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

8 giugno 2026 aggiornato da: 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.

Panoramica dello studio

Stato

Non ancora reclutamento

Condizioni

Intervento / Trattamento

Tipo di studio

Interventistico

Iscrizione (Stimato)

150

Fase

  • Fase 3

Contatti e Sedi

Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.

Contatto studio

Luoghi di studio

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

Criteri di partecipazione

I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.

Criteri di ammissibilità

Età idonea allo studio

  • Adulto
  • Adulto più anziano

Accetta volontari sani

No

Descrizione

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

Piano di studio

Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.

Come è strutturato lo studio?

Dettagli di progettazione

  • Scopo principale: Trattamento
  • Assegnazione: Randomizzato
  • Modello interventistico: Assegnazione parallela
  • Mascheramento: Nessuno (etichetta aperta)

Armi e interventi

Gruppo di partecipanti / Arm
Intervento / Trattamento
Sperimentale: Experimental group
Discontinuation of riociguat
Droga: Discontinuation of riociguat
Discontinuation of riociguat after randomization
Nessun intervento: Control group
Continuation of riociguat

Cosa sta misurando lo studio?

Misure di risultato primarie

Misura del risultato
Misura Descrizione
Lasso di tempo
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
Lasso di tempo: 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

Misure di risultato secondarie

Misura del risultato
Misura Descrizione
Lasso di tempo
To compare the effect of discontinuation versus continuation of riociguat monotherapy on 6-minute walk distance (6MWD)
Lasso di tempo: 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
Lasso di tempo: 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
Lasso di tempo: 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
Lasso di tempo: 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)
Lasso di tempo: 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 :
Lasso di tempo: 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
Lasso di tempo: 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
Lasso di tempo: 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
Lasso di tempo: 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 compare the effect of discontinuation versus continuation of riociguat monotherapy on quality of life
Lasso di tempo: Month 3, 6, 12 and every 6 months with maximum of 48 months
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
Lasso di tempo: 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
Lasso di tempo: Month 12
Change from baseline in Treatment burden questionnaire
Month 12

Collaboratori e investigatori

Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.

Sponsor

Assistance Publique - Hôpitaux de Paris

Studiare le date dei record

Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.

Studia le date principali

Inizio studio (Stimato)

1 ottobre 2026

Completamento primario (Stimato)

31 gennaio 2031

Completamento dello studio (Stimato)

31 gennaio 2031

Date di iscrizione allo studio

Primo inviato

1 giugno 2026

Primo inviato che soddisfa i criteri di controllo qualità

8 giugno 2026

Primo Inserito (Effettivo)

12 giugno 2026

Aggiornamenti dei record di studio

Ultimo aggiornamento pubblicato (Effettivo)

12 giugno 2026

Ultimo aggiornamento inviato che soddisfa i criteri QC

8 giugno 2026

Ultimo verificato

1 giugno 2026

Maggiori informazioni

Termini relativi a questo studio

Parole chiave

Altri numeri di identificazione dello studio

  • APHP251608

Informazioni su farmaci e dispositivi, documenti di studio

Studia un prodotto farmaceutico regolamentato dalla FDA degli Stati Uniti

No

Studia un dispositivo regolamentato dalla FDA degli Stati Uniti

No

Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .

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Condizioni

Malattie rare

Interventi farmacologici

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Sponsor / Collaboratori

Sedi

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