| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary arterial hypertension |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with clinical symptoms due abnormally high blood pressure in the lung blood vessels |
|
| 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 | 14.1 |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the effect of 1, 1.5, 2, and 2.5 mg riociguat tid (dose titration) administered simultaneously with sildenafil on blood pressure in subjects with symptomatic pulmonary arterial hypertension. |
|
| E.2.2 | Secondary objectives of the trial |
| To investigate the safety of the riociguat/sildenafil combination and changes in 6-minute walk test, WHOf unctional class, N terminal pro-brain natriuretic peptide, and variables obtained during right-heart catheterization after 12 weeks of treatment; pharmacokinetics of riociguat and sildenafil. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•18 to 75 years of age at Visit 1 (the lower age limit may be higher if legally requested in the participating countries).
•Male and female subjects with symptomatic PAH (Group I Dana Point Updated Clinical Classification 2008), a 6-min walking distance (6MWD) of more than 150 m, a pulmonary vascular resistance (PVR) >300 dyn*s*cm-5, and a mean pulmonary artery pressure (PAPmean) ≥ 25 mmHg either due to:
-Idiopathic PAH.
-Heritable PAH.
-Associated PAH due to connective tissue disease.
-Associated PAH due to congenital heart disease (ie atrial septal defect, ventricle septal defect, persistent ductus arteriosus), if subjects underwent surgical correction >360 days before study inclusion.
-Associated PAH due to portal hypertension with liver cirrhosis. (Note: subjects with clinical relevant hepatic dysfunction are excluded; see exclusions related to disorders in organ function.)
-Associated PAH due to anorexigen or amphetamine use.
Note: Other PAH subtypes of Dana Point Updated Clinical Classification Group I than the ones listed above, for example (eg) PAH associated with human immunodeficiency virus (HIV) infection, are excluded from the trial (see exclusion criteria).
Note: With respect to the verification of the inclusion criteria, PAPmean and PVR are considered as calculated parameters.
Note: Subjects who originally failed screening due to the upper limit of the 6MWD in the original study protocol can be re-screened.
•For Study Part 1: subjects on stable pretreatment with sildenafil at a dose of 20 mg tid.
“Stable” is defined as no change in the respective daily dose for at least 90 days prior to randomization.
•Unspecific treatments which may also be used for the treatment of PAH such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen supplementation are permitted. However, treatment with anticoagulants (if indicated) must have been started at least 30 days before Visit 1 and treatment with diuretics needs to be stable for at least 30 days before Visit 1.
•Subjects with supplemental long-term oxygen therapy may be included, if the amount of supplemental oxygen and the delivery method was stable on average for at least 90 days before Visit 1.
•SBP >/=95 mmHg and heart rate (HR) </=105 beats per minute (BPM) in the first 2 h after intake of sildenafil (measured at Visits 0 and 1).
•Women without child-bearing potential defined as postmenopausal women (ie permanent absence of monthly periods for more than 2 years), women with bilateral tubal ligation, women with bilateral ovarectomy, and women with hysterectomy can be included in the study. Women with childbearing potential may only be included in the study if a serological pregnancy test is negative and a combination of 2 effective methods of birth control (eg prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method, male partner sterilization) are used throughout the study.
•Subjects who are able to understand and follow instructions and who are able to participate in the study for the entire period.
•Subjects 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 |
•Subject’s participating in another clinical trial or who have done so within 30 days before Visit 1.
•Previous assignment to treatment during this study.
•Pregnant women (ie positive serum beta-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 methods of birth control (eg prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method, male partner sterilization) throughout the study.
•Subjects with a medical disorder, condition, or history of such that would impair the subject’s ability to participate or complete this study in the opinion of the investigator.
•Subjects with substance abuse (eg alcohol or drug abuse) within the previous 180 days before Visit 1.
•Subjects with underlying medical disorders with an anticipated life expectancy below 2 years (eg active cancer disease with localized and/or metastasized tumor mass).
•Subjects with a history of severe allergies or multiple drug allergies.
•Subjects with hypersensitivity to the investigational drug or any of the excipients.
•Subjects unable to perform a valid 6MWD test, eg subjects with a severe peripheral artery occlusive disease.
