Pulmonary Hypertension
Conditions
Keywords
Chronic thromboembolic pulmonary hypertension, PH, soluble Guanylate Cyclase Stimulator, sGC
Brief summary
The aim of the study is to assess the efficacy and safety of different doses of BAY63-2521, given orally for 16 weeks, in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH).
Detailed description
Adverse event data will be covered in Adverse events section.
Interventions
DRUGRiociguat (Adempas, BAY63-2521)
BAY63-2521: 1 mg tid - 2,5 mg tid orally for 16 weeks.
DRUGPlacebo
Matching Placebo tid orally for 16 weeks
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients with CTEPH either inoperable or with persistent or recurrent PH after surgery.
Exclusion criteria
* All types of pulmonary hypertension except subtypes 4.1 and 4.2 of the Venice Clinical Classification of Pulmonary Hypertension.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6 Minutes Walking Distance (6MWD) - Change From Baseline to Week 16 | Baseline and week 16 | 6-minute walking distance (6MWD) is a measure for the objective evaluation of a participant's functional exercise capacity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) - Change From Baseline to Week 16 | Baseline and week 16 | N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in the blood are used for screening, diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure. |
| World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 | Baseline and week 16 | The WHO functional assessment of pulmonary arterial hypertension ranged from functional class I (Patients with PH but without resulting limitation of physical activity) to class IV (Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure.). Changes to a lower WHO functional class resemble improvement; changes to a higher functional class resemble deterioration of PAH. |
| Percentage of Participants With Clinical Worsening | At week 16 | The combined endpoint time to clinical worsening, made up of the following components, defined by the first occurrence: all-cause mortality; heart/lung transplantation; rescue endarterectomy; first hospitalization due to pulmonary hypertension; start of a new pulmonary hypertension treatment; persistent worsening of 6MWD or WHO functional class due to deterioration of PH. |
| Pulmonary Vascular Resistance (PVR) - Change From Baseline to Week 16 | Baseline and week 16 | The pulmonary vascular resistance (PVR) is a calculated hemodynamic parameter. PVR is derived from the directly measured parameters mean pulmonary arterial pressure (PAPmean) and pulmonary capillary wedge pressure (PCWP), divided by the cardiac output (CO). PVR and PAPmean are acquired during a right heart catheterization. CO is a calculated hemodynamic parameter, too. Formula: PVR = 80\*(PAPmean - PCWP)/CO |
| EQ-5D Utility Score - Change From Baseline to Week 16 | Baseline and week 16 | EQ-5D utility score is a Quality-of-Life participant reported outcome measure. The utility score is calculated based on five questions concerning problems with mobility, self-care, usual activities, pain/discomfort and anxiety/depression. An increase in the utility score represents an improvement in quality of life. The score ranges from -0.594 (worst answer in all five questions) to 1 (best answer in all five questions). |
| Living With Pulmonary Hypertension (LPH) Questionnaire - Change From Baseline to Week 16 | Baseline and week 16 | The self-reported Living with Pulmonary Hypertension (LPH) questionnaire is designed to measure the effects of PH and PH-specific treatments on an individual's quality of life. The LPH total score can range from 0 (best) to 105 (worst). |
| Borg CR 10 Scale - Change From Baseline to Week 16 | Baseline and week 16 | The Borg CR10 Scale is a participant reported outcome measure used in clinical diagnosis of e.g. breathlessness and dyspnea. It documents the participant's exertion during a physical test. Low values indicate low levels of exertion; high values indicate more intense exertion reported by the participant. The score ranges from 0 (Nothing at all) to 10 (Extremely strong - Maximal). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Aspartate Aminotransferase (AST) - Change From Baseline to Week 16 | Baseline and week 16 | Aspartate Aminotransferase (AST) is a standard clinical chemistry parameter. Normal range: 0 to 41 U/L. |
| Alkaline Phosphatase (AP) - Change From Baseline to Week 16 | Baseline and week 16 | Alkaline phosphatase (AP) is a standard clinical chemistry parameter. Normal range: 40 to 129 U/L (males), 35 to 104 U/L (females) |
| Bilirubin - Change From Baseline to Week 16 | Baseline and week 16 | Bilirubin is a standard clinical chemistry parameter. Normal range: 0.1 to 1.2 mg/dL |
| Creatinine - Change From Baseline to Week 16 | Baseline and week 16 | Creatinine is a standard clinical chemistry parameter. Normal range: 0.25 to 1.20 mg/dL (males), 0.46 to 1.00 mg/dL (females) |
| Creatinine Clearance - Change From Baseline to Week 16 | Baseline and week 16 | Creatinine clearance is a standard clinical chemistry parameter. Normal range: 90 to 140 mL/min (males), 80 to 125 mL/min (females) |
| Creatine Kinase (CK) - Change From Baseline to Week 16 | Baseline and week 16 | Creatine Kinase is a standard clinical chemistry parameter. Normal range: 35 to 232 U/L (males), 26 to 145 U/L (females) |
| Erythrocytes (RBC) - Change From Baseline to Week 16 | Baseline and week 16 | Erythrocytes (red blood cells, RBC) is a standard clinical hematology parameter. Normal range: 4.6 to 5.8\*10\^12 cells/L (males), 4.1 to 5.2\*10\^12 cells/L (females) |
| Leukocytes (WBC) - Change From Baseline to Week 16 | Baseline and week 16 | Leukocytes (white blood cells, WBC) is a standard clinical hematology parameter. Normal range: 4.0 to 10.7\*10\^9 cells/L |
| Lymphocytes - Change From Baseline to Week 16 | Baseline and week 16 | Total lymphocytes is a standard clinical hematology parameter. Normal range: 1.0 to 4.0\*10\^9 cells/L |
| Neutrophils - Change From Baseline to Week 16 | Baseline and week 16 | Neutrophils is a standard clinical hematology parameter. Normal range: 1.6 to 7.4\*10\^9 cells/L |
| Hemoglobin - Change From Baseline to Week 16 | Baseline and week 16 | Hemoglobin is a standard clinical hematology parameter. Normal range: 13.5 to 17.5 g/dL (males), 12.0 to 16.0 g/dL (females) |
| Hematocrit - Change From Baseline to Week 16 | Baseline and week 16 | Hematocrit is a standard clinical hematology parameter. Normal range: 40 to 52% (males), 36 to 46% (females) |
| Potassium - Change From Baseline to Week 16 | Baseline and week 16 | Potassium is a standard clinical chemistry parameter. Normal range: 3.5 to 5.3 mmol/L |
| Urate - Change From Baseline to Week 16 | Baseline and week 16 | Urate is a standard clinical chemistry parameter. Normal range: 4.0 to 8.5 mg/dL (males, 16-59 years), 3.4 to 8.7 mg/dL (males, \>60 years) 2.5 to 7.5 mg/dL (females) |
| Urea (BUN) - Change From Baseline to Week 16 | Baseline and week 16 | Urea (blood urea nitrogen, BUN) is a standard clinical chemistry parameter. Normal range: 4 to 25 mg/dL |
| Cystatin C - Change From Baseline to Week 16 | Baseline and week 16 | Cystatin C is a biomarker. Normal range: 0.53 to 1.01 ng/mL |
| Triacylglycerol Lipase - Change From Baseline to Week 16 | Baseline and week 16 | Triacylglycerol lipase is a standard clinical chemistry parameter. Normal range: 7 to 60 U/L |
| Arterial Partial Pressure of Carbon Dioxide (PaCO2) - Change From Baseline to Week 16 | Baseline and week 16 | Arterial partial pressure of carbon dioxide (PaCO2) is performed as part of the capillary or arterial blood gas analysis. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn. |
| Mean PR Duration (PRmean) - Change From Baseline to Week 16 | Baseline and week 16 | PR duration was evaluated as part of the 12-lead electrocardiogram. electrocardiograms (ECGs) were recorded after the participant had been at rest for 15 minutes in a supine position. |
| Oxygen Saturation (SaO2) - Change From Baseline to Week 16 | Baseline and week 16 | Oxygen saturation (SaO2) is measured as part of the capillary or arterial blood gas analysis. Normal blood oxygen saturation is considered 95-100 percent. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn. |
| Mean QRS Duration (QRSmean) - Change From Baseline to Week 16 | Baseline and week 16 | QRS duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. |
| Mean QT Duration (QTmean) - Change From Baseline to Week 16 | Baseline and week 16 | QT duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. |
| Mean QTcB Duration (Bazett's Correction Formula, QTcB) - Change From Baseline to Week 16 | Baseline and week 16 | Bazett-corrected QTcB duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. |
| Mean QTcF Duration (Fridericia's Correction Formula, QTcF) - Change From Baseline to Week 16 | Baseline and week 16 | Fridericia-corrected QTcF duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. |
| Mean RR Duration (RRmean) - Change From Baseline to Week 16 | Baseline and week 16 | RR duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. |
| Mean Ventricular Rate (VRmean) - Change From Baseline to Week 16 | Baseline and week 16 | Ventricular rate was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position |
| Arterial Partial Oxygen Pressure (PaO2) - Change From Baseline to Week 16 | Baseline and week 16 | Arterial partial pressure of oxygen (PaO2) is performed as part of the capillary or arterial blood gas analysis. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn. |
| All Caused Mortality | At visit 6 (week 16) | All cause mortality (including cardiovascular mortality) was one component of the composite endpoint time to clinical worsening. |
| Mean Pulmonary Artery Pressure (PAPmean) - Change From Baseline to Week 16 | Baseline and week 16 | Mean pulmonary arterial pressure (PAPmean) is a directly measured hemodynamic parameter. PAPmean is recorded during a right heart catheterization. |
| Cardiac Index (CI) - Change From Baseline to Week 16 | Baseline and week 16 | The cardiac index (CI) is a calculated hemodynamic parameter. CI is derived from the directly measured parameters cardiac output (CO), divided by the body surface area (BSA). BSA is a calculated parameter, using the subject's height and weight in the DuBois formula. Formula: BSA = (W \[kg\]\*0.425)\*(H \[cm\]\*0.725)\*0.007184 (m\^2) |
| Systolic Blood Pressure (SBP) - Change From Baseline to Week 16 | Baseline and week 16 | Systolic systemic arterial blood pressure (SBP) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: 95 - 180 mmHg. |
| Diastolic Blood Pressure (DBP) - Change From Baseline to Week 16 | Baseline and week 16 | Diastolic systemic arterial blood pressure (DBP) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: \<= 110 mmHg. |
| Heart Rate (HR) - Change From Baseline to Week 16 | Baseline and week 16 | Heart rate (HR) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: 50 -105 beats per minute (bpm) at rest. |
| Alanine Aminotransferase (ALT) - Change From Baseline to Week 16 | Baseline and week 16 | Alanine Aminotransferase (ALT) is a standard clinical chemistry parameter. Normal range: 0 to 45 U/L. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Czechia, Denmark, France, Germany, Italy, Japan, Mexico, Netherlands, Poland, Portugal, Russia, Slovakia, South Korea, Spain, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Only subjects with symptomatic chronic thromboembolic pulmonary hypertension (CTEPH) could participate in this study. CTEPH was defined either as inoperable or as persisting or recurrent PH after pulmonary endarterectomy.
Pre-assignment details
446 subjects were screened in 89 study centers in 26 countries worldwide. 184 of the 446 screened subjects were not randomized (adverse event \[1\], death \[4\], protocol violation \[164\], withdrawal by subject \[15\]). 262 of the 446 subjects were randomized. 261 of the 262 randomized subjects received study medication.
Participants by arm
| Arm | Count |
|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks | 173 |
| Placebo Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks | 88 |
| Total | 261 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up Period (FUP) | Adverse Event | 0 | 1 |
| Follow-up Period (FUP) | Death | 0 | 1 |
| Follow-up Period (FUP) | Lost to Follow-up | 3 | 0 |
| Follow-up Period (FUP) | Missing | 1 | 0 |
| Follow-up Period (FUP) | Withdrawal by Subject | 4 | 0 |
| Treatment Period | Adverse Event | 4 | 2 |
| Treatment Period | Death | 2 | 2 |
| Treatment Period | Lack of Efficacy | 2 | 1 |
| Treatment Period | Non-compliance | 1 | 0 |
| Treatment Period | Not treated | 1 | 0 |
| Treatment Period | Protocol Violation | 2 | 0 |
| Treatment Period | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Total | Placebo |
|---|---|---|---|
| 6-minute walking distance | 342.3 Meters STANDARD_DEVIATION 81.9 | 346.9 Meters STANDARD_DEVIATION 79.7 | 356.0 Meters STANDARD_DEVIATION 74.7 |
| Age, Continuous | 59.3 Years STANDARD_DEVIATION 13.9 | 59.3 Years STANDARD_DEVIATION 13.5 | 59.2 Years STANDARD_DEVIATION 12.7 |
| Body Mass Index | 27.13 kg/m^2 STANDARD_DEVIATION 5.75 | 27.33 kg/m^2 STANDARD_DEVIATION 5.6 | 27.73 kg/m^2 STANDARD_DEVIATION 5.3 |
| Operability Inoperable CTEPH | 121 Participants | 189 Participants | 68 Participants |
| Operability Postoperative CTEPH | 52 Participants | 72 Participants | 20 Participants |
| Pulmonary vascular resistance | 790.68 dyn*s*cm^-5 STANDARD_DEVIATION 431.57 | 786.68 dyn*s*cm^-5 STANDARD_DEVIATION 420.21 | 779.32 dyn*s*cm^-5 STANDARD_DEVIATION 400.94 |
| Race/Ethnicity, Customized Asian | 37 Participants | 57 Participants | 20 Participants |
| Race/Ethnicity, Customized Black or African American | 7 Participants | 8 Participants | 1 Participants |
| Race/Ethnicity, Customized Mixed | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not reported | 8 Participants | 10 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 120 Participants | 185 Participants | 65 Participants |
| Sex: Female, Male Female | 118 Participants | 172 Participants | 54 Participants |
| Sex: Female, Male Male | 55 Participants | 89 Participants | 34 Participants |
| WHO (World Health Organization) functional class I | 3 Participants | 3 Participants | 0 Participants |
| WHO (World Health Organization) functional class II | 55 Participants | 80 Participants | 25 Participants |
| WHO (World Health Organization) functional class III | 107 Participants | 167 Participants | 60 Participants |
| WHO (World Health Organization) functional class IV | 8 Participants | 10 Participants | 2 Participants |
| WHO (World Health Organization) functional class missing | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 146 / 173 | 67 / 88 |
| serious Total, serious adverse events | 34 / 173 | 14 / 88 |
Outcome results
Primary
6 Minutes Walking Distance (6MWD) - Change From Baseline to Week 16
6-minute walking distance (6MWD) is a measure for the objective evaluation of a participant's functional exercise capacity.
Time frame: Baseline and week 16
Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | 6 Minutes Walking Distance (6MWD) - Change From Baseline to Week 16 | 38.9 Meters | Standard Deviation 79.3 |
| Placebo | 6 Minutes Walking Distance (6MWD) - Change From Baseline to Week 16 | -5.5 Meters | Standard Deviation 84.3 |
Comparison: Missing values for participants who withdrew/died before 16 weeks were imputed with a worst value of 0m in case of death/clinical worsening without termination visit and with the last observed value otherwise. Comparison was done using analysis of covariance (ANCOVA), with baseline 6MWD as a covariate and treatment group and region as main effects. The primary statistical method was the stratified Wilcoxon test if the Shapiro-Wilk test for normality of residuals was statistically significant.p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: <0.000195% CI: [24.74, 66.63]ANCOVA
Comparison: Shapiro-Wilk test for normality of ANCOVA residuals.p-value: 0.0001Shapiro-Wilk
Secondary
Borg CR 10 Scale - Change From Baseline to Week 16
The Borg CR10 Scale is a participant reported outcome measure used in clinical diagnosis of e.g. breathlessness and dyspnea. It documents the participant's exertion during a physical test. Low values indicate low levels of exertion; high values indicate more intense exertion reported by the participant. The score ranges from 0 (Nothing at all) to 10 (Extremely strong - Maximal).
Time frame: Baseline and week 16
Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Borg CR 10 Scale - Change From Baseline to Week 16 | -0.83 Scores on a scale | Standard Deviation 2.39 |
| Placebo | Borg CR 10 Scale - Change From Baseline to Week 16 | 0.17 Scores on a scale | Standard Deviation 2.42 |
Comparison: Missing values for participants who withdrew or died before 16 weeks were imputed with a worst value of 10 in case of death or clinical worsening without termination visit and with the last observed value otherwise.p-value: 0.0035Wilcoxon (Mann-Whitney)
Secondary
EQ-5D Utility Score - Change From Baseline to Week 16
EQ-5D utility score is a Quality-of-Life participant reported outcome measure. The utility score is calculated based on five questions concerning problems with mobility, self-care, usual activities, pain/discomfort and anxiety/depression. An increase in the utility score represents an improvement in quality of life. The score ranges from -0.594 (worst answer in all five questions) to 1 (best answer in all five questions).
Time frame: Baseline and week 16
Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered. Participants with a missing baseline were excluded from the analysis of the EQ5D utility score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | EQ-5D Utility Score - Change From Baseline to Week 16 | 0.0615 Scores on a scale | Standard Deviation 0.2768 |
| Placebo | EQ-5D Utility Score - Change From Baseline to Week 16 | -0.0819 Scores on a scale | Standard Deviation 0.3446 |
Comparison: Missing values at baseline were imputed using last available observation prior to start of study treatment. Missing values for participants who withdrew or died before 16 weeks were imputed with a worst value of -0.594 in case of death or clinical worsening without termination visit and with the last observed value otherwise.p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: 0.000295% CI: [0.06, 0.21]ANCOVA
Comparison: Shapiro-Wilk test for normality of ANCOVA residuals.p-value: 0.0001Shapiro-Wilk
Secondary
Living With Pulmonary Hypertension (LPH) Questionnaire - Change From Baseline to Week 16
The self-reported Living with Pulmonary Hypertension (LPH) questionnaire is designed to measure the effects of PH and PH-specific treatments on an individual's quality of life. The LPH total score can range from 0 (best) to 105 (worst).
Time frame: Baseline and week 16
Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered. Participants with a missing baseline were excluded from the analysis of the LPH questionnaire.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Living With Pulmonary Hypertension (LPH) Questionnaire - Change From Baseline to Week 16 | -6.72 Scores on a scale | Standard Deviation 18.62 |
| Placebo | Living With Pulmonary Hypertension (LPH) Questionnaire - Change From Baseline to Week 16 | -2.09 Scores on a scale | Standard Deviation 19.31 |
Comparison: Missing values at baseline were imputed using last available observation prior to start of study treatment. Missing values for participants who withdrew or died before 16 weeks were imputed with a worst value of 105 in case of death or clinical worsening without termination visit and with the last observed value otherwise.p-value: 0.122Wilcoxon (Mann-Whitney)
p-value: 0.016595% CI: [-10.45, -1.06]ANCOVA
Comparison: Shapiro-Wilk test for normality of ANCOVA residuals.p-value: 0.0001Shapiro-Wilk
Secondary
N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) - Change From Baseline to Week 16
N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in the blood are used for screening, diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure.
Time frame: Baseline and week 16
Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one post-baseline measurement were included in the analysis of NT-proBNP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) - Change From Baseline to Week 16 | -290.69 pg/mL | Standard Deviation 1716.9 |
| Placebo | N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) - Change From Baseline to Week 16 | 76.35 pg/mL | Standard Deviation 1446.63 |
Comparison: Missing values at week 16 were imputed using the last available post-baseline observation. Same analysis method as for primary efficacy parameter.p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: 0.029395% CI: [-842.95, -45.03]ANCOVA
Comparison: Shapiro-Wilk test for normality of ANCOVA residuals.p-value: 0.0001Shapiro-Wilk
Secondary
Percentage of Participants With Clinical Worsening
The combined endpoint time to clinical worsening, made up of the following components, defined by the first occurrence: all-cause mortality; heart/lung transplantation; rescue endarterectomy; first hospitalization due to pulmonary hypertension; start of a new pulmonary hypertension treatment; persistent worsening of 6MWD or WHO functional class due to deterioration of PH.
