Apabetalone for Pulmonary Arterial Hypertension: a Pilot Study (APPRoAcH-p)

April 22, 2022 updated by: Steeve Provencher

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

7

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Alberta
      • Calgary, Alberta, Canada, T1Y 6J4
        • Peter Lougheed Center
    • Quebec
      • Quebec City, Quebec, Canada, G1V 4G5
        • IUCPQ-UL

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Adults (18-75 yrs) with PAH of idiopathic or hereditary origin, associated with connective tissue diseases, or anorexigen use.

  2. Mean PA pressure ≥25mmHg, with pulmonary artery wedge pressure ≤15mmHg. In addition, subjects will be required meet the following hemodynamic criteria:

    1. PVR >480 dyn.s.cm-5
    2. Negative vasoreactivity test mandatory in idiopathic, heritable, and drug/toxin induced PAH (at baseline or during previous RHC).
  3. World Health Organization functional class (WHO FC) II or III.
  4. Appropriate stable therapy for PAH for ≥4 months before screening, including endothelin receptor antagonists (ERAs) other than bosentan and/or phosphodiesterase type 5 (PDE-5) inhibitors and/or prostanoids.
  5. Two 6-min walk tests of 150-550m inclusive and within ±15% of each other (the latter being used as baseline value).
  6. Patients must be able to understand the study procedures and agree to participate in the study by providing written informed consent.
  7. Patients of childbearing potential must have a negative serum pregnancy test (β-hCG) within 72 hours prior to receiving the first dose of study treatment.
  8. 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, from enrollment through 3 months after the last dose of study treatment.

Exclusion Criteria:

  1. PAH related to HIV infection, portal hypertension or congenital heart disease.
  2. Pulmonary hypertension due to left heart disease (WHO PH group 2), lung disease and/or hypoxia (WHO PH group 3), chronic thromboembolic pulmonary hypertension (WHO PH group 4), or unclear multifactorial mechanisms (WHO PH group 5).
  3. Known or suspected pulmonary veno-occlusive disease (PVOD).
  4. Severe restrictive lung disease (Total Lung Capacity <60% predicted)
  5. Severe obstructive lung disease (FEV1/FVC < 60% after a bronchodilator)
  6. DLCO <40%
  7. Systolic blood pressure <90 mmHg
  8. Resting heart rate in the awake patient <50 BPM or >110 BPM
  9. Clinically unstable right heart failure within the last 3 months or are WHO FC IV.
  10. Received any investigational drug within 30 days of screening.
  11. Body mass index (BMI) <18 or >40 kg/m2 at screening.
  12. Patients must not be pregnant, breastfeeding, or expecting to conceive children while receiving study treatment and for 3 months after the last dose of study treatment.
  13. Cardiopulmonary rehabilitation program based on exercise (planned or started ≤12 weeks prior to Day 1).

  14. Presence of ≥3 of the following risk factors for heart failure with preserved ejection fraction at screening:

    1. BMI >30 kg/m2.
    2. Diabetes mellitus of any type.
    3. Essential hypertension.
    4. Coronary artery disease, i.e., any of the following:

    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.

  15. A ventilation-perfusion lung scan or pulmonary angiography indicative of thromboembolic disease.

  16. Evidence of organ dysfunction other than right heart failure, including:

    1. Creatinine clearance <45 ml/min (using the Cockroft-Gault formula).
    2. Serum AST or ALT >3 x ULN.
    3. Total bilirubin > 1.5 x ULN.
    4. Childs-Pugh class B-C liver cirrhosis.
    5. Hemoglobin <100 g/L.
    6. Absolute neutrophil count < 1,500/μL .
    7. Platelets < 150,000/μL .
  17. Anticipated survival less than 1 year due to concomitant disease.
  18. History of cancer in the past 5 years (except for low grade and fully resolved non-melanoma skin cancer).
  19. Hypersensitivity to the components of apabetalone or any excipient of their formulations.

Forbidden concomitant therapy:

  • Any investigational drug other than the study treatment.
  • Based on in vitro data and clinical exposure data, apabetalone is considered unlikely to cause clinically significant drug interactions through inhibition or induction of cytochrome P450 enzyme activity. Nonetheless, as the contribution of metabolic clearance to total drug clearance in man is unknown, potent inhibitors (ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfanavir) or inducers (Phenytoin, rifampicin, carbamazepine and phenobarbitone, nevirapine, modafinil and St John's Wort) of CYP3A4 must not be used during this study for any patient receiving apabetalone to ensure patient safety. Moreover, bosentan has been associated with a 5-10% risk or reversible raised in LFTs. Although there is no evidence of increased risk of apabetalone-related increases in LFTs amongst bosentan users, the use of bosentan will be forbidden during this study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Screening
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Apabetalone
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.
Other Names:
  • BRD4 inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Baseline,and 16 weeks later

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
At screening and 16 weeks later
Change in cardiac output (L/min)
Time Frame: At screening and 16 weeks later
Catheterization
At screening and 16 weeks later
Change in right atrial pressure (RAP), mmHg
Time Frame: At screening and 16 weeks later
Catheterization
At screening and 16 weeks later
Change in mixed venous oxygen saturation (SvO2), %
Time Frame: At screening and 16 weeks later
Catheterization
At screening and 16 weeks later
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.
Screening, Week 0 (baseline), Week 4, Week 8 and Week 16
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.
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
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.
Week 0 (baseline), Week 8, and Week 16
Change in Quality of life (QoL) using Emphasis-10 questionnaire
Time Frame: Week 0 (baseline), and Week 16
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.
Week 0 (baseline), and Week 16
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)
Week 0 (baseline), Week 8, and Week 16

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Steeve Provencher

Collaborators

Resverlogix Corp

Investigators

  • Study Director: Pascale Blais-Lecours, PhD, IUCPQ-UL

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 22, 2019

Primary Completion (Actual)

October 15, 2021

Study Completion (Actual)

December 13, 2021

Study Registration Dates

First Submitted

August 28, 2018

First Submitted That Met QC Criteria

August 29, 2018

First Posted (Actual)

August 31, 2018

Study Record Updates

Last Update Posted (Actual)

April 25, 2022

Last Update Submitted That Met QC Criteria

April 22, 2022

Last Verified

April 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CER-21723

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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