(Note: Subjects, who require walking aids, may be included if in the opinion of the investigator the walking distance is not impaired.)
•Subjects with a relative difference (ie absolute difference/mean) of more than 15% between the eligibility- and the baseline 6MWD test
•All types of pulmonary hypertension except subtypes of Updated Clinical Classification of PH (Dana Point 2008) Group I specified in the inclusion criteria.
•Moderate to severe obstructive lung disease (forced expiratory volume <60% predicted). The predicted forced expiratory volume in 1 second (FEV1) is a calculated value.
•Severe restrictive lung disease (total lung capacity <70% predicted). The predicted total lung capacity (TLC) is a calculated value.
•Severe congenital abnormalities of the lungs, thorax, and diaphragm.
•Oxygen saturation (SaO2) <88% despite supplemental oxygen therapy.
•Arterial partial oxygen pressure (PaO2) <55 mmHg despite supplemental oxygen therapy.
•Arterial partial pressure of carbon dioxide (PaCO2) >45 mmHg.
•Uncontrolled arterial hypertension (SBP >180 mmHg and /or diastolic blood pressure >110 mmHg). [exclusion criteria about SBP and Resting heart rate deleted]
•Atrial fibrillation within the last 90 days before Visit 1.
•Pulmonary venous hypertension with pulmonary capillary wedge pressure >15 mmHg.
•Hypertrophic obstructive cardiomyopathy.
•Severe proven or suspected coronary artery disease (subjects with Canadian Cardiovascular Society Angina Classification class 2 to 4, and/or requiring nitrates, and/or myocardial infarction within the last 90 days before Visit 1).
•Clinical evidence of symptomatic atherosclerotic disease (eg peripheral artery disease with reduced walking distance, history of stroke with persistent neurological deficit etc).
•Congenital or acquired valvular or myocardial disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension.
•Clinical relevant hepatic dysfunction indicated by:
- Bilirubin >2 times upper limit normal (ULN)
- and/or ALT (alanine aminotransferase) or AST (aspartate aminotransferase) >3 times ULN
- and/or signs of severe hepatic insufficiency (eg impaired albumin synthesis with an albumin <32 g/L, hepatic encephalopathy > grade 1.
•Renal insufficiency (glomerular filtration rate <30 mL/min, eg calculated based on the Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formulas |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| •Maximum change in supine SBP from baseline within 4 h of dosing with riociguat for the individual dose steps or placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every two weeks over 8 weeks |
|
| E.5.2 | Secondary end point(s) |
Secondary pharmacodynamic endpoints:
- Maximum change in standing SBP from baseline within 4 h of dosing with study medication.
- Maximum change in standing diastolic blood pressure (DBP) from baseline within 4 h of dosing with study medication.
- Maximum change in supine DBP from baseline within 4 h of dosing with study medication.
- Maximum change in supine and standing HR from baseline within 4 h of dosing with study medication.
- Area under effect curve (AUEC) for change from baseline in standing and supine systolic and diastolic BP, and HR within 6 h of dosing with riociguat or placebo.
Exploratory efficacy endpoints:
- Change from baseline in 6MWD after 12 weeks.
- Change from baseline in NT-proBNP after 12 weeks.
- Change from baseline in WHO functional class after 12 weeks.
- Time to clinical worsening.
- Change from baseline in Borg CR 10 scale (measured at the end of the 6MWD test) after 12 weeks.
Safety endpoints:
Safety of riociguat/sildenafil combination
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary pharmacodynamic endpoints
Every 2 weeks over 8 weeks:
-Maximum change in standing SBP...
-Maximum change in standing diastolic blood pressure...
-Maximum change in supine DBP...
-Maximum change in supine and standing HR...
Within 6 h of dosing with riociguat or placebo:
-AUEC for change from baseline in standing and supine systolic and diastolic BP, and HR
Exploratory efficacy endpoints:
After 12 weeks:
-Change from baseline in 6MWD
-Change from baseline in NT-proBNP
-Change from baseline in WHO functional class
-Time to clinical worsening.
-Change from baseline in Borg CR 10 scale
Safety endpoints:
At every visit |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| Last visit of the last patient undergoing the trial. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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