Time frame: At week 16
Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Percentage of Participants With Clinical Worsening | Any Event | 2.3 Percentage of participants |
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Percentage of Participants With Clinical Worsening | Hospitalization due to pulmonary hypertension | 0 Percentage of participants |
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Percentage of Participants With Clinical Worsening | Start of new pulmonary hypertension | 1.2 Percentage of participants |
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Percentage of Participants With Clinical Worsening | Decrease in 6MWT due to pulmonary hypertension | 0.6 Percentage of participants |
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Percentage of Participants With Clinical Worsening | Persistant worsening of functional class due to PH | 0 Percentage of participants |
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Percentage of Participants With Clinical Worsening | Death | 1.2 Percentage of participants |
| Placebo | Percentage of Participants With Clinical Worsening | Persistant worsening of functional class due to PH | 1.1 Percentage of participants |
| Placebo | Percentage of Participants With Clinical Worsening | Any Event | 5.7 Percentage of participants |
| Placebo | Percentage of Participants With Clinical Worsening | Decrease in 6MWT due to pulmonary hypertension | 2.3 Percentage of participants |
| Placebo | Percentage of Participants With Clinical Worsening | Hospitalization due to pulmonary hypertension | 1.1 Percentage of participants |
| Placebo | Percentage of Participants With Clinical Worsening | Death | 3.4 Percentage of participants |
| Placebo | Percentage of Participants With Clinical Worsening | Start of new pulmonary hypertension | 1.1 Percentage of participants |
Comparison: Test for difference of occurence of Any event.p-value: 0.172495% CI: [-8.72, 1.99]Log Rank
Secondary
Pulmonary Vascular Resistance (PVR) - Change From Baseline to Week 16
The pulmonary vascular resistance (PVR) is a calculated hemodynamic parameter. PVR is derived from the directly measured parameters mean pulmonary arterial pressure (PAPmean) and pulmonary capillary wedge pressure (PCWP), divided by the cardiac output (CO). PVR and PAPmean are acquired during a right heart catheterization. CO is a calculated hemodynamic parameter, too. Formula: PVR = 80\*(PAPmean - PCWP)/CO
Time frame: Baseline and week 16
Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one post-baseline measurement were included in the analysis of PVR.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Pulmonary Vascular Resistance (PVR) - Change From Baseline to Week 16 | -225.68 dyn*s*cm^-5 | Standard Deviation 247.52 |
| Placebo | Pulmonary Vascular Resistance (PVR) - Change From Baseline to Week 16 | 23.07 dyn*s*cm^-5 | Standard Deviation 273.53 |
Comparison: Missing values at week 16 were imputed using the last available post-baseline observation. Same analysis method as for primary efficacy parameter.p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: <0.000195% CI: [-303.33, -189.53]ANCOVA
Comparison: Shapiro-Wilk test for normality of ANCOVA residuals.p-value: 0.0001Shapiro-Wilk
Secondary
World Health Organization (WHO) Functional Class - Change From Baseline to Week 16
The WHO functional assessment of pulmonary arterial hypertension ranged from functional class I (Patients with PH but without resulting limitation of physical activity) to class IV (Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure.). Changes to a lower WHO functional class resemble improvement; changes to a higher functional class resemble deterioration of PAH.
Time frame: Baseline and week 16
Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered. Participants with a missing baseline were excluded from the analysis of WHO functional class.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 | -2 | 2.3 Percentage of Participants |
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 | -1 | 30.6 Percentage of Participants |
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 | 0 | 61.8 Percentage of Participants |
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 | 1 | 4.0 Percentage of Participants |
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 | 2 | 0.6 Percentage of Participants |
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 | 3 | 0.6 Percentage of Participants |
| Placebo | World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 | 2 | 3.4 Percentage of Participants |
| Placebo | World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 | -2 | 0 Percentage of Participants |
| Placebo | World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 | 1 | 3.4 Percentage of Participants |
| Placebo | World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 | -1 | 14.9 Percentage of Participants |
| Placebo | World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 | 3 | 0 Percentage of Participants |
| Placebo | World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 | 0 | 78.2 Percentage of Participants |
Comparison: Missing values for participants who withdrew or died before 16 weeks were imputed with a worst value of IV in case of clinical worsening without termination visit or measurement at that termination visit and with a worst value of V in case of death and with the last observed value otherwise.p-value: 0.0026Wilcoxon (Mann-Whitney)
Other Pre-specified
Alanine Aminotransferase (ALT) - Change From Baseline to Week 16
Alanine Aminotransferase (ALT) is a standard clinical chemistry parameter. Normal range: 0 to 45 U/L.
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Alanine Aminotransferase (ALT) - Change From Baseline to Week 16 | -1.2 U/L | Standard Deviation 16.2 |
| Placebo | Alanine Aminotransferase (ALT) - Change From Baseline to Week 16 | 2.2 U/L | Standard Deviation 13.6 |
Other Pre-specified
Alkaline Phosphatase (AP) - Change From Baseline to Week 16
Alkaline phosphatase (AP) is a standard clinical chemistry parameter. Normal range: 40 to 129 U/L (males), 35 to 104 U/L (females)
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Alkaline Phosphatase (AP) - Change From Baseline to Week 16 | -3.8 U/L | Standard Deviation 19.4 |
| Placebo | Alkaline Phosphatase (AP) - Change From Baseline to Week 16 | 2.5 U/L | Standard Deviation 20.2 |
Other Pre-specified
All Caused Mortality
All cause mortality (including cardiovascular mortality) was one component of the composite endpoint time to clinical worsening.
Time frame: At visit 6 (week 16)
Population: Intent to Treat (ITT) - a randomized subject was valid for ITT analyses if at least one dose of study medication was administered.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | All Caused Mortality | 2 Participants |
| Placebo | All Caused Mortality | 3 Participants |
Other Pre-specified
Arterial Partial Oxygen Pressure (PaO2) - Change From Baseline to Week 16
Arterial partial pressure of oxygen (PaO2) is performed as part of the capillary or arterial blood gas analysis. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn.
