Clinical trial NCT06715280: Switching of Sildenafil to Riociguat in CTEPH Patients
Official title: Switching Sildenafil to Riociguat in Chronic Thromboembolic Pulmonary Hypertension After Balloon Pulmonary Angioplasty
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Chronic Thromboembolic Pulmonary Hypertension
Keywords: CTEPH
BPA
Riociguat
Sildenafil
Lead sponsor: Chinese University of Hong Kong
Sponsor class: OTHER
First posted: 2024-12-04
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Prospective, open-labelled, single-arm study
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in mean pulmonary artery pressure (mPAP)
timeFrame: 26 weeks
measure: Change in pulmonary vascular resistance (PVR)
timeFrame: 26 weeks
Secondary outcomes:
measure: Change in cardiac output (CO)
timeFrame: 26 weeks
measure: Change in cardiac index (CI)
timeFrame: 26 weeks
measure: Change in pulmonary artery wedge pressure (PAWP)
timeFrame: 26 weeks
measure: Change in The World Health Organization (WHO) functional class
timeFrame: 26 weeks
measure: Change in N-terminal pro b-type natriuretic peptide (NT-proBNP) level
timeFrame: 26 weeks
measure: Change in walk distance by 6-minutes walk test
timeFrame: 26 weeks
measure: Change in Pulmonary Embolism Quality of Life Questionnaire (PEmb-QoL) score
timeFrame: 26 weeks
measure: Change in REVEAL lite 2 risk score
timeFrame: 26 weeks
measure: Change in tricuspid regurgitation pressure gradient (TRPG)
timeFrame: 26 weeks
measure: Change in tricuspid annular plane systolic excursion (TAPSE)
timeFrame: 26 weeks
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hospital
Study officials:
References: