Initial Dual Oral Combination Therapy Versus Standard-of-care Initial Oral Monotherapy Prior to Balloon Pulmonary Angioplasty in Patients With Inoperable Chronic Thromboembolic Pulmonary Hypertension

Summary

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by an obstruction of proximal or more distal pulmonary arteries by residual organized thrombi, combined with a variable microscopic pulmonary vasculopathy (microvasculopathy). Besides lifelong anticoagulation, surgical pulmonary endarterectomy is the treatment of choice in subjects with proximal CTEPH affecting large pulmonary arteries. However, around half of CTEPH subjects are not operated, mainly because of distal lesions inaccessible to surgery. International data have reported survival rates of 88, 79, and 70% at 1, 2, and 3 years, respectively, in subjects with inoperable CTEPH, underscoring the need for better treatment strategies. In those subjects, current guidelines recommend medical therapy with or without balloon pulmonary angioplasty (BPA). Currently, only one drug (riociguat), targeting the NO pathway, is approved and reimbursed in Europe. Thus, riociguat monotherapy is considered as the standard-of-care treatment for subjects newly diagnosed with inoperable CTEPH. Recently, macitentan, targeting the endothelin-1 pathway, showed to be also effective in subjects with inoperable CTEPH. However, macitentan is currently not approved for CTEPH in Europe.

BPA has been also reported to improve hemodynamics, symptoms and exercise capacity. However, complications, including mainly vascular injury, may occur during this procedure and it has been shown that the risk of BPA-related complications was strongly related to the level of pre-BPA mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR). Medical therapy and BPA have in fact complementary effects since they target different lesions. Indeed, BPA targets fibrotic organized thrombi in the segmental arteries down to small pulmonary arteries of 2-5 mm in diameter. Medical therapy, for its part, targets microvasculopathy, similar to that observed in pulmonary arterial hypertension (PAH), in vessels less than 0.5 mm in diameter. Therefore, it is strongly believed that the use of medical therapy prior to BPA may reduce the risk of BPA-related complications by improving pulmonary hemodynamics and may improve global efficacy. In PAH, initial dual oral combination therapy with drugs targeting the NO and endothelin pathways is considered as a standard of care, more efficacious than monotherapy and safe. In contrast, there are no data from controlled trials regarding the efficacy and safety of initial combination therapy regimens versus standard-of-care monotherapy in treatment-naïve subjects with inoperable CTEPH.

The investigators hypothesize that initial dual oral combination therapy may be superior to standard-of-care riociguat monotherapy for improving pulmonary hemodynamics prior to BPA and for reducing the risk of BPA-related complications.

Conditions

• Thromboembolic Pulmonary Hypertension
• Chronic Disease
• Inoperable Disease

Interventions

DRUG

Macitentan 10mg

Macitentan 10 mg will be initiated at Day 8 (+/- 3 days) until week 42 (+/- week). The recommended dose is 10 mg once daily by oral administration

DRUG

Placebo

Placebo 10 mg will be initiated at Day 8 (+/- 3 days) until week 42 (+/- week). The recommended dose is 10 mg once daily by oral administration

Sponsors & Collaborators

• Janssen, LP

  collaborator INDUSTRY

• Assistance Publique - Hôpitaux de Paris

  lead OTHER

Principal Investigators

• Xavier JAIS, Dr · Assistance Publique - Hôpitaux de Paris

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

80 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2021-06-14

Primary Completion

2025-07-03

Completion

2025-07-03

Countries

• France

Study Locations