Effects of Riociguat on RIght VEntricular Size and Function in PAH and CTEPH

NCT04954742 | Terminated Phase 4

• 1 other identifier: 2020-06RCT
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, single-armed, prospective single-centre clinical study to evaluate the effect of riociguat on right heart size and function in patients with manifest PAH and CTEPH.

Conditions

Primary Pulmonary Arterial Hypertension; Chronic Thromboembolic Pulmonary Hypertension

Keywords

pulmonary arterial hypertension; Chronic Thromboembolic Pulmonary Hypertension; riociguat; right heart function

Outcome Measures

Primary Outcomes (2)

• Change in RV (right ventricular) area

  echocardiographic analysis right atrial (RA) area, measured by echocardiography.

  Baseline to 24 weeks

• Change in RA (right atrial) area

  echocardiographic analysis

  Baseline to 24 weeks

Secondary Outcomes (106)

• Change in RV Area

  baseline to 12 weeks

• Change in RA Area

  baseline to 12 weeks

• Change in systolic pulmonary artery pressure (sPAP)

  baseline to 12 weeks

• Change in systolic pulmonary artery pressure (sPAP)

  baseline to 24 weeks

• Change in RV fractional area change (FAC)

  baseline to 24 weeks

Study Arms (1)

Riociguat

OTHER

Riociguat (1 mg, 1.5 mg, 2 mg and 2.5 mg three times daily) starting at 1.0 mg three times daily at the beginning of the study. Dosage will be individually up-titrated up to a maximum dosage of 2.5 mg three times daily after 8 weeks. Study medication will be provided orally with or without food. Tablets should be taken three times daily approximately 6 to 8 hours apart.

Drug: Riociguat

Interventions

Riociguat DRUG

Treatment will be initiated and individually adjusted according to systolic blood pressure and tolerability. During the titration phase, each patient will be asked to measure their peripheral systolic blood pressure and the heart rate at home three times per day and document the values in the patient diary. The results will be examined by the investigator during each visit/phone call-visit. Provided that the systolic blood pressure is ≥ 95 mmHg measured at trough before intake of each dose and the patient has no signs or symptoms of hypotension, the dose of study medication will be titrated by +0.5 mg tid every 2 weeks until maximal tolerated dosage (maximal permitted dose: of 2.5 mg tid). After the titration period, blood pressure should be measured upon signs or symptoms of hypotension. Maintenance dose: The established individual dose should be maintained unless signs and symptoms of hypotension occur.

Also known as: MK-4836, ATC code: C02KX05

Riociguat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female patients with symptomatic PAH with a mean pulmonary artery pressure (mPAP) \>20 mmHg and pulmonary vascular resistance (PVR) ≥2 Wood Units (WU), pulmonary arterial wedge pressure (PAWP) ≤15 mmHg (Group I / Nice Clinical Classification of Pulmonary Hypertension) or CTEPH (Group IV / Nice Clinical Classification of Pulmonary Hypertension) defined as inoperable measured at least 3 months after start of full anticoagulation and mPAP \>20 mmHg and PVR ≥2 WU, PAWP ≤15 mmHg; or with persisting or recurrent PH after pulmonary endarterectomy (mPAP \>20 mmHg and PVR ≥2 WU, PAWP ≤15 mmHg measured at least 6 months after surgery (acc. to Simonneau et al. 2018).
• Treatment naïve patients (with respect to PAH specific medication) and patients pre-treated with an endothelin receptor antagonist or a prostacyclin analogue, pre-treated for 2 months before screening at most (according to upfront combination treatment).\*
• \*Pre-treated patients need to be stable on endothelin receptor antagonists or prostacyclin treatment for at least two weeks prior to Visit 1. "Stable" is defined as no change in the type of endothelin receptor antagonists or prostacyclin analogue and the respective daily dose.
• A patient may also be enrolled, if a persisting phosphodiesterase type 5 (PDE-5) inhibitor treatment (pre-treated for 2 months before screening at most) with or without combination treatment with an endothelin receptor antagonist or prostacyclin analogue is to be switched to riociguat by clinical indication, particularly when the patient´s risk-profile remained in intermediate risk group despite adequate initial treatment including PDE5i (defined as at least 3 of the following parameters: clinical signs of progression, persistent WHO-FC III, 6MWD between 165-440m, peak V02 11-15ml/min/kg (35-65% predicted), NTproBNP 300-1400 ng/l, RA-area 18-26cm2,RAP 8-14mmHg, CI 2,0-2,4 l/min) or in case of PDE5i intolerance. Any decision to switch will be made by the clinicians at a regular clinical follow-up visit.
• Unspecific treatments which may also be used for the treatment of PH such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen supplementation are permitted. However, treatment with anticoagulants (if indicated) must have been started at least 1 month before visit in patients with PAH 1.
• RHC results must not be older than 6 months at screening (will be considered as baseline values) and must have been measured in the participating centre 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 workup, they have to be performed as a part of the study during the pre-study phase (after the patient signed the informed consent).
• Women without childbearing potential defined as postmenopausal women aged 50 years or older, women with bilateral tubal ligation, women with bilateral ovariectomy, and women with hysterectomy can be included in the study.
• Women of childbearing potential can only be included in the study if all of the following applies (listed below): a. Negative serum pregnancy test at Screening and a negative urine pregnancy test at study start (visit 1). b. 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. c. Agreement to follow the contraception scheme as specified from Screening until at least 30 days after study treatment discontinuation.
• Patients who are able to understand and follow instructions and who are able to participate in the study for the entire period.
• 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.

