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

Efficacy and Safety of Riociguat (MK-4836) in Incipient Pulmonary Vascular Disease as an Indicator for Early Pulmonary Arterial Hypertension Double-blind, Randomized, Multicenter, Multinational, Placebo-controlled Phase IIa Study (ESRA)

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.

Study Overview

• Status: Terminated
• Conditions: Systemic Sclerosis; Pulmonary Vascular Disorder; Primary Pulmonary Hypertension; Other Systemic Involvement of Connective Tissue
• Intervention / Treatment: Drug: Riociguat Oral Tablet; Other: Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • LKH-Univ. Klinikum Graz Universitätsklinik für Innere Medizin Klinische Abteilung für Pulmonologie
  • Linz, Austria, 4020
    • Ordensklinikum Linz GmbH Elisabethinen
• France
  • Lille, France, 59037
    • 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
• Germany
  • Dresden, Germany
    • Carl Gustav Carus University Hospital at the TU Dresden, Medical Department I, Center for PH
  • Heidelberg, Germany, 69126
    • Centre for Pulmonary Hypertension at the Thoraxklinik Heidelberg, Heidelberg University Hospital Heidelberg
• Italy
  • Napoli, Italy, 80131
    • Università Degli Studi Di Napoli Federico II Scuola Di Medicina E Chirurgia
• Switzerland
  • Zurich, Switzerland, 8091
    • Universitätsspital Zürich Pulmonale Hypertonie, Klinik für Pneumologie
• United Kingdom
  • London, United Kingdom
    • Royal Free London NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 tissue disease (CTD) or as idiopathic/heritable form (see Group I / Nice Clinical Classification of Pulmonary Hypertension) (acc. to Simonneau et al. 2019). Patients with rheumatoid arthritis or connective tissue disease of any kind, except systemic lupus erythematosus, may also be included. Patients in group b will be mainly enrolled as long as patients in group a are not defined as having pulmonary arterial hypertension 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 pulmonary hypertension such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen supplementation are permitted. Permitted are also treatments of the rheumatologic disease. However, these drugs must have been started at least 1 month before right heart catheterization.
5. Right-heart catheterization results must not be older than 1 month at Visit 1 (will be considered as baseline values, the time frame can be prolonged up to 6 months, if the patient has had no signs of clinical changes defined as >10% change of 6MWD, WHO FC, > 30% change in NT-proBNP) and must have been measured in the participating center under standardized conditions (refer to the study specific Swan Ganz catheterization manual). If the respective measurements have not been performed in context with the patient's regular diagnostic work up, they have to be performed as a part of the study during the pre-study phase (after the patient signed the informed consent).
6. Women without childbearing potential defined as postmenopausal women aged 55 years or older, women with bilateral tubal ligation, women with bilateral ovariectomy, and women with hysterectomy can be included in the study.

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

   1. Negative serum pregnancy test at screening and at study start (visit 1).
   2. Agreement to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation. These tests should be performed by the patient at home.
   3. Agreement to use a highly effective contraception method as specified from screening until at least 30 days after last dose of study medication.
8. Patients who are able to understand and follow instructions and who are able to participate in the study for the entire period.
9. Patients must have given their written informed consent to participate in the study after having received adequate previous information and prior to any study-specific procedures.

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 receptor antagonists and prostacyclin analogues due to digital ulcers is contraindicated and must not be taken during the study period. Such drugs must have a washout-phase of 3 days at the time of right heart catheterization at screening. Intravenous treatment with prostacyclin analogues should not be performed within 1 week of right heart catheterization. Any decision to discontinue above-mentioned drugs will be made by the clinicians and the patient at screening, which takes part during the patients' regular routine visit. The discontinuation of above-mentioned drugs will be evaluated by considering the presence or absence of digital ulcers and their frequency of appearance in the patient's medical history.
4. Pulmonary hypertension explained by other cause including group 2, 3, 4 and 5 PH according 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, left atrial enlargement >20 cm², atrial fibrillation, left ventricular ejection fraction <50%.
6. Pulmonary comorbidity, defined as forced vital capacity (FVC) ≤70; forced expiratory volume in 1 second (FEV1) ≤50%; diffusion capacity of the lung (DLCO) ≤40%. FVC may be <70/ if high resolution computed tomography shows <20% lung fibrosis.
7. Patients with a medical disorder, condition, or history of such that would impair the patient's ability to participate or complete this study in the opinion of the investigator.
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 allergic reactions 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 this study and/or patient, who is scheduled to receive an investigational medicinal product (IMP) during the course of this study
13. Background therapy with highly anti-fibrotic drugs (pirfenidone) or nintedanib, prednisolone >10 mg/day

