Comparison of Initial Dual Oral Therapy with Riociguat and Macitentan Versus Standard Monotherapy in Inoperable Chronic Thromboembolic Pulmonary Hypertension

Trial ID: 2024-513672-17-00
Protocol: APHP201037
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Pulmonary hypertension

Objectives

The primary objective of this study is to compare the effect of an initial dual oral treatment with **riociguat** and **macitentan** versus standard-of-care initial oral monotherapy with riociguat and placebo on pulmonary vascular resistance (PVR) prior to balloon pulmonary angioplasty (BPA) in newly diagnosed and treatment-naïve subjects with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). This is clinically relevant as reducing PVR is crucial in managing CTEPH, potentially improving patient outcomes and quality of life.

Secondary objectives include:

Comparing the effect of the dual treatment versus monotherapy on other clinical measures of pulmonary hypertension before and after potential BPA, pulmonary vascular resistance after potential BPA, the rate of BPA procedure-related complications, disease progression, and quality of life.
Analyzing the safety profile of the initial dual oral treatment.
Analyzing health economics aspects of the initial dual oral treatment.

Participants

The clinical trial involves participants diagnosed with **inoperable chronic thromboembolic pulmonary hypertension** (CTEPH), a condition within the field of pneumology. The study population includes both male and female subjects aged between 18 and 80 years. Participants are newly diagnosed and treatment-naïve, with CTEPH deemed inoperable due to surgically inaccessible lesions, yet eligible for balloon pulmonary angioplasty. The trial does not involve a vulnerable population. Participants must have symptomatic pulmonary hypertension classified as WHO Functional Class II or higher. They are required to have been anticoagulated for at least three months prior to the baseline right-heart catheterization. Women of childbearing potential must adhere to specific contraceptive measures. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of an initial dual oral treatment with **macitentan** and riociguat compared to standard-of-care initial oral monotherapy with riociguat and placebo in patients with inoperable **chronic thromboembolic pulmonary hypertension** (CTEPH). This is a randomized, double-blind, controlled trial with an estimated duration extending until December 31, 2025. The trial involves multiple study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, diagnosis, and treatment history. Participants will be randomly assigned to one of the treatment groups and will undergo regular follow-up visits to monitor their response to the treatment and assess primary and secondary endpoints.

The primary endpoint is the change in pulmonary vascular resistance (PVR) at rest at week 16, expressed as a percentage of the baseline resting PVR. Secondary endpoints include changes in the 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, Borg dyspnea score, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, and quality of life as measured by the EQ-5D-3L scale at various time points up to week 42. The trial will also evaluate the frequency and type of complications related to balloon pulmonary angioplasty (BPA) procedures and the time to the first pulmonary hypertension-related disease progression event.

Participants are expected to be involved in the study for a maximum treatment period of 297 days, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The end-of-study visit will conclude the trial, where final assessments will be conducted to gather comprehensive data on the treatment's impact. The trial's design ensures rigorous monitoring and data collection to provide robust evidence on the comparative effectiveness of the treatment regimens in managing inoperable CTEPH.

Treatment

The clinical trial involves the administration of **macitentan**, an experimental medication, in the form of a **film-coated tablet**. The active substance, macitentan, is a chemical compound with the EU substance number SUB89247. The medication is administered orally at a dosage of 10 mg per day. The maximum treatment period is 297 days, with a total maximum dose of 2970 mg. The tablets are provided in a specific clinical trial formulation, packaged in bottles containing 36 film-coated tablets. Participant compliance with the dosing schedule is monitored throughout the study.

A **placebo** is used as a comparator treatment in this study. The placebo is designed to mimic the macitentan 10 mg film-coated tablet in appearance and is also administered orally. The placebo serves as a control to evaluate the efficacy of the experimental treatment. Participants receiving the placebo follow the same dosing schedule as those receiving macitentan, ensuring consistency in administration and monitoring.

In addition to the experimental and placebo treatments, the study includes the administration of **riociguat**, a standard-of-care therapy. Riociguat is used in both the experimental group, in combination with macitentan, and in the control group, in combination with the placebo. The objective is to compare the effects of dual oral therapy (riociguat and macitentan) versus standard-of-care monotherapy (riociguat and placebo) on pulmonary vascular resistance in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) prior to balloon pulmonary angioplasty.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change in **pulmonary vascular resistance (PVR)** at rest, expressed as a percentage of the baseline resting PVR, measured at week 16. Secondary endpoints include changes from baseline to week 16 and week 42 in several parameters: 6-minute walk distance (6MWD), World Health Organization (WHO) functional class (FC), Borg dyspnea score, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Additionally, quality of life will be evaluated using the EQ-5D-3L scale.

Further secondary endpoints involve the percentage of subjects achieving a PVR of less than 240 dyn.sec.cm-5 at week 42, the frequency and type of complications related to the balloon pulmonary angioplasty (BPA) procedure, and the time from randomization to the first pulmonary hypertension (PH)-related disease progression event. This includes events such as death from any cause, the need for lung transplantation, hospitalization due to PH, initiation of parenteral prostanoid therapy, and clinical worsening defined by a significant decrease in 6MWD combined with WHO FC III or IV. Efficacy assessments will be conducted at specified time points, including weeks 16, 29, and 42, to ensure comprehensive evaluation of the treatment's impact over time.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed informed consent
Male or female ≥18 and ≤ 80 years of age at inclusion
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: a. Symptomatic pulmonary hypertension (PH) in WHO FC ≥ II. b. 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: a. Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg b. Pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg or left ventricular end diastolic pressure ≤ 15 mmHg c. 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.
6MWD ≥ 50m
Women of childbearing potential must: a. Have a negative pre-treatment serum pregnancy test b. Agree to use reliable contraception from screening up to 1 month following discontinuation of the last study treatment.

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Exclusion Criteria

Previous pulmonary endarterectomy
Previous balloon pulmonary angioplasty
Any PAH-targeted therapy (e.g., any endothelin receptor antagonist (ERA), phosphodiesterase-5 inhibitor (PDE-5i), soluble guanylate cyclase stimulator, prostacyclin, prostacyclin analog, or prostacyclin receptor agonist) at any time prior to inclusion.
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).
Symptomatic coronary artery disease requiring nitrate use or intervention (e.g., Percutaneous Coronary Intervention, Coronary Artery Bypass Graft) anticipated in the 6-month period after inclusion.
Acute myocardial infarction ≤ 12 weeks prior to inclusion.
Left heart failure with an ejection fraction less than 40%.
Cerebrovascular events (e.g., transient ischemic attack, stroke) ≤ 12 weeks prior to inclusion.
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.
Treatment with strong cytochrome P450 3A4 (CYP3A4) inducers (e.g., rifabutin, rifampicin, carbamazepine, phenobarbital, phenytoin, St. John’s wort) ≤ 28 days prior to inclusion.
Treatment with strong multi pathway P-glycoprotein (P-gp)/ breast cancer resistance protein (BCRP) inhibitors (e.g., lopinavir/ritonavir) ≤ 28 days prior to inclusion
Treatment with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) or a moderate dual CYP3A4/CYP2C9 inhibitor (e.g., fluconazole, amiodarone) or co-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors ≤ 28 days prior to inclusion.
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.
Subjects with underlying medical disorders and anticipated life expectancy < 12 months (eg active cancer disease with localized and/or metastasized tumor mass).
Alcohol abuse (at investigator discretion).
Subject not covered by social security service.
Any factor or condition likely to affect protocol compliance of the subject, as judged by the investigator.