- Change in mean Pulmonary Artery Pressure (mPAP), mmHg [ Time Frame: At screening and 16 weeks later ]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.
- Change in cardiac output (L/min) [ Time Frame: At screening and 16 weeks later ]Catheterization
- Change in right atrial pressure (RAP), mmHg [ Time Frame: At screening and 16 weeks later ]Catheterization
- Change in mixed venous oxygen saturation (SvO2), % [ Time Frame: At screening and 16 weeks later ]Catheterization
- Change in the 6-min walk distance (6MWD), meters [ Time Frame: Screening, Week 0 (baseline), Week 4, Week 8 and Week 16 ]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.
- Change in WHO functional class [ Time Frame: Screening, Week 0 (baseline), Week 4, Week 8, Week 16 and end of study ]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.
- Change in plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration [ Time Frame: Week 0 (baseline), Week 8, and Week 16 ]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.
- Change in Quality of life (QoL) using CAMPHOR questionnaire [ Time Frame: Week 0 (baseline), and Week 16 ]The CAMPHOR is made up of 3 main dimensions which assess symptoms, functioning and quality of life (QoL). The symptom dimension is made up of 25 symptoms and is broken up into 3 subscales: energy, breathlessness and mood. The QoL scale has 25 items which focus on socialization, role, acceptance, self-esteem, independence, and security. The activity scale has 15 items. Response options include true and not true. Scores for QoL and symptoms range from 0-25, with higher scores indicating worse quality of life. Activity scores range from 0-30, with higher scores indicating more physical limitations.
- Change in biomarker samples [ Time Frame: Week 0 (baseline), Week 8, and Week 16 ]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)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03655704
|Contact: Steeve Provencher, MD, MSc||418 656 email@example.com|
|Contact: Sarah Bernard, PhD, FAHA||418 656 8711 ext firstname.lastname@example.org|
|Peter Lougheed Center||Not yet recruiting|
|Calgary, Alberta, Canada, T1Y 6J4|
|Contact: Marilyn Dougherty, RN 403-943-4759 Marilyn.Dougherty@albertahealthservices.ca|
|Principal Investigator: Jason Weatherald, MD|
|IUCPQ-UL||Not yet recruiting|
|Quebec City, Quebec, Canada, G1V 4G5|
|Contact: Steeve Provencher, MD, MSc 418-656-4747 email@example.com|
|Contact: Luce Bouffard, RN 418 656 8711 ext 2449 firstname.lastname@example.org|
|Principal Investigator: Steeve Provencher, MD, MSc|
|Principal Investigator: Sébastien Bonnet, PhD, FAHA|
|Principal Investigator:||Steeve Provencher, MD, MSc||IUCPQ-UL|
|Principal Investigator:||Sébastien Bonnet, PhD, FAHA||IUCPQ-UL|
|Study Director:||Sarah Bernard, MSc||IUCPQ-UL|