Symptomatic pulmonary arterial hypertension with a mean pulmonary artery pressure >20 mmHg and pulmonary vascular resistance =2 Wood Units, pulmonary arterial wedge pressure =15 mmHg (Group I / Nice Clinical Classification of Pulmonary Hypertension (PH)) or CTEPH (Group IV) with hemodynamics as stated above defined as inoperable measured at least 3 months after start of full anticoagulation or with persisting or recurrent PH after pulmonary endarterectomy at least 6 months after surgery MedDRA
Conditions
Interventions
Product Name: Riociguat
Product Code: MK-4836
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: RIOCIGUAT
CAS Number: 625115-55-1
Current Sponsor code: MK-4836
Other descriptive name: BAY 6
Sponsors
Thoraxklinik Heidelberg gGmbH
Eligibility
Sex/Gender
All
Inclusion criteria
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 (mean pulmonary artery pressure >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. 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 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. Women with childbearing potential can only be included in the study if a serological pregnancy test is negative and a combination of condoms with a safe and highly effective contraception method (hormonal contraception with implants or combined oral contraceptives, certain IUDs) is used. 9. Patients who are able to understand and follow instructions and who are able to participate in the study for the entire period. 10. 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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 22 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 8
Exclusion criteria
Exclusion criteria: 1. Pregnant women, or breast-feeding women, or women with childbearing potential not using a combination of condoms and a safe and highly effective contraception method (hormonal contraception with implants or combined oral contraceptives, certain IUDs). 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 allergies 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: a) Parenteral prostacyclin analogues b) Specific (e.g. sildenafil or tadalafil) or unspecific phosphodiesterase inhibitors (e.g. dipyridamole, theophylline) c) NO donors (e.g. Nitrates) 9. Pulmonary diseases exclusions a) Moderate to severe bronchial asthma or COPD (Forced Expiratory Volume 180 mmHg and /or diastolic blood pressure >110 mmHg). b) Systolic blood pressure 15 mmHg. e) Hypertrophic obstructive cardiomyopathy. f) 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). g) 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 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).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Investigate the effect of riociguat on RV and RA area, measured by echocardiography. The effect of riociguat on RV and RA area will be compared during therapy in each patient (from baseline to 12 and 24 weeks; primary endpoint baseline vs. 24 weeks riociguat therapy).;Secondary Objective: Compare the effect of riociguat on RV and hemodynamic properties in patients with PAH or CTEPH (comparison from baseline to 24 weeks) with right heart catheterization. Secondary efficacy analysis comprises of further echocardiographic measurements and correlation between echocardiography and clinical data such as haemodynamics, vital signs, electrocardiogram, echocardiography, laboratory parameters NT-proBNP, pulmonary function, WHO-FC, 6MWD (from baseline to 12 and 24 weeks) and quality of life (QoL) parameters by questionnaire SF-36.;Primary end point(s): The evaluation of the primary efficacy endpoint will be the change from baseline to 24 weeks in RV and RA area. The primary analysis set will be the intention to treat set. The per-protocol analysis will be supportive. The main comparison will be the difference between baseline and follow-up. 95% confidence intervals of treatment difference will also be calculated. The primary comparison will be an ANCOVA model including baseline scores as covariate. If the preconditions for an ANCOVA analysis are not met, the primary endpoint will be analysed by robust, two-sided t-test (Welch-test). ;Timepoint(s) of evaluation of this end point: •Screening Phase: up to 28 days before treatment start •Treatment phase: 24 weeks ± 14 days including 8 weeks titration phase and 16 weeks continuation phase. •Safety follow-up: patient’s well-being will be monitored by phone after 30 ± 7 days after last intake of study. •Survival follow-up: survival at study termination / last patient out | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary parameters at baseline and during follow-up will be compared. Data will be displayed by means and standard deviations, medians and variances with respective 95% confidence intervals. p-values <0.05 will be considered as statistically significant. It is assumed that WHO functional class will either remain the same, improve by one or two categories, or deteriorate by one category in most cases. A change score (baseline minus end of study) will be calculated, which could go from -3 (class IV at baseline and class I at end of study) to +4 (class I at baseline, death at end of study), but in practice for those patients still alive at the end of the study it will most likely range from -2 to +1. The safety analysis will be performed in the population valid for safety. All tabulations will be descriptive only. Tables will be produced for drug-related treatment-emergent adverse events and serious adverse events. Further tables will be produced for serious and/or drug-related treatment-emergent adverse events. Mortality will be summarized descriptively. Any deaths in the study period (until survival follow-up) will be listed, with day of death relative to start and stop of study drug and cause of death. ;Timepoint(s) of evaluation of this end point: Data will be obtained at baseline, after 12 and 24 weeks. 30 days after last study drug intake, a safety follow-up by phone will be performed. At study Termination, survival will be assessed by phone. | — |
Countries
Germany
Contacts
Public ContactProf. Dr. med. Ekkehard Grünig
Thoraxklinik Heidelberg gGmbH
Outcome results
None listed