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

Systemic Sclerosis Clinical Trial

— ESRA  

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05339087
• Other study ID #: 2020-01RCT
• Status: Recruiting
• Phase: Phase 2
• Start date: October 24, 2022
• Est. completion date: June 2026

Study information

• Verified date: March 2024
• Source: Heidelberg University
• Contact: Ekkehard Grünig, MD
• Phone: +49 6221 396
• Email: ekkehard.gruenig[@]med.uni-heidelberg.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 70
• Est. completion date: June 2026
• Est. primary completion date: October 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Hypertension, Pulmonary
• Primary Pulmonary Hypertension
• Pulmonary Arterial Hypertension
• Pulmonary Vascular Disorder
• Scleroderma, Diffuse
• Scleroderma, Systemic
• Systemic Sclerosis
• Vascular Diseases

Intervention

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:
• Placebo
Sham titration and adjustment to maintenance dose will be performed according to individual tolerability as in the experimental arm.

Locations

Country	Name	City	State
Austria	LKH-Univ. Klinikum Graz Universitätsklinik für Innere Medizin Klinische Abteilung für Pulmonologie	Graz
Austria	Ordensklinikum Linz GmbH Elisabethinen	Linz
France	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
Germany	Carl Gustav Carus University Hospital at the TU Dresden, Medical Department I, Center for PH	Dresden
Germany	Centre for Pulmonary Hypertension at the Thoraxklinik Heidelberg, Heidelberg University Hospital Heidelberg	Heidelberg
Italy	Università Degli Studi Di Napoli Federico II Scuola Di Medicina E Chirurgia	Napoli
Switzerland	Universitätsspital Zürich Pulmonale Hypertonie, Klinik für Pneumologie	Zürich

Sponsors (2)

Lead Sponsor	Collaborator
Heidelberg University	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

Austria,  France,  Germany,  Italy,  Switzerland, 

References & Publications (5)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	change in WHO functional class	change score	baseline to 12 weeks
Other	change in quality of life	SF-36 questionnaire	baseline to 12 weeks
Other	FEV1 (forced expiratory volume in 1 second)	Lung function and lung diffusing capacity	baseline to 24 weeks
Other	TLC (total lung capacity)	Lung function and lung diffusing capacity	baseline to 24 weeks
Other	DLCO (diffusing capacity of the lung)	Lung function and lung diffusing capacity	baseline to 24 weeks
Other	sPAP (systolic pulmonary arterial pressure)	echocardiography	baseline to 24 weeks
Other	RV-area (right ventricular area)	echocardiography	baseline to 24 weeks
Other	RA-area (right atrial area)	echocardiography	baseline to 24 weeks
Other	TAPSE (tricuspid annular plane systolic excursion)	echocardiography	baseline to 24 weeks
Other	LV-EI (left ventricular eccentricity index)	echocardiography	baseline to 24 weeks
Other	NT-pro BNP	blood analysis	baseline to 12 weeks
Other	NT-pro BNP	blood analysis	baseline to 24 weeks
Other	oxygen partial pressure	blood gas analysis	baseline to 24 weeks
Other	carbon dioxide partial pressure	blood gas analysis	baseline to 24 weeks
Other	oxygen saturation of the blood (SpO2)	blood gas analysis	baseline to 24 weeks
Other	pH	blood gas analysis	baseline to 24 weeks
Other	bicarbonates	blood gas analysis	baseline to 24 weeks
Other	base excess	blood gas analysis	baseline to 24 weeks
Other	sPAP	Pulmonary hemodynamics by right heart catheterization	baseline to 24 weeks
Other	mPAP	Pulmonary hemodynamics by right heart catheterization	baseline to 24 weeks
Other	dPAP (diastolic pulmonary artery pressure)	Pulmonary hemodynamics by right heart catheterization	baseline to 24 weeks
Other	PAWP (pulmonary artery wedge pressure)	Pulmonary hemodynamics by right heart catheterization	baseline to 24 weeks
Other	RAP (right atrial pressure)	Pulmonary hemodynamics by right heart catheterization	baseline to 24 weeks
Other	cardiac output and ejection fraction (CO)	Pulmonary hemodynamics by right heart catheterization	baseline to 24 weeks
Other	central venous saturation (SvO2)	blood gas analysis from pulmonary artery	baseline to 24 weeks
Primary	change of PVR	Pulmonary hemodynamics by right heart catheterization	baseline to 24 weeks
Secondary	change of cardiac index at rest	Pulmonary hemodynamics by right heart catheterization	baseline to 24 weeks
Secondary	change of total pulmonary resistance	Pulmonary hemodynamics by right heart catheterization	baseline to 24 weeks
Secondary	change of diffusion capacity of the lung	Change in lung function tests	baseline to 24 weeks
Secondary	change of 6-minute walking distance	Change in exercise capacity	baseline to 24 weeks
Secondary	change of WHO functional class	change score	baseline to 24 weeks
Secondary	change in quality of life	SF-36 questionnaire	baseline to 24 weeks