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of blood gas parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Arterial Partial Oxygen Pressure (PaO2) - Change From Baseline to Week 16 | -3.01 mmHg | Standard Deviation 14.71 |
| Placebo | Arterial Partial Oxygen Pressure (PaO2) - Change From Baseline to Week 16 | -4.95 mmHg | Standard Deviation 12.05 |
Other Pre-specified
Arterial Partial Pressure of Carbon Dioxide (PaCO2) - Change From Baseline to Week 16
Arterial partial pressure of carbon dioxide (PaCO2) is performed as part of the capillary or arterial blood gas analysis. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn.
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of blood gas parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Arterial Partial Pressure of Carbon Dioxide (PaCO2) - Change From Baseline to Week 16 | 0.34 mmHg | Standard Deviation 4.05 |
| Placebo | Arterial Partial Pressure of Carbon Dioxide (PaCO2) - Change From Baseline to Week 16 | 0.56 mmHg | Standard Deviation 4.52 |
Other Pre-specified
Aspartate Aminotransferase (AST) - Change From Baseline to Week 16
Aspartate Aminotransferase (AST) is a standard clinical chemistry parameter. Normal range: 0 to 41 U/L.
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Aspartate Aminotransferase (AST) - Change From Baseline to Week 16 | 0.3 U/L | Standard Deviation 14.4 |
| Placebo | Aspartate Aminotransferase (AST) - Change From Baseline to Week 16 | 2.8 U/L | Standard Deviation 12 |
Other Pre-specified
Bilirubin - Change From Baseline to Week 16
Bilirubin is a standard clinical chemistry parameter. Normal range: 0.1 to 1.2 mg/dL
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Bilirubin - Change From Baseline to Week 16 | 0.010 mg/dL | Standard Deviation 0.483 |
| Placebo | Bilirubin - Change From Baseline to Week 16 | 0.189 mg/dL | Standard Deviation 0.453 |
Other Pre-specified
Cardiac Index (CI) - Change From Baseline to Week 16
The cardiac index (CI) is a calculated hemodynamic parameter. CI is derived from the directly measured parameters cardiac output (CO), divided by the body surface area (BSA). BSA is a calculated parameter, using the subject's height and weight in the DuBois formula. Formula: BSA = (W \[kg\]\*0.425)\*(H \[cm\]\*0.725)\*0.007184 (m\^2)
Time frame: Baseline and week 16
Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered.~Only participants with a baseline and at least one post-baseline measurement were included in the analysis of CI.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Cardiac Index (CI) - Change From Baseline to Week 16 | 0.45 L/min/m^2 | Standard Deviation 0.56 |
| Placebo | Cardiac Index (CI) - Change From Baseline to Week 16 | -0.01 L/min/m^2 | Standard Deviation 0.58 |
Comparison: Missing values at week 16 were imputed using the last available post-baseline observation. Same analysis as for primary efficacy parameter.p-value: <0.000195% CI: [0.33, 0.62]ANCOVA
p-value: <0.0001Wilcoxon (Mann-Whitney)
Comparison: Shapiro-Wilk test for normality of ANCOVA residuals.p-value: 0.116Shapiro-Wilk
Other Pre-specified
Creatine Kinase (CK) - Change From Baseline to Week 16
Creatine Kinase is a standard clinical chemistry parameter. Normal range: 35 to 232 U/L (males), 26 to 145 U/L (females)
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Creatine Kinase (CK) - Change From Baseline to Week 16 | 7.9 U/L | Standard Deviation 64.9 |
| Placebo | Creatine Kinase (CK) - Change From Baseline to Week 16 | 5.6 U/L | Standard Deviation 65.7 |
Other Pre-specified
Creatinine - Change From Baseline to Week 16
Creatinine is a standard clinical chemistry parameter. Normal range: 0.25 to 1.20 mg/dL (males), 0.46 to 1.00 mg/dL (females)
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Creatinine - Change From Baseline to Week 16 | 0.003 mg/dL | Standard Deviation 0.338 |
| Placebo | Creatinine - Change From Baseline to Week 16 | 0.032 mg/dL | Standard Deviation 0.178 |
Other Pre-specified
Creatinine Clearance - Change From Baseline to Week 16
Creatinine clearance is a standard clinical chemistry parameter. Normal range: 90 to 140 mL/min (males), 80 to 125 mL/min (females)
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Creatinine Clearance - Change From Baseline to Week 16 | 2.25 mL/min | Standard Deviation 15.53 |
| Placebo | Creatinine Clearance - Change From Baseline to Week 16 | -0.93 mL/min | Standard Deviation 11.36 |
Other Pre-specified
Cystatin C - Change From Baseline to Week 16
Cystatin C is a biomarker. Normal range: 0.53 to 1.01 ng/mL
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Cystatin C - Change From Baseline to Week 16 | 16.1 ng/ml | Standard Deviation 241.1 |
| Placebo | Cystatin C - Change From Baseline to Week 16 | 62.9 ng/ml | Standard Deviation 198 |
Other Pre-specified
Diastolic Blood Pressure (DBP) - Change From Baseline to Week 16
Diastolic systemic arterial blood pressure (DBP) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: \<= 110 mmHg.
