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
brief 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.
detailed description
The Screening period will last up 28 days maximum. It begins at the first screening assessment and ends with subject inclusion. The Screening visit date is the date when the first screening assessment is performed.
The Treatment period will start at Day 1 with the first dose of riociguat and ends at Week 42 / End-of-Treatment (EOT) visit.
On Day 8, the experimental treatment with macitentan / placebo will be started.
During this period, regular hospital visits will be performed (Week 16, Week 29).
In addition, laboratory tests will be performed every 4 weeks as part of standard of care.
Subjects who are still symptomatic (WHO FC II to IV) and have PVR≥ 240 dyn.sec.cm-5 at week 16 will be offered additional treatment by BPA.
Safety follow-up period: After study drug discontinuation, all subjects will enter a Safety follow-up period which ends with safety follow up visit/end of study, 30-35 days after the last intake to the study drug.
All subjects who prematurely and definitively discontinue study drug before Week 42 must have a premature EOT visit as soon as possible but no later than 7 days after the decision of definitive discontinuation of study drug and have a safety follow-up visit as described above.
Post-Treatment Observational Period: Subjects are to remain in the study after premature EOT and safety visit and undergo all study assessments up to Week 42, except subjects discontinuing study drug due to PH-related disease progression who will have a premature EOT visit and Safety follow-up visit and will be withdrawn from the study.
A total of 96 newly diagnosed and treatment-naïve subjects with inoperable CTEPH will be randomly assigned in a 1:1 ratio to receive either macitentan (n=48) or placebo (n=48) combined with standard of care with riociguat.
official title
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