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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03655704
Recruitment Status : Completed
First Posted : August 31, 2018
Last Update Posted : April 25, 2022
Sponsor:
Collaborator:
Resverlogix Corp
Information provided by (Responsible Party):
Steeve Provencher, Laval University

Tracking Information
First Submitted Date  ICMJE August 28, 2018
First Posted Date  ICMJE August 31, 2018
Last Update Posted Date April 25, 2022
Actual Study Start Date  ICMJE August 22, 2019
Actual Primary Completion Date October 15, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 29, 2018)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: December 11, 2019)
  • 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 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.
  • 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)
Original Other Pre-specified Outcome Measures
 (submitted: August 29, 2018)
  • 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).[6] 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)
 
Descriptive Information
Brief Title  ICMJE Apabetalone for Pulmonary Arterial Hypertension: a Pilot Study
Official Title  ICMJE Apabetalone for Pulmonary Arterial Hypertension: a Pilot Study
Brief 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.

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  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: N/A
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)
Primary Purpose: Screening
Condition  ICMJE Pulmonary Arterial Hypertension
Intervention  ICMJE 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 Name: BRD4 inhibitor
Study Arms  ICMJE Experimental: Apabetalone
100mg BID for 16 weeks.
Intervention: Drug: Apabetalone
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 27, 2021)
7
Original Estimated Enrollment  ICMJE
 (submitted: August 29, 2018)
10
Actual Study Completion Date  ICMJE December 13, 2021
Actual Primary Completion Date October 15, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03655704
Other Study ID Numbers  ICMJE CER-21723
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Steeve Provencher, Laval University
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Steeve Provencher
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Resverlogix Corp
Investigators  ICMJE
Principal Investigator: Steeve Provencher, MD, MSc IUCPQ-UL
Principal Investigator: Sébastien Bonnet, PhD, FAHA IUCPQ-UL
Study Director: Pascale Blais-Lecours, PhD IUCPQ-UL
PRS Account Laval University
Verification Date April 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP