| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Trombo Embolic Pulmonary Hypertention |
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| E.1.1.1 | Medical condition in easily understood language |
Persistent pulmonary hypertension caused by obstruction of a major pulmonary artery by an unresolved embolus or multiple small pulmonary emboli.
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| 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 | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068740 |
| E.1.2 | Term | CTEPH |
| E.1.2 | System Organ Class | 100000004855 |
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| 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 assess safety and tolerability, clinical effects of riociguat..
•To provide access to riociguat for patients with in-operable chronic thromboembolic pulmonary hypertension (CTEPH), or recurrent or persisting pulmonary hypertension (PH) after surgical treatment who are not satisfactorily treated and cannot participate in any other CTEPH trial.
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•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.
•18 to 80 years of age at screening
•Patients with inoperable CTEPH
•The diagnosis is based on pre-existing measurements which should have been performed within 1 year of screening.
o Historical pulmonary angiogram , and/or
o CT or MR pulmonary angiogram , and/or
o Ventilation /Perfusion (V/Q) Scan AND
o Historical right heart catheter test confirming mean pulmonary arterial pressure (mPAP) > 25 mmHg and pulmonary capillary wedge pressure (PCWP)<=15mmHg
Patients on full anti-coagulation therapy for at least 3 months prior to entry into study
o Diagnosis has to be confirmed by a surgeon/physician experienced in diagnosing and treating CTEPH (see Declaration of Experienced Investigator or Surgeon/Physician in Appendix 14.5.2)
• Post-PEA patients with recurrent or residual PH having at least 90 days of full anti-coagulation after surgery
o Right heart catheter (RHC) test measured at least 180 days after surgery confirming:
o mPAP > 25 mmHg and pulmonary capillary wedge pressure (PCWP) <= 15 mmHg
o Pulmonary vascular resistance (PVR)>300 dyn*sec*cm-5
• No treatment with riociguat or PDE5-inhibitor, endothelin receptor antagonist (ERA) or prostanoid with a minimum time frame of at least 3 days, or more at the discretion of the investigator prior to start of riociguat treatment.
• Patients who are able to understand and follow instructions and who should be able to participate in the study for the entire period.
• Unspecific treatments which may also be used for the treatment of pulmonary hypertension such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen supplementation are permitted. However, treatment with anticoagulants must have been started at least 90 days before Week 0 (Visit 1)
• Women without childbearing potential defined as postmenopausal women (= 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 can only be included in the study if a serological or urine pregnancy test is negative and a combination of safe contraception methods is used throughout the study.
• Women of childbearing potential and men must agree to use adequate contraception when sexually active. This applies since signing of the informed consent form until the time point of safety follow-up of 30 days after the last study drug administration. Acceptable methods of contraception include (i) condoms (male or female) with or without a spermicidal agent; (ii) diaphragm or cervical cap with spermicide; (iii) intra-uterine device; (iv) hormone-based contraception
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| E.4 | Principal exclusion criteria |
General exclusions
• All types of pulmonary hypertension except the one according to the Dana Point Classification Group 4 (1)
• Pregnant women, or breast feeding women, or women with childbearing potential not using a combination of condoms and a safe and highly effective contraception method (hormonal contraception with implants or combined oral contraceptives, certain IUDs).
• Patients participating in another clinical trial or who have done so within 4 weeks before screening.
• Patients with hypersensitivity to the investigational drug or any of the excipients.
Pulmonary diseases exclusions
• Operable patients listed for PEA
• Patients listed for urgent lung transplantation.
Medication/treatment exclusions
• Chronic treatment with NO-donors (e.g., nitrates at any time) less or equal to 3 days prior to prior to start of riociguat treatment .
• Phosphodiesterase type 5 (PDE-5) inhibitors, ERAs and prostanoids* less or equal to 3 days days prior to prior to start of riociguat treatment .
*Single applications of vasoactive drugs in connection with diagnostic vasoreactive testing (e.g. prostacyclines) need not to be considered
• If the above medication/treatment exclusions are deemed to be medically required in the opinion of the investigator, the patient cannot be enrolled in the study.
Cardiovascular and pulmonary exclusions
• Uncontrolled arterial hypertension (Systolic blood pressure >180 mmHg and /or diastolic blood pressure >110 mmHg).
• Systolic blood pressure <95 mmHg.
• Resting heart rate in the awake patient <50 beats per minute (BPM) or >105 BPM.
• History of uncontrolled atrial fibrillation within the last 3 months before screening.
• Left heart failure with an ejection fraction less than 40%.
• Pulmonary venous hypertension with pulmonary capillary wedge pressure >15 mmHg.
• Hypertrophic obstructive cardiomyopathy.
• Severe proven or suspected coronary artery disease (patients with Canadian Cardiovascular Society Angina Classification class 2-4, and/or requiring nitrates, and/or myocardial infarction within the last 3 months before screening).
• Clinical evidence of symptomatic atherosclerotic disease (e.g. peripheral artery disease).
• History of stroke within last 3 months prior to screening.
• Congenital or acquired valvular or myocardial disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension. Evidence for recurrent thromboembolism despite sufficient (documented) oral anticoagulation - also when pulmonary arteries are not affected.
• History or active state of serious hemoptysis / pulmonary hemorrhage including those managed by bronchial artery embolization.
Exclusion criteria related to disorders in organ function
• clinical relevant hepatic dysfunction indicated by:
o Bilirubin >2 times upper limit normal (ULN) at screening and/or
o ALT (alanine aminotransferase) or AST (aspartate aminotransferase) >3 times ULN at screening and/or
o Signs of severe hepatic insufficiency (e.g. impaired albumin synthesis with an albumin <2 g/L, hepatic encephalopathy > grade 1 according to West Haven Criteria of Altered Mental Status in Hepatic Encephalopathy [7]) at screening.
• Renal insufficiency (glomerular filtration rate <30 mL/min, e.g. calculated based on the Cockcroft-Gault formulas at screening.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| This is open-label long- term surveillance study safety and tolerability as well as clinical effects will be measured. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| In general, data will be displayed as measured at each scheduled time point and individual values will be presented as well as the corresponding changes from baseline (change value = post-baseline value – baseline value). |
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| E.5.2 | Secondary end point(s) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Colombia |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Portugal |
| Russian Federation |
| Spain |
| Sweden |
| Switzerland |
| Turkey |
| United States |
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| 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
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| As for the study, the primary outcome will be analyzed after last patient last visit, the end of the study as a whole will be the date when the clean data base is available. |
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| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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