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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: CTEPH
• Intervention / Treatment: Drug: Discontinuation of riociguat

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Mitja JEVNIKAR, MD; Phone Number: +33 145217876; Email: mitja.jevnikar@aphp.fr

Study Locations

• France
  • Angers, France, 49000
    • CHU Angers
    • Contact: Frédéric GAGNADOUX, PUPH; Phone Number: +33241353695; Email: frgagnadoux@chu-angers.fr
  • Bordeaux, France, 33600
    • Hôpital Haut Levêque
    • Contact: François PICARD, PUPH; Phone Number: +33557656267; Email: francois.picard@chubordeaux.fr
  • Brest, France, 29200
    • Hôpital de la Cavale blanche
    • Contact: Cécile TROMEUR, PUPH; Phone Number: +33230337602; Email: cecile.tromeur@chu-brest.fr
  • Caen, France, 14034
    • CHU Caen
    • Contact: Emmanuel BERGOT, PUPH; Phone Number: +33331064677; Email: bergot-e@chu-caen.fr
  • Clermont-Ferrand, France, 63000
    • Hôpital Gabriel Montpied
    • Contact: Romain TRESORIER, MD; Phone Number: +33473751412; Email: rtresorier@chuclermontferrand.fr
  • Dijon, France, 21000
    • Chu Dijon Bourgogne
    • Contact: Nicolas FAVROLT, MD; Phone Number: +33380293772; Email: Nicolas.favrolt@chu-dijon.fr
  • Grenoble, France, 38700
    • CHU Grenoble Alpes
    • Contact: Hélène BOUVAIST, MD; Phone Number: +33476768888; Email: hbouvaist@chu-grenoble.fr
  • Le Kremlin-Bicêtre, France, 94270
    • Hôpital Bicêtre
    • Contact: Mitja JEVNIKAR, MD; Phone Number: +33 145217876; Email: mitja.jevnikar@aphp.fr
  • Lille, France, 59037
    • Institut Cœur-Poumon
    • Contact: Nicolas LAMBLIN, PUPH; Phone Number: +33320445038; Email: Nicolas.lamblin@chru-lille.fr
  • Marseille, France, 13005
    • Hopital de La Timone
    • Contact: Sébastien RENARD, MD; Phone Number: +33491385978; Email: sebastien.renard@ap-hm.fr
  • Marseille, France, 13915
    • Hôpital Nord
    • Contact: Martine REYNAUD GAUBERT, PUPH; Phone Number: +33491966145; Email: martine.reynaud@ap-hm.fr
  • Montpellier, France, 34295
    • CHU Montpellier
    • Contact: Arnaud BOURDIN, PUPH; Email: a-bourdin@chu-montpellier.fr
  • Nantes, France, 44800
    • Hôpital Laënnec
    • Contact: Delphine HOREAU LANGLARD, MD; Phone Number: +33240165229; Email: delphine.horeaulanglard@chu-nantes.fr
  • Paris, France, 75015
    • Hôpital Européen Georges Pompidou
    • Contact: Olivier SANCHEZ, PUPH; Phone Number: +33 156093461; Email: olivier.sanchez@aphp.fr
  • Poitiers, France, 86000
    • CHU Poitiers
    • Contact: Magali CROQUETTE, MD; Phone Number: +33549443570; Email: magali.croquette@chu-poitiers.fr
  • Rennes, France, 35000
    • Hôpital Pontchaillou
    • Contact: Céline CHABANNE, MD; Phone Number: +33299282473; Email: celine.chabanne@chu-rennes.fr
  • Rouen, France, 76031
    • CHU Rouen
    • Contact: Elise ARTAUD-MACARI, MD; Phone Number: +33232885992; Email: Elise.artaud-macari@chu-rouen.fr
  • Saint-Etienne, France, 42270
    • CHU Saint Etienne
    • Contact: Laurent BERTOLETTI, PUPH; Phone Number: +33477127770; Email: laurent.bertoletti@chu-st-etienne.fr
  • Strasbourg, France, 67091
    • Nouvel Hôpital Civil
    • Contact: Marianne RIOU, MD; Phone Number: +33369551145; Email: marianne.riou@chru-strasbourg.fr
  • Toulouse, France, 31059
    • Hôpital Larrey
    • Contact: Elise NOEL SAVINA, MD; Phone Number: +33567771744; Email: noel-savina.e@chu-toulouse.fr
  • Tours, France, 37044
    • Hôpital Bretonneau
    • Contact: Pascal MAGRO, PUPH; Phone Number: +33247478784; Email: magro@med.univ-tours.fr
  • Vandœuvre-lès-Nancy, France, 54500
    • Hôpital Brabois
    • Contact: Ari CHAOUAT, PUPH; Phone Number: +33383154021; Email: a.chaouat@chru-nancy.fr

