A prospective, randomized, international, multicenter, double-arm, controlled, open label study of Riociguat in patients with pulmonary arterial hypertension (PAH) who are on a stable dose of phosphodiesterase-5 inhibitors (PDE-5i) with or without endothelin receptor antagonist (ERA), but not at treatment goal.
- Conditions
- high blood pressure in the pulmonary arteriespulmonary arterial hypertension10007521
- Registration Number
- NL-OMON45410
- Lead Sponsor
- Bayer
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 5
Patients who fulfill the following inclusion criteria are eligible to enter the study:
1. Male and female patients aged 18 to 75 years.
2. 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:
* a. Idiopathic
* b. Hereditary
* c. Drug and toxin induced PAH
* d. 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)
3. 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).
4. WHO FC III at screening and at randomization.
5. 6MWD test between 165 m and 440 m at screening and at randomization.
6. Stable dose of diuretics, if used, for at least 30 days prior to and at randomization.
7. Patients who are able to understand and follow instructions and who are able to participate in the study for the entire study.
8. 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.
9. 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.
Patients who fulfill any of the exclusion criteria are not eligible to enter the study:
1. Participation in another interventional clinical study within 30 days prior to screening.
2. Previous randomization to treatment during this study (no re-randomization).
3. Previous treatment with riociguat.
4. 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 no. 8) throughout the study.
5. 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.
6. Patients with substance abuse (e.g., alcohol or drug abuse) within the previous 3 months prior to and at randomization.
7. 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).
8. Patients with a history of severe allergies or multiple drug allergies.
9. Patients with hypersensitivity to the investigational drug or any of the excipients.
10. Patients unable to perform a valid 6MWD test (e.g., orthopedic disease, peripheral artery occlusive disease, which affects the patient*s ability to walk). Note: Patients, who require walking aids, may be included if in the opinion of the investigator the walking distance is not impaired. Patients with a variance of more than 15% between the screening and the randomization (i.e., baseline) 6MWD test.
11. Participation at a supportive physical training program, defined as a structured exercise and rehabilitation program supervised by a physician and/or a physiotherapist within 12 weeks prior to screening. Participants enrolled in an exercise program for pulmonary rehabilitation > 12 weeks prior to screening may enter the study if they agree to maintain their current level of rehabilitation during the screening and the 24 weeks of the study.
12. Excluded medication/treatment:
a. Patients who are screened for possible participation in the study must not be withdrawn from treatments which are medically required. If such treatments are not in-line with the entry criteria of this study, the patient must not be enrolled. Concomitant use with riociguat of the following specific medications for treatment of PAH is not allowed at any time during the study:
* PDE 5i (e.g., sildenafil, tadalafil or vardenafil) must not be co-administered with riociguat
* Non-specific PDE-inhibitors (e.g., dipyridamole, theophylline)
* NO donors (e.g., nitrates, amyl nitrite)
b. Prostacyclin analogues (PCA) and prostacyclin-receptor agonists (PRA) by any administration route within 30 days prior to and at randomization (except for vasoreactivity testing).
13. Exclusion criteria related to pulmonary disease:
a. All types of PH (including PH-IIP) except subtypes of Dana Point Group I specified in the inclusion criteria.
b. Evidence of clinically significant restrictive or obstructive parenchymal lung diseases in the judgment of the investigator (e.g., based on a clean computed tomography lung scan).
c. Severe congenital abnormalities of the lungs, thorax, and diaphragm.
d. Severe restrictive lung disease (total lung capacity [TLC] < 60%).
e. Moderate obstructive
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The primary efficacy endpoint *satisfactory clinical response* is defined as<br /><br>the composite endpoint comprising the following components (independent central<br /><br>adjudication):<br /><br>* 2 of 3 must be fulfilled<br /><br>* 6MWD increase by * 10% or * 30 m from baseline to Week 24<br /><br>* WHO FC I or II at Week 24<br /><br>* NT-proBNP reduction * 30% from baseline to Week 24 (NT-proBNP Week<br /><br>24/baseline ratio * 0.7), AND<br /><br>* No clinical worsening (i.e, death of any cause, hospitalization due to<br /><br>worsening PAH, disease progression)</p><br>
- Secondary Outcome Measures
Name Time Method <p>not applicable</p><br>