Efficacy and Safety of Riociguat in Incipient Pulmonary Vascular Disease as an Indicator for Early PAH

Last updated: July 8, 2025
Sponsor: Heidelberg University
Overall Status: Active - Not Recruiting

Phase

2

Condition

Pulmonary Arterial Hypertension

Vascular Diseases

Williams Syndrome

Treatment

Placebo

Riociguat Oral Tablet

Clinical Study ID

NCT05339087
2020-01RCT
  • Ages > 18
  • All Genders

Study Summary

This is a randomized, double-blind, placebo-controlled, multicenter, multinational study investigating the effect of riociguat (MK-4836) in patients with early pulmonary vascular disease.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  1. ≥18 years of age at time of inclusion.

  2. Male and female patients with early pulmonary vascular disease, defined as either a)mean pulmonary arterial pressure (mPAP) ≥25 mmHg with pulmonary vascular resistance (PVR) ≥2 to <3 WU and pulmonary arterial wedge pressure (PAWP) ≤15 mmHg or b) mPAP 21-<25 mmHg with PVR ≥2 WU, and PAWP ≤15 mmHg associated with connective tissuedisease (CTD) or as idiopathic/heritable form (see Group I / Nice ClinicalClassification of Pulmonary Hypertension) (acc. to Simonneau et al. 2019). Patientswith rheumatoid arthritis or connective tissue disease of any kind, except systemiclupus erythematosus, may also be included. Patients in group b will be mainlyenrolled as long as patients in group a are not defined as having pulmonary arterialhypertension according to European pulmonary hypertension guidelines.

  3. Treatment naïve patients (with respect to PAH specific medication)

  4. Unspecific treatments which may also be used for the treatment of pulmonaryhypertension such as oral anticoagulants, diuretics, digitalis, calcium channelblockers or oxygen supplementation are permitted. Permitted are also treatments ofthe rheumatologic disease. However, these drugs must have been started at least 1month before right heart catheterization.

  5. Right-heart catheterization results must not be older than 1 month at Visit 1 (willbe considered as baseline values, the time frame can be prolonged up to 6 months, ifthe patient has had no signs of clinical changes defined as >10% change of 6MWD, WHOFC, > 30% change in NT-proBNP) and must have been measured in the participatingcenter under standardized conditions (refer to the study specific Swan Ganzcatheterization manual). If the respective measurements have not been performed incontext with the patient's regular diagnostic work up, they have to be performed asa part of the study during the pre-study phase (after the patient signed theinformed consent).

  6. Women without childbearing potential defined as postmenopausal women aged 55 yearsor older, women with bilateral tubal ligation, women with bilateral ovariectomy, andwomen with hysterectomy can be included in the study.

  7. Women of childbearing potential can only be included in the study if all of thefollowing applies (listed below):

  8. Negative serum pregnancy test at screening and at study start (visit 1).

  9. Agreement to undertake monthly urine pregnancy tests during the study and up toat least 30 days after study treatment discontinuation. These tests should beperformed by the patient at home.

  10. Agreement to use a highly effective contraception method as specified fromscreening until at least 30 days after last dose of study medication.

  11. Patients who are able to understand and follow instructions and who are able toparticipate in the study for the entire period.

  12. Patients must have given their written informed consent to participate in the studyafter having received adequate previous information and prior to any study-specificprocedures.

Exclusion

Exclusion Criteria:

  1. Patients with systemic lupus erythematosus.

  2. Concomitant PAH-targeted treatment is not allowed during the study.

  3. Concomitant treatment with phosphodiesterase 5 inhibitors, endothelin receptorantagonists and prostacyclin analogues due to digital ulcers is contraindicated andmust not be taken during the study period. Such drugs must have a washout-phase of 3days at the time of right heart catheterization at screening. Intravenous treatmentwith prostacyclin analogues should not be performed within 1 week of right heartcatheterization. Any decision to discontinue above-mentioned drugs will be made bythe clinicians and the patient at screening, which takes part during the patients'regular routine visit. The discontinuation of above-mentioned drugs will beevaluated by considering the presence or absence of digital ulcers and theirfrequency of appearance in the patient's medical history.

  4. Pulmonary hypertension explained by other cause including group 2, 3, 4 and 5 PHaccording to the current guidelines.

  5. Cardiac comorbidity, defined with three or more of the following conditions:uncontrolled arterial hypertension, diabetes mellitus, body mass index >35, leftatrial enlargement >20 cm², atrial fibrillation, left ventricular ejection fraction <50%.

