Switching of Sildenafil to Riociguat in CTEPH Patients (S2R)

Switching Sildenafil to Riociguat in Chronic Thromboembolic Pulmonary Hypertension After Balloon Pulmonary Angioplasty

This study was designed to investigate the safety and efficacy of replacing phosphodiesterase 5 inhibitors (PDE5i) with riociguat in patients with Chronic thromboembolic pulmonary hypertension (CTEPH) who have undergone pulmonary angioplasty (BPA) and remains symptomatic despite treatments with PDE5i.

Study Overview

• Status: Recruiting
• Conditions: Chronic Thromboembolic Pulmonary Hypertension
• Intervention / Treatment: Drug: Riociguat (Adempas)

Detailed Description

Chronic thromboembolic pulmonary hypertension (CTEPH) results from the obstruction of the pulmonary arteries by organised fibrotic thrombi and the associated microvasculopathy, leading to increased pulmonary vascular resistance and progressive right-sided heart failure. CTEPH is associated with significant mortality and morbidity, so prompt initiation of treatments are necessary to improve the prognosis.

For those with accessible pulmonary arteries occlusions, surgical pulmonary endarterectomy (PEA) is the treatment of choice. Nevertheless, about 40% of CTEPH patients are not considered to be operable due to occlusion of distal pulmonary vessels. For patients with inoperative CTEPH, current treatment options include balloon pulmonary angioplasty (BPA) and medical therapies.

Several medical therapies that target microvascular components of CTEPH, such as phosphodiesterase type 5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), have been used off-label, as the efficacy of those medications in inoperable CTEPH has not been proven in randomised controlled trials or registry data. The CHEST-1 randomised controlled trial demonstrated that the soluble guanylate cyclase stimulator (sGCs), riociguat, significantly reduced pulmonary vascular resistance and improved exercise capacity in patients with inoperative CTEPH or persistent or recurrent pulmonary hypertension after PEA. Based on the finding of this study, riociguat has been approved for treatment for symptomatic inoperable patients with CTEPH.

Both PDE5i and sGCs act via the same nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway, but these two classes of medications target different molecular targets in the same pathway. PDE5i inhibits the degradation of cGMP, so its efficacy is dependent on a functioning NO-sGC-cGMP axis and the presence of intracellular cGMP. In contrast, riociguat stimulates sGC directly, thus it increases intracellular cGMP level regardless the presence of NO. Therefore, based on this biological rationale, it is postulated that riociguat may be more effective in increasing intracellular cGMP compared to PDE5i. Currently there is no head-to-head trials comparing the efficacy of PDE5i and riociguat in treating pulmonary hypertension. Nevertheless, 2 clinical trials have demonstrated improvement in the clinical and biochemical parameters after switching from PDE5i to sGCs in selected patients with pulmonary arterial hypertension (PAH) with insufficient response to PDE5i. It is currently unknown whether this switching will also apply to patients with CTEPH as those 2 clinical trials do not include patients with CTEPH.

In addition to medical therapies, BPA, an endovascular procedure to dilate the occlusions and stricture in segmental or subsegmental pulmonary arteries, has emerged as a treatment for patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after PEA. Two randomised controlled trials comparing BPA and riociguat have demonstrated that BPA was associated with a greater improvement in mean pulmonary artery pressure and reduction in pulmonary vascular resistance in inoperable CTEPH patients.

Currently, the data of safety and efficacy of switching PDE5i to sGCs after BPA is lacking. Therefore, this study was designed to investigate the safety and efficacy of replacing PDE5i with riociguat in patients with CTEPH who have undergone BPA and remains symptomatic despite treatments with PDE5i.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Daniel Xu Nurse; Phone Number: +85235051518; Email: danielxu@cuhk.edu.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • Prince of Wales Hospital
    • Contact: Daniel Xu Nurse; Phone Number: +85235051518; Email: danielxu@cuhk.edu.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with established diagnosis of CTEPH who are symptomatic after Balloon pulmonary angioplasty (BPA)
2. Patients who are on stable maximally tolerated dose of sildenafil for at least 6 weeks as monotherapy, or in combination with other pulmonary hypertension specific therapies
3. WHO functional class III at screening
4. Stable dose of diuretics (if used) for at least 30 days at screening
5. No recent hospitalisation due to pulmonary hypertension or heart failure for at least 30 days

Exclusion Criteria:

