E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 7.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10007554 |
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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 |
Primary objective is to test the hypothesis that levosimendan is superior to placebo in the composite endpoint called “Patient Journey” during the 60 days following randomisation.
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are • to validate the primary variable (“Patient Journey”) for phase III • to evaluate the efficacy of levosimendan on mortality, morbidity, symptoms and quality of life compared to placebo • to compare the efficacy, safety and pharmacokinetics of the two levosimendan doses • to compare the efficacy, safety and pharmacokinetics of levosimendan in rapid and slow acetylators • to evaluate the safety of levosimendan compared to placebo
An optional pharmacogenetic substudy will be carried out under a seperate protocol. This substudy will be conducted in order to develop a better understanding of heart failure and to evaluate how patients respond to treatment with levosimendan. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1. Written Informed Consent obtained 2. Male and female patients over 18 years of age. Women of reproductive age and potential must refrain from breastfeeding, must have a negative pregnancy test and must commit to using an acceptable method of barrier or hormonal contraception (e.g. condoms, diaphragms, oral contraceptives and long acting progestin agents) if sexually active during the study and for 1 month after the last dose of the study treatment. Women who are postmenopausal (1 year since last menstrual cycle), surgically sterilised or who have undergone a hysterectomy are considered not to be of childbearing potential 3. Chronic heart failure diagnosed at least 3 months before screening 4. Treatment for at least 1 month before screening with angiotensin converting enzyme (ACE) inhibitor or beta-blocker and additionally at least one of the following: diuretics, digitalis, aldosterone antagonist or angiotensin II receptor blocker 5. Left ventricular ejection fraction less than or equal to 30% as assessed by echocardiography, radionuclide ventriculography or contrast angiography within 12 months before screening 6. NYHA IIIb-IV symptoms (dyspnoea on minimal exertion or at rest) at screening and at baseline 7. Further evidence of severely compromised heart failure as evidenced by one of the following at screening: - History of at least one hospitalisation or visit to out-patient clinic for worsening heart failure requiring treatment either with intravenous (i.v.) diuretics, i.v. vasodilators, and/or i.v. inotropic agents within 6 months before screening; the index hospitalisation may be currently on-going at screening but if so, the patient must be ready to be discharged - Plasma N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) above or equal to 1000 pg/ml at screening |
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E.4 | Principal exclusion criteria |
1. Severe obstruction of ventricular outflow tracts such as haemodynamically significant uncorrected primary valve disease or hypertrophic cardiomyopathy or impaired ventricular filling such as restrictive cardiomyopathy 2. Cardiac surgery or coronary angioplasty within 30 days before screening 3. Acute myocardial infarction within 30 days before screening 4. Patients who are scheduled to receive a heart transplant or left ventricular assist device or are scheduled for coronary by-pass or angioplasty in the next 6 months 5. History of life-threatening ventricular arrhythmia within 3 months defined as an episode of resuscitated sudden death, ventricular fibrillation or sustained or haemodynamically destabilising ventricular tachycardia (wide complex tachycardia >100/min, either for >15 seconds or accompanied by hypotension, presyncope or syncope). Patients with one of these three arrhythmias may be enrolled if the episode was followed by placement of an intracardiac cardioverter-defibrillator (ICD) (and the ICD has not fired within 30 days) 6. History of Torsades de Pointes or family history of long QT-syndrome 7. Stroke or transient ischaemic attack within 3 months before screening 8. Systolic blood pressure less than 85 mmHg at screening and baseline 9. Heart rate 100 bpm or greater at screening and baseline 10. Serum potassium less than 3.5 mmol/l at screening 11. Severe renal insufficiency (serum creatinine >450 µmol/l [5.0 mg/dl]) or on dialysis 12. Severe anaemia (blood haemoglobin <10 g/dl) at screening 13. Significant hepatic impairment at discretion of the investigator 14. Hypersensitivity to levosimendan 15. Other serious diseases limiting life expectancy considerably (e.g. end-stage cancer) 16. Participation in a clinical trial with any experimental treatment within 30 days prior to screening or previous participation in the present study 17. Administration of levosimendan within 30 days prior to screening
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E.5 End points |
E.5.1 | Primary end point(s) |
“Patient Journey” is a composite end-point consisting of Patient’s Global Assessment, worsening heart failure and mortality during the 60 days after randomisation. The 6-point symmetric scale of Patient’s Global Assessment, the days with worsening heart failure and days dead will be converted to numeric scale according to the Table below. The Global Assessment score at each visit/telephone contact represents the current day. The days between two visits/telephone contacts will be scored carrying forwards and backwards the scores to the mid-point of the two contacts. However, if the patient is experiencing worsening heart failure between two visits/telephone contacts, the Global Assessment score will be overruled and the score will be -0.5 for those days. All days after death (including the day of death) will be counted as -1.0.
Scores of the “Patient Journey” Patient’s Global Assessment Score Very good 1.0 Good 0.8 Fairly good 0.6 Fairly bad 0.4 Bad 0.2 Very bad 0.0 Worsening heart failure -0.5 Death -1.0 |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Yes |
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 | 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 | 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.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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 | 6 |
E.8.9.1 | In the Member State concerned days | |
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 | 6 |