| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Thromboembolic Pulmonary Disease (CTEPH) |
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| E.1.1.1 | Medical condition in easily understood language |
| A long term condition where there is increased blood pressure in the blood vessels that deliver blood from the heart to the lungs. The increased blood pressure is a result of blockages in the vessels. |
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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 | 20.0 |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to assess the efficacy of riociguat on preoperative PVR in patients with operable CTEPH. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are the following:
• To assess the efficacy of riociguat on other preoperative pulmonary haemodynamic parameters in patients with operable CTEPH
• To assess the efficacy of riociguat on postoperative pulmonary haemodynamic parameters in patients with operable CTEPH
• To assess the effect of riociguat on safety and efficacy aspects during PEA in patients with operable CTEPH
• To assess the safety and tolerability of riociguat in patients with operable CTEPH
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet all of the following criteria to be enrolled in this study:
1. Is a male or nonpregnant and nonlactating female patient aged from 18 to 80 years, both inclusive
2. Is diagnosed with operable CTEPH and anticipating symptomatic and/or prognostic benefit from PEA
3. Has PVR >800 dyn·s·cm-5
4. Has undergone RHC not more than 180 days before Visit 1
5. Has been treated with anticoagulants for at least 90 days before Visit 1
6. Has ability to swallow oral medication
7. Has ability and willingness to participate and access to the health facility
8. Is capable of understanding the written informed consent and provides signed and witnessed written informed consent
9. Female patient must be either surgically sterile, postmenopausal (no menses for the previous 12 months), or must be practicing an effective method of birth control as determined by the investigator (eg, oral contraceptives, double barrier methods, hormonal injectable or implanted contraceptives, tubal ligation, or male partner with vasectomy or complete abstinence)
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| E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria will be excluded from the study:
1. Has known hypersensitivity, allergic, or adverse reactions to riociguat or any of the excipients comprising riociguat tablets
2. Has known active hepatitis A immunoglobulin M, hepatitis B surface antigen, or hepatitis C antibody
3. Is human immunodeficiency virus positive
4. Has pulmonary veno-occlusive disease
5. Has symptomatic hypotension
6. Has symptomatic carotid disease
7. Has significant coronary atherosclerotic disease in need of intervention
8. Has severe left heart disease in need of intervention
9. Has redo sternotomy
10. Has received any background therapy for PAH in the preceding 30 days before Visit 1 including ERAs, PDE5 inhibitors, or prostanoids
11. Is receiving nitrates, NO donors (eg, amyl nitrite), ERAs, prostanoids, specific PDE5 inhibitors, nonspecific phosphodiesterase inhibitors (eg, dipyridamole, theophylline)
12. Is receiving strong cytochrome P450 and P-glycoprotein/breast cancer resistance protein inhibitors
13. Is receiving strong cytochrome P450 3A inducers
14. Has creatinine clearance <15 mL/min or is on any form of dialysis
15. Has severe hepatic impairment classified as Child-Pugh B or C
16. Has received an investigational drug within the past 4 weeks before Visit 1
17. Is a lactating or pregnant (as demonstrated by a serum pregnancy test) woman, or not willing to take measures not to become pregnant during the 3-month treatment study period and 1 month after the last dose of study drug administered
18. Has smoked or used tobacco in any form, including snuff or chewing within 3 months prior to Visit 1
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is percent change from baseline in PVR immediately before PEA at Visit 2. Unless otherwise specified, the baseline will be defined as the last valid assessment, including assessments from the unscheduled visit, prior to the study drug.
The PVR assessment from Visit 2 needs to be within 7 days prior to PEA. Assessments out of the time frame will be considered invalid and be treated as missing. In the case of patients who do not undergo PEA, the PVR at Visit 2 will be treated as missing.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline PVR at screening visit (Day 0) to Visit 2 (at day 90). |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints for the study are mentioned below.
1. PVR (6 months after PEA): percent change from baseline in PVR at Visit 4.
PVR assessment at Visit 4 will use the nominal visit information collected in eCRF without considering the time window because PVR status is expected to be stable after PEA.
2. Composite clinical endpoints (6 months after PEA), including patients with any one of the following clinical endpoints, from immediately after PEA to Visit 4.
• All-cause death
All deaths that happen after randomisation until the date of Visit 4, 6 months after the PEA, will be included.
• PH-related hospitalisation
All PH-related hospitalisation except the in-hospital care after PEA from randomisation until 6 months after PEA will be included.
• Need for PAH-targeted therapy
All PAH-targeted therapy from randomisation until 6 months after PEA will be included.
• Functional class unchanged or worse
When comparing the functional class assessment at Visit 1 with the functional class assessment at other visits, the same class will be defined as unchanged, and a higher class will be defined as worse. The worst case after treatment will be used.
3. Perioperative findings at Visit 2:
• Circulatory arrest time
• Surgery-related complications (Section 6.2.7)
4. Surgical evaluation of specimen (difficulty to withdraw obstructive material):
• Ease of dissection plane, classed as easier than normal (1), normal (2), more difficult than normal (3)
• Completeness of disease clearance, classed as better than expected (1), as expected (2), worse than expected (3)
• Both clot and vessel wall will be measured as score of 1 to 3 with the following scores: more solid than usual (1), normal (2) more friable than usual (3).
Surgical evaluations of specimen are from perioperative measures. The data will be treated as an ordinal response. A higher score means a worse case.
5. All-cause death
All deaths that happen during the whole course of the study will be included.
6. Withdrawal during randomised treatment phase
Only withdrawals after randomisation but before PEA will be included.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From baseline PVR at Visit 2 at Day 90 to Visit 4 at Day 276 (6 months after PEA) |
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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 | No |
| 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) | 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 | 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 | Yes |
| 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
| 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 | 3 |
| 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 |
| France |
| Germany |
| United Kingdom |
| United States |
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| 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
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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 | 1 |
| 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 | 1 |
| 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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