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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Primary Pulmonary Arterial Hypertension, Chronic Thromboembolic Pulmonary Hypertension

Intervention / Treatment
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* Drug: Riociguat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥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. 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. Exclusion Criteria: 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) 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: 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Riociguat<br>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<br>* 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.<br>* Other names: ATC code: C02KX05;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pulmonary arterial hypertension, Chronic Thromboembolic Pulmonary Hypertension, riociguat, right heart function