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

9 september 2026 bijgewerkt door: Assistance Publique - Hôpitaux de Paris
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.

Studie Overzicht

Toestand

Nog niet aan het werven

Conditie

Interventie / Behandeling

Studietype

Ingrijpend

Inschrijving (Geschat)

150

Fase

  • Fase 3

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studiecontact

Studie Locaties

  • Frankrijk
      • Angers, Frankrijk, 49000
      • Bordeaux, Frankrijk, 33600
      • Brest, Frankrijk, 29200
      • Caen, Frankrijk, 14034
      • Clermont-Ferrand, Frankrijk, 63000
      • Dijon, Frankrijk, 21000
      • Grenoble, Frankrijk, 38700
      • Le Kremlin-Bicêtre, Frankrijk, 94270
      • Lille, Frankrijk, 59037
      • Marseille, Frankrijk, 13005
      • Marseille, Frankrijk, 13915
      • Montpellier, Frankrijk, 34295
      • Nantes, Frankrijk, 44800
      • Paris, Frankrijk, 75015
        • Hôpital Europeén Georges Pompidou
        • Contact:
      • Poitiers, Frankrijk, 86000
      • Rennes, Frankrijk, 35000
      • Rouen, Frankrijk, 76031
      • Saint-Etienne, Frankrijk, 42270
      • Strasbourg, Frankrijk, 67091
      • Toulouse, Frankrijk, 31059
      • Tours, Frankrijk, 37044
      • Vandœuvre-lès-Nancy, Frankrijk, 54500

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

  • Volwassen
  • Oudere volwassene

Accepteert gezonde vrijwilligers

Nee

Beschrijving

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

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

  • Primair doel: Behandeling
  • Toewijzing: Gerandomiseerd
  • Interventioneel model: Parallelle opdracht
  • Masker: Geen (open label)

Wapens en interventies

Deelnemersgroep / Arm
Interventie / Behandeling
Experimenteel: Experimental group
Discontinuation of riociguat
Geneesmiddel: Discontinuation of riociguat
Discontinuation of riociguat after randomization
Geen tussenkomst: Control group
Continuation of riociguat

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
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
Tijdsspanne: At the longest follow-up, minimum 12 months

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

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
To compare the effect of discontinuation versus continuation of riociguat monotherapy on 6-minute walk distance (6MWD)
Tijdsspanne: Month 3, 6, 12 and every 6 months with maximum of 48 months
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
Tijdsspanne: Month 3, 6, 12 and every 6 months with maximum of 48 months
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
Tijdsspanne: Month 3, 6, 12 and every 6 months with maximum of 48 months
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
Tijdsspanne: Month 3, 6, 12 and every 6 months with maximum of 48 months
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)
Tijdsspanne: Month 12
Change from baseline in Pulmonary vascular resistance (PVR)
Month 12
To compare the effect of discontinuation versus continuation of riociguat monotherapy on hemodynamic parameters :
Tijdsspanne: Month 12
Change from baseline in Right atrial pressure
Month 12
To compare the effect of discontinuation versus continuation of riociguat monotherapy on hemodynamic parameters
Tijdsspanne: Month 12
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
Tijdsspanne: Month 12
Change from baseline in Cardiac output
Month 12
To compare the effect of discontinuation versus continuation of riociguat monotherapy on quality of life
Tijdsspanne: Month 3, 6, 12 and every 6 months with maximum of 48 months
Change from baseline in EQ-5D-5L questionnaire
Month 3, 6, 12 and every 6 months with maximum of 48 months
To assess the health economic impact of riociguat discontinuation
Tijdsspanne: At the longest follow-up, minimum 12 months
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
Tijdsspanne: Month 12
Change from baseline in Treatment burden questionnaire
Month 12
To compare the effect of discontinuation versus continuation of riociguat monotherapy on quality of life
Tijdsspanne: Month 3, 6, 12 and every 6 months with maximum of 48 months
Change from baseline in EmPHasis-10 questionnaire (scale from 0 (best) to 5 (worst)
Month 3, 6, 12 and every 6 months with maximum of 48 months

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Assistance Publique - Hôpitaux de Paris

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Geschat)

1 november 2026

Primaire voltooiing (Geschat)

31 januari 2031

Studie voltooiing (Geschat)

31 januari 2031

Studieregistratiedata

Eerst ingediend

1 juni 2026

Eerst ingediend dat voldeed aan de QC-criteria

8 juni 2026

Eerst geplaatst (Werkelijk)

12 juni 2026

Updates van studierecords

Laatste update geplaatst (Werkelijk)

14 september 2026

Laatste update ingediend die voldeed aan QC-criteria

9 september 2026

Laatst geverifieerd

1 september 2026

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Andere studie-ID-nummers

  • APHP251608
  • 2026-525351-81-00 (Ctis)

Informatie over medicijnen en apparaten, studiedocumenten

Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel

Nee

Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

Nee

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