E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary arterial Hypertension (PAH) |
Pulmonale arterielle Hypertonie (PAH) |
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E.1.1.1 | Medical condition in easily understood language |
Pulmonary arterial Hypertension |
Lungenhochdruck |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10037403 |
E.1.2 | Term | Pulmonary hypertension NOS |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
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 |
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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 | 10077729 |
E.1.2 | Term | Pulmonary arterial hypertension WHO functional class III |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 | 10077740 |
E.1.2 | Term | Pulmonary arterial hypertension WHO functional class II |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 |
Investigation of the therapeutic effect of both groups as measured by the change in systolic and diastolic RV function within 12 weeks after starting medication to plan a larger Phase II study. |
Ermittlung des Therapieeffektes beider Gruppen gemessen an der Veränderung der systolischen und diastolischen RV-Funktion innerhalb von 12 Wochen nach Beginn der Medikamenteneinnahme zur Planung einer größeren Phase II Studie.
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E.2.2 | Secondary objectives of the trial |
Recruiting feasibility procentual Right ventricular contractility (end-systolic elastance = Ees) from baseline to 12 weeks Arterial elastance (Ee) Ratio Ees/Ea Maximum and minimum increase in right ventricular pressure curve Diastolic right ventricular function (Tau, EDPVR) Diastolic RV function via the fibrosis degree in MRT using late enhancement, T1 mapping preload recruitable stroke work, (PRSW) Swan-Ganz measurement: Heart-time volume, venous oxygen saturation, pulmonary arterial pressure, pulmonary capillary wedge pressure. EDV, ESV, SV, EF, strain Analysis of RV (not obligatory), RV and LV mass, RV EDV / LV EDV, Late enhancement Stiffness of the pulmonary artery, capacity of the pulmonary artery, elastance of the pulmonary artery, total power, oscillatory power, mean power EDP (end-diastolic pressure), ESP (endsystolic pressure) Heart rate Starling contractility-index 6-Minute Walk Test lung function Acquisition of Adverse Events
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Rekrutierbarkeit Durchführbarkeit Prozentuale Änderung der RV-Kontraktilität (= endsystolische Elastance, Ees) zwischen Baseline und 12 Wochen RV-Kontraktilität (Ees) arterielle Elastance (Ea) Verhältnis Ees/Ea maximale bzw. minimale Steigerung der rechts-ventrikulären Druckkurve [(dp/dt) max und min], diastolische RV-Funktion (Tau, EDPVR) diastolische RV-Funktion über den Fibrosegrad im MRT mittels late-enhancement, T1-Mapping Druckabhängige Herzarbeit Swan-Ganz-Messwerte: Herz-Zeit-Volumen, venöse Sauerstoffsättigung, pulmonal-arterieller Druck, pulmonal-kapillärer Verschlussdruck. EDV, ESV, SV, EF, strain Analyse des RV (nicht obligat), RV- und LV-Masse, RV EDV/LV EDV, Late enhancement Stiffness, Capacity und Elastance der Pulmonalarterie, Total power, oscillatory power, mean power EDP (enddiastolischer Druck), ESP (endsystolischer Druck) Herzfrequenz Starling-contractility-index 6-Minuten-Gehtest Lungenfunktion Erfassung der Adverse Events
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Man or woman 18 to 85 years of age - Invasive confirmed diagnosis of pulmonary hypertension, group 1 according to the Nice Classificationto (PAH), WHO Functional Classes II and III - Clinical need to perform onece more the right heart catheterization, (according to the recommendation of the current Cologne Consensus Conference) - Ability to understand the study information and study objectives - Hemodynamic criteria: will be measured during right heart catheter examination: pulmonary vascular resistance (PVR) > 240dyn x sec x cm-5, mean pulmonary arterial pressure (mPAP) ≥ 25mmHg - For clinical reasons, need to receive an approved drug for the treatment of PAH - Potentially child-bearing women must be able to practice highly effective methods of contraception, either by abstinence or by using at least two methods of gestational contraception from the date of consent to one month after the end of the study. Effective pregnancy protection consists of the combination of a hormonal contraceptive (oral, injectable or implant) and a barrier method (condom or diaphragm with a vaginal spermicide) - Signed informed consent form by the patient according to local regulations
