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

9 de setembro de 2026 atualizado por: 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.

Visão geral do estudo

Status

Ainda não está recrutando

Condições

Intervenção / Tratamento

Tipo de estudo

Intervencional

Inscrição (Estimado)

150

Estágio

  • Fase 3

Contactos e Locais

Esta seção fornece os detalhes de contato para aqueles que conduzem o estudo e informações sobre onde este estudo está sendo realizado.

Contato de estudo

Locais de estudo

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

Critérios de participação

Os pesquisadores procuram pessoas que se encaixem em uma determinada descrição, chamada de critérios de elegibilidade. Alguns exemplos desses critérios são a condição geral de saúde de uma pessoa ou tratamentos anteriores.

Critérios de elegibilidade

Idades elegíveis para estudo

  • Adulto
  • Adulto mais velho

Aceita Voluntários Saudáveis

Não

Descrição

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

Plano de estudo

Esta seção fornece detalhes do plano de estudo, incluindo como o estudo é projetado e o que o estudo está medindo.

Como o estudo é projetado?

Detalhes do projeto

  • Finalidade Principal: Tratamento
  • Alocação: Randomizado
  • Modelo Intervencional: Atribuição Paralela
  • Mascaramento: Nenhum (rótulo aberto)

Armas e Intervenções

Grupo de Participantes / Braço
Intervenção / Tratamento
Experimental: Experimental group
Discontinuation of riociguat
Medicamento: Discontinuation of riociguat
Discontinuation of riociguat after randomization
Sem intervenção: Control group
Continuation of riociguat

O que o estudo está medindo?

Medidas de resultados primários

Medida de resultado
Descrição da medida
Prazo
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
Prazo: 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

Medidas de resultados secundários

Medida de resultado
Descrição da medida
Prazo
To compare the effect of discontinuation versus continuation of riociguat monotherapy on 6-minute walk distance (6MWD)
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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)
Prazo: 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 :
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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

Colaboradores e Investigadores

É aqui que você encontrará pessoas e organizações envolvidas com este estudo.

Patrocinador

Assistance Publique - Hôpitaux de Paris

Datas de registro do estudo

Essas datas acompanham o progresso do registro do estudo e os envios de resumo dos resultados para ClinicalTrials.gov. Os registros do estudo e os resultados relatados são revisados ​​pela National Library of Medicine (NLM) para garantir que atendam aos padrões específicos de controle de qualidade antes de serem publicados no site público.

Datas Principais do Estudo

Início do estudo (Estimado)

1 de novembro de 2026

Conclusão Primária (Estimado)

31 de janeiro de 2031

Conclusão do estudo (Estimado)

31 de janeiro de 2031

Datas de inscrição no estudo

Enviado pela primeira vez

1 de junho de 2026

Enviado pela primeira vez que atendeu aos critérios de CQ

8 de junho de 2026

Primeira postagem (Real)

12 de junho de 2026

Atualizações de registro de estudo

Última Atualização Postada (Real)

14 de setembro de 2026

Última atualização enviada que atendeu aos critérios de controle de qualidade

9 de setembro de 2026

Última verificação

1 de setembro de 2026

Mais Informações

Termos relacionados a este estudo

Palavras-chave

Outros números de identificação do estudo

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

Informações sobre medicamentos e dispositivos, documentos de estudo

Estuda um medicamento regulamentado pela FDA dos EUA

Não

Estuda um produto de dispositivo regulamentado pela FDA dos EUA

Não

Essas informações foram obtidas diretamente do site clinicaltrials.gov sem nenhuma alteração. Se você tiver alguma solicitação para alterar, remover ou atualizar os detalhes do seu estudo, entre em contato com register@clinicaltrials.gov. Assim que uma alteração for implementada em clinicaltrials.gov, ela também será atualizada automaticamente em nosso site .

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