Primary Pulmonary Arterial HypertensionPhase 4RIVERIINCT04954742
Effects of Riociguat on RIght VEntricular Size and Function in PAH and CTEPH
A Phase 4 study testing Riociguat in people with Primary Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension, run by Heidelberg University at 1 site in Germany.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Primary Pulmonary Arterial Hypertension, Chronic Thromboembolic Pulmonary Hypertension
- What is being tested?
- Riociguat
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteGermany
- Study dates
- 13 Apr 2022to 13 Aug 2025
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- ≥18 years of age at time of inclusion.
- 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.
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- 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.
Who cannot join
- 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.
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- 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)
- Pulmonary diseases exclusions
- 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)
- Cardiovascular exclusions:
- Uncontrolled arterial hypertension (systolic blood pressure >180 mmHg and /or diastolic blood pressure >110 mmHg).
- Systolic blood pressure <95 mmHg.
- Left heart failure with an ejection fraction less than 40%.
- Pulmonary venous hypertension with pulmonary arterial wedge pressure >15 mmHg.
- Hypertrophic obstructive cardiomyopathy.
- Severe proven or suspected coronary artery disease according to investigators opinion (patients with Canadian Cardiovascular Society Angina Classification class 2-4, and/or requiring nitrates, and/or myocardial infarction within the last 3 months before Visit 1).
- Clinical evidence of symptomatic atherosclerotic disease (e.g. peripheral artery disease with reduced walking distance, history of stroke with persistent neurological deficit etc).
- Exclusions related to disorders in organ function:
- Clinically relevant hepatic dysfunction indicated by: i. bilirubin >2 times upper limit normal ii. and / or hepatic transaminases >3 times upper limit normal iii. and / or signs of severe hepatic insufficiency (e.g. impaired albumin synthesis with an albumin < 32 g/l, hepatic encephalopathy > grade 1a: West Haven Criteria of Altered Mental Status In Hepatic Encephalopathy) b) Renal insufficiency (glomerular filtration rate <30 ml/min e.g. calculated based on the Cockcroft formula).
Trial locations and contacts
1 site in 1 country.
Germany1 site
Centre for Pulmonary Hypertension at the Thoraxklinik Heidelberg, Heidelberg University Hospital
Heidelberg, 69126
About this study
Official title: An Open-label, Prospective, Single Centre Study of the Effects of Riociguat on RIght VEntricular Size and Function in Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension
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.
Read the detailed description
Right heart size and function are of utmost prognostic importance in PAH/CTEPH. RV performance measured by echocardiography and enlarged RA area have been shown to be independent prognostic factors in PAH. Recently, a retrospective single centre study has shown that riociguat treatment was associated with a significant reduction of RV and RA area after 3, 6 and 12 months compared to baseline. RA area significantly decreased after 12 months and RV systolic function assessed with tricuspid annular plane systolic excursion (TAPSE) improved after 6 and 12 months of riociguat therapy. The results were confirmed by a recent retrospective multicentre study. It is therefore reasonable to assume a beneficial effect of riociguat on right heart size and function.
The primary efficacy endpoint in this study is the change in RV and RA area from baseline to 24 weeks. Treatment will be initiated and individually adjusted according to systolic blood pressure and tolerability. Patients who discontinue medication prematurely will be asked to continue with study assessments and perform study visits as outlined in the protocol.
Medical examinations comprise medical history, physical examination, electrocardiogram (ECG), blood gas analyses, lung function tests, laboratory testing (including NT-proBNP), echocardiography at rest, and right heart catheterization (RHC) according to clinical practice of the PH centre.
The prospective period of data collection comprises a 24-week study period a follow-up phase of about 30±7 days.
Outcome (survival and transplant-free survival) of all patients will be assessed when the last patient has terminated his/her 24-week observation period.
- Being tested
- Riociguat
- Keywords
- pulmonary arterial hypertension, Chronic Thromboembolic Pulmonary Hypertension, riociguat, right heart function
- Medical subject headings
- Pulmonary Arterial Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RiociguatDrug
Also called MK-4836, ATC code: C02KX05
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Riociguat |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in RV (Right Ventricular) Area
echocardiographic analysis right ventricular (RV) area, measured by echocardiography.
Measured: Baseline to 24 weeks
Change in RA (Right Atrial) Area
echocardiographic analysis
Measured: Baseline to 24 weeks
Secondary outcomes (128)
Change in RV (Right Ventricular) Area
echocardiographic analysis
Measured: baseline to 12 weeks
Change in RA (Right Atrial) Area
echocardiographic analysis
Measured: baseline to 12 weeks
Change in Systolic Pulmonary Artery Pressure (sPAP)
echocardiographic analysis
Measured: baseline to 12 weeks
Change in Systolic Pulmonary Artery Pressure (sPAP)
echocardiographic analysis
Measured: baseline to 24 weeks
Change in RV Fractional Area Change (FAC)
echocardiographic analysis
Measured: baseline to 24 weeks
Change in RV Fractional Area Change (FAC)
echocardiographic analysis
Measured: baseline to 12 weeks
Change in Peak Velocity of Tricuspid Regurgitation (TRV)
echocardiographic analysis
Measured: baseline to 12 weeks
Change in Peak Velocity of Tricuspid Regurgitation (TRV)
echocardiographic analysis
Measured: baseline to 24 weeks
Change in Inferior Vena Cava (IVC) Diameter
echocardiographic analysis
Measured: baseline to 24 weeks
Change in Inferior Vena Cava (IVC) Diameter
echocardiographic analysis
Measured: baseline to 12 weeks
Change in Right Ventricle Outflow Tract Velocity Time Integral (RVOT VTI)
echocardiographic analysis
Measured: baseline to 12 weeks
Change in Eccentricity Index (EI)
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-perpendicular left ventricular diameters in parasternal short-axis view; normal = 1, increased (≥ 1.1) indicates right ventricular pressure/volume overload
Measured: baseline to 24 weeks
Change in Eccentricity Index (EI)
Change in left ventricular eccentricity index (LV-EI) from baseline at 12 weeks assessed by echocardiography.
LV-EI is the ratio of septical-parallel to septical-perpendicular left ventricular diameters in parasternal short-axis view; normal = 1, increased (≥ 1.1) indicates right ventricular pressure/volume overload
Measured: baseline to 12 weeks
Change in Tricuspid Annular Plane Systolic Excursion (TAPSE)
echocardiographic analysis
Measured: baseline to 12 weeks
Change in Tricuspid Annular Plane Systolic Excursion (TAPSE)
echocardiographic analysis
Measured: baseline to 24 weeks
Change in Right Ventricular Pump Function (Qualitative)
echocardiographic analysis
Measured: baseline to 24 weeks
Change in Left Ventricular Pump Function (Qualitative)
echocardiographic analysis
Measured: baseline to 24 weeks
Change in Right Ventricular Pump Function (Qualitative)
echocardiographic analysis
Measured: baseline to 12 weeks
Change in Left Ventricular Pump Function (Qualitative)
echocardiographic analysis
Measured: baseline to 12 weeks
Change in Left Atrial (LA) Diameter
echocardiographic analysis
Measured: baseline to 12 weeks
Change in Left Atrial (LA) Diameter
echocardiographic analysis
Measured: baseline to 24 weeks
Change in Left Ventricular (LV) Diastolic Function
echocardiographic Analysis measured as: (LV transmitral E wave and A wave, E' wave of interventricular septum and lateral wall pulsed tissue Doppler, isovolumic relaxation time, mitral deceleration time)
Measured: baseline to 12 weeks
Change in Diameters of Pulmonary Artery (PA)
echocardiographic Analysis
Measured: baseline to 12 weeks
Change in Diameters of Pulmonary Artery (PA)
echocardiographic Analysis
Measured: baseline to 24 weeks
Change in Cardiac Index (CI)
Pulmonary hemodynamics by right heart catheterization
Measured: baseline and after 24 weeks
Change in Cardiac Output (CO)
Pulmonary hemodynamics by right heart catheterization
Measured: baseline and after 24 weeks
Change in Systolic Pulmonary Arterial Pressure (sPAP)
Pulmonary hemodynamics by right heart catheterization
Measured: baseline and after 24 weeks
Change in Diastolic Pulmonary Arterial Pressure (dPAP)
Pulmonary hemodynamics by right heart catheterization
Measured: baseline and after 24 weeks
Change in Mean Pulmonary Arterial Pressure (mPAP)
Pulmonary hemodynamics by right heart catheterization
Measured: baseline and after 24 weeks
Change in Pulmonary Arterial Wedge Pressure (PAWP)
Pulmonary hemodynamics by right heart catheterization
Measured: baseline and after 24 weeks
Change in Right Atrial Pressure (RAP)
Pulmonary hemodynamics by right heart catheterization
Measured: baseline and after 24 weeks
Change in Pulmonary Vascular Resistance (PVR)
Pulmonary hemodynamics by right heart catheterization
Measured: baseline and after 24 weeks
Change in Central Venous Saturation From Pulmonary Artery
Pulmonary hemodynamics by right heart catheterization
Measured: baseline and after 24 weeks
Change in 6-minute Walking Distance
Change in exercise capacity
Measured: baseline to 12 weeks
Change in 6-minute Walking Distance
Change in exercise capacity
Measured: baseline to 24 weeks
Forced Vital Capacity (FVC)
Change in Lung function Tests
Measured: baseline to 12 weeks
Forced Vital Capacity (FVC)
Change in Lung function Tests
Measured: baseline to 24 weeks
Change in Forced Expiratory Volume in One Second (FEV1)
Change in Lung function Tests
Measured: baseline to 12 weeks
Change in Forced Expiratory Volume in One Second (FEV1)
Change in Lung function Tests
Measured: baseline to 24 weeks
Change in FEV1% of Maximal Vital Capacity (VC Max)
Change in Lung function Tests
Measured: baseline to 12 weeks
Change in FEV1% of Maximal Vital Capacity (VC Max)
Change in Lung function Tests
Measured: baseline to 24 weeks
Change in Total Lung Capacity (TLC)
Change in Lung function Tests
Measured: baseline to 12 weeks
Change in Total Lung Capacity (TLC)
Change in Lung function Tests
Measured: baseline to 24 weeks
Change in Residual Volume (RV)
Change in Lung function Tests
Measured: baseline to 12 weeks
Change in Residual Volume (RV)
Change in Lung function Tests
Measured: baseline to 24 weeks
Change in Diffusion-limited Carbon Monoxide (DLCO)
Change in Lung function Tests
Measured: baseline to 24 weeks
Change in Diffusion-limited Carbon Monoxide (DLCO)
Change in Lung function Tests
Measured: baseline to 12 weeks
Change in DLCO/VA (Krogh) Factor
Change in Lung function Tests
Measured: baseline to 12 weeks
Change in DLCO/VA (Krogh) Factor
Change in Lung function Tests
Measured: baseline to 24 weeks
Change in Partial Pressure of Oxygen (pO2)
Change in capillary or arterial blood gas analysis
Measured: baseline to 12 weeks
Change in Partial Pressure of Oxygen (pO2)
Change in capillary or arterial blood gas analysis
Measured: baseline to 24 weeks
Change in Partial Pressure of Carbon Dioxide (pCO2)
Change in capillary or arterial blood gas analysis
Measured: baseline to 12 weeks
Change in Partial Pressure of Carbon Dioxide (pCO2)
Change in capillary or arterial blood gas analysis
Measured: baseline to 24 weeks
Change in Oxygen Saturation (SaO2)
Change in capillary or arterial blood gas analysis
Measured: baseline to 12 weeks
Change in Oxygen Saturation (SaO2)
Change in capillary or arterial blood gas analysis
Measured: baseline to 24 weeks
Change in pH
Change in capillary or arterial blood gas analysis
Measured: baseline to 24 weeks
Change in pH
Change in capillary or arterial blood gas analysis
Measured: baseline to 12 weeks
Change in Blood Pressure
Change in Cardiopulmonary exercise testing
Measured: baseline to 12 weeks
Change in Blood Pressure
Change in Cardiopulmonary exercise testing
Measured: baseline to 24 weeks
Change in Heart Rate
Change in Cardiopulmonary exercise testing
Measured: baseline to 12 weeks
Change in Heart Rate
Change in Cardiopulmonary exercise testing
Measured: baseline to 24 weeks
Change in Workload
Change in Cardiopulmonary exercise testing
Measured: baseline to 12 weeks
Change in Workload
Change in Cardiopulmonary exercise testing
Measured: baseline to 24 weeks
Change in Oxygen Consumption as Total (VO2)
Change in Cardiopulmonary exercise testing
Measured: baseline to 24 weeks
Change in Oxygen Consumption as Total (VO2)
Change in Cardiopulmonary exercise testing
Measured: baseline to 12 weeks
Change in Exhaled Carbon Dioxide (VCO2)
Change in Cardiopulmonary exercise testing
Measured: baseline to 12 weeks
Change in Exhaled Carbon Dioxide (VCO2)
Change in Cardiopulmonary exercise testing
Measured: baseline to 24 weeks
Change in Oxygen Saturation (SpO2)
Change in Cardiopulmonary exercise testing
Measured: baseline to 12 weeks
Change in Oxygen Saturation (SpO2)
Change in Cardiopulmonary exercise testing
Measured: baseline to 24 weeks
Change in Oxygen Pulse
Change in Cardiopulmonary exercise testing
Measured: baseline to 12 weeks
Change in Oxygen Pulse
Change in Cardiopulmonary exercise testing
Measured: baseline to 24 weeks
Change in Minute Ventilation (VE)
Change in Cardiopulmonary exercise testing
Measured: baseline to 12 weeks
Change in Minute Ventilation (VE)
Change in Cardiopulmonary exercise testing
Measured: baseline to 24 weeks
Change in Respiratory Equivalents for Oxygen at Rest
Change in Cardiopulmonary exercise testing: The respiratory equivalent for oxygen represents the ratio of minute ventilation (VE) to oxygen uptake (VO₂) and reflects the efficiency of ventilation relative to oxygen consumption.
Measured: baseline to 12 weeks
Change in Respiratory Equivalents for Oxygen at Rest
Change in Cardiopulmonary exercise testing: The respiratory equivalent for oxygen represents the ratio of minute ventilation (VE) to oxygen uptake (VO₂) and reflects the efficiency of ventilation relative to oxygen consumption.
Measured: baseline to 24 weeks
Change in Respiratory Equivalents for Carbon Dioxide
Change in Cardiopulmonary exercise testing: The respiratory equivalent for carbon dioxide represents the ratio of minute ventilation (VE) to carbon dioxide production (VCO₂) and reflects ventilatory efficiency with respect to carbon dioxide elimination.
Measured: baseline to 12 weeks
Change in Respiratory Equivalents for Carbon Dioxide
Change in Cardiopulmonary exercise testing: The respiratory equivalent for carbon dioxide represents the ratio of minute ventilation (VE) to carbon dioxide production (VCO₂) and reflects ventilatory efficiency with respect to carbon dioxide elimination.
Measured: baseline to 24 weeks
Change in Respiratory Reserve
Change in Cardiopulmonary exercise testing
Measured: baseline to 12 weeks
Change in Respiratory Reserve
Change in Cardiopulmonary exercise testing
Measured: baseline to 24 weeks
WHO FC
Change in WHO functional class
Measured: baseline to 12 weeks
WHO FC
Change in WHO functional class
Measured: baseline to 24 weeks
NT-proBNP
Change in laboratory parameters
Measured: baseline to 12 weeks
NT-proBNP
Change in laboratory parameters
Measured: baseline to 24 weeks
Haemoglobin Changes
Change in laboratory parameters
Measured: baseline to 12 weeks
Haemoglobin Changes
Change in laboratory parameters
Measured: baseline to 24 weeks
Haematocrit Changes
Change in laboratory parameters
Measured: baseline to 12 weeks
Haematocrit Changes
Change in laboratory parameters
Measured: baseline to 24 weeks
SGOT/AST Changes
Change in liver enzymes
Measured: baseline to 12 weeks
SGOT/AST Changes
Change in liver enzymes
Measured: baseline to 24 weeks
SGPT/ALT Changes
Change in liver enzymes
Measured: baseline to 12 weeks
SGPT/ALT Changes
Change in liver enzymes
Measured: baseline to 24 weeks
Bilirubin Changes
Change in liver enzymes
Measured: baseline to 12 weeks
Bilirubin Changes
Change in liver enzymes
Measured: baseline to 24 weeks
CRP Changes
Change in laboratory parameters
Measured: baseline to 12 weeks
CRP Changes
Change in laboratory parameters
Measured: baseline to 24 weeks
Sodium Changes
Change in laboratory parameters
Measured: baseline to 12 weeks
Sodium Changes
Change in laboratory parameters
Measured: baseline to 24 weeks
Urea Changes
Change in renal parameters
Measured: baseline to 12 weeks
Urea Changes
Change in renal parameters
Measured: baseline to 24 weeks
Creatinine Changes
Change in renal parameters
Measured: baseline to 12 weeks
Creatinine Clearance Changes
Change in renal parameters
Measured: baseline to 12 weeks
Creatinine Changes
Change in renal parameters
Measured: baseline to 24 weeks
Creatinine Clearance Changes
Change in renal parameters
Measured: baseline to 24 weeks
Change in IVC Collapse
echocardiographic analysis
Measured: baseline to 12 weeks
Change in IVC Collapse
echocardiographic analysis
Measured: baseline to 24 weeks
SF-36: Physical Functioning
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 24 weeks
SF-36: Physical Role Function
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 24 weeks
SF-36: Pain
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 24 weeks
SF-36: General Health Perception
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 24 weeks
SF-36: Vitality
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 24 weeks
SF-36: Social Functioning
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 24 weeks
SF-36: Emotional Role Function
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 24 weeks
SF-36: Mental Well-being
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 24 weeks
SF-36: Physical Summation Score
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 24 weeks
SF-36: Mental Summation Score
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 24 weeks
SF-36: Physical Functioning
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 12 weeks
SF-36: Physical Role Function
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 12 weeks
SF-36: Pain
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 12 weeks
SF-36: General Health Perception
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 12 weeks
SF-36: Vitality
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 12 weeks
SF-36: Social Functioning
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 12 weeks
SF-36: Emotional Role Function
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 12 weeks
SF-36: Mental Well-being
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 12 weeks
SF-36: Physical Summation Score
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 12 weeks
SF-36: Mental Summation Score
Measure Description: Quality of Life (QoL) was assessed using the 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.
Measured: baseline to 12 weeks
Change in Oxygen Consumption Per kg Body Weight (VO2/kg)
Change in Cardiopulmonary Exercise testing
Measured: Baseline to 24 weeks
Change in Oxygen Consumption Per kg Body Weight (VO2/kg)
Change in cardiopulmonary exercise testing
Measured: Baseline to 12weeks
Change in Right Ventricle Outflow Tract Velocity Time Integral (RVOT VTI)
echocardiographic analysis
Measured: baseline to 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Jul 2021
- Study start13 Apr 2022
- Primary completion13 Aug 2025
- Study completion13 Aug 2025
Why it stopped: Strategic re-prioritization by the IMP supplier. Decision not safety-related
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Primary Pulmonary Arterial HypertensionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Heidelberg University
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Principal investigator, Prof. Dr. med. Ekkehard Gruenig, Heidelberg University
- Investigators
- Ekkehard HD Grünig, MD, Principal investigator, Thoraxklinik at the University of Heidelberg
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04954742
- Sponsor's protocol ID
- 2020-06RCT
- Acronym
- RIVERII
- Status last verified
- May 2026
- First submitted
- 29 Jun 2021
- Last updated
- 17 Jun 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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.
PubMed 11923049Bossone 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.
PubMed 23140849Austin 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.
