What side effects are associated with this type of intervention?

Common treatments for Pulmonary Arterial Hypertension (PAH) include endothelin receptor antagonists (ERAs) such as bosentan and macitentan, which can cause hepatotoxicity and fluid retention. Phosphodiesterase-5 inhibitors (PDE5Is) like sildenafil and tadalafil are associated with headaches, flushing, and potential hypotension. Prostacyclin analogues such as epoprostenol and treprostinil often lead to side effects like jaw pain, nausea, and infusion site pain. Apabetalone, a BRD4 inhibitor under study, has shown a good safety profile in clinical development.

What prior FDA approvals exist?

The FDA has approved several classes of drugs for the treatment of Pulmonary Arterial Hypertension (PAH), including endothelin receptor antagonists (ERAs) like bosentan, ambrisentan, and macitentan, phosphodiesterase-5 inhibitors (PDE5Is) such as sildenafil and tadalafil, and prostacyclin analogues like epoprostenol and treprostinil. These drugs target different pathways involved in PAH pathophysiology, such as vasodilation and inhibition of smooth muscle cell proliferation. While Apabetalone, a BRD4 inhibitor, is still in clinical development, it represents a novel approach by targeting epigenetic regulation, which is distinct from the mechanisms of currently approved therapies.

What other types of research exist?

Promising novel alternatives to Apabetalone for PAH treatment include: 1) Macitentan, an endothelin receptor antagonist, which has shown benefits in delaying disease progression and improving exercise capacity. 2) Tadalafil, a phosphodiesterase-5 inhibitor, which has demonstrated efficacy in improving exercise capacity and delaying clinical worsening when added to background therapy. 3) Riociguat, a soluble guanylate cyclase stimulator, which has shown improvements in exercise capacity and hemodynamics. These therapies target different pathways involved in PAH and have shown positive outcomes in clinical trials.

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Apabetalone for Pulmonary Arterial Hypertension (APPROACH-2 Trial)

Phase 2

Waitlist Available

Led By Steeve Provencher, MD, MSc

Research Sponsored by Institut universitaire de cardiologie et de pneumologie de Québec, University Laval

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

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

WHO functional class II or III

Must not have

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)

Significant restrictive (total lung capacity <70% predicted) or obstructive (FEV1/FVC<60% after a bronchodilator) lung disease

Timeline

Screening 3 weeks

Treatment Varies

Follow Up baseline, week 8 and week 24

Summary

This trial tests a new pill that may help reduce the severity of Pulmonary Arterial Hypertension (PAH) and improve heart and lung function in adults who are already on stable treatment.

Who is the study for?

Adults aged 18-75 with Pulmonary Arterial Hypertension (PAH) who are stable on current PAH medication for at least 3 months can join. They must be able to walk at least 150 meters and have a life expectancy of more than 28 weeks. Participants need normal organ function, not be pregnant or breastfeeding, and agree to use contraception if necessary.

What is being tested?

The trial is testing the effectiveness of Apabetalone as an additional treatment for PAH over a period of 24 weeks. It will compare changes in pulmonary vascular resistance (PVR) between those taking Apabetalone and those given a placebo while continuing their usual PAH therapy.

What are the potential side effects?

While specific side effects for this trial aren't listed, common ones from similar medications include headache, dizziness, nausea, diarrhea, rash or swelling where the drug enters the body. More serious risks could involve liver problems or blood cell count changes.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My pulmonary arterial hypertension is due to genetics, drugs, toxins, or related to a heart defect that was corrected over a year ago.

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My heart or lung condition mildly or moderately affects my daily activities.

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My blood, liver, and kidney functions are within normal ranges.

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I can walk 150 meters or more without stopping.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My pulmonary hypertension is not caused by left heart diseases, lung diseases, chronic blood clots, or multiple factors.

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I have severe lung disease that affects my breathing.

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I am not currently using strong medication inhibitors or have stopped them for 2 weeks.

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I have not had major surgery in the last 2 weeks or have fully recovered from it.

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I might have a rare lung blood vessel disorder.

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My pulmonary arterial hypertension is due to HIV or liver issues.

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I am unable to give consent by myself.

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I haven't had a whole blood transfusion in the last 4 months.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ baseline, week 8 and week 24

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~baseline, week 8 and week 24

This trial's timeline: 3 weeks for screening, Varies for treatment, and baseline, week 8 and week 24 for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Placebo-corrected change from baseline in PVR at week 24

Secondary study objectives

Change at week 24 in HRQoL assessed using the EmPHasis-10 questionnaire

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

Change in cardiac output (L/min)

+5 more

Other study objectives

Change in PBMC expression of BMPR2

Change in clinical worsening events

Circulating levels change in whole blood markers of DNA damage

+3 more

Trial Design

2Treatment groups

Active Control

Placebo Group

Group I: ApabetaloneActive Control1 Intervention

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

Group II: PlaceboPlacebo Group1 Intervention

24-week (168±3 days) period.

0 / 12Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Pulmonary Arterial Hypertension (PAH) include endothelin receptor antagonists (ERAs), phosphodiesterase-5 inhibitors (PDE5Is), and prostacyclin analogs. ERAs, such as bosentan and ambrisentan, work by blocking endothelin-1, a potent vasoconstrictor, thereby reducing pulmonary vascular resistance and improving blood flow. PDE5Is, like sildenafil and tadalafil, enhance nitric oxide signaling, leading to vasodilation and improved exercise capacity. Prostacyclin analogs, such as epoprostenol and iloprost, mimic the effects of prostacyclin, promoting vasodilation and inhibiting platelet aggregation. Emerging treatments like Apabetalone, a BRD4 inhibitor, target epigenetic regulation and have shown promise in reversing disease progression in animal models. These mechanisms are crucial for PAH patients as they address the underlying vascular dysfunction, improve hemodynamics, and potentially enhance long-term outcomes.