E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart failure with normal left ventricle systolic function (HFNEF) are common causes of hospitalisation mainly in the elderly population and are frequently associated with pulmonary hypertension. It is commonly seen, that patients with left heart disease and pulmonary hypertension with right ventricle dysfunction have a worse prognosis. The medical condition to be investigated is HFNEF (Ejection fraction > 50%) and secondary pulmonary hypertension. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000158 |
E.1.2 | Term | Abnormal liver function tests |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019171 |
E.1.2 | Term | Hb decreased |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10005890 |
E.1.2 | Term | Body fluid retention |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019211 |
E.1.2 | Term | Headache |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10040850 |
E.1.2 | Term | Skin flushed |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024127 |
E.1.2 | Term | Leg edema |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10014264 |
E.1.2 | Term | Edematous weight gain |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10017884 |
E.1.2 | Term | Gastrooesophageal reflux |
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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 |
Change on exercise capacity in patients with heart failure due to diastolic dysfunction (HFNEF > 50%) and secondary pulmonary hypertension (pulmonary venous hypertension – PVH) who are under guideline conform therapy of left ventricle dysfunction and additionally are treated with bosentan or placebo. |
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E.2.2 | Secondary objectives of the trial |
a) combined endpoint of clinical worsening ( death, re-hospitalisation, drug intervention because of clinically worsening, symptomatic worsening) b) Hemodynamics accessed by echocardiography in a 3 and 6 months follow up periode c) Laboratory testing: change in NTpBNP, C-reactive protein and Endothelin-1 d) safety of the intake of Bosentan |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Screening phase a) Clinically signs or history of congestive heart failure NYHA II-III: (Fatigue, dyspnoea on excertion, lung crepitations, pulmonary oedema, ankle and or lower leg swelling, jugular pressure enhancement, hepatomegaly) b) Echocardiographic signs of diastolic dysfunction: Echocardiographic requirements for definition of heart failure with normal ejection fraction E/E` > 15 E/E` > 8 + NTpBNP > 220 pg/dl E/E` > 8 + E:A < 0.5 + DT > 280 ms or Ard-Ad > 30 ms or atrial enlargement or atrial fibrillation NTpBNP > 220 + combination 3.) IVRT – IVRTm < 0 septal und lateral c) Right ventricle enlargement with pulmonary hypertension: Echocardiographic requirements for pulmonary hypertension and right ventricle dysfunction RVEDD > 30 mm short axis parasternal, and one of the following Tricuspid valve regurgitation velocity (TRV) > 3 m/s; RV-anular systolc velocity < 10 cm/sec (TDI) TAPSE < 18 mm d) 6 minute walking distance > 150 m < 400 m
2) Randomisation Phase a) Right Heart Catheterization: Mean PAP > 25 mmHg PCWP > 15 mmHg
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E.4 | Principal exclusion criteria |
Patients who are not on guideline conform treatments for cardio-vascular disease. Left ventricle systolic dysfunction (EF < 50 %), aortic stenosis with peak gradient (instantane) > 40 mm Hg, moderate and severe mitral regurgitation, acute coronary disease, stable coronary artery disease or peripheral vascular disease limiting exercise. Other causes of pulmonary – artery – hypertension: relevant obstructive ventilatory disease > stage II (lung function tests for obstructive ventilation disturbances) collagen disease (Tests: MSCT and ANA, ANCA), chronic thrombo- embolic pulmonary arterial hypertension (MSCT), sleep disorder. HIV, HCV, HBV infection. Drug related PAH. Orthopaedic disease, immobility, inability to perform 6MWT and cancer. Liver disease Child-Pugh B and C, three fold above normal elevated liver enzymes, anaemia Hb < 10 mg/dl, drug therapy with cyclosporine A , tacrolimus, Sirolimus, Rifampicin and Glibenclamide; other specific therapies treating pulmonary hypertension, known adverse reactions to bosentan and pregnancy. Patients with child bearing potential need to be tested for pregnancy.
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in 6 Minute Walk Test after 12 weeks of Bosentan medication
Secondary end points: Clinical, laboratory and physical parameters a) NYHA classification after 3 and 6 months in comparison to the screening phase b) Borg Index (after 3 and 6 months) c) Quality of life SF 36 / Minnesota living with heart failure score (3 and 6 months) d) Echocardiography: Echocardiographic assessments at 3 and 6 months in contrast to the begining of the study (EF, E:E`, E:A, DT, Ard, Ad, LA-diameter, IVRT - IVRTm RV-diameter, excentricity index, TAPSE, RV-anular systolc velocity, TR-gradient and assumed systolic right ventricular pressure) e) Exercise capacity 6MWT after 6 months. f) Measurements of clinical worsening (Death, or Rehospitalisation because of clinically worsening, or Drug intervention because of clinically worsening, or Symptomatic worsening defined as: Appearance or worsening in heart failure, or Decline of 6 MWD ≥ 10% in two tests within two weeks, or Decline of 6 MWD ≥ 5 % in two tests within two weeks additionally to increasing Borg Index ≥ 2) g) explorative end points: NTpBPN, C-reactive protein, Endothelin-1 after 3 and 6 months h) safety end-points: appearance and number of Adverse Events/ severe Adverse Events |
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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 | Yes |
E.7.1.3.1 | Other trial type description |
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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.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
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 | Information not present in EudraCT |
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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The trial is ended up after 12 weeks of oral Bosentan intake. At the end there will be a visit (visit 6). 1 month after the last Bosentan intake there will be a safety visit.
The study contains also a follow up periode. The follow up will last another 12 weeks from the end of study- visit (visit 6). |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |