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

Chronic Thromboembolic Pulmonary Hypertension Clinical Trial

— RIVERII  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04954742
• Other study ID #: 2020-06RCT
• Status: Recruiting
• Phase: Phase 4
• Start date: April 13, 2022
• Est. completion date: March 2026

Study information

• Verified date: March 2024
• Source: Heidelberg University
• Contact: Ekkehard HD 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 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: March 2026
• Est. primary completion date: March 2026
• 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 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).

3. 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).*

4. *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.

5. 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.

6. 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.

7. 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).

8. 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.

9. 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.

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

11. 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. Pregnant women, or breast-feeding women, or women of childbearing potential not able or willing to comply with study-mandated contraception methods specified above.

2. Patients with PH specific treatment <2 months before screening.

3. 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.

4. 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).

5. Patients with a history of severe or multiple drug allergies

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

7. Patients unable to perform a valid 6MWD test (e.g. orthopaedic disease, peripheral artery occlusive disease, which affects the patient´s ability to walk).

8. The following specific medications for concomitant treatment of PH or medications which may exert a pharmacodynamic interaction with the study drug are not allowed:

1. Parenteral prostacyclin analogues

2. Specific phosphodiesterase inhibitors (e.g. sildenafil or tadalafil): may be switched to riociguat but not be given in addition to the study drug

3. or unspecific phosphodiesterase inhibitors (e.g. dipyridamole, theophylline)

4. NO donors (e.g. Nitrates)

9. Pulmonary diseases exclusions

1. 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.

2. Severe congenital abnormalities of the lungs, thorax, and diaphragm.

3. Clinical or radiological evidence of Pulmonary-Veno-Occlusive Disease (PVOD) or Pulmonary Capillary Haemangiomatosis (PCH) or PH and idiopathic interstitial pneumonia (PH-IIP)

10. Cardiovascular exclusions:

1. Uncontrolled arterial hypertension (systolic blood pressure >180 mmHg and /or diastolic blood pressure >110 mmHg).

2. Systolic blood pressure <95 mmHg.

3. Left heart failure with an ejection fraction less than 40%.

4. Pulmonary venous hypertension with pulmonary arterial wedge pressure >15 mmHg.

5. Hypertrophic obstructive cardiomyopathy.

6. 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).

7. Clinical evidence of symptomatic atherosclerotic disease (e.g. peripheral artery disease with reduced walking distance, history of stroke with persistent neurological deficit etc).

11. Exclusions related to disorders in organ function:

a) 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).

Related Conditions & MeSH terms

• Chronic Thromboembolic Pulmonary Hypertension
• Familial Primary Pulmonary Hypertension
• Hypertension
• Hypertension, Pulmonary
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Riociguat
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.

Locations

Country	Name	City	State
Germany	Centre for Pulmonary Hypertension at the Thoraxklinik Heidelberg, Heidelberg University Hospital	Heidelberg

Sponsors (2)

Lead Sponsor	Collaborator
Heidelberg University	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

Germany, 

References & Publications (5)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in RV (right ventricular) area	echocardiographic analysis right atrial (RA) area, measured by echocardiography.	Baseline to 24 weeks
Primary	Change in RA (right atrial) area	echocardiographic analysis	Baseline to 24 weeks
Secondary	Change in RV Area	echocardiographic analysis	baseline to 12 weeks
Secondary	Change in RA Area	echocardiographic analysis	baseline to 12 weeks
Secondary	Change in systolic pulmonary artery pressure (sPAP)	echocardiographic analysis	baseline to 12 weeks
Secondary	Change in systolic pulmonary artery pressure (sPAP)	echocardiographic analysis	baseline to 24 weeks
Secondary	Change in RV fractional area change (FAC)	echocardiographic analysis	baseline to 24 weeks
Secondary	Change in RV fractional area change (FAC)	echocardiographic analysis	baseline to 12 weeks
Secondary	Change in Peak velocity of tricuspid regurgitation (TRV)	echocardiographic analysis	baseline to 12 weeks
Secondary	Change in Peak velocity of tricuspid regurgitation (TRV)	echocardiographic analysis	baseline to 24 weeks
Secondary	Change in inferior vena cava (IVC) diameter and IVC collapse	echocardiographic analysis	baseline to 24 weeks
Secondary	Change in inferior vena cava (IVC) diameter and IVC collapse	echocardiographic analysis	baseline to 12 weeks
Secondary	Change in Right Ventricle Outflow Tract Velocity Time Integral (RVOT VTI)	echocardiographic analysis	baseline to 12 weeks
Secondary	Change in Right Ventricle Outflow Tract Velocity Time Integral (RVOT VTI)	echocardiographic analysis	baseline to 24 weeks
Secondary	Change in Eccentricity index (EI)	echocardiographic analysis	baseline to 24 weeks
Secondary	Change in Eccentricity index (EI)	echocardiographic analysis	baseline to 12 weeks
Secondary	Change in Tricuspid Annular Plane Systolic Excursion (TAPSE)	echocardiographic analysis	baseline to 12 weeks
Secondary	Change in Tricuspid Annular Plane Systolic Excursion (TAPSE)	echocardiographic analysis	baseline to 24 weeks
Secondary	Change in Right ventricular pump function (qualitative)	echocardiographic analysis	baseline to 24 weeks
Secondary	Change in left ventricular pump function (qualitative)	echocardiographic analysis	baseline to 24 weeks
Secondary	Change in Right ventricular pump function (qualitative)	echocardiographic analysis	baseline to 12 weeks
Secondary	Change in left ventricular pump function (qualitative)	echocardiographic analysis	baseline to 12 weeks
Secondary	Change in Left Atrial (LA) diameter	echocardiographic analysis	baseline to 12 weeks
Secondary	Change in Left Atrial (LA) diameter	echocardiographic analysis	baseline to 24 weeks
Secondary	Change in 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)	baseline to 24 weeks
Secondary	Change in 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)	baseline to 12 weeks
Secondary	Change in Diameters of pulmonary artery	echocardiographic Analysis	baseline to 12 weeks
Secondary	Change in Diameters of pulmonary artery	echocardiographic Analysis	baseline to 24 weeks
Secondary	Change in cardiac index	Pulmonary hemodynamics by right heart catheterization	baseline and after 24 weeks
Secondary	Change in cardiac output	Pulmonary hemodynamics by right heart catheterization	baseline and after 24 weeks
Secondary	Change in sPAP	Pulmonary hemodynamics by right heart catheterization	baseline and after 24 weeks
Secondary	Change in dPAP	Pulmonary hemodynamics by right heart catheterization	baseline and after 24 weeks
Secondary	Change in mPAP	Pulmonary hemodynamics by right heart catheterization	baseline and after 24 weeks
Secondary	Change in PAWP	Pulmonary hemodynamics by right heart catheterization	baseline and after 24 weeks
Secondary	Change in right atrial pressure (RAP)	Pulmonary hemodynamics by right heart catheterization	baseline and after 24 weeks
Secondary	Change in PVR	Pulmonary hemodynamics by right heart catheterization	baseline and after 24 weeks
Secondary	Change in Central venous saturation from pulmonary artery	Pulmonary hemodynamics by right heart catheterization	baseline and after 24 weeks
Secondary	Change in 6-minute walking distance	Change in exercise capacity	baseline to 12 weeks
Secondary	Change in 6-minute walking distance	Change in exercise capacity	baseline to 24 weeks
Secondary	forced vital capacity (FVC)	Change in Lung function Tests	baseline to 12 weeks
Secondary	forced vital capacity (FVC)	Change in Lung function Tests	baseline to 24 weeks
Secondary	Change in forced expiratory volume in one second (FEV1)	Change in Lung function Tests	baseline to 12 weeks
Secondary	Change in forced expiratory volume in one second (FEV1)	Change in Lung function Tests	baseline to 24 weeks
Secondary	Change in FEV1% of maximal vital capacity (VC max)	Change in Lung function Tests	baseline to 12 weeks
Secondary	Change in FEV1% of maximal vital capacity (VC max)	Change in Lung function Tests	baseline to 24 weeks
Secondary	Change in total lung capacity (TLC)	Change in Lung function Tests	baseline to 12 weeks
Secondary	Change in total lung capacity (TLC)	Change in Lung function Tests	baseline to 24 weeks
Secondary	Change in residual volume	Change in Lung function Tests	baseline to 12 weeks
Secondary	Change in residual volume	Change in Lung function Tests	baseline to 24 weeks
Secondary	Change in diffusion-limited carbon monoxide (DLCO)	Change in Lung function Tests	baseline to 24 weeks
Secondary	Change in diffusion-limited carbon monoxide (DLCO)	Change in Lung function Tests	baseline to 12 weeks
Secondary	Change in DLCO/VA (Krogh) factor	Change in Lung function Tests	baseline to 12 weeks
Secondary	Change in DLCO/VA (Krogh) factor	Change in Lung function Tests	baseline to 24 weeks
Secondary	Change in partial pressure of oxygen	Change in capillary or arterial blood gas analysis	baseline to 12 weeks
Secondary	Change in partial pressure of oxygen	Change in capillary or arterial blood gas analysis	baseline to 24 weeks
Secondary	Change in partial pressure of carbon dioxide	Change in capillary or arterial blood gas analysis	baseline to 12 weeks
Secondary	Change in partial pressure of carbon dioxide	Change in capillary or arterial blood gas analysis	baseline to 24 weeks
Secondary	Change in SaO2	Change in capillary or arterial blood gas analysis	baseline to 12 weeks
Secondary	Change in SaO2	Change in capillary or arterial blood gas analysis	baseline to 24 weeks
Secondary	Change in pH	Change in capillary or arterial blood gas analysis	baseline to 24 weeks
Secondary	Change in pH	Change in capillary or arterial blood gas analysis	baseline to 12 weeks
Secondary	Change in Blood pressure	Change in Cardiopulmonary exercise testing	baseline to 12 weeks
Secondary	Change in Blood pressure	Change in Cardiopulmonary exercise testing	baseline to 24 weeks
Secondary	Change in heart rate	Change in Cardiopulmonary exercise testing	baseline to 12 weeks
Secondary	Change in heart rate	Change in Cardiopulmonary exercise testing	baseline to 24 weeks
Secondary	Change in workload	Change in Cardiopulmonary exercise testing	baseline to 12 weeks
Secondary	Change in workload	Change in Cardiopulmonary exercise testing	baseline to 24 weeks
Secondary	Change in oxygen consumption as total and per kg body weight	Change in Cardiopulmonary exercise testing	baseline to 12 weeks
Secondary	Change in oxygen consumption as total and per kg body weight	Change in Cardiopulmonary exercise testing	baseline to 24 weeks
Secondary	Change in exhaled carbon dioxide (VCO2)	Change in Cardiopulmonary exercise testing	baseline to 12 weeks
Secondary	Change in exhaled carbon dioxide (VCO2)	Change in Cardiopulmonary exercise testing	baseline to 24 weeks
Secondary	Change in oxygen saturation	Change in Cardiopulmonary exercise testing	baseline to 12 weeks
Secondary	Change in oxygen saturation	Change in Cardiopulmonary exercise testing	baseline to 24 weeks
Secondary	Change in oxygen pulse	Change in Cardiopulmonary exercise testing	baseline to 12 weeks
Secondary	Change in oxygen pulse	Change in Cardiopulmonary exercise testing	baseline to 24 weeks
Secondary	Change in minute ventilation	Change in Cardiopulmonary exercise testing	baseline to 12 weeks
Secondary	Change in minute ventilation	Change in Cardiopulmonary exercise testing	baseline to 24 weeks
Secondary	Change in respiratory equivalents for oxygen	Change in Cardiopulmonary exercise testing	baseline to 12 weeks
Secondary	Change in respiratory equivalents for oxygen	Change in Cardiopulmonary exercise testing	baseline to 24 weeks
Secondary	Change in respiratory equivalents for carbon dioxide	Change in Cardiopulmonary exercise testing	baseline to 12 weeks
Secondary	Change in respiratory equivalents for carbon dioxide	Change in Cardiopulmonary exercise testing	baseline to 24 weeks
Secondary	Change in respiratory reserve	Change in Cardiopulmonary exercise testing	baseline to 12 weeks
Secondary	Change in respiratory reserve	Change in Cardiopulmonary exercise testing	baseline to 24 weeks
Secondary	WHO FC	Change in WHO functional class	baseline to 12 weeks
Secondary	WHO FC	Change in WHO functional class	baseline to 24 weeks
Secondary	SF-36	Change in Quality of life parameters by questionnaire SF-36	baseline to 24 weeks
Secondary	NT-proBNP	Change in laboratory parameters	baseline to 12 weeks
Secondary	NT-proBNP	Change in laboratory parameters	baseline to 24 weeks
Secondary	haemoglobin changes	Change in laboratory parameters	baseline to 12 weeks
Secondary	haemoglobin changes	Change in laboratory parameters	baseline to 24 weeks
Secondary	haematocrit changes	Change in laboratory parameters	baseline to 12 weeks
Secondary	haematocrit changes	Change in laboratory parameters	baseline to 24 weeks
Secondary	AST changes	Change in liver enzymes	baseline to 12 weeks
Secondary	AST changes	Change in liver enzymes	baseline to 24 weeks
Secondary	ALT changes	Change in liver enzymes	baseline to 12 weeks
Secondary	ALT changes	Change in liver enzymes	baseline to 24 weeks
Secondary	Bilirubin changes	Change in liver enzymes	baseline to 12 weeks
Secondary	Bilirubin changes	Change in liver enzymes	baseline to 24 weeks
Secondary	CRP changes	Change in laboratory parameters	baseline to 12 weeks
Secondary	CRP changes	Change in laboratory parameters	baseline to 24 weeks
Secondary	sodium changes	Change in laboratory parameters	baseline to 12 weeks
Secondary	sodium changes	Change in laboratory parameters	baseline to 24 weeks
Secondary	Urea changes	Change in renal parameters	baseline to 12 weeks
Secondary	Urea changes	Change in renal parameters	baseline to 24 weeks
Secondary	creatinine changes	Change in renal parameters	baseline to 12 weeks
Secondary	creatinine clearance changes	Change in renal parameters	baseline to 12 weeks
Secondary	creatinine changes	Change in renal parameters	baseline to 24 weeks
Secondary	creatinine clearance changes	Change in renal parameters	baseline to 24 weeks