You may not qualify if:

• Pregnant women, or breast-feeding women, or women of childbearing potential not able or willing to comply with study-mandated contraception methods specified above.
• Patients with PH specific treatment \<2 months before screening.
• 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.
• Patients with underlying medical disorders with an anticipated life expectancy below 2 years (e.g. active cancer disease with localized and/or metastasized tumour mass).
• Patients with a history of severe or multiple drug allergies
• Patients with hypersensitivity to the investigational drug or any of the excipients.
• Patients unable to perform a valid 6MWD test (e.g. orthopaedic disease, peripheral artery occlusive disease, which affects the patient´s ability to walk).
• The following specific medications for concomitant treatment of PH or medications which may exert a pharmacodynamic interaction with the study drug are not allowed:
• Parenteral prostacyclin analogues
• Specific phosphodiesterase inhibitors (e.g. sildenafil or tadalafil): may be switched to riociguat but not be given in addition to the study drug
• or unspecific phosphodiesterase inhibitors (e.g. dipyridamole, theophylline)
• NO donors (e.g. Nitrates)
• Moderate to severe bronchial asthma or COPD (Forced Expiratory Volume \<60% predicted) or severe restrictive lung disease (Total Lung Capacity \< 70% predicted) and/or defined as if high resolution computed tomography shows \<20% parenchymal lung disease.
• Severe congenital abnormalities of the lungs, thorax, and diaphragm.
• Clinical or radiological evidence of Pulmonary-Veno-Occlusive Disease (PVOD) or Pulmonary Capillary Haemangiomatosis (PCH) or PH and idiopathic interstitial pneumonia (PH-IIP)

Sponsors & Collaborators

• Heidelberg University: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

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

Heidelberg, 69126, Germany

Location

Related Publications (5)

• Raymond RJ, Hinderliter AL, Willis PW, Ralph D, Caldwell EJ, Williams W, Ettinger NA, Hill NS, Summer WR, de Boisblanc B, Schwartz T, Koch G, Clayton LM, Jobsis MM, Crow JW, Long W. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002 Apr 3;39(7):1214-9. doi: 10.1016/s0735-1097(02)01744-8.

  PMID: 11923049 BACKGROUND

• Bossone E, D'Andrea A, D'Alto M, Citro R, Argiento P, Ferrara F, Cittadini A, Rubenfire M, Naeije R. Echocardiography in pulmonary arterial hypertension: from diagnosis to prognosis. J Am Soc Echocardiogr. 2013 Jan;26(1):1-14. doi: 10.1016/j.echo.2012.10.009. Epub 2012 Nov 8.

  PMID: 23140849 BACKGROUND

• Austin C, Alassas K, Burger C, Safford R, Pagan R, Duello K, Kumar P, Zeiger T, Shapiro B. Echocardiographic assessment of estimated right atrial pressure and size predicts mortality in pulmonary arterial hypertension. Chest. 2015 Jan;147(1):198-208. doi: 10.1378/chest.13-3035.

  PMID: 25211049 BACKGROUND

• Marra AM, Egenlauf B, Ehlken N, Fischer C, Eichstaedt C, Nagel C, Bossone E, Cittadini A, Halank M, Gall H, Olsson KM, Lange TJ, Grunig E. Change of right heart size and function by long-term therapy with riociguat in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Int J Cardiol. 2015 Sep 15;195:19-26. doi: 10.1016/j.ijcard.2015.05.105. Epub 2015 May 19.

  PMID: 26011408 BACKGROUND

• Marra AM, Halank M, Benjamin N, Bossone E, Cittadini A, Eichstaedt CA, Egenlauf B, Harutyunova S, Fischer C, Gall H, Ghofrani HA, Hoeper MM, Lange TJ, Olsson KM, Klose H, Grunig E. Right ventricular size and function under riociguat in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (the RIVER study). Respir Res. 2018 Dec 19;19(1):258. doi: 10.1186/s12931-018-0957-y.

  PMID: 30567595 BACKGROUND

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

riociguat

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Ekkehard HD Grünig, MD

  Thoraxklinik at the University of Heidelberg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of centre for pulmonary hypertension

Study Record Dates

• First Submitted: June 29, 2021
• First Posted: July 8, 2021
• Study Start: April 13, 2022
• Primary Completion: August 13, 2025
• Study Completion: August 13, 2025
• Last Updated: September 15, 2025

Record last verified: 2025-09

Locations

DE (1)