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Diastolic Blood Pressure (DBP) - Change From Baseline to Week 16 | -8.17 mmHg | Standard Deviation 10.81 |
| Placebo | Diastolic Blood Pressure (DBP) - Change From Baseline to Week 16 | -3.40 mmHg | Standard Deviation 10.38 |
Other Pre-specified
Erythrocytes (RBC) - Change From Baseline to Week 16
Erythrocytes (red blood cells, RBC) is a standard clinical hematology parameter. Normal range: 4.6 to 5.8\*10\^12 cells/L (males), 4.1 to 5.2\*10\^12 cells/L (females)
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Erythrocytes (RBC) - Change From Baseline to Week 16 | -0.14 *10^12 cells/L | Standard Deviation 0.39 |
| Placebo | Erythrocytes (RBC) - Change From Baseline to Week 16 | 0.04 *10^12 cells/L | Standard Deviation 0.31 |
Other Pre-specified
Heart Rate (HR) - Change From Baseline to Week 16
Heart rate (HR) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: 50 -105 beats per minute (bpm) at rest.
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Heart Rate (HR) - Change From Baseline to Week 16 | 0.83 Beats/min | Standard Deviation 11.74 |
| Placebo | Heart Rate (HR) - Change From Baseline to Week 16 | 1.67 Beats/min | Standard Deviation 12.37 |
Other Pre-specified
Hematocrit - Change From Baseline to Week 16
Hematocrit is a standard clinical hematology parameter. Normal range: 40 to 52% (males), 36 to 46% (females)
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Hematocrit - Change From Baseline to Week 16 | -2.0 Volume percentage of red blood cells | Standard Deviation 4.1 |
| Placebo | Hematocrit - Change From Baseline to Week 16 | 0.5 Volume percentage of red blood cells | Standard Deviation 3.5 |
Other Pre-specified
Hemoglobin - Change From Baseline to Week 16
Hemoglobin is a standard clinical hematology parameter. Normal range: 13.5 to 17.5 g/dL (males), 12.0 to 16.0 g/dL (females)
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Hemoglobin - Change From Baseline to Week 16 | -0.69 g/dL | Standard Deviation 1.17 |
| Placebo | Hemoglobin - Change From Baseline to Week 16 | 0.02 g/dL | Standard Deviation 0.88 |
Other Pre-specified
Leukocytes (WBC) - Change From Baseline to Week 16
Leukocytes (white blood cells, WBC) is a standard clinical hematology parameter. Normal range: 4.0 to 10.7\*10\^9 cells/L
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Leukocytes (WBC) - Change From Baseline to Week 16 | -0.55 *10^9 cells/L | Standard Deviation 1.77 |
| Placebo | Leukocytes (WBC) - Change From Baseline to Week 16 | 0.23 *10^9 cells/L | Standard Deviation 1.69 |
Other Pre-specified
Lymphocytes - Change From Baseline to Week 16
Total lymphocytes is a standard clinical hematology parameter. Normal range: 1.0 to 4.0\*10\^9 cells/L
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Lymphocytes - Change From Baseline to Week 16 | -0.16 *10^9 cells/L | Standard Deviation 0.48 |
| Placebo | Lymphocytes - Change From Baseline to Week 16 | 0.00 *10^9 cells/L | Standard Deviation 0.53 |
Other Pre-specified
Mean PR Duration (PRmean) - Change From Baseline to Week 16
PR duration was evaluated as part of the 12-lead electrocardiogram. electrocardiograms (ECGs) were recorded after the participant had been at rest for 15 minutes in a supine position.
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of ECG parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Mean PR Duration (PRmean) - Change From Baseline to Week 16 | -0.32 ms | Standard Deviation 14.21 |
| Placebo | Mean PR Duration (PRmean) - Change From Baseline to Week 16 | 0.87 ms | Standard Deviation 11.16 |
Other Pre-specified
Mean Pulmonary Artery Pressure (PAPmean) - Change From Baseline to Week 16
Mean pulmonary arterial pressure (PAPmean) is a directly measured hemodynamic parameter. PAPmean is recorded during a right heart catheterization.
