Discontinuation Versus Continuation of Riociguat Monotherapy in Chronic Thromboembolic Pulmonary Hypertension Successfully Treated With Balloon Pulmonary Angioplasty

NCT07644377 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: APHP251608
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 22

Brief Summary

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but severe complication of acute pulmonary embolism, characterized by persistent obstruction of the pulmonary arteries by organized thrombi and secondary microvasculopathy. International guidelines recommend a multimodal approach combining pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), and medical treatment with riociguat, to address the full spectrum of CTEPH lesions. BPA and riociguat are recommended for symptomatic patients with inoperable CTEPH or persistent pulmonary hypertension after PEA. Riociguat is administered before BPA to reduce periprocedural complications by improving pulmonary hemodynamics. While this pre-BPA strategy is well established, post-BPA management is poorly studied, especially in patients achieving therapeutic goals, defined as WHO functional class I or II and near-normal resting pulmonary hemodynamics (70 to 80% of cases). In such cases, riociguat monotherapy is often continued long-term, despite its cost, burden, and potential side effects, which may negatively impact patients' quality of life. Retrospective single-center studies suggest that discontinuation of medical treatment does not lead to significant clinical deterioration. Therefore, we propose conducting a multicenter trial using a PROBE (prospective, randomized, open-label, blinded endpoint) design and a Bayesian approach to test if stopping riociguat monotherapy after successful BPA is associated with an acceptably low risk of clinical worsening over a follow-up period of at least one year compared to continuation. The trial will also assess the cost-effectiveness of riociguat discontinuation.

Conditions

CTEPH

Keywords

riociguat discontinuation

Outcome Measures

Primary Outcomes (1)

• To evaluate whether the discontinuation of riociguat monotherapy after successful BPA in CTEPH patients is associated with an acceptably low risk of clinical worsening compared to continuation

  Clinical worsening which is the composite of : * death due to any cause, * hospitalisation due to worsening including : a) documented right heart failure, b) need for lung transplantation, c) need for intraveinous diuretics/inotropic support or d) need for parental prostanoids * decline in 6 minutes walk distance by 15% from baseline, combined with WHO functional class III or IV

  At the longest follow-up, minimum 12 months

Secondary Outcomes (12)

• To compare the effect of discontinuation versus continuation of riociguat monotherapy on 6-minute walk distance (6MWD)

  Month 3, 6, 12 and every 6 months with maximum of 48 months

• To compare the effect of discontinuation versus continuation of riociguat monotherapy on WHO functionnal class

  Month 3, 6, 12 and every 6 months with maximum of 48 months

• To compare the effect of discontinuation versus continuation of riociguat monotherapy on WHO functionnal class

  Month 3, 6, 12 and every 6 months with maximum of 48 months

• To compare the effect of discontinuation versus continuation of riociguat monotherapy on other clinical measures of pulmonary hypertension

  Month 3, 6, 12 and every 6 months with maximum of 48 months

• To compare the effect of discontinuation versus continuation of riociguat monotherapy on pulmonary vascular resistance (PVR)

  Month 12

Study Arms (2)

Experimental group

EXPERIMENTAL

Discontinuation of riociguat

Drug: Discontinuation of riociguat

Control group

NO INTERVENTION

Continuation of riociguat

Interventions

Discontinuation of riociguat DRUG

Discontinuation of riociguat after randomization

Experimental group

Eligibility Criteria

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

You may qualify if:

• \. Signed informed consent and willingness to accept either discontinuation or continuation of riociguat monotherapy
• \. Age ≥18 years
• \. Diagnosis of inoperable CTEPH or persistent PH after PEA, with achievement of therapeutic goals following BPA, defined as:
• WHO FC I or II
• Pulmonary vascular resistance (PVR) \< 3 Wood units
• Mean pulmonary artery pressure (mPAP) \< 30 mmHg
• \. Treatment with riociguat monotherapy for ≥6 months, with stable dose for ≥3 months prior to enrollment
• \. Last BPA session performed ≥6 months prior to enrollment
• \. 6-minute walk distance (6MWD) ≥ 150 meters
• \. For women of childbearing potential: highly effective contraception

You may not qualify if:

