Apabetalone for Pulmonary Arterial Hypertension

NCT04915300 | Unknown Phase 2 DMC

• 1 other identifier: 2021-3625
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 1

Brief Summary

Throughout the past twenty years, numerous specific pharmacologic agents targeting the endothelial dysfunction associated with PAH have emerged. Short term placebo-controlled randomized trials assessing PAH-specific monotherapy with these molecules have reported improvements in pulmonary hemodynamics and exercise capacity. A recent meta-analysis also documented a reduction in short-term mortality of about ≈40% with such therapies. Several randomized clinical trials evaluating PAH-specific combination therapy have been conducted. Our recent meta-analysis showed that combination therapy was associated with a 35% risk reduction for the occurrence of clinical worsening compared to monotherapy. Nonetheless, the investigators also showed 17% of PAH patients receiving combination therapy still experienced clinical worsening over a median exposure of 16 weeks. Moreover, long-term survival on PAH-specific also therapy remains poor in the modern era, with a yearly mortality rate of 15 % in incident idiopathic PAH. The identification of innovative therapeutic targets and validation of these complementary therapeutic interventions are thus urgently needed in PAH. The investigators and others (K. Stenmark, University of Colorado and H. Bogaard, VU University Medical Center, Amsterdam, personal communications), have published strong evidence that BRD4 plays a key role in the pathological phenotype in PAH accounting for disease progression and showed 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. The overall objective of the study is to explore the efficacy and safety of apabetalone as an add-on therapy for adult PAH patients and to inform the conduct and the design of a Phase 3 trial. The primary objective of the study is to assess the efficacy of apabetalone as evaluated by the change in PVR over a period of 24 weeks compared to placebo in adult subjects with PAH on stable background therapy. Secondary objectives include changes at week 24 in 6MWD, plasma NT-proBNP concentration, WHO functional class, ESC/ERS risk stratification score, health-related quality of life and additional hemodynamic data from right heart. Exploratory objectives are to evaluate the effects of apabetalone compared to placebo in adult subjects with PAH on mortality and clinically relevant morbidity events, and on circulating levels and transcription changes in whole blood markers of metabolism, vascular calcification, inflammation, DNA damage and leucocyte expression of BMPR2.

Conditions

Pulmonary Arterial Hypertension

Keywords

Bromodomain-Containing Protein 4 (BRD4); Apabetalone; Pulmonary Arterial Hypertension; BRD4 inhibitor; Phase 2 clinical trial; Double-blind trial; Placebo-controlled trial

Outcome Measures

Primary Outcomes (1)

• Placebo-corrected change from baseline in PVR at week 24

  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 24 weeks later

Secondary Outcomes (9)

• Changes at week 24 in 6MWD

  Baseline, week 8 and week 24

• Changes at week 24 in plasma NT-proBNP concentration

  Baseline, week 8 and week 24

• Changes at week 24 in WHO functional class

  Baseline, week 8 and week 24

• Changes at week 24 in European Respiratory Society (ERS)/European Society of Cardiology (ESC) risk stratification score

  Screening and Week 24

• Change at week 24 in mean Pulmonary Artery Pressure (mPAP), mmHg obtained from right heart catheterization

  Screening and Week 24

Other Outcomes (6)

• Change in clinical worsening events

  Baseline and Week 24

• Circulating levels change in whole blood markers of metabolism

  Baseline and Week 24

• Circulating levels change in whole blood markers of vascular calcification

  Baseline and Week 24

Study Arms (2)

Apabetalone

ACTIVE COMPARATOR

100mg BID, 24-week (168±3 days) Treatment Period.

Drug: Apabetalone

Placebo

PLACEBO COMPARATOR

24-week (168±3 days) period.

Drug: Placebo

Interventions

Apabetalone DRUG

Apabetalone 100mg p.o. (tablets) BID for 24 weeks treatment period.

Apabetalone

Placebo DRUG

Placebo p.o. (tablets) BID for 24 weeks treatment period.

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Laval University: lead
• Canadian Institutes of Health Research (CIHR): collaborator
• Resverlogix Corp: collaborator

Study Sites (1)

IUCPQ-UL

Québec, G1V 4G5, Canada

Location

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

apabetalone

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Steeve Provencher, MD, MSc

  IUCPQ-UL

  PRINCIPAL INVESTIGATOR

• Pascale Blais-Lecours, PhD

  IUCPQ-UL

  STUDY DIRECTOR

Central Study Contacts

Steeve Provencher, MD, MSc

CONTACT

418-656-4747; steeve.provencher@criucpq.ulaval.ca

Pascale Blais-Lecours, PhD

CONTACT

418-656-8711; pascale.blais-lecours@criucpq.ulaval.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Randomized, double-blind, placebo-controlled study

Study Record Dates

• First Submitted: May 19, 2021
• First Posted: June 7, 2021
• Study Start: October 1, 2023
• Primary Completion: March 1, 2025
• Study Completion: March 1, 2025
• Last Updated: April 18, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)