Time frame: Baseline and week 16
Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered.~Only participants with a baseline and at least one post-baseline measurement were included in the analysis of PAPmean.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Mean Pulmonary Artery Pressure (PAPmean) - Change From Baseline to Week 16 | -4.31 mmHg | Standard Deviation 6.7 |
| Placebo | Mean Pulmonary Artery Pressure (PAPmean) - Change From Baseline to Week 16 | 0.76 mmHg | Standard Deviation 7.26 |
Comparison: Shapiro-Wilk test for normality of ANCOVA residuals.p-value: 0.0231Shapiro-Wilk
Comparison: Missing values at week 16 were imputed using the last available post-baseline observation. Same analysis as for primary efficacy parameter.p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: <0.000195% CI: [-6.75, -3.16]ANCOVA
Other Pre-specified
Mean QRS Duration (QRSmean) - Change From Baseline to Week 16
QRS duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of ECG parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Mean QRS Duration (QRSmean) - Change From Baseline to Week 16 | -0.19 ms | Standard Deviation 4.49 |
| Placebo | Mean QRS Duration (QRSmean) - Change From Baseline to Week 16 | -0.05 ms | Standard Deviation 4.3 |
Other Pre-specified
Mean QTcB Duration (Bazett's Correction Formula, QTcB) - Change From Baseline to Week 16
Bazett-corrected QTcB duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of ECG parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Mean QTcB Duration (Bazett's Correction Formula, QTcB) - Change From Baseline to Week 16 | -4.30 ms | Standard Deviation 14.44 |
| Placebo | Mean QTcB Duration (Bazett's Correction Formula, QTcB) - Change From Baseline to Week 16 | -0.51 ms | Standard Deviation 15.58 |
Other Pre-specified
Mean QTcF Duration (Fridericia's Correction Formula, QTcF) - Change From Baseline to Week 16
Fridericia-corrected QTcF duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of ECG parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Mean QTcF Duration (Fridericia's Correction Formula, QTcF) - Change From Baseline to Week 16 | -2.34 ms | Standard Deviation 13.71 |
| Placebo | Mean QTcF Duration (Fridericia's Correction Formula, QTcF) - Change From Baseline to Week 16 | -1.02 ms | Standard Deviation 13.29 |
Other Pre-specified
Mean QT Duration (QTmean) - Change From Baseline to Week 16
QT duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of ECG parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Mean QT Duration (QTmean) - Change From Baseline to Week 16 | 1.19 ms | Standard Deviation 24.89 |
| Placebo | Mean QT Duration (QTmean) - Change From Baseline to Week 16 | -2.00 ms | Standard Deviation 25.56 |
Other Pre-specified
Mean RR Duration (RRmean) - Change From Baseline to Week 16
RR duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of ECG parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Mean RR Duration (RRmean) - Change From Baseline to Week 16 | 3.89 ms | Standard Deviation 132.02 |
| Placebo | Mean RR Duration (RRmean) - Change From Baseline to Week 16 | -14.00 ms | Standard Deviation 131.93 |
Other Pre-specified
Mean Ventricular Rate (VRmean) - Change From Baseline to Week 16
Ventricular rate was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of ECG parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Mean Ventricular Rate (VRmean) - Change From Baseline to Week 16 | -0.70 beats per minute (bpm) | Standard Deviation 11.96 |
| Placebo | Mean Ventricular Rate (VRmean) - Change From Baseline to Week 16 | 1.60 beats per minute (bpm) | Standard Deviation 11.68 |
Other Pre-specified
Neutrophils - Change From Baseline to Week 16
Neutrophils is a standard clinical hematology parameter. Normal range: 1.6 to 7.4\*10\^9 cells/L
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Neutrophils - Change From Baseline to Week 16 | -0.31 *10^9 cells/L | Standard Deviation 1.55 |
| Placebo | Neutrophils - Change From Baseline to Week 16 | 0.26 *10^9 cells/L | Standard Deviation 1.57 |
Other Pre-specified
Oxygen Saturation (SaO2) - Change From Baseline to Week 16
Oxygen saturation (SaO2) is measured as part of the capillary or arterial blood gas analysis. Normal blood oxygen saturation is considered 95-100 percent. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn.
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of blood gas parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Oxygen Saturation (SaO2) - Change From Baseline to Week 16 | -1.5 Percentage of oxygen saturation | Standard Deviation 4.4 |
| Placebo | Oxygen Saturation (SaO2) - Change From Baseline to Week 16 | -3.1 Percentage of oxygen saturation | Standard Deviation 8 |
Other Pre-specified
Potassium - Change From Baseline to Week 16
Potassium is a standard clinical chemistry parameter. Normal range: 3.5 to 5.3 mmol/L
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Potassium - Change From Baseline to Week 16 | -0.08 mmol/L | Standard Deviation 0.48 |
| Placebo | Potassium - Change From Baseline to Week 16 | -0.02 mmol/L | Standard Deviation 0.56 |
Other Pre-specified
Systolic Blood Pressure (SBP) - Change From Baseline to Week 16
Systolic systemic arterial blood pressure (SBP) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: 95 - 180 mmHg.
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Systolic Blood Pressure (SBP) - Change From Baseline to Week 16 | -10.49 mmHg | Standard Deviation 14.17 |
| Placebo | Systolic Blood Pressure (SBP) - Change From Baseline to Week 16 | -5.28 mmHg | Standard Deviation 14.61 |
Other Pre-specified
Triacylglycerol Lipase - Change From Baseline to Week 16
Triacylglycerol lipase is a standard clinical chemistry parameter. Normal range: 7 to 60 U/L
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Triacylglycerol Lipase - Change From Baseline to Week 16 | -4.2 U/L | Standard Deviation 12.9 |
| Placebo | Triacylglycerol Lipase - Change From Baseline to Week 16 | 0.1 U/L | Standard Deviation 17.5 |
Other Pre-specified
Urate - Change From Baseline to Week 16
Urate is a standard clinical chemistry parameter. Normal range: 4.0 to 8.5 mg/dL (males, 16-59 years), 3.4 to 8.7 mg/dL (males, \>60 years) 2.5 to 7.5 mg/dL (females)
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Urate - Change From Baseline to Week 16 | -0.405 mg/dL | Standard Deviation 1.415 |
| Placebo | Urate - Change From Baseline to Week 16 | 0.209 mg/dL | Standard Deviation 1.577 |
Other Pre-specified
Urea (BUN) - Change From Baseline to Week 16
Urea (blood urea nitrogen, BUN) is a standard clinical chemistry parameter. Normal range: 4 to 25 mg/dL
Time frame: Baseline and week 16
Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521)_individual Dose Titration | Urea (BUN) - Change From Baseline to Week 16 | -0.60 mg/dL | Standard Deviation 15.26 |
| Placebo | Urea (BUN) - Change From Baseline to Week 16 | 0.99 mg/dL | Standard Deviation 13.62 |