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 1. Signed informed consent and willingness to accept either discontinuation or continuation of riociguat monotherapy
• 2. Age ≥18 years

• 3. Diagnosis of inoperable CTEPH or persistent PH after PEA, with achievement of therapeutic goals following BPA, defined as:

  1. WHO FC I or II
  2. Pulmonary vascular resistance (PVR) < 3 Wood units
  3. Mean pulmonary artery pressure (mPAP) < 30 mmHg
• 4. Treatment with riociguat monotherapy for ≥6 months, with stable dose for ≥3 months prior to enrollment
• 5. Last BPA session performed ≥6 months prior to enrollment
• 6. 6-minute walk distance (6MWD) ≥ 150 meters
• 7. For women of childbearing potential: highly effective contraception

Exclusion Criteria:

• 1. 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)
• 2. Post-capillary pulmonary hypertension, defined as pulmonary artery wedge pressure (PAWP) > 15 mmHg
• 3. 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)
• 4. Severe hepatic impairment, defined as:
• Child-Pugh class B or C
• and/or liver aminotransferase levels > 3× upper limit of normal (ULN)
• 5. Severe renal impairment (estimated creatinine clearance ≤ 30 mL/min/1.73 m²).
• 6. Left heart failure with left ventricular ejection fraction (LVEF) < 40%
• 7. Ongoing or planned treatment with organic nitrates.
• 8. Concomitant treatment with strong cytochrome P450 3A4 (CYP3A4) inducers (e.g., rifabutin, rifampicin, carbamazepine, phenobarbital, phenytoin, St. John's wort)
• 9. Concomitant treatment with strong multi pathway P-glycoprotein (P-gp)/ breast cancer resistance protein (BCRP) inhibitors (e.g., lopinavir/ritonavir).
• 10. 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.
• 11. History of life-threatening hemoptysis (>100 mL within 24 hours) or prior bronchial artery embolization for hemoptysis
• 12. Pregnancy, breastfeeding, or intention to become pregnant during the study period
• 13. Severe comorbidities or underlying conditions with an anticipated life expectancy < 12 months, including active malignancy with localized or metastatic disease
• 14. Lack of coverage by national health or social security systems
• 15. Alcohol abuse, as determined by the investigator
• 16. Any condition or factor likely to interfere with protocol compliance, in the opinion of the investigator
• 17. Patient under guardianship or curatorship
• 18. Participation in another interventional trial or being in the exclusion period following a previous research involving the human person

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group; Discontinuation of riociguat	Drug: Discontinuation of riociguat; Discontinuation of riociguat after randomization
No Intervention: Control group; Continuation of riociguat

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
To compare the effect of discontinuation versus continuation of riociguat monotherapy on 6-minute walk distance (6MWD)	Change from baseline in 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	Change from baseline in 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	Change from baseline in Borg dyspnea	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	Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels	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)	Change from baseline in Pulmonary vascular resistance (PVR)	Month 12
To compare the effect of discontinuation versus continuation of riociguat monotherapy on hemodynamic parameters :	Change from baseline in Right atrial pressure	Month 12
To compare the effect of discontinuation versus continuation of riociguat monotherapy on hemodynamic parameters	Change from baseline in Mean pulmonary arterial pressure (mPAP)	Month 12
To compare the effect of discontinuation versus continuation of riociguat monotherapy on hemodynamic parameters	Change from baseline in Cardiac output	Month 12
To compare the effect of discontinuation versus continuation of riociguat monotherapy on quality of life	Change from baseline in EQ-5D-5L questionnaire	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 quality of life	Change from baseline in EmPHasis-10 questionnaire	Month 3, 6, 12 and every 6 months with maximum of 48 months
To assess the health economic impact of riociguat discontinuation	Incremental cost-effectiveness ratio (ICER), defined as the difference in in quality-adjusted life years (QALYS), for the strategy of riociguat monotherapy discontinuation from the perspective of the French public health system	At the longest follow-up, minimum 12 months
To assess treatment burden	Change from baseline in Treatment burden questionnaire	Month 12

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): January 31, 2031
• Study Completion (Estimated): January 31, 2031

Study Registration Dates

• First Submitted: June 1, 2026
• First Submitted That Met QC Criteria: June 8, 2026
• First Posted (Actual): June 12, 2026

Study Record Updates

• Last Update Posted (Actual): June 12, 2026
• Last Update Submitted That Met QC Criteria: June 8, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: riociguat discontinuation
• Other Study ID Numbers: APHP251608

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No