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

NCT04780932 | Completed Phase 2 DMC

• 1 other identifier: APHP201037
• Study Type: interventional
• Target: 96
• Locations: 1 country
• Sites: 1

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.

Conditions

Thromboembolic Pulmonary Hypertension; Chronic Disease; Inoperable Disease

Outcome Measures

Primary Outcomes (1)

• To compare the effect of an initial dual oral treatment (riociguat, macitentan) vs. standard-of-care initial oral monotherapy (riociguat, placebo) on pulmonary vascular resistance (PVR) prior to BPA.

  Pulmonary vascular resistance (PVR) at rest at week 16 expressed as a percentage of the baseline resting PVR.

  Week 16

Secondary Outcomes (15)

• To compare the effect of an initial dual oral treatment (riociguat, macitentan) vs. standard-of-care initial oral monotherapy (riociguat, placebo) on other clinical measures of pulmonary hypertension prior to BPA

  Week 16

• To compare the effect of an initial dual oral treatment (riociguat, macitentan) vs. standard-of-care initial oral monotherapy (riociguat, placebo) on other clinical measures of pulmonary hypertension prior to BPA

  Week 16

• To compare the effect of an initial dual oral treatment (riociguat, macitentan) vs. standard-of-care initial oral monotherapy (riociguat, placebo) on other clinical measures of pulmonary hypertension prior to BPA

  Week 16

• To compare the effect of an initial dual oral treatment (riociguat, macitentan) vs. standard-of-care initial oral monotherapy (riociguat, placebo) on other clinical measures of pulmonary hypertension prior to BPA

  Week 16

• To compare the effect of an initial dual oral treatment (riociguat, macitentan) vs. standard-of-care initial oral monotherapy (riociguat, placebo) on quality of life prior to BPA

  Week 16

Study Arms (2)

Control Arm

PLACEBO COMPARATOR

Oral Standard-of care riociguat from Day 1 to Week 42 (+/- 1 week). Posology 1mg tid - 2,5 mg tid. Oral Placebo 10 mg/day from Day 8 (+/- 3 days) to Week 42 (+/- 1 week). At week 16, subjects who are still symptomatic (WHO functional II to IV) and have PVR ≥ 240 dyn.sec.cm-5 will be offered additional treatment by BPA.

Drug: Placebo

Experimental Arm

EXPERIMENTAL

Oral Standard-of care riociguat from Day 1 to Week 42 (+/- 1 week). Posology 1mg tid - 2,5 mg tid. Oral Macitentan 10 mg/day from Day 8 (+/- 3 days) to Week 42 (+/- 1 week). At week 16, subjects who are still symptomatic (WHO functional II to IV) and have PVR ≥ 240 dyn.sec.cm-5 will be offered additional treatment by BPA.

Drug: Macitentan 10mg

Interventions

Macitentan 10mg DRUG

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

Experimental Arm

Placebo DRUG

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

Control Arm

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent.
• Newly diagnosed and treatment-naïve subjects with CTEPH judged as inoperable due to surgically inaccessible lesions but eligible for balloon pulmonary angioplasty, riociguat and macitentan by multidisciplinary team assessment and fulfilling the following criteria:
• Symptomatic pulmonary hypertension (PH) in WHO FC ≥ II.
• Confirmation of diagnosis based on 2 of the 3 following methods:
• i. Ventilation-perfusion lung scan ii. Digital subtraction pulmonary angiography (DSA) iii. CT pulmonary angiography (CTPA).
• Confirmation of inoperability based on CTPA scan and/or DSA.
• Right-heart catheterization (RHC) in the 12-week period prior to screening visit or during screening period showing the following:
• Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg
• Pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg or left ventricular end diastolic pressure ≤ 15 mmHg
• PVR at rest ≥ 400 dyn.sec.cm-5.
• Subject anticoagulated (with either vitamin K antagonists or direct oral anticoagulants \[e.g., factor IIa inhibitors, factor Xa inhibitors\]), or treated with unfractionated heparin or low molecular weight heparin for at least 3 months prior to baseline RHC.
• MWD ≥ 50m
• Women of childbearing potential must:
• Have a negative pre-treatment serum pregnancy test
• Agree to use reliable contraception from screening up to 1 month following discontinuation of the last study treatment.

You may not qualify if:

• Previous pulmonary endarterectomy.
• Previous balloon pulmonary angioplasty.
• Ongoing or planned treatment with organic nitrates.
• Known moderate-to-severe restrictive lung disease (i.e., total lung capacity \< 60% of predicted value) or obstructive lung disease (i.e., forced expiratory volume in one second \[FEV1\] \< 60% of predicted, with FEV1 / forced vital capacity \< 65%) or known significant chronic lung disease diagnosed by chest imaging (e.g., interstitial lung disease, emphysema).
• Left heart failure with an ejection fraction less than 40%.
• History of life-threatening hemoptysis (\>100 mL in 24 h) or subjects who have previously undergone bronchial arterial embolization for hemoptysis.
• Hemoglobin \< 100 g/L.
• Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 3 × upper limit of the normal range.
• Documented severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin \> 3 × upper limit of the normal range (ULN) accompanied by aspartate aminotransferase (AST) \> ULN; and/or Child-Pugh Class C.
• Severe renal impairment (estimated creatinine clearance ≤ 30 mL/min/1.73 m²).
• Systolic blood pressure \<95mmHg.
• Known hypersensitivity to riociguat or macitentan or to any excipient of their formulation.
• History of severe allergic-like reaction to intravascular administration of iodinated contrast media (including diffuse edema or facial edema with dyspnea, diffuse erythema with hypotension, laryngeal edema with stridor and/or hypoxia, bronchospasm, anaphylactic shock with hypotension and tachycardia).
• Subject who cannot remain in a supine position for at least 120 min for any reason.
• Pregnancy, breastfeeding, or intention to become pregnant during the study.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Janssen, LP: collaborator

Study Sites (1)

Hôpital Bicêtre

Le Kremlin-Bicêtre, Île-de-France Region, 94270, France

Location

MeSH Terms

Conditions

Chronic Disease

Interventions

macitentan

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Xavier JAIS, Dr

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 15, 2021
• First Posted: March 4, 2021
• Study Start: June 14, 2021
• Primary Completion: July 3, 2025
• Study Completion: July 3, 2025
• Last Updated: July 20, 2025

Record last verified: 2025-07

Locations

FR (1)