| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Symptomatic pulmonary arterial hypertension with a mean pulmonary artery pressure >20 mmHg and pulmonary vascular resistance ≥2 Wood Units, pulmonary arterial wedge pressure ≤15 mmHg (Group I / Nice Clinical Classification of Pulmonary Hypertension (PH)) or CTEPH (Group IV) with hemodynamics as stated above defined as inoperable measured at least 3 months after start of full anticoagulation or with persisting or recurrent PH after pulmonary endarterectomy at least 6 months after surgery |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with increased pressure and resistance of pulmonary 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 | HLT |
| E.1.2 | Classification code | 10037401 |
| E.1.2 | Term | Pulmonary hypertensions |
| 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 |
| Investigate the effect of riociguat on RV and RA area, measured by echocardiography. The effect of riociguat on RV and RA area will be compared during therapy in each patient (from baseline to 12 and 24 weeks; primary endpoint baseline vs. 24 weeks riociguat therapy). |
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| E.2.2 | Secondary objectives of the trial |
| Compare the effect of riociguat on RV and hemodynamic properties in patients with PAH or CTEPH (comparison from baseline to 24 weeks) with right heart catheterization. Secondary efficacy analysis comprises of further echocardiographic measurements and correlation between echocardiography and clinical data such as haemodynamics, vital signs, electrocardiogram, echocardiography, laboratory parameters NT-proBNP, pulmonary function, WHO-FC, 6MWD (from baseline to 12 and 24 weeks) and quality of life (QoL) parameters by questionnaire SF-36. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ≥18 years of age at time of inclusion.
2. Male and female patients with symptomatic PAH with a mean pulmonary artery pressure (mPAP) >20 mmHg and pulmonary vascular resistance (PVR) ≥2 Wood Units (WU), pulmonary arterial wedge pressure (PAWP) ≤15 mmHg (Group I / Nice Clinical Classification of Pulmonary Hypertension) or CTEPH (Group IV / Nice Clinical Classification of Pulmonary Hypertension) defined as inoperable measured at least 3 months after start of full anticoagulation and mPAP >20 mmHg and PVR ≥2 WU, PAWP ≤15 mmHg; or with persisting or recurrent PH after pulmonary endarterectomy (mean pulmonary artery pressure >20 mmHg and PVR ≥2 WU, PAWP ≤15 mmHg measured at least 6 months after surgery (acc. to Simonneau et al. 2018).
3. Treatment naïve patients (with respect to PAH specific medication) and patients pre-treated with an endothelin receptor antagonist or a prostacyclin analogue, pre-treated for 2 months before screening at most (according to upfront combination treatment).*
4. *Pre-treated patients need to be stable on endothelin receptor antagonists or prostacyclin treatment for at least two weeks prior to Visit 1. “Stable” is defined as no change in the type of endothelin receptor antagonists or prostacyclin analogue and the respective daily dose.
5. A patient may also be enrolled, if a persisting phosphodiesterase type 5 (PDE-5) inhibitor treatment (pre-treated for 2 months before screening at most) with or without combination treatment with an endothelin receptor antagonist or prostacyclin analogue is to be switched to riociguat by clinical indication.
6. Unspecific treatments which may also be used for the treatment of PH 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 1 month before visit 1.
7. RHC results must not be older than 6 months at screening (will be considered as baseline values) and must have been measured in the participating centre under standardized conditions (refer to the study specific Swan Ganz catheterization manual). If the respective measurements have not been performed in context with the patient’s regular diagnostic workup, they have to be performed as a part of the study during the pre-study phase (after the patient signed the informed consent).
8. Women without childbearing potential defined as postmenopausal women aged 50 years or older, women with bilateral tubal ligation, women with bilateral ovariectomy, and women with hysterectomy can be included in the study. Women with childbearing potential can only be included in the study if a serological pregnancy test is negative and a combination of condoms with a safe and highly effective contraception method (hormonal contraception with implants or combined oral contraceptives, certain IUDs) is used.
9. Patients who are able to understand and follow instructions and who are able to participate in the study for the entire period.
10. 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.
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| E.4 | Principal exclusion criteria |
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).
2. Patients with PH specific treatment >2 months before screening.
3. 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.
4. Patients with underlying medical disorders with an anticipated life expectancy below 2 years (e.g. active cancer disease with localized and/or metastasized tumour mass).
5. Patients with a history of severe allergies or multiple drug allergies.
6. Patients with hypersensitivity to the investigational drug or any of the excipients.
7. Patients unable to perform a valid 6MWD test (e.g. orthopaedic disease, peripheral artery occlusive disease, which affects the patient´s ability to walk).