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Riociguat; patients will undergo a titration phase starting with 1mg riociguat oral tablets tid (three times daily) up to a maximum dosage of 2.5mg tid that will be continued for the remainder of the study.	Drug: Riociguat Oral Tablet; Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily) Titration phase: dose will be individually adjusted in accordance with the in-label titration regimen. Dose adjustment will be performed every two weeks by phone taking the systemic blood pressure of the patient, the subjects and physicians' subjective estimation and occurrence of adverse reactions into account. At week 8 the maintenance dose will be established and continued for the rest of the study; Other Names: MK-4836; ATC Code: C02KX05
Placebo Comparator: Placebo; Placebo tablets with the same treatment regimen (tid) as the verum therapy will be provided. Patients will undergo a sham titration phase with sham doses individually adjusted as in the experimental arm	Other: Placebo; Sham titration and adjustment to maintenance dose will be performed according to individual tolerability as in the experimental arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of Pulmonary Vascular Resistance (PVR)	Change in pulmonary hemodynamics assessed by right heart catheterization	baseline, 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of Cardiac Index (CI) at Rest From Baseline at 24 Weeks	Change in pulmonary hemodynamics assessed by right heart catheterization	baseline, 24 weeks
Change of Total Pulmonary Resistance (TPR) From Baseline at 24 Weeks	Change in Pulmonary hemodynamics assessed by right heart catheterization Hierarchical testing of secondary endpoints stopped after first step.	baseline, 24 weeks
Change of Diffusion Capacity of the Lung (DLCO) From Baseline at 24 Weeks	Change assessed by lung function tests. Hierarchical testing of secondary endpoints stopped after first step.	baseline, 24 weeks
Change in 6-minute Walking Distance (6MWD)	Change in exercise capacity assessed by 6-minute walking distance test Hierarchical testing of secondary endpoints stopped after first step.	baseline, 24 weeks
Change of World Health Organization- Functional Class (WHO-FC) From Baseline at 24 Weeks	Change of WHO functional class, change score The World Health Organization (WHO) functional class (FC) describes the severity of pulmonary hypertension (PH) symptoms. FC I is considered the mildest and FC IV the most severe form of PH.	baseline, 24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of World Health Organization- Functional Class (WHO-FC) From Baseline at 12 Weeks	Change of WHO functional class, change score The World Health Organization (WHO) functional class (FC) describes the severity of pulmonary hypertension (PH) symptoms. FC I is considered the mildest and FC IV the most severe form of PH.	baseline, 12 weeks
Change in Quality of Life (QoL) From Baseline at 24 Weeks	Quality of Life (QoL) was assessed using the Short Form (SF) 36-questionnaire. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale, i.e. a score of 0 is equivalent to maximum disability and a score of 100 is equivalent to no disability. Sections: vitality; physical functioning; bodily pain; general health perceptions; physical role functioning; emotional role functioning; social role functioning; mental health. Two summation scores, physical and mental summation score, were calculated	baseline, 24 weeks
Change in Forced Expiratory Volume in 1 Second (FEV1) From Baseline at 24 Weeks	Lung function and lung diffusing capacity	baseline, 24 weeks
Change in Total Lung Capacity (TLC) From Baseline at 24 Weeks	Lung function and lung diffusing capacity	baseline, 24 weeks
Change in Diffusing Capacity of the Lung (DLCO)	Lung function and lung diffusing capacity	baseline, 24 weeks
Change in Systolic Pulmonary Arterial Pressure (sPAP) From Baseline at 24 Weeks	Change in systolic pulmonary arterial pressure (sPAP) from baseline at 24 weeks assessed by echocardiography	baseline, 24 weeks
Change in Right Ventricular Area (RV-area) From Baseline at 24 Weeks	Change in right ventricular area (RV-area) from baseline at 24 weeks assessed by echocardiography	baseline, 24 weeks
Change in Right Atrial Area (RA-area) From Baseline at 24 Weeks	Change in right atrial area (RA-area) from baseline at 24 weeks assessed by echocardiography	baseline, 24 weeks
Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) From Baseline at 24 Weeks	Change in tricuspid annular plane systolic excursion (TAPSE) from baseline at 24 weeks assessed by echocardiography	baseline, 24 weeks
Change in Left Ventricular Eccentricity Index (LV-EI) From Baseline at 24 Weeks	Change in left ventricular eccentricity index (LV-EI) from baseline at 24 weeks assessed by echocardiography. LV-EI is the ratio of septical-parallel to septical-perdendicular left ventricular diameters in parasternal short-axis view; normal = 1, increased (≥ 1.1) indicates right ventricular pressure/volume overload	baseline, 24 weeks
Change in N-terminal Prohormone of Brain Natriuretic Peptide (NT-pro BNP) From Baseline at 12 Weeks	blood analysis	baseline, 12 weeks
Change in N-terminal Prohormone of Brain Natriuretic Peptide (NT-pro BNP) From Baseline at 24 Weeks	blood analysis	baseline, 24 weeks
Change in Oxygen Partial Pressure (PaO2) From Baseline at 24 Weeks	Change in oxygen partial pressure (PaO2) from baseline at 24 weeks assessed by blood gas analysis	baseline, 24 weeks
Change in Carbon Dioxide Partial Pressure (PCO2)	blood gas analysis	baseline, 24 weeks
Change Oxygen Saturation of the Blood (SaO2)	Change oxygen saturation of the blood (SaO2) assessed by blood gas analysis	baseline, 24 weeks
Change in pH	blood gas analysis	baseline,24 weeks
Change in Bicarbonates	blood gas analysis	baseline, 24 weeks
Change in Base Excess	Change in base excess assessed by blood gas analysis	baseline, 24 weeks
Change in Systolic Pulmonary Arterial Pressure (sPAP)	Pulmonary hemodynamics assessed by right heart catheterization	baseline, 24 weeks
Change in Mean Pulmonary Arterial Pressure (mPAP)	Pulmonary hemodynamics assessed by right heart catheterization	baseline, 24 weeks
Change in dPAP (Diastolic Pulmonary Artery Pressure)	Pulmonary hemodynamics assessed by right heart catheterization	baseline, 24 weeks
Change in PAWP (Pulmonary Artery Wedge Pressure)	Pulmonary hemodynamics assessed by right heart catheterization	baseline, 24 weeks
Change in RAP (Right Atrial Pressure)	Pulmonary hemodynamics assessed by right heart catheterization	baseline, 24 weeks
Change in Cardiac Output and Ejection Fraction (CO)	Pulmonary hemodynamics assessed by right heart catheterization	baseline, 24 weeks
Change in Central Venous Saturation (SvO2)	blood gas analysis	baseline, 24 weeks