• \. Background treatment with any PH-targeted therapy other than riociguat, (e.g., any endothelin receptor antagonist (ERA), phosphodiesterase-5 inhibitor (PDE-5i), parenteral prostanoids, prostacyclin receptor agonist)
• \. Post-capillary pulmonary hypertension, defined as pulmonary artery wedge pressure (PAWP) \> 15 mmHg
• \. Significant obstructive or restrictive lung disease, defined as:
• FEV₁ \< 60% predicted, with FEV₁/FVC \< 65%
• and/or total lung capacity (TLC) \< 60% predicted
• or known significant chronic lung disease on imaging (e.g., interstitial lung disease, emphysema)
• \. Severe hepatic impairment, defined as:
• Child-Pugh class B or C
• and/or liver aminotransferase levels \> 3× upper limit of normal (ULN)
• \. Severe renal impairment (estimated creatinine clearance ≤ 30 mL/min/1.73 m²).
• \. Left heart failure with left ventricular ejection fraction (LVEF) \< 40%
• \. Ongoing or planned treatment with organic nitrates.
• \. Concomitant treatment with strong cytochrome P450 3A4 (CYP3A4) inducers (e.g., rifabutin, rifampicin, carbamazepine, phenobarbital, phenytoin, St. John's wort)
• \. Concomitant treatment with strong multi pathway P-glycoprotein (P-gp)/ breast cancer resistance protein (BCRP) inhibitors (e.g., lopinavir/ritonavir).
• \. 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.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (22)

CHU Angers

Angers, 49000, France

Location

Hôpital Haut Levêque

Bordeaux, 33600, France

Location

Hôpital de la Cavale blanche

Brest, 29200, France

Location

CHU Caen

Caen, 14034, France

Location

Hôpital Gabriel Montpied

Clermont-Ferrand, 63000, France

Location

CHU Dijon Bourgogne

Dijon, 21000, France

Location

CHU Grenoble Alpes

Grenoble, 38700, France

Location

Hôpital Bicêtre

Le Kremlin-Bicêtre, 94270, France

Location

Institut Cœur-Poumon

Lille, 59037, France

Location

Hôpital de la Timone

Marseille, 13005, France

Location

Hôpital Nord

Marseille, 13915, France

Location

CHU Montpellier

Montpellier, 34295, France

Location

Hôpital Laënnec

Nantes, 44800, France

Location

Hôpital Européen Georges Pompidou

Paris, 75015, France

Location

CHU Poitiers

Poitiers, 86000, France

Location

Hôpital Pontchaillou

Rennes, 35000, France

Location

CHU Rouen

Rouen, 76031, France

Location

CHU Saint Etienne

Saint-Etienne, 42270, France

Location

Nouvel Hôpital Civil

Strasbourg, 67091, France

Location

Hôpital Larrey

Toulouse, 31059, France

Location

Hôpital Bretonneau

Tours, 37044, France

Location

Hôpital Brabois

Vandœuvre-lès-Nancy, 54500, France

Location

Central Study Contacts

Mitja JEVNIKAR, MD

CONTACT

+33 145217876; mitja.jevnikar@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a multicenter trial using a PROBE design conducted in patients with inoperable CTEPH or persistent PH after PEA, who have been receiving riociguat monotherapy for ≥6 months and have achieved therapeutic goals following BPA. Eligible patients will be randomly assigned in a 1:1 ratio to two treatment groups: * Experimental group: discontinuation of riociguat * Control group: continuation of riociguat Regular hospital visits will be conducted at months 3, 6, and 12, including WHO FC assessment, clinical examination, 6MWD, routine blood tests (including NT-proBNP), and quality of life assessment (EmPHasis-10 and EQ-5D-5L). At month 12, an RHC will be also performed to assess hemodynamic parameters. Thereafter, patients will be evaluated every 6 months until the last enrolled patient has completed the minimum 12-month follow-up. Adjudication of all clinical worsening events will be performed by an independent Clinical Event Committee (CEC)

Study Record Dates

• First Submitted: June 1, 2026
• First Posted: June 12, 2026
• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): January 31, 2031
• Study Completion (Estimated): January 31, 2031
• Last Updated: June 12, 2026

Record last verified: 2026-06

Locations

FR (22)