1. Previous treatment with riociguat other sGCs, or documented severe drug reaction or intolerance to sGCs
2. Use of nitrates or nitric oxide donors (eg, nitroglycerin, amyl nitrite, isosorbide dinitrate etc) by any administration routes within 30 days of screening
3. Pregnant women or breast-feeding women, or women with childbearing potential not using of combination of two effective contraception methods throughout study
4. Renal impairment with glomerular filtration rate <15mL /min
5. Child-Pugh C hepatic impairment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Patients with Chronic Thromboembolic Pulmonary Hypertension; Patients with Chronic Thromboembolic Pulmonary Hypertension under Sildenafil treatment	Drug: Riociguat (Adempas); Oral riociguat administered according to established dose-adjustment scheme. Riociguat will be administered starting at at 1mg three times per day. If patient systolic blood pressure maintains at 95mmHg or higher, the dose will be increased 0.5mg every 2 weeks up to a maximum dose 2.5mg three times per day over 8-week period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mean pulmonary artery pressure (mPAP)	Change in mean pulmonary artery pressure (mPAP) measured in right heart catheterization at baseline and at week 26. Pulmonary hypertension (PH) is defined as pulmonary artery pressure (PAP) ≥ 25 mmHg. And the normal resting PAP is 8-20 mmHg.	26 weeks
Change in pulmonary vascular resistance (PVR)	Change in pulmonary vascular resistance (PVR) measured in right heart catheterization at baseline and at week 26. Pulmonary vascular resistance (PVR) is similar to systemic vascular resistance (SVR) except it refers to the arteries that supply blood to the lungs.	26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cardiac output (CO)	Change in cardiac output (CO) measured in right heart catheterization. Cardiac output (CO) is the product of the heart rate (HR), i.e. the number of heartbeats per minute (bpm), and the stroke volume (SV), which is the volume of blood pumped from the left ventricle per beat.	26 weeks
Change in cardiac index (CI)	Change in cardiac index (CI) measured in right heart catheterization. The cardiac index (CI) is a hemodynamic measure that represents the cardiac output (CO) of an individual divided by their body surface area (BSA). It is crucial in assessing patients with heart failure and other cardiovascular conditions	26 weeks
Change in pulmonary artery wedge pressure (PAWP)	Change in pulmonary artery wedge pressure (PAWP) measured in right heart catheterization. It is the pressure measured by wedging a pulmonary artery catheter with an inflated balloon into a small pulmonary arterial branch	26 weeks
Change in The World Health Organization (WHO) functional class	Change in WHO functional class describes how severe a patient's pulmonary hypertension (PH) symptoms. There are four different classes - I is the mildest and IV the most severe form of PH.	26 weeks
Change in N-terminal pro b-type natriuretic peptide (NT-proBNP) level	Change in NT-proBNP level which is a protein that's an "ingredient" for making the BNP hormone. Like BNP, your heart makes larger amounts of NT-proBNP when it has to work harder to pump blood.	26 weeks
Change in walk distance by 6-minutes walk test	Change in walk distance by 6-minutes walk test which is a sub-maximal exercise test used to assess aerobic capacity and endurance.	26 weeks
Change in REVEAL lite 2 risk score	Change in REVEAL lite 2 risk score which is quickly calculate patient's risk score and to help determine whether treatment escalation may be needed	26 weeks
Change in tricuspid regurgitation pressure gradient (TRPG)	Change in tricuspid regurgitation pressure gradient (TRPG) which reflects the difference in pressure between the right ventricle and right atrium on echocardiogram	26 weeks
Change in tricuspid annular plane systolic excursion (TAPSE)	Change in tricuspid annular plane systolic excursion (TAPSE) which a parameter of global RV function which describes apex-to-base shortening on echocardiogram	26 weeks
Change in Pulmonary Embolism Quality of Life Questionnaire (PEmb-QoL) score	Change in Pulmonary Embolism Quality of Life Questionnaire score which is a reliable instrument to specifically assess Quality of Life following Pulmonary Embolism, which is helpful in the identification of patients with decreased Quality of Life following acute Pulmonary Embolism.	26 weeks

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Actual): July 25, 2024
• Primary Completion (Estimated): July 22, 2026
• Study Completion (Estimated): January 22, 2027

Study Registration Dates

• First Submitted: November 26, 2024
• First Submitted That Met QC Criteria: December 3, 2024
• First Posted (Actual): December 4, 2024

Study Record Updates

• Last Update Posted (Actual): May 29, 2025
• Last Update Submitted That Met QC Criteria: May 23, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Sildenafil; CTEPH; BPA; Riociguat
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; Riociguat
• Other Study ID Numbers: 2023.577

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No