Collaborators and Investigators

• Sponsor: Heidelberg University
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Ekkehard Grünig, MD, Thoraxklinik at the University of Heidelberg

Publications and helpful links

General Publications

• Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013 Jul 25;369(4):319-29. doi: 10.1056/NEJMoa1209657.
• Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 2015 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. Rev Esp Cardiol (Engl Ed). 2016 Feb;69(2):177. doi: 10.1016/j.rec.2016.01.002. No abstract available.
• Grunig E, Barner A, Bell M, Claussen M, Dandel M, Dumitrescu D, Gorenflo M, Holt S, Kovacs G, Ley S, Meyer JF, Pabst S, Riemekasten G, Saur J, Schwaiblmair M, Seck C, Sinn L, Sorichter S, Winkler J, Leuchte HH. [Non-invasive diagnosis of pulmonary hypertension: ESC/ERS Guidelines with commentary of the Cologne Consensus Conference 2010]. Dtsch Med Wochenschr. 2010 Oct;135 Suppl 3:S67-77. doi: 10.1055/s-0030-1263314. Epub 2010 Sep 22. German.
• Pan Z, Marra AM, Benjamin N, Eichstaedt CA, Blank N, Bossone E, Cittadini A, Coghlan G, Denton CP, Distler O, Egenlauf B, Fischer C, Harutyunova S, Xanthouli P, Lorenz HM, Grunig E. Early treatment with ambrisentan of mildly elevated mean pulmonary arterial pressure associated with systemic sclerosis: a randomized, controlled, double-blind, parallel group study (EDITA study). Arthritis Res Ther. 2019 Oct 26;21(1):217. doi: 10.1186/s13075-019-1981-0.
• Rubin LJ, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, Keogh A, Langleben D, Fritsch A, Menezes F, Davie N, Ghofrani HA. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J. 2015 May;45(5):1303-13. doi: 10.1183/09031936.00090614. Epub 2015 Jan 22.

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2022
• Primary Completion (Actual): July 31, 2025
• Study Completion (Actual): July 31, 2025

Study Registration Dates

• First Submitted: April 14, 2022
• First Submitted That Met QC Criteria: April 14, 2022
• First Posted (Actual): April 21, 2022

Study Record Updates

• Last Update Posted (Actual): January 21, 2026
• Last Update Submitted That Met QC Criteria: January 15, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: pulmonary hypertension; riociguat; early pulmonary vascular disease
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Connective Tissue Diseases; Respiratory Tract Diseases; Lung Diseases; Skin Diseases; Hypertension; Skin and Connective Tissue Diseases; Scleroderma, Systemic; Hypertension, Pulmonary; Familial Primary Pulmonary Hypertension; Substandard Drugs; Pharmaceutical Preparations; riociguat
• Other Study ID Numbers: 2020-01RCT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No