  6. Pulmonary comorbidity, defined as forced vital capacity (FVC) ≤70; forced expiratoryvolume in 1 second (FEV1) ≤50%; diffusion capacity of the lung (DLCO) ≤40%. FVC maybe <70/ if high resolution computed tomography shows <20% lung fibrosis.

  7. Patients with a medical disorder, condition, or history of such that would impairthe patient's ability to participate or complete this study in the opinion of theinvestigator.

  8. Patients with underlying medical disorders with an anticipated life expectancy below 2 years (e.g. active cancer disease with localized and/or metastasized tumor mass).

  9. Patients with a history of severe or multiple drug allergies (defined as allergicreactions to three or more structurally unrelated drugs).

  10. Patients with hypersensitivity to the investigational drug or any of the excipients.

  11. Contraindications according to summary of product characteristics of riociguat (e.g.arterial hypotension with systolic blood pressure <95 mmHg; nitrates)

  12. Participation in any clinical drug trial within 4 weeks prior to screening of thisstudy and/or patient, who is scheduled to receive an investigational medicinalproduct (IMP) during the course of this study

  13. Background therapy with highly anti-fibrotic drugs (pirfenidone) or nintedanib,prednisolone >10 mg/day

Study Design

Total Participants: 70
Treatment Group(s): 2
Primary Treatment: Placebo
Phase: 2
Study Start date:
October 24, 2022
Estimated Completion Date:
July 31, 2025

Study Description

Chronic pulmonary arterial hypertension (PAH) is associated with impaired exercise capacity, quality of life and right ventricular function characterized by an increase of pulmonary vascular resistance (PVR) and pulmonary arterial pressure, leading to right heart insufficiency.

Riociguat tratment is approved for both PAH and chronic thromboembolic pulmonary hypertension (CTEPH).

Data on early treatment of patients with mildly elevated pulmonary arterial pressures is still scarce but there is evindence that such patients may benefit from early targeted therapy.

For instance, in a trial on systemic sclerosis (SSc)-patients with mildly elevated mean pulmonary artery pressure (mPAP) and/or exercise pulmonary hypertension, without significant left heart or lung disease, ambrisentan, an endothelin receptor antagonist resulted in an improvement of PVR as secondary endpoint, which may be of prognostic relevance in this patient cohort and requires further research.

Besides its prognostic significance among patients with SSc-APAH, PVR may be an indicator of early pulmonary vascular disease and previous studies proved the positive effects of riociguat on right heart size and PVR (secondary endpoint in phase III studies). Thus, PVR was chosen as primary endpoint of this study aiming to investigate the effect of riociguat (MK-4836) on PVR, clinical parameters, safety and tolerability in patients with early pulmonary vascular disease.

Eligible subjects will be randomized in a 1:1 ratio to receive either riociguat or placebo.

Medical examinations include medical history, physical examination, electrocardiogram, blood gas analyses, lung function tests, laboratory testing (including NT-proBNP), echocardiography at rest, and right heart catheterization.

The prospective period of data collection comprises a 24-week treatment phase diveded into an 8-week titration phase followed by a 16-week main study phase as well as a safety follow-up of 30±14 days.

Connect with a study center

  • LKH-Univ. Klinikum Graz Universitätsklinik für Innere Medizin Klinische Abteilung für Pulmonologie

    Graz, 8036
    Austria

    Site Not Available

  • Ordensklinikum Linz GmbH Elisabethinen

    Linz, 4020
    Austria

    Site Not Available

  • Centre de référence des Maladies Auto-Immunes Systémiques rares du Nord et Nord-Ouest (CeRAINO) Service de Médecine Interne et Immunologie Clinique Hôpital Claude Huriez, CHU

    Lille, 59037
    France

    Site Not Available

  • Carl Gustav Carus University Hospital at the TU Dresden, Medical Department I, Center for PH

    Dresden,
    Germany

    Site Not Available

  • Centre for Pulmonary Hypertension at the Thoraxklinik Heidelberg, Heidelberg University Hospital Heidelberg

    Heidelberg, 69126
    Germany

    Site Not Available

  • Università Degli Studi Di Napoli Federico II Scuola Di Medicina E Chirurgia

    Napoli, 80131
    Italy

    Site Not Available

  • Universitätsspital Zürich Pulmonale Hypertonie, Klinik für Pneumologie

    Zürich, 8091
    Switzerland

    Site Not Available

  • Royal Free London NHS Foundation Trust

    London,
    United Kingdom

    Site Not Available

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