Apabetalone for Pulmonary Arterial Hypertension: a Pilot Study

Pulmonary Arterial Hypertension Clinical Trial

— APPRoAcH-p  

Official title:

Apabetalone for Pulmonary Arterial Hypertension: a Pilot Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03655704
• Other study ID #: CER-21723
• Status: Completed
• Phase: Early Phase 1
• Start date: August 22, 2019
• Est. completion date: December 13, 2021

Study information

• Verified date: April 2022
• Source: Laval University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7
• Est. completion date: December 13, 2021
• Est. primary completion date: October 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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 (ß-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.

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

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.

Locations

Country	Name	City	State
Canada	Peter Lougheed Center	Calgary	Alberta
Canada	IUCPQ-UL	Quebec City	Quebec

Sponsors (2)

Lead Sponsor	Collaborator
Steeve Provencher	Resverlogix Corp

Country where clinical trial is conducted

Canada, 

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Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.	At screening and 16 weeks later
Other	Change in cardiac output (L/min)	Catheterization	At screening and 16 weeks later
Other	Change in right atrial pressure (RAP), mmHg	Catheterization	At screening and 16 weeks later
Other	Change in mixed venous oxygen saturation (SvO2), %	Catheterization	At screening and 16 weeks later
Other	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.	Screening, Week 0 (baseline), Week 4, Week 8 and Week 16
Other	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.	Screening, Week 0 (baseline), Week 4, Week 8, Week 16 and end of study
Other	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.	Week 0 (baseline), Week 8, and Week 16
Other	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.	Week 0 (baseline), and Week 16
Other	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)	Week 0 (baseline), Week 8, and Week 16
Primary	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.	Baseline,and 16 weeks later