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- Weibliche und männliche Probanden, 18 Jahre ≤ Alter ≤ 85 Jahre - Invasive gesicherte Diagnose einer Pulmonalen Hypertonie Gruppe 1 nach Nizza Definition (PAH), WHO Funktionsklassen II und III - Bestehende klinische Notwendigkeit erneut eine Rechtsherzkatheter-Untersuchung durchzuführen (laut Empfehlung der jeweils aktuellen Kölner Konsensuskonferenz) - Fähigkeit die Studienaufklärung- und Studienziele zu verstehen und diesen zuzustimmen - Hämodynamische Kriterien: Folgende während einer Rechtsherzkatheter-Untersuchung gemessene Werte: - Pulmonal-vaskulärer Widerstand (PVR) > 240dyn x sec x cm-5 - mittlerer pulmonal-arterieller Druck (mPAP) ≥ 25mmHg - Aus klinischen Gründen bestehende Notwendigkeit, erstmals eine Behandlung mit einem für die Therapie der PAH zugelassenen Medikament zu erhalten - Potentiell gebärfähige Frauen müssen einverstanden sein, hochwirksame Methoden der Empfängnisverhütung zu praktizieren, entweder durch Abstinenz oder durch die Verwendung von mindestens zwei Methoden der Schwangerschaftsverhütung ab dem Datum der Zustimmung bis ein Monat nach Ende der Studie. Ein effektiver Schwangerschaftsschutz besteht in der Kombination von einem hormonellen Verhütungsmittel (oral, injizierbar oder Implantat) und einer Barrieremethode (Kondom oder Diaphragma mit einem vaginalen Spermizid) - Einwilligung in die klinische Studie
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E.4 | Principal exclusion criteria |
- Treatment with positive inotropic drugs e.g. Catecholamine (incl. Noradrenaline, Dobutamin, Suprarenin) - Pregnancy or breastfeeding - General contraindications to perform scheduled examinations during the study - Hypersensitivity to the active substances or to a component of the study drugs (in particular lactose and soya) - Simultaneous participation in another drug therapy study, - Simultaneous participation in another non-drug study, which would oppose participation in this study - Participation within one month after completion of another therapy study - Severe hepatic impairment - Existing increase in liver aminotransferase values (aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT))> 3 × ULN - Systolic blood pressure <95 mmHg at the beginning of treatment - Pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP) - anemia (Hb <10 g / dl) - Accompanying medication with potential interaction with macitentan and riociguat in accordance with the relevant information of the specialist information - Severe renal impairment - Severe hemoptysis - Bronchial artery embolisation in prehistory - Smokers
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- Bestehende Therapie mit positiv inotropen Medikamenten wie z.B. Catecholaminen (u.a. Noradrenalin, Dobutamin, Suprarenin) - Schwangerschaft oder Stillzeit - Allgemeine Kontraindikation für die Durchführung der Untersuchung im Rahmen der Studie - Überempfindlichkeit gegenüber den Wirkstoffen oder einem Bestandteil der Studienmedikamente (insbesondere Lactose und Soja) - Gleichzeitige Teilnahme an einer anderen medikamentösen Therapiestudie, - Gleichzeitige Teilnahme an einer anderen nicht-medikamentösen Studie, welche einer Teilnahme an dieser Studie entgegenstehen würde - Teilnahme innerhalb eines Monats nach Beendigung einer weiteren Therapiestudie - Schwerere Leberfunktionsstörungen - Bestehende Erhöhung der Leber-Aminotransferasewerte (Aspartat-Aminotransferase (AST) und/oder Alanin-Aminotransferase (ALT)) > 3 × ULN - Systolischer Blutdruck < 95 mmHg bei Behandlungsbeginn - Pulmonale Hypertonie verbunden mit idiopathischen interstitiellen Pneumonien (PH-IIP) - Anämie (Hb <10 g/dl) - Begleitmedikation mit potentieller Interaktion zu Macitentan und Riociguat gemäß den entsprechenden Angaben der Fachinformationen - Schwere Nierenfunktionsstörungen - Schwerwiegende Hämoptoe - Bronchialarterienembolisation in der Vorgeschichte - Raucher
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E.5 End points |
E.5.1 | Primary end point(s) |
please see E.2 Objectives of the Trial |
please see E.2 Objectives of the Trial |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
please see E.2 Objectives of the Trial |
please see E.2 Objectives of the Trial |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Pilotstudy to investigate feasibility of a bigger Phase II trial |
Pilotstudie zur Überprüfung der Machbarkeit einer größeren Phase II Studie |
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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 | No |
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 | 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 | 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
| 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 and database closure |
Letzter Patient, letzte Visite und Datenbankschluss |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 29 |