| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension (PAH) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pulmonary Arterial Hypertension (PAH) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064911 |
| E.1.2 | Term | Pulmonary arterial hypertension |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess the proportion of patients in each treatment arm with a satisfactory clinical response as defined by a composite primary
endpoint at Week 24. |
|
| E.2.2 | Secondary objectives of the trial |
| To demonstrate safety and clinical effect at Week 24 indicated by change in 6-minute walking distance (6MWD), N-terminal pro-brain natriuretic peptide (NT-proBNP), World Health Organization Functional Class (WHO FC) and clinical worsening from baseline in each treatment arm. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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) within 12 months prior to screening. 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. 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. |
|
| E.4 | Principal exclusion criteria |
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, or breast feeding women, or women with childbearing potential not using a combination of safe contraception methods.
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).
11. Participation at a supportive physical training program, defined as a structured exercise and rehabilitation program supervised by a physician and/or a physiotherapist is not allowed during the pretreatment and the treatment phase of the study (up to the EOS visit).
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 must not be co-administered with riociguat
• Non-specific PDE-inhibitors
• NO donors
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 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
c. Severe congenital abnormalities of the lungs, thorax, and diaphragm.
d. Severe restrictive lung disease (total lung capacity [TLC] < 60%).
e. Moderate obstructive lung disease (forced expiratory volume in one second/forced vital capacity [FEV1/FVC] < 50%).
f. Confirmed obstructive sleep apnea
g. Severe diffusion impairment (diffusing capacity of the lung for carbon monoxide < 30% predicted).
h. History or active state of serious hemoptysis/pulmonary hemorrhage including those managed by bronchial artery embolization
14. Exclusion criterion related to hypoxia (pulse oximeter at rest):
a. Peripheral capillary oxygen saturation (SpO2) < 88% despite supplemental oxygen therapy (< 4 L/min) at rest.
15. Cardiovascular exclusion criteria:
a. Uncontrolled arterial hypertension (SBP > 180 mmHg and/or diastolic BP > 110 mmHg).
b. SBP < 95 mmHg prior to and at randomization.
c. Resting heart rate in the awake patient < 50 bpm or > 105 bpm.
d. Permanent atrial fibrillation and new onset of atrial fibrillation within the last 3 months prior to screening.
e. Left ventricular systolic dysfunction by echocardiography (left ventricular ejection fraction [LVEF] < 40%, Simpson’s methodology).
f. Hypertrophic obstructive cardiomyopathy.
g. Severe proven or suspected coronary artery disease (patients with Canadian Cardiovascular Society Angina Classification class 2 to 4, and/or requiring nitrates, and/or acute coronary syndrome, or coronary interventions (PCI,CABG) within the last 3 months prior to and at randomization).
h. Clinical evidence of symptomatic atherosclerotic disease (e.g., peripheral artery disease with reduced walking distance, history of stroke with persistent neurological deficit etc.).
i. History of stroke within 3 months prior to and at randomization.
j. Congenital or acquired valvular or myocardial disease if clinically significant apart from tricuspid valvular insufficiency due to PAH.
k.Three or more of the following left ventricular disease/ dysfunction risk factors:
• Body Mass Index (BMI) ≥ 30
• History of Essential Hypertension
• Diabetes mellitus of any type
• History of significant Coronary Disease
16. Exclusion criteria related to disorders in organ function:
a. Clinical relevant hepatic dysfunction indicated by:
• Bilirubin > 2 times upper limit of normal (ULN), and/or
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times ULN
b. Signs of severe hepatic insufficiency, and/or
c. Renal insufficiency
17. Other exclusion criteria:
a. Other co-morbidities impairing exercise capacity |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint ‘satisfactory clinical response’ is defined as the composite endpoint comprising the following components (independent central adjudication):
2 of 3 must be fulfilled
- 6MWD increase by ≥ 10% or ≥ 30 m from baseline to Week 24
- WHO FC I or II at Week 24
- NT-proBNP reduction ≥ 30% from baseline to Week 24 (NT-proBNP ratio Week 24/baseline ≤ 0.7), AND
- No clinical worsening (for definition, see protocol) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Change from baseline in 6MWD (blinded assessment)
- Change from baseline in NT-proBNP
- Change from baseline in WHO FC (blinded assessment)
- Clinical worsening |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Greece |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| New Zealand |
| Portugal |
| Spain |
| Switzerland |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 5 |
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