8. The following specific medications for concomitant treatment of PH or medications which may exert a pharmacodynamic interaction with the study drug are not allowed:
a) Parenteral prostacyclin analogues
b) Specific (e.g. sildenafil or tadalafil) or unspecific phosphodiesterase inhibitors (e.g. dipyridamole, theophylline)
c) NO donors (e.g. Nitrates)
9. Pulmonary diseases exclusions
a) Moderate to severe bronchial asthma or COPD (Forced Expiratory Volume <60% predicted).
b) Severe restrictive lung disease (Total Lung Capacity < 70% predicted).
c) Severe congenital abnormalities of the lungs, thorax, and diaphragm.
d) Clinical or radiological evidence of Pulmonary-Veno-Occlusive Disease (PVOD) or Pulmonary Capillary Haemangiomatosis (PCH) or PH and idiopathic interstitial pneumonia (PH-IIP)
10. Cardiovascular exclusions:
a) Uncontrolled arterial hypertension (systolic blood pressure >180 mmHg and /or diastolic blood pressure >110 mmHg).
b) Systolic blood pressure <95 mmHg.
c) Left heart failure with an ejection fraction less than 40%.
d) Pulmonary venous hypertension with pulmonary arterial wedge pressure >15 mmHg.
e) Hypertrophic obstructive cardiomyopathy.
f) Severe proven or suspected coronary artery disease according to investigators opinion (patients with Canadian Cardiovascular Society Angina Classification class 2-4, and/or requiring nitrates, and/or myocardial infarction within the last 3 months before Visit 1).
g) Clinical evidence of symptomatic atherosclerotic disease (e.g. peripheral artery disease with reduced walking distance, history of stroke with persistent neurological deficit etc).
11. Exclusions related to disorders in organ function:
a) Clinically relevant hepatic dysfunction indicated by:
i. bilirubin >2 times upper limit normal
ii. and / or hepatic transaminases >3 times upper limit normal
iii. and / or signs of severe hepatic insufficiency (e.g. impaired albumin synthesis with an albumin < 32 g/l, hepatic encephalopathy > grade 1a: West Haven Criteria of Altered Mental Status In Hepatic Encephalopathy)
b) Renal insufficiency (glomerular filtration rate <30 ml/min e.g. calculated based on the Cockcroft formula). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The evaluation of the primary efficacy endpoint will be the change from baseline to 24 weeks in RV and RA area. The primary analysis set will be the intention to treat set. The per-protocol analysis will be supportive.
The main comparison will be the difference between baseline and follow-up. 95% confidence intervals of treatment difference will also be calculated. The primary comparison will be an ANCOVA model including baseline scores as covariate.
If the preconditions for an ANCOVA analysis are not met, the primary endpoint will be analysed by robust, two-sided t-test (Welch-test).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Screening Phase: up to 28 days before treatment start
• Treatment phase: 24 weeks ± 14 days including 8 weeks titration phase and 16 weeks continuation phase.
• Safety follow-up: patient’s well-being will be monitored by phone after 30 ± 7 days after last intake of study.
• Survival follow-up: survival at study termination / last patient out
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| E.5.2 | Secondary end point(s) |
Secondary parameters at baseline and during follow-up will be compared. Data will be displayed by means and standard deviations, medians and variances with respective 95% confidence intervals. p-values <0.05 will be considered as statistically significant.
It is assumed that WHO functional class will either remain the same, improve by one or two categories, or deteriorate by one category in most cases. A change score (baseline minus end of study) will be calculated, which could go from -3 (class IV at baseline and class I at end of study) to +4 (class I at baseline, death at end of study), but in practice for those patients still alive at the end of the study it will most likely range from -2 to +1.
The safety analysis will be performed in the population valid for safety. All tabulations will be descriptive only. Tables will be produced for drug-related treatment-emergent adverse events and serious adverse events. Further tables will be produced for serious and/or drug-related treatment-emergent adverse events.
Mortality will be summarized descriptively. Any deaths in the study period (until survival follow-up) will be listed, with day of death relative to start and stop of study drug and cause of death. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Data will be obtained at baseline, after 12 and 24 weeks.
30 days after last study drug intake, a safety follow-up by phone will be performed.
At study Termination, survival will be assessed by phone. |
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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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | No |
| 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 | 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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| LVLS including Survival follow-up by phone for all patients. |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
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