Apabetalone for Pulmonary Arterial Hypertension: a Pilot Study

• Register: ClinicalTrials.gov
• Last refreshed on: 2 May 2022
• Main ID: NCT03655704
• Date of registration: 28/08/2018
• Prospective Registration: Yes
• Primary sponsor: Steeve Provencher
• Public title: Apabetalone for Pulmonary Arterial Hypertension: a Pilot Study APPRoAcH-p
• Scientific title: Apabetalone for Pulmonary Arterial Hypertension: a Pilot Study
• Date of first enrolment: August 22, 2019
• Target sample size: 7
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03655704
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Screening. Masking: None (Open Label).
• Phase: Early Phase 1

Countries of recruitment

Canada

Contacts

• Name: Steeve Provencher, MD, MSc
• Affiliation: IUCPQ-UL

• Name: Pascale Blais-Lecours, PhD
• Affiliation: IUCPQ-UL

• Name: Sébastien Bonnet, PhD, FAHA
• Affiliation: IUCPQ-UL

Key inclusion & exclusion criteria

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.



Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension

Intervention(s)

Drug: Apabetalone

Primary Outcome(s)

Change in Pulmonary Vascular Resistance (PVR), dyn·s·cm-5 [Time Frame: Baseline,and 16 weeks later]

Secondary ID(s)

CER-21723

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Resverlogix Corp