early pulmonary vascular disease, defined as either a) mean pulmonary arterial pressure (mPAP) =25 mmHg with pulmonary vascular resistance (PVR) =2 to <3 WU and pulmonary arterial wedge pressure (PAWP) =15 mmHg or b) mPAP 21-<25 mmHg with PVR =2 WU, and PAWP =15 mmHg associated with connective tissue disease (CTD) or as idiopathic/heritable form. MedDRA version: 20.0 Level: HLT Classification code 10037455 Term: Pulmonary vascular disorders NEC System Organ Class: 100000004866
Conditions
Interventions
Product Name: Riociguat
Product Code: MK-4836
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: RIOCIGUAT
CAS Number: 625115-55-1
Other descriptive name: BAY 63-2521
Concentration unit: mg
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 early pulmonary vascular disease, defined as either a) mean pulmonary arterial pressure (mPAP) =25 mmHg with pulmonary vascular resistance (PVR) =2 to 10% change of 6MWD, WHO FC, > 30% change in NTproBNP) 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 work up, they have to be performed as a part of the study during the Pre-Study Phase (after the patient signed the informed consent). 6. Women without childbearing potential defined as postmenopausal women aged 55 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 stated from screening until at least 30 days after study treatment discontinuation. 7. Patients who are able to understand and follow instructions and who are able to participate in the study for the entire period. 8. 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 50 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20
Exclusion criteria
Exclusion criteria: 1. Patients with systemic lupus erythematosus. 2. Concomitant PAH-targeted treatment is not allowed during the study. 3. Concomitant treatment with phosphodiesterase 5 inhibitors, endothelin receptor antagonists and prostacyclin analogues due to digital ulcers is contraindicated and should have a washout-phase of 3 days at the time of right heart catheterization. Intravenous treatment with prostacyclin analogues should not be performed within 1 week of right heart catheterization. Any decision to discontinue above-mentioned drugs will be made by the clinicians and the patient at screening. 4. Pulmonary hypertension explained by other cause including group 2, 3, 4 and 5 PH according to the current guidelines. 5. Cardiac comorbidity, defined with three or more of the following conditions: uncontrolled arterial hypertension, diabetes mellitus, body mass index >35, left atrial enlargement >20 cm², atrial fibrillation, left ventricular ejection fraction 10 mg/day or any other PAH specific treatment.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To investigate the change pulmonary vascular resistance among patients with early pulmonary vascular disease treated with riociguat (MK-4836) versus placebo for 24 weeks.;Secondary Objective: - To investigate, the effect of treatment with riociguat (MK-4836) on further hemodynamic and clinical parameters in patients with early pulmonary vascular disease, defined as stated above as change from baseline to 24 weeks of Treatment. - To assess safety and tolerability of riociguat (MK-4836) treatment in patients with early pulmonary vascular disease, defined as stated above as change from baseline to 24 weeks of Treatment.;Primary end point(s): The evaluation of the primary efficacy endpoint will be the change from baseline to 24 weeks in pulmonary vascular resistance. The primary analysis set will be the intention to treat set. The main comparison will be the difference in treatment effect between riociguat (MK-4836) and placebo. 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 between groups comparing the difference between baseline and follow-up visits. 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. Secondary endpoints will be statistically analysed by a hierarchical testing strategy using the two-sided student’s t-test with comparison of the differences between riociguat (MK-4836) and placebo. 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 in the 24-week period of the study will be summarized descriptively. Any deaths in the study period 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
Austria, France, Germany, Italy, Norway, Switzerland, United Kingdom
Contacts
Public ContactProf. Dr. med. Ekkehard Grünig
Thoraxklinik Heidelberg gGmbH
Outcome results
None listed