PubMed 25211049Marra 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.
PubMed 26011408Marra 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.
PubMed 30567595Harutyunova S, Heinz J, Benjamin N, Bruckner L, Sehic F, Egenlauf B, Cittadini A, Marra AM, Grunig E, Xanthouli P. Effects of riociguat on right ventricular size and function in pulmonary arterial hypertension (RIVER II): a prospective, phase IV study. Respir Res. 2026 Jul 28;27(1):296. doi: 10.1186/s12931-026-03843-8.
PubMed 42538528
Study at a glance
From the registry record, last updated by the sponsor on 17 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-label, Prospective, Single Centre Study of the Effects of Riociguat on RIght VEntricular Size and Function in Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension
- ClinicalTrials.gov ID
- NCT04954742
- Acronym / sponsor ID
- RIVERII / 2020-06RCT
- Keywords
- pulmonary arterial hypertension, Chronic Thromboembolic Pulmonary Hypertension, riociguat, right heart function
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Strategic re-prioritization by the IMP supplier. Decision not safety-related
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Heidelberg UniversityUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- 13 Apr 2022 (actual)
- Primary completion
- 13 Aug 2025 (actual)
- Study completion
- 13 Aug 2025 (actual)
- First posted
- 8 Jul 2021 (actual)
- Results
- Posted 17 Jun 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Right heart size and function are of utmost prognostic importance in PAH/CTEPH. RV performance measured by echocardiography and enlarged RA area have been shown to be independent prognostic factors in PAH. Recently, a retrospective single centre study has shown that riociguat treatment was associated with a significant reduction of RV and RA area after 3, 6 and 12 months compared to baseline. RA area significantly decreased after 12 months and RV systolic function assessed with tricuspid annular plane systolic excursion (TAPSE) improved after 6 and 12 months of riociguat therapy. The results were confirmed by a recent retrospective multicentre study. It is therefore reasonable to assume a beneficial effect of riociguat on right heart size and function.
The primary efficacy endpoint in this study is the change in RV and RA area from baseline to 24 weeks. Treatment will be initiated and individually adjusted according to systolic blood pressure and tolerability. Patients who discontinue medication prematurely will be asked to continue with study assessments and perform study visits as outlined in the protocol.
Medical examinations comprise medical history, physical examination, electrocardiogram (ECG), blood gas analyses, lung function tests, laboratory testing (including NT-proBNP), echocardiography at rest, and right heart catheterization (RHC) according to clinical practice of the PH centre.
The prospective period of data collection comprises a 24-week study period a follow-up phase of about 30±7 days.
Outcome (survival and transplant-free survival) of all patients will be assessed when the last patient has terminated his/her 24-week observation period.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Riociguat | Other | Drug: RiociguatRiociguat (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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- ≥18 years of age at time of inclusion.
- 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.
Key exclusion criteria (26 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RiociguatAlso: MK-4836, ATC code: C02KX05Treatment 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. | Drug | Riociguat |
Primary outcome
Change in RV (Right Ventricular) Area
Time frame: Baseline to 24 weeks
echocardiographic analysis right ventricular (RV) area, measured by echocardiography.
