Pulmonary Arterial Hypertension
Conditions
Brief summary
To demonstrate the effectiveness of riociguat as replacement of phosphodiesterase-5 inhibitors (PDE-5i) therapy in pulmonary arterial hypertension (PAH) patients
Detailed description
Data from a previous single arm study (RESPITE) indicate that transition from PDE5i to riociguat may be feasible, safe and beneficial in patients not adequately responding to PDE5i. REPLACE is a randomized controlled study to confirm the potential clinical benefit of transition from PDE5i to riociguat. Satisfactory clinical response in patients who are on a stable dose of phosphodiesterase-5inhibitors (PDE-5i) with or without endothelin receptor antagonist (ERA), but not at treatment goal will be compared between one group of patients randomized to maintain current treatment and another group where the PDE5i is replaced by riociguat.
Interventions
DRUGRiociguat (Adempas, BAY63-2521)
Film-coated tablets will be used in this study at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg. Tablets will be administered orally.The starting dose is 1 mg TID; the intervals between drug intakes should be 6 to 8 hours. The dosage should be increased by 0.5 mg increments in 2 week intervals to 1.5 mg, 2.0 mg, and 2.5 mg TID (maximal total daily dose).
DRUGSildenafil
Patients randomized to the control arm will continue to receive stable doses of tadalafil (daily dose 20 to 40 mg) or sildenafil (daily dose at least 60 mg) as well as other supportive treatments at the discretion of the investigator.
DRUGTadalafil
Patients randomized to the control arm will continue to receive stable doses of tadalafil (daily dose 20 to 40 mg) or sildenafil (daily dose at least 60 mg) as well as other supportive treatments at the discretion of the investigator.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients aged 18 to 75 years. * Patients with symptomatic PAH with a pulmonary vascular resistance (PVR) \> 400 dyn\*sec\*cm-5, mean pulmonary artery pressure ≥ 25 mmHg, and pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg as assessed by the most recent right heart catheterization (RHC) from medical history prior to screening to confirm the diagnosis. Alternatively, PCWP can be replaced by left ventricular end-diastolic pressure (≤ 15 mmHg). PAH of the following types: * Idiopathic * Hereditary * Drug and toxin induced PAH * Associated with PAH due to: * Connective tissue disease (CTD) * Congenital heart disease, but only if the patient underwent surgical repair more than one year before enrolment * Portal hypertension with liver cirrhosis (Note: patients with clinical relevant hepatic dysfunction are excluded; see exclusions related to disorders in organ function) * Patients who are on stable doses of a PDE-5i and ERA combination therapy or on stable PDE-5i monotherapy 6 weeks prior to and at randomization but not at treatment goal (tadalafil 20 to 40 mg once daily or sildenafil at least 60 mg daily dose). * WHO FC III at screening and at randomization. * 6MWD test between 165 m and 440 m at screening and at randomization. * Stable dose of diuretics, if used, for at least 30 days prior to and at randomization. * Patients who are able to understand and follow instructions and who are able to participate in the study for the entire study. * Women of childbearing potential must agree to use adequate contraception when sexually active. Adequate contraception is defined as any combination of at least 2 effective methods of birth control, of which at least 1 is a physical barrier (e.g. condom with hormonal contraception like implants or combined oral contraceptives, condom with intrauterine devices). This applies beginning with signing of the informed consent form until 30 (+5) days after the last administration of study drug. * 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
* Participation in another interventional clinical study within 30 days prior to screening. * All types of PH (including PH-IIP) except subtypes of Dana Point Group I specified in the inclusion criteria. * Previous treatment with riociguat. * Pregnant women (i.e., positive serum ß-human-chorionic-gonadotropin test or other signs of pregnancy), or breast feeding women, or women with childbearing potential not using a combination of 2 effective contraception methods (as laid out in inclusion criterion) throughout the study. * 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. * Relevant obstructive and restrictive or other lung diseases. * Patients with underlying medical disorders with an anticipated life expectancy below 2 years (e.g., active cancer disease with localized and/or metastasized tumor mass). * Cardiovascular
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Satisfactory Clinical Response at Week 24 | At Week 24 | The treatment is assessed as efficient (participants with satisfactory clinical response) in case at least 2 out of the following 3 criteria were fulfilled * 6 Minute Walking Distance increase by ≥ 10% or ≥ 30 m from baseline to Week 24 * World Health Organization Functional Class (WHO FC) I or II at Week 24 * N-terminal pro-brain natriuretic peptide (NT-proBNP) reduction ≥ 30% from baseline to Week 24 (NT-proBNP ratio Week 24/baseline ≤ 0.7) and in absence of the defined criteria of clinical worsening |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in 6 Minute Walking Distance (6MWD) With Last Observation Carried Forward From Baseline to 24 Weeks | From baseline and up to 24 weeks | Six-minute walk distance (6MWD) was conducted to test the physical limitations of the participant by assessing the participant's exercise capacity. The distance walked by the participant in 6 minutes was measured. |
| Change in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) With Last Observation Carried Forward at Week 24 | From baseline and up to 24 weeks | 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. |
| Change in World Health Organization Functional Class (WHO FC) With Last Observation Carried Forward From Baseline to Week 24 | From baseline and up to 24 weeks | The participant's functional class was determined by using the WHO classification. Possible classes range from I (patients with pulmonary hypertension (PH) but without resulting limitation of physical activity) to IV (patients with PH with inability to carry out any physical activity without symptoms). |
| Number of Participants With Adjudicated Clinical Worsening at Week 24 | Up to 24 weeks | Clinical worsening was defined as death of any cause, hospitalization due to worsening pulmonary arterial hypertension (PAH) (adjudicated) or disease progression (adjudicated). |
Countries
Austria, Belgium, Brazil, Canada, Czechia, Denmark, France, Germany, Greece, Italy, Japan, Mexico, Netherlands, Poland, Portugal, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Study was conducted at multiple centers in 21 countries between 11-JAN-2017 (first participant first visit) and 03-MAR-2020 (last participant last visit).
Pre-assignment details
293 participants were screened in this study. Of these, 67 participants did not enter the treatment period (60 screening failures; 2 withdraw during screening; 2 withdraw following physician decision; 3 withdraw due to other reasons). 226 participants were randomized, of which 1 participant withdraw before treated.
Participants by arm
| Arm | Count |
|---|---|
| Riociguat Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks. | 111 |
| PDE-5i Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator. | 114 |
| Total | 225 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | Death | 0 | 4 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | PDE-5i | Total | Riociguat |
|---|---|---|---|
| Age, Continuous | 49.2 years STANDARD_DEVIATION 15.64 | 49.3 years STANDARD_DEVIATION 15.86 | 49.4 years STANDARD_DEVIATION 16.16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants | 63 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 80 Participants | 155 Participants | 75 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 36 Participants | 17 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 9 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) White | 89 Participants | 175 Participants | 86 Participants |
| Sex: Female, Male Female | 95 Participants | 177 Participants | 82 Participants |
| Sex: Female, Male Male | 19 Participants | 48 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 111 | 4 / 114 |
| other Total, other adverse events | 77 / 111 | 72 / 114 |
| serious Total, serious adverse events | 8 / 111 | 19 / 114 |
Outcome results
Primary
Number of Participants With Satisfactory Clinical Response at Week 24
The treatment is assessed as efficient (participants with satisfactory clinical response) in case at least 2 out of the following 3 criteria were fulfilled * 6 Minute Walking Distance increase by ≥ 10% or ≥ 30 m from baseline to Week 24 * World Health Organization Functional Class (WHO FC) I or II at Week 24 * N-terminal pro-brain natriuretic peptide (NT-proBNP) reduction ≥ 30% from baseline to Week 24 (NT-proBNP ratio Week 24/baseline ≤ 0.7) and in absence of the defined criteria of clinical worsening
Time frame: At Week 24
Population: Full Analysis Set (FAS) with evaluable participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Riociguat | Number of Participants With Satisfactory Clinical Response at Week 24 | With satisfactory clinical response | 45 Participants |
| Riociguat | Number of Participants With Satisfactory Clinical Response at Week 24 | Without satisfactory clinical response | 66 Participants |
| PDE-5i | Number of Participants With Satisfactory Clinical Response at Week 24 | With satisfactory clinical response | 23 Participants |
| PDE-5i | Number of Participants With Satisfactory Clinical Response at Week 24 | Without satisfactory clinical response | 90 Participants |
p-value: 0.000795% CI: [1.526, 5.06]Mantel Haenszel
Secondary
Change in 6 Minute Walking Distance (6MWD) With Last Observation Carried Forward From Baseline to 24 Weeks
Six-minute walk distance (6MWD) was conducted to test the physical limitations of the participant by assessing the participant's exercise capacity. The distance walked by the participant in 6 minutes was measured.
Time frame: From baseline and up to 24 weeks
Population: Full Analysis Set (FAS) with evaluable participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change in 6 Minute Walking Distance (6MWD) With Last Observation Carried Forward From Baseline to 24 Weeks | 36.448 meters (m) | Standard Deviation 65.9748 |
| PDE-5i | Change in 6 Minute Walking Distance (6MWD) With Last Observation Carried Forward From Baseline to 24 Weeks | 13.884 meters (m) | Standard Deviation 67.1552 |
p-value: 0.054295% CI: [5.03, 40.1]t-test, 2 sided
Secondary
Change in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) With Last Observation Carried Forward at Week 24
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: From baseline and up to 24 weeks
Population: Full Analysis Set (FAS) with evaluable participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) With Last Observation Carried Forward at Week 24 | -88.234 picograms per milliliter (pg/mL) | Standard Deviation 533.9179 |
| PDE-5i | Change in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) With Last Observation Carried Forward at Week 24 | 81.414 picograms per milliliter (pg/mL) | Standard Deviation 1267.6142 |
p-value: 0.106795% CI: [-426.18, 86.88]t-test, 2 sided
Secondary
Change in World Health Organization Functional Class (WHO FC) With Last Observation Carried Forward From Baseline to Week 24
The participant's functional class was determined by using the WHO classification. Possible classes range from I (patients with pulmonary hypertension (PH) but without resulting limitation of physical activity) to IV (patients with PH with inability to carry out any physical activity without symptoms).
Time frame: From baseline and up to 24 weeks
Population: Full Analysis Set (FAS) with evaluable participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change in World Health Organization Functional Class (WHO FC) With Last Observation Carried Forward From Baseline to Week 24 | -0.5 class | Standard Deviation 0.58 |
| PDE-5i | Change in World Health Organization Functional Class (WHO FC) With Last Observation Carried Forward From Baseline to Week 24 | -0.2 class | Standard Deviation 0.62 |
p-value: 0.000795% CI: [-0.42, -0.11]t-test, 2 sided
Secondary
Number of Participants With Adjudicated Clinical Worsening at Week 24
Clinical worsening was defined as death of any cause, hospitalization due to worsening pulmonary arterial hypertension (PAH) (adjudicated) or disease progression (adjudicated).
Time frame: Up to 24 weeks
Population: Full Analysis Set (FAS) with evaluable participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Number of Participants With Adjudicated Clinical Worsening at Week 24 | 1 Participants |
| PDE-5i | Number of Participants With Adjudicated Clinical Worsening at Week 24 | 10 Participants |
p-value: 0.004795% CI: [0.013, 0.725]Mantel Haenszel