Change in RA (Right Atrial) Area
Time frame: Baseline to 24 weeks
echocardiographic analysis
128 secondary outcomes
Change in RV (Right Ventricular) Area
Time frame: baseline to 12 weeks
Change in RA (Right Atrial) Area
Time frame: baseline to 12 weeks
Change in Systolic Pulmonary Artery Pressure (sPAP)
Time frame: baseline to 12 weeks
Change in Systolic Pulmonary Artery Pressure (sPAP)
Time frame: baseline to 24 weeks
Change in RV Fractional Area Change (FAC)
Time frame: baseline to 24 weeks
Change in RV Fractional Area Change (FAC)
Time frame: baseline to 12 weeks
Change in Peak Velocity of Tricuspid Regurgitation (TRV)
Time frame: baseline to 12 weeks
Change in Peak Velocity of Tricuspid Regurgitation (TRV)
Time frame: baseline to 24 weeks
Change in Inferior Vena Cava (IVC) Diameter
Time frame: baseline to 24 weeks
Change in Inferior Vena Cava (IVC) Diameter
Time frame: baseline to 12 weeks
Change in Right Ventricle Outflow Tract Velocity Time Integral (RVOT VTI)
Time frame: baseline to 12 weeks
Change in Eccentricity Index (EI)
Time frame: baseline to 24 weeks
Change in Eccentricity Index (EI)
Time frame: baseline to 12 weeks
Change in Tricuspid Annular Plane Systolic Excursion (TAPSE)
Time frame: baseline to 12 weeks
Change in Tricuspid Annular Plane Systolic Excursion (TAPSE)
Time frame: baseline to 24 weeks
Change in Right Ventricular Pump Function (Qualitative)
Time frame: baseline to 24 weeks
Change in Left Ventricular Pump Function (Qualitative)
Time frame: baseline to 24 weeks
Change in Right Ventricular Pump Function (Qualitative)
Time frame: baseline to 12 weeks
Change in Left Ventricular Pump Function (Qualitative)
Time frame: baseline to 12 weeks
Change in Left Atrial (LA) Diameter
Time frame: baseline to 12 weeks
Change in Left Atrial (LA) Diameter
Time frame: baseline to 24 weeks
Change in Left Ventricular (LV) Diastolic Function
Time frame: baseline to 12 weeks
Change in Diameters of Pulmonary Artery (PA)
Time frame: baseline to 12 weeks
Change in Diameters of Pulmonary Artery (PA)
Time frame: baseline to 24 weeks
Change in Cardiac Index (CI)
Time frame: baseline and after 24 weeks
Change in Cardiac Output (CO)
Time frame: baseline and after 24 weeks
Change in Systolic Pulmonary Arterial Pressure (sPAP)
Time frame: baseline and after 24 weeks
Change in Diastolic Pulmonary Arterial Pressure (dPAP)
Time frame: baseline and after 24 weeks
Change in Mean Pulmonary Arterial Pressure (mPAP)
Time frame: baseline and after 24 weeks
Change in Pulmonary Arterial Wedge Pressure (PAWP)
Time frame: baseline and after 24 weeks
Change in Right Atrial Pressure (RAP)
Time frame: baseline and after 24 weeks
Change in Pulmonary Vascular Resistance (PVR)
Time frame: baseline and after 24 weeks
Change in Central Venous Saturation From Pulmonary Artery
Time frame: baseline and after 24 weeks
Change in 6-minute Walking Distance
Time frame: baseline to 12 weeks
Change in 6-minute Walking Distance
Time frame: baseline to 24 weeks
Forced Vital Capacity (FVC)
Time frame: baseline to 12 weeks
Forced Vital Capacity (FVC)
Time frame: baseline to 24 weeks
Change in Forced Expiratory Volume in One Second (FEV1)
Time frame: baseline to 12 weeks
Change in Forced Expiratory Volume in One Second (FEV1)
Time frame: baseline to 24 weeks
Change in FEV1% of Maximal Vital Capacity (VC Max)
Time frame: baseline to 12 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jun 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 11923049Raymond 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.
- Background: PubMed 23140849Bossone 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.
- Background: PubMed 25211049Austin 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.
- Background: PubMed 26011408Marra 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.
- Background: PubMed 30567595Marra 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.
- Derived from this study: PubMed 42538528Harutyunova S, Heinz J, Benjamin N, Bruckner L, Sehic F, Egenlauf B, Cittadini A, Marra AM, Grunig E, Xanthouli P. Effects of riociguat on right ventricular size and function in pulmonary arterial hypertension (RIVER II): a prospective, phase IV study. Respir Res. 2026 Jul 28;27(1):296. doi: 10.1186/s12931-026-03843-8.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ekkehard HD Grünig, MD principal investigator
Thoraxklinik at the University of Heidelberg
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Riociguat in people with Primary Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension, run by Heidelberg University at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 17 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Jun 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in RV (Right Ventricular) Area (time frame: Baseline to 